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Foundations of Behavioral Neuroscience Neil R. Carlson Ninth Edition

Pearson Education Limited Edinburgh Gate Harlow Essex CM20 2JE England and Associated Companies throughout the world Visit us on the World Wide Web at: www.pearsoned.co.uk © Pearson Education Limited 2014 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior written permission of the publisher or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency Ltd, Saffron House, 6–10 Kirby Street, London EC1N 8TS. All trademarks used herein are the property of their respective owners. The use of any trademark in this text does not vest in the author or publisher any trademark ownership rights in such trademarks, nor does the use of such trademarks imply any afﬁliation with or endorsement of this book by such owners.

ISBN 10: 1-292-02196-9 ISBN 13: 978-1-292-02196-6

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Printed in the United States of America

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Table of Contents

1. Origins of Behavioral Neuroscience Neil R. Carlson

2. Structure and Functions of Cells of the Nervous System Neil R. Carlson

3. Structure of the Nervous System Neil R. Carlson

4. Psychopharmacology Neil R. Carlson

5. Methods and Strategies of Research Neil R. Carlson

107

6. Vision Neil R. Carlson

135

7. Audition, the Body Senses, and the Chemical Senses Neil R. Carlson

167

8. Sleep and Biological Rhythms Neil R. Carlson

203

9. Reproductive Behavior Neil R. Carlson

235

10. Emotion Neil R. Carlson

267

11. Ingestive Behavior Neil R. Carlson

293

12. Learning and Memory Neil R. Carlson

331

13. Human Communication Neil R. Carlson

371

14. Neurological Disorders Neil R. Carlson

405

15. Autistic, Attention-Deficit, Stress, and Substance Abuse Disorders Neil R. Carlson

437

16. Schizophrenia, Affective Disorders, and Anxiety Disorders

Neil R. Carlson

473

Index

505

OUTLINE ■

Origins of Behavioral Neuroscience

Understanding Human Consciousness: A Physiological Approach Split Brains

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The Nature of Behavioral Neuroscience The Goals of Research Biological Roots of Behavioral Neuroscience

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Natural Selection and Evolution Functionalism and the Inheritance of Traits Evolution of the Human Brain Ethical Issues in Research with Animals

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Careers in Neuroscience

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Strategies for Learning

ORNL/Science Source/Photo Researchers, Inc.

LEARNING OBJECTIVES

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1. Describe the behavior of people with split brains and explain what study of this phenomenon contributes to our understanding of self-awareness.

5. Describe the evolution of the human species.

2. Describe the goals of scientiﬁc research.

7. Describe career opportunities in neuroscience.

6. Discuss the value of research with animals and ethical issues concerning their care.

3. Describe the biological roots of behavioral neuroscience. 4. Describe the role of natural selection in the evolution of behavioral traits.

PROLOGUE

| René’s Inspiration

René, a lonely and intelligent young man of eighteen years, had secluded himself in Saint-Germain, a village to the west of Paris. He had recently suffered a nervous breakdown and chose the retreat to recover. Even before coming to Saint-Germain, he had heard of the fabulous royal gardens built for Henri IV and Marie de Médicis, and one sunny day he decided to visit them. The guard stopped him at the gate, but when he identified himself as a student at the King’s School at La Flèche, he was permitted to enter. The gardens consisted of a series of six large terraces overlooking the Seine, planted in the symmetrical, orderly fashion so loved by the French. Grottoes were cut into the limestone hillside at the end of each terrace; René entered one of them. He heard eerie music accompanied by the gurgling of water but at first could see nothing in the darkness. As his eyes became accustomed to the gloom, he could make out a figure illuminated by a flickering torch. He approached the figure, which he soon recognized as that of a young woman. As he drew closer, he saw that she was actually a bronze statue of Diana, bathing in a pool of water. Suddenly, the Greek goddess fled and hid behind a bronze rosebush. As René pursued her,

an imposing statue of Neptune rose in front of him, barring the way with his trident. René was delighted. He had heard about the hydraulically operated mechanical organs and the moving statues, but he had not expected such realism. As he walked back toward the entrance to the grotto, he saw the plates buried in the ground that controlled the valves operating the machinery. He spent the rest of the afternoon wandering through the grottoes, listening to the music and being entertained by the statues. During his stay in Saint-Germain, René visited the royal gardens again and again. He had been thinking about the relationship between the movements of animate and inanimate objects, which had concerned philosophers for some time. He thought he saw in the apparently purposeful, but obviously inanimate, movements of the statues an answer to some important questions about the relationship between the mind and the body. Even after he left SaintGermain, René Descartes revisited the grottoes in his memory. He even went so far as to name his daughter Francine after their designers, the Francini brothers of Florence.

he last frontier in this world—and perhaps the greatest one—lies within us. The human nervous system makes possible all that we can do, all that we can know, and all that we can experience. Its complexity is immense, and the task of studying it and understanding it dwarfs all previous explorations our species has undertaken. One of the most universal of all human characteristics is curiosity. We want to explain what makes things happen. In ancient times, people believed that natural phenomena were caused by animating spirits. All moving objects—animals, the wind and tides, the sun, moon, and stars— were assumed to have spirits that caused them to move. For example, stones fell when they were dropped because their animating spirits wanted to be reunited with Mother Earth. As our ancestors became more sophisticated and learned more about nature, they abandoned this approach (which we call animism) in favor of physical explanations for inanimate moving objects. But they still used spirits to explain human behavior. From the earliest historical times, people have believed that they possessed something intangible that animated them—a mind, a soul, or a spirit. This belief stems from the fact that each of us is aware of our own existence. When we think or act, we feel as though something inside us is thinking or deciding to act. But what is the nature of the human mind? We have physical bodies with muscles that move them and sensory organs such as eyes and ears that perceive information about the world around us. Within our bodies the nervous system plays a central role, receiving information from the sensory organs and controlling the movements of the muscles. But what is the mind, and what role does it play? Does it control the nervous system? Is it a part of the nervous system? Is it physical and tangible, like the rest of the body, or is it a spirit that will always remain hidden? Behavioral neuroscientists take an empirical and practical approach to the study of human nature. Most of us believe that the mind is a phenomenon produced by the workings of the nervous system. We believe that once we understand the workings of the human body—especially the workings of the nervous system—we will be able to explain how we perceive, how we think, how we remember, and how we act. We will even be able to explain the nature of our own selfawareness. Of course, we are far from understanding the workings of the nervous system, so only time will tell whether this belief is justified.

Origins of Behavioral Neuroscience

Scientists and engineers have developed research methods that enable neuroscientists to study activity of the human brain. AJ Photo/Photo Researchers, Inc.

Understanding Human Consciousness: A Physiological Approach How can behavioral neuroscientists study human consciousness? First, let’s define our terms. The word consciousness can be used to refer to a variety of concepts, including simple wakefulness. Thus, a researcher may write about an experiment using “conscious rats,” referring to the fact that the rats were awake and not anesthetized. By consciousness, I am referring to something else: the fact that we humans are aware of—and can tell others about—our thoughts, perceptions, memories, and feelings. We know that brain damage or drugs can profoundly affect consciousness. Because consciousness can be altered by changes in the structure or chemistry of the brain, we may hypothesize that consciousness is a physiological function, just as behavior is. We can even speculate about the origins of this self-awareness. Consciousness and the ability to communicate seem to go hand in hand. Our species, with its complex social structure and enormous capacity for learning, is well served by our ability to communicate: to express intentions to one another and to make requests of one another. Verbal communication makes cooperation possible and permits us to establish customs and laws of behavior. Perhaps the evolution of this ability is what has given rise to the phenomenon of consciousness. That is, our ability to send and receive messages with other people enables us to send and receive our own messages inside our own heads—in other words, to think and to be aware of our own existence. (See Figure 1.)

Split Brains Studies of humans who have undergone a particular surgical procedure demonstrate dramatically how disconnecting parts of the brain that are involved with perceptions from parts involved with verbal behavior also disconnects them from consciousness. These results suggest that the parts of the brain involved in verbal behavior may be the ones responsible for consciousness. The surgical procedure is one that has been used for people with very severe epilepsy that cannot be controlled by drugs. In these people, nerve cells in one side of the brain become overactive, and the overactivity is transmitted to the other side of the brain by a structure called the corpus callosum. The corpus callosum is a large bundle of nerve fibers that connects corresponding parts of one side of the brain with those of the other. Both sides of the brain then engage in wild activity and stimulate each other, causing a generalized epileptic seizure. These seizures can occur many times each day, preventing the person from leading a normal life. Neurosurgeons discovered that cutting the corpus callosum (the split-brain operation) greatly reduced the frequency of the epileptic seizures.

FIGURE 1 Studying the Brain. Will the human brain ever completely understand its own workings? A sixteenthcentury woodcut from the first edition of De humani corporis fabrica (On the Workings of the Human Body) by Andreas Vesalius. National Library of Medicine.

corpus callosum (core pus ka low sum) A large bundle of nerve fibers that connects corresponding parts of one side of the brain with those of the other. split-brain operation Brain surgery that is occasionally performed to treat a form of epilepsy; the surgeon cuts the corpus callosum, which connects the two hemispheres of the brain.

Origins of Behavioral Neuroscience

Figure 2 shows a drawing of the split-brain operation. We see the brain being sliced down the middle, from front to back, dividing it into its two symmetrical halves. A “window” has been opened in the left side of the brain so Cutting device that we can see the corpus callosum being cut by the neurosurgeon’s special knife. (See Figure 2.) Sperry (1966) and Gazzaniga and his associates (Gazzaniga and LeDoux, 1978; Gazzaniga, 2005) have studied these patients extensively. The largest part Top of the brain consists of two symmetrical parts, called the cerebral hemispheres, Corpus callosum which receive sensory information from the opposite sides of the body. They also control movements of the opposite sides. The corpus callosum enables the two hemispheres to share information so that each side knows what the other side is perceiving and doing. After the split-brain operation is performed, the Front two hemispheres are disconnected and operate independently. Their sensory mechanisms, memories, and motor systems can no longer exchange information. The effects of these disconnections are not obvious to the casual observer, for the simple reason that only one hemisphere—in most people, the left— controls speech. The right hemisphere of an epileptic person with a split brain appears to be able to understand verbal instructions reasonably well, but it is incapable of producing speech. Because only one side of the brain can talk about what it is experiencing, F I G U R E 2 The Split-Brain Operation. A “window” has been people who speak with a person with a split brain are conversing with only one opened in the side of the brain so that we can see the corpus hemisphere: the left. The actions of the right hemisphere are more difficult to callosum being cut at the midline of the brain. detect. Even the patient’s left hemisphere has to learn about the independent existence of the right hemisphere. One of the first things that these patients say they notice after the operation is that their left hand seems to have a “mind of its own.” For example, patients may find themselves putting down a book held in the left hand, even if they have been reading it with great interest. This conflict occurs because the right hemisphere, which controls the left hand, cannot read and therefore finds the book boring. At other times, these cerebral hemispheres The two patients surprise themselves by making obscene gestures (with the left hand) when they do not symmetrical halves of the brain; they constitute the major part of the brain. intend to. A psychologist once reported that a man with a split brain had attempted to beat his wife with one hand and protect her with the other. Did he really want to hurt her? Yes and no, I guess. Left One exception to the crossed representation of senhand chooses sory information is the olfactory system. That is, when a a rose Perfume with person sniffs a flower through the left nostril, only the left Left nostril aroma of rose brain receives a sensation of the odor. Thus, if the right is plugged is presented nostril of a patient with a split brain is closed, leaving to right nostril only the left nostril open, the patient will be able to tell us Person Olfactory denies what the odors are (Gordon and Sperry, 1969). However, information smelling ifthe odor enters the right nostril, the patient will say that anything he or she smells nothing. But, in fact, the right brain has Control of perceived the odor and can identify it. To show this, we speech ask the patient to smell an odor with the right nostril and then reach for some objects that are hidden from view by Control a partition. If asked to use the left hand, controlled by the of left hemisphere that detected the smell, the patient will select hand the object that corresponds to the odor—a plastic flower for a floral odor, a toy fish for a fishy odor, a model tree for the odor of pine, and so forth. But if asked to use the right hand, the patient fails the test because the right hand is connected to the left hemisphere, which did not smell Left hemisphere Right hemisphere the odor. (See Figure 3.) The effects of cutting the corpus callosum reinforce Corpus callosum the conclusion that we become conscious of something has been cut only if information about it is able to reach the parts of the brain responsible for verbal communication, which F I G U R E 3 Smelling with a Split Brain. Identification of an object occurs in response to an olfactory stimulus by a person with a split brain. are located in the left hemisphere. If the information does

Origins of Behavioral Neuroscience

notreach these parts of the brain, then that information does not reach the consciousness associated with these mechanisms. We still know very little about the physiology of consciousness, but studies of people with brain damage are beginning to provide us with some useful insights.

SECTION SUMMARY Understanding Human Consciousness: A Physiological Approach The concept of the mind has been with us for a long time—probably from the earliest history of our species. Modern science has concluded that the world consists of matter and energy and that what we call the mind can be explained by the same laws that govern all other natural phenomena. Studies of the functions of the human nervous system tend to support this position, as the specific example of the split brain shows. Brain damage, by disconnecting brain functions from the speech mechanisms in the left hemisphere, reveals that the mind does not have direct access to all brain functions. When sensory information about a particular object is presented only to the right hemisphere of a person who has had a split-brain operation, the person is not aware of the object but can, nevertheless, indicate by movements of the left hand that the object has been perceived. This phenomenon suggests that consciousness involves operations of the verbal mechanisms of the left hemisphere. Indeed, consciousness may be, in large part, a matter of us “talking to ourselves.” Thus, once we understand the language functions of the brain, we may have gone a long way to understanding how the brain can be conscious of its own existence.

Thought Questions 1. Could a sufficiently large and complex computer ever be programmed to be aware of itself? Suppose that someone someday claims to have done just that. What kind of evidence would you need to prove or disprove this claim? 2. Is consciousness found in animals other than humans? Is the ability of some animals to communicate with each other and with humans evidence for at least some form of awareness of self and others? 3. Clearly, the left hemisphere of a person with a split brain is conscious of the information it receives and of its own thoughts. It is not conscious of the mental processes of the right hemisphere. But is it possible that the right hemisphere is conscious too, but is just unable to talk to us? How could we possibly find out whether it is? Do you see some similarities between this issue and the one raised in the first question?

The Nature of Behavioral Neuroscience The modern history of behavioral neuroscience has been written by psychologists who have combined the experimental methods of psychology with those of physiology and have applied them to the issues that concern all psychologists. Thus, we have studied perceptual processes, control of movement, sleep and waking, reproductive behaviors, ingestive behaviors, emotional behaviors, learning, and language. In recent years we have also begun to study the physiology of pathological conditions, such as addictions and mental disorders.

The Goals of Research The goal of all scientists is to explain the phenomena they study. But what do we mean by explain? Scientific explanation takes two forms: generalization and reduction. Most psychologists deal with generalization. They explain particular instances of behavior as examples of general laws, which they deduce from their experiments. For instance, most psychologists would explain a pathologically strong fear of dogs as an example of a particular form of learning called classical conditioning. Presumably, the person was frightened earlier in life by a dog. An unpleasant stimulus was paired with the sight of the animal (perhaps the person was knocked down by an exuberant dog or was attacked by a vicious one), and the subsequent sight of dogs evokes the earlier response: fear. Most physiologists deal with reduction. They explain complex phenomena in terms of simpler ones. For example, they may explain the movement of a muscle in terms of the changes in the membranes of muscle cells, the entry of particular chemicals, and the interactions among protein molecules within these cells. By contrast, a molecular biologist would explain these events in terms of forces that bind various molecules together and cause various parts of the molecules to be attracted to one another. In turn, the job of an atomic physicist is to describe matter and

generalization Type of scientific explanation; a general conclusion based on many observations of similar phenomena. reduction Type of scientific explanation; a phenomenon is described in terms of the more elementary processes that underlie it.

Origins of Behavioral Neuroscience

energy themselves and to account for the various forces found in nature. Practitioners of each branch of science use reduction to call on sets of more elementary generalizations to explain the phenomena they study. The task of the behavioral neuroscientist is to explain behavior in physiological terms. But behavioral neuroscientists cannot simply be reductionists. It is not enough to observe behaviors and correlate them with physiological events that occur at the same time. Identical behaviors may occur for different reasons and thus may be initiated by different physiological mechanisms. Therefore, we must understand “psychologically” why a particular behavior occurs before we can understand what physiological events made it occur. Let me provide a specific example: Mice, like many other mammals, often build nests. Behavioral observations show that mice will build nests under two conditions: when the air temperature is low and when the animal is pregnant. A nonpregnant mouse will build a nest only if the weather is cool, whereas a Studies of people with brain damage have given us insights into the brain mechanisms involved in language, perception, memory, and emotion. pregnant mouse will build one regardless of the temperature. The same behavior occurs for different reasons. In fact, nest-building Neil Carlson. behavior is controlled by two different physiological mechanisms. Nest building can be studied as a behavior related to the process of temperature regulation, or it can be studied in the context of parental behavior. In practice, the research efforts of behavioral neuroscientists involve both forms of explanation: generalization and reduction. Ideas for experiments are stimulated by the investigator’s knowledge both of psychological generalizations about behavior and of physiological mechanisms. A good behavioral neuroscientist must therefore be both a good psychologist and a good physiologist.

Biological Roots of Behavioral Neuroscience

reflex An automatic, stereotyped movement produced as the direct result of a stimulus.

Study of (or speculations about) the physiology of behavior has its roots in antiquity. Because its movement is necessary for life, and because emotions cause it to beat more strongly, many ancient cultures, including the Egyptian, Indian, and Chinese, considered the heart to be the seat of thought and emotions. The ancient Greeks did, too, but Hippocrates (460–370 b.c.) concluded that this role should be assigned to the brain. Not all ancient Greek scholars agreed with Hippocrates. Aristotle did not; he thought the brain served to cool the passions of the heart. But Galen (a.d. 130–200), who had the greatest respect for Aristotle, concluded that Aristotle’s role for the brain was “utterly absurd, since in that case Nature would not have placed the encephalon [brain] so far from the heart, . . . and she would not have attached the sources of all the senses [the sensory nerves] to it” (Galen, 1968 translation, p. 387). Galen thought enough of the brain to dissect and study the brains of cattle, sheep, pigs, cats, dogs, weasels, monkeys, and apes (Finger, 1994). René Descartes, a seventeenth-century French philosopher and mathematician, has been called the father of modern philosophy. Although he was not a biologist, his speculations about the roles of the mind and brain in the control of behavior provide a good starting point in the history of behavioral neuroscience. Descartes assumed that the world was a purely mechanical entity that, once having been set in motion by God, ran its course without divine interference. Thus, to understand the world, one had only to understand how it was constructed. To Descartes, animals were mechanical devices; their behavior was controlled by environmental stimuli. His view of the human body was much the same: It was a machine. As Descartes observed, some movements of the human body were automatic and involuntary. For example, if a person’s finger touched a hot object, the arm would immediately withdraw from the source of stimulation. Reactions like this did not require participation of the mind; they occurred automatically. Descartes called these actions reflexes (from the Latin reflectere, “to bend back upon itself”). Energy coming from the outside source would be reflected back through the nervous system to the muscles, which would contract. The term is still in use today, but of course we explain the operation of a reflex differently.

Origins of Behavioral Neuroscience

Like most philosophers of his time, Descartes believed that each person possesses a mind—a uniquely human attribute that is not subject to the laws of the universe. But his thinking differed from that of his predecessors in one important way: He was the first to suggest that a link exists between the human mind and its purely physical housing, the brain. He believed that the sense organs of the body supply the mind with information about what is happening in the environment, and that the mind, using this information, controls the body’s movements. In particular, he hypothesized that the interaction between mind and body takes place in the pineal body, a small organ situated on top of the brain stem, buried beneath the cerebral hemispheres. He noted that the brain contains hollow chambers (the ventricles) that are filled with fluid, and he believed that this fluid was under pressure. In his theory, when the mind decides to perform an action, it tilts the pineal body in a particular direction like a little joystick, causing pressurized F I G U R E 4 Descartes’s Theory. This woodcut appears in fluid to flow from the brain into the appropriate set of nerves. This flow of fluid De homine by René Descartes, which was published in 1662. causes the same muscles to inflate and move. (See Figure 4.) Descartes believed that the “soul” (what we would today call As we saw in the prologue, the young René Descartes was greatly impressed the mind) controls the movements of the muscles through by the moving statues in the royal gardens (Jaynes, 1970). These devices served as its influence on the pineal body. According to his theory, the models for Descartes in theorizing about how the body worked. The pressurized eyes sent visual information to the brain, where it could be water of the moving statues was replaced by pressurized fluid in the ventricles; the examined by the soul. When the soul decided to act, it would pipes were replaced by nerves; the cylinders by muscles; and finally, the hidden tilt the pineal body (labeled H in the diagram), which would valves by the pineal body. This story illustrates one of the first times that a techno- divert pressurized fluid through nerves to the appropriate muscles. His explanation is modeled on the mechanism that logical device was used as a model for explaining how the nervous system works. In animated statues in the royal gardens near Paris. science, a model is a relatively simple system that works on known principles and is George Bernard/Photo Researchers, Inc. able to do at least some of the things that a more complex system can do. For example, when scientists discovered that elements of the nervous system communicate by means of electrical impulses, researchers developed models of the brain based upon telephone switchboards and, more recently, computers. Abstract models, which are completely mathematical in their properties, have also been developed. Descartes’s model was useful because, unlike purely philosophical speculations, it could be tested experimentally. In fact, it did not take long for biologists to prove that Descartes was wrong. Luigi Galvani, a seventeenth-century Italian physiologist, found that electrical stimulation of a frog’s nerve caused contraction of the muscle to which it was attached. Contraction occurred even when the nerve and muscle were detached from the rest of the body; therefore, Galvani concluded that the muscle’s ability to contract and the nerve’s ability to send a message to the muscle were characteristics of these tissues themselves. Thus, the brain did not inflate muscles by directing pressurized fluid through the nerve. Galvani’s experiment prompted others to study the nature of the message transmitted by the nerve and the means by which muscles contracted. The results of these efforts gave rise to an accumulation of knowledge about the physiology of behavior. One of the most important figures in the development of experimental physiology was Johannes Müller, a nineteenth-century German physiologist. (See Figure 5.) Müller was a forceful advocate of the application of experimental techniques to physiology. Previously, the activities of most natural scientists were limited to observation and classification. Although these activities are essential, F I G U R E 5 Johannes Müller Müller insisted that major advances in our understanding of the workings of the body would be (1801–1858). achieved only by experimentally removing or isolating animals’ organs, testing their responses to National Library of Medicine. various chemicals, and otherwise altering the environment to see how the organs responded. His most important contribution to the study of the physiology of behavior was his doctrine of specific nerve energies. Müller observed that although all nerves carry the same basic message—an electrical impulse—we perceive the messages of different nerves in different ways. For example, messages carried by the optic nerves produce sensations of visual images, and those carried by the auditory nerves model A mathematical or physical produce sensations of sounds. How can different sensations arise from the same basic message? analogy for a physiological process; for example, computers have been used as The answer is that the messages occur in different channels. The portion of the brain that models for various functions of the brain. receives messages from the optic nerves interprets the activity as visual stimulation, even if the doctrine of specific nerve energies nerves are actually stimulated mechanically. (For example, when we rub our eyes, we see flashes of Müller’s conclusion that because all light.) Because different parts of the brain receive messages from different nerves, the brain must nerve fibers carry the same type of be functionally divided: Some parts perform some functions, while other parts perform others. message, sensory information must be Müller’s advocacy of experimentation and the logical deductions from his doctrine of specific specified by the particular nerve fibers that are active. nerve energies set the stage for performing experiments directly on the brain. Indeed, Pierre Flourens,

Origins of Behavioral Neuroscience

a nineteenth-century French physiologist, did just that. Flourens removed various parts of animals’ brains and observed their behavior. By seeing what the animal could no longer do, he could infer the function of the missing portion of the brain. This method is called experimental ablation (from the Latin ablatus, “carried away”). Flourens claimed to have discovered the regions of the brain that control heart rate and breathing, purposeful movements, and visual and auditory reflexes. Soon after Flourens performed his experiments, Paul Broca, a French surFront geon, applied the principle of experimental ablation to the human brain. Of course, he did not intentionally remove parts of human brains to see how they worked. Instead, he observed the behavior of people whose brains had been damaged by strokes. In 1861 he performed an autopsy on the brain of a man who had had a stroke that resulted in the loss of the ability to speak. Broca’s observations led him to conclude that a portion of the cerebral cortex on the front part of the left side of the brain performs functions necessary for speech. (See Figure 6.) Other physicians soon obtained evidence supporting his conclusions. Further studies would F I G U R E 6 Broca’s Area. This region of the brain is named show the control of speech is not localized in a particular region of the brain. Infor French surgeon Paul Broca, who discovered that damage to a part of the left side of the brain disrupted a person’s deed, speech requires many different functions, which are organized throughout ability to speak. the brain. Nonetheless, the method of experimental ablation remains important to our understanding of the brains of both humans and laboratory animals. As I mentioned earlier, Luigi Galvani used electricity to demonstrate that muscles contain the source of the energy that powers their contractions. In 1870, German physiologists Gustav Fritsch and Eduard Hitzig used electrical stimulation as a tool for understanding the physiology of the brain. They applied weak electrical current to the exposed surface of a dog’s brain and observed the effects of the stimulation. They found that stimulation of different portions of a specific region of the brain caused contraction of specific muscles on the opposite side of the body. We now refer to this region as the primary motor cortex, and we know that nerve cells there communicate directly with those that cause muscular contractions. We also know that other regions of the brain communicate with the primary motor cortex and thus control behaviors. For example, the region that Broca found necessary for speech communicates with, and controls, the portion of the primary motor cortex that controls the muscles of the lips, tongue, and throat, which we use to speak. One of the most brilliant contributors to nineteenth-century science was the German physicist and physiologist Hermann von Helmholtz. Helmholtz devised a mathematical formulation of the law of conservation of energy; invented the ophthalmoscope (used to examine the retina of the eye); devised an important and influential theory of color vision and color blindness; and studied audition, music, and many physiological processes. Helmholtz was also the first scientist to attempt to measure the speed of conduction through nerves. Scientists had previously believed that such conduction was identical to the conduction that occurs in wires, traveling at approximately the speed of light. But Helmholtz found that neural conduction was much slower—only about ninety feet per second. This measurement proved that neural conduction was more than a simple electrical message. experimental ablation The research Twentieth-century developments in experimental physiology include many important inmethod in which the function of a part ventions, such as sensitive amplifiers to detect weak electrical signals, neurochemical techniques of the brain is inferred by observing to analyze chemical changes within and between cells, and histological techniques to see cells and the behaviors an animal can no longer their constituents. perform after that part is damaged. Top

Broca’s area

SECTION SUMMARY The Nature of Behavioral Neuroscience All scientists hope to explain natural phenomena. In this context, the term explanation has two basic meanings: generalization and reduction. Generalization refers to the classification of phenomena according to their essential features so that general laws can be formulated. For example, observing that gravitational attraction is related to the mass of two bodies and to the distance between them

helps to explain the movement of planets. Reduction refers to the description of phenomena in terms of more basic physical processes. For example, gravitation can be explained in terms of forces and subatomic particles. Behavioral neuroscientists use both generalization and reduction to explain behavior. In large part, generalizations use the traditional

Origins of Behavioral Neuroscience

Section Summary (continued) methods of psychology. Reduction explains behaviors in terms of physiological events within the body—primarily within the nervous system. Thus, behavioral neuroscience builds upon the tradition of both experimental psychology and experimental physiology. The behavioral neuroscience of today is rooted in important developments of the past. When René Descartes proposed a model of the brain based on hydraulically activated statues, his model stimulated observations that produced important discoveries. The results of Galvani’s experiments eventually led to an understanding of the nature of the message transmitted by nerves between the brain and the sensory

organs and muscles. Müller’s doctrine of specific nerve energies paved the way for study of the functions of specific parts of the brain through the methods of experimental ablation and electrical stimulation.

Thought Questions 1. What is the value of studying the history of behavioral neuroscience? Is it a waste of time? 2. Suppose we studied just the latest research and ignored explanations that we now know to be incorrect. Would we be spending our time more profitably, or might we miss something?

Natural Selection and Evolution Following the tradition of Müller and von Helmholtz, other biologists continued to observe, classify, and think about what they saw, and some of them arrived at valuable conclusions. The most important of these scientists was Charles Darwin. (See Figure 7.) Darwin formulated the principles of natural selection and evolution, which revolutionized biology.

Functionalism and the Inheritance of Traits Darwin’s theory emphasized that all of an organism’s characteristics—its structure, its coloration, its behavior—have functional significance. For example, the strong talons and sharp beaks of eagles permit them to catch and eat prey. Most caterpillars that eat green leaves are themselves green, and their color makes it difficult for birds to see them against their usual background. Mother mice construct nests, which keep their offspring warm and out of harm’s way. Obviously, the behavior itself is not inherited—how can it be? What is inherited is a brain that causes the behavior to occur. Thus, Darwin’s theory gave rise to functionalism, a belief that characteristics of living organisms perform useful functions. So, to understand the physiological basis of various behaviors, we must first discover what these behaviors accomplish. We must therefore understand something about the natural history of the species being studied so that the behaviors can be seen in context. To understand the workings of a complex piece of machinery, we should know what its functions are. This principle is just as true for a living organism as it is for a mechanical device. However, an important difference exists between machines and organisms: Machines have inventors who had a purpose when they designed them, whereas organisms are the result of a long series of accidents. Thus, strictly speaking, we cannot say that any physiological mechanisms of living organisms have a purpose. But they do have functions, and these we can try to determine. For example, the forelimbs shown in Figure 8 are adapted for different uses in different species of mammals. (See Figure 8.)

F I G U R E 7 Charles Darwin (1809–1882). Darwin’s theory of evolution revolutionized biology and strongly influenced early psychologists. North Wind Picture Archives.

(a)

(d)

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F I G U R E 8 Bones of the Forelimb. The figure shows the bones of a (a) human, (b) bat, (c) whale, and (d) dog. Through the process of natural selection, these bones have been adapted to suit many different functions.

functionalism The principle that the best way to understand a biological phenomenon (a behavior or a physiological structure) is to try to understand its useful functions for the organism.

Origins of Behavioral Neuroscience

F I G U R E 9 The Owl Butterfly. This butterfly displays its eyespots when approached by a bird. The bird usually will fly away. Neil Carlson.

natural selection The process by which inherited traits that confer a selective advantage (increase an animal’s likelihood to live and reproduce) become more prevalent in the population. evolution A gradual change in the structure and physiology of plant and animal species—generally producing more complex organisms—as a result of natural selection. mutation A change in the genetic information contained in the chromosomes of sperms or eggs, which can be passed on to an organism’s offspring; provides genetic variability. selective advantage A characteristic of an organism that permits it to produce more than the average number of offspring of its species.

A good example of the functional analysis of an adaptive trait was demonstrated in an experiment by Blest (1957). Certain species of moths and butterflies have spots on their wings that resemble eyes—particularly the eyes of predators such as owls. (See Figure 9.) These insects normally rely on camouflage for protection; the backs of their wings, when folded, are colored like the bark of a tree. However, when a bird approaches, the insect’s wings flip open, and the hidden eyespots are suddenly displayed. The bird then tends to fly away, rather than eat the insect. Blest performed an experiment to see whether the eyespots on a moth’s or butterfly’s wings really disturbed birds that saw them. He placed mealworms on different backgrounds and counted how many worms the birds ate. Indeed, when the worms were placed on a background that contained eyespots, the birds tended to avoid them. Darwin formulated his theory of evolution to explain the means by which species acquired their adaptive characteristics. The cornerstone of this theory is the principle of natural selection. Darwin noted that members of a species were not all identical and that some of the differences they exhibited were inherited by their offspring. If an individual’s characteristics permit it to reproduce more successfully, some of the individual’s offspring will inherit the favorable characteristics and will themselves produce more offspring. As a result, the characteristics will become more prevalent in that species. He observed that animal breeders were able to develop strains that possessed particular traits by mating together only animals that possessed the desired traits. If artificial selection, controlled by animal breeders, could produce so many varieties of dogs, cats, and livestock, perhaps natural selection could be responsible for the development of species. Of course, it was the natural environment, not the hand of the animal breeder, that shaped the process of evolution. To evolve means to develop gradually (from the Latin evolvere, “to unroll”). The process of evolution is a gradual change in the structure and physiology of plant and animal species as a result of natural selection. New species evolve when organisms develop novel characteristics that can take advantage of unexploited opportunities in the environment. Darwin and his fellow scientists knew nothing about the mechanism by which the principle of natural selection works. In fact, the principles of molecular genetics were not discovered until the middle of the twentieth century. Briefly, here is how the process works: Every sexually reproducing multicellular organism consists of a large number of cells, each of which contains chromosomes. Chromosomes are large, complex molecules that contain the recipes for producing the proteins that cells need to grow and to perform their functions. In essence, the chromosomes contain the blueprints for the construction (that is, the prenatal development) of a particular member of a particular species. If the plans are altered, a different organism is produced. The plans do get altered; mutations occur from time to time. Mutations are accidental changes in the chromosomes of sperms or eggs that join together and develop into new organisms. For example, cosmic radiation might strike a chromosome in a cell of an animal’s testis or ovary, thus producing a mutation that affects that animal’s offspring. Most mutations are deleterious; the offspring either fails to survive or survives with some sort of defect. However, a small percentage of mutations are beneficial and confer a selective advantage to the organism that possesses them. That is, the animal is more likely than other members of its species to live long enough to reproduce and hence to pass on its chromosomes to its own offspring. Many different kinds of traits can confer a selective advantage: resistance to a particular disease, the ability to digest new kinds of food, more effective weapons for defense or for procurement of prey, and even a more attractive appearance to members of the other sex (after all, one must reproduce in order to pass on one’s chromosomes). Naturally, the traits that can be altered by mutations are physical ones; chromosomes make proteins, which affect the structure and chemistry of cells. But the effects of these physical alterations can be seen in an animal’s behavior. Thus, the process of natural selection can act on behavior indirectly. For example, if a particular mutation results in changes in the brain that cause a small animal to stop moving and freeze when it perceives a novel stimulus, that animal is more likely to escape undetected when a predator passes nearby. This tendency makes the animal more likely to survive and produce offspring, thus passing on its genes to future generations. Other mutations are not immediately favorable, but because they do not put their possessors at a disadvantage, they are inherited by at least some members of the species. As a result of thousands of such mutations, the members of a particular species possess a variety of genes and are all at least somewhat different from one another. Variety is a definite advantage for a species.

Origins of Behavioral Neuroscience

Different environments provide optimal habitats for different kinds of organisms. When the environment changes, species must adapt or run the risk of becoming extinct. If some members of the species possess assortments of genes that provide characteristics that permit them to adapt to the new environment, their offspring will survive, and the species will continue.

Evolution of the Human Brain

1.2%

Our early human ancestors possessed several characteristics that enabled them to compete with other species. Their agile hands enabled them to make and use tools. Their excellent color vision helped them to spot ripe fruit, game animals, and dangerous predators. Their mastery of fire enabled them to cook food, provide warmth, and frighten nocturnal predators. Their upright posture and bipedalism (the ability to walk on two feet) made it possible for them to walk long distances efficiently, with their eyes far enough from the ground to see long distances across the plains. Bipedalism also permitted them to carry tools and food with them, which meant that they could bring fruit, roots, and pieces of meat back to their tribe. Their linguistic abilities enabled them to combine the collective knowledge of all the members of the tribe, to make plans, to pass information on to subsequent generations, and to form complex civilizations that established their status as the dominant species. All of these characteristics required a larger brain. A large brain requires a large skull, and an upright posture limits the size of a woman’s birth canal. A newborn baby’s head is about as large as it can be. As it is, the birth of a baby is much more arduous than the birth of mammals with proportionally smaller heads, including those of our closest primate relatives. Because a baby’s brain is not large or complex enough to perform the physical and intellectual abilities of an adult, it must continue to grow after the baby is born. In fact, all mammals (and all birds, for that matter) require parental care for a period of time while the nervous system develops. The fact that young mammals (and, particularly, young humans) are guaranteed to be exposed to the adults who care for them means that a period of apprenticeship is possible. Consequently, the evolutionary process did not have to produce a brain that consisted solely of specialized circuits of nerve cells that performed specialized tasks. Instead, it could simply produce a larger brain with an abundance of neural circuits that could be modified by experience. Adults would nourish and protect their offspring and provide them with the skills they would need as adults. Some specialized circuits were necessary, of course (for example, those involved in analyzing the complex sounds we use for speech), but by and large, the brain is a general-purpose, programmable computer. neoteny A slowing of the process of Our closest living relatives—the only present-day hominids (humanlike apes) besides maturation, allowing more time for ourselves—are the chimpanzees, gorillas, and orangutans. DNA analysis shows that genetically growth; an important factor in the there is very little difference between these four species. For example, humans and chimpanzees share development of large brains. 98.8 percent of their DNA. (See Figure10.) What types of genetic changes are required to produce a larger brain? The most important principle appears to be a slowing of the pro1.8% cess of maturation, allowing more time for growth. As we will see, the Chimpanzee prenatal period of cell division in the brain is prolonged in humans, 2.4% 1.2 which results in a brain weighing an average of 350 g and containing % approximately 100 billion neurons. After birth, the brain continues to grow. Production of new neurons almost ceases, but those that are already present grow and establish connections with each other; other types of brain cells, which protect and support neurons, then begin to % 1.4 proliferate. Not until late adolescence does the human brain reach its Orangutan Human adult size of approximately 1400 g—about four times the weight of a newborn’s brain. This prolongation of maturation is known as neoteny (roughly translated as “extended youth”). The mature human head and brain retain some infantile characteristics, including their disproportionate size relative to the rest of the body. Figure 11 shows fetal and Gorilla adult skulls of chimpanzees and humans. As you can see, the fetal skulls F I G U R E 10 DNA Among Species of Hominids. A pyramid are much more similar than those of the adults. The grid lines show the illustrating the percentage differences in DNA among the four major pattern of growth, indicating much less change in the human skull from species of hominids. birth to adulthood. (See Figure 11.) Redrawn from Lewin, R. Human Evolution: An Illustrated Introduction. Boston: Blackwell Scientific Publications, 1993.

Origins of Behavioral Neuroscience

Chimp fetus

Chimp adult

Human fetus

Human adult

F I G U R E 11 Neoteny in Evolution of the Human Skull. The skulls of fetal humans and chimpanzees are much more similar than are those of the adults. The grid lines show the pattern of growth, indicating much less change in the human skull from birth to adulthood. Redrawn from Lewin, R. Human Evolution: An Illustrated Introduction, 3rd ed. Boston: Blackwell Scientific Publications, 1993.

SECTION SUMMARY Natural Selection and Evolution Darwin’s theory of evolution, which was based on the concept of natural selection, provided an important contribution to modern behavioral neuroscience. The theory asserts that we must understand the functions performed by an organ or body part or by a behavior. Through random mutations, changes in an individual’s genetic material cause different proteins to be produced, which results in the alteration of some physical characteristics. If the changes confer a selective advantage on the individual, the new genes will be transmitted to more and more members of the species. Even behaviors can evolve, through the selective advantage of alterations in the structure of the nervous system. The evolution of large brains made possible the development of toolmaking, fire building, and language, which in turn permitted the development of complex social structures. Large brains also provided a large memory capacity and the abilities to recognize patterns of events in the past and to plan for the future. Because an upright posture limits the size of a woman’s birth canal and therefore the size of the head that passes through it, much of the brain’s growth must take place after birth,

which means that children require an extended period of parental care. This period of apprenticeship enables the developing brain to be modified by experience. Although human DNA differs from that of chimpanzees by only 1.2 percent, our brains are more than three times larger, which means that a small number of genes is responsible for the increase in the size of our brains. These genes appear to retard the events that stop brain development, resulting in a phenomenon known as neoteny.

Thought Questions 1. What useful functions are provided by the fact that a human can be self-aware? How was this trait selected for during the evolution of our species? 2. Are you surprised that the difference in the DNA of humans and chimpanzees is only 1.2 percent? How do you feel about this fact? 3. If our species continues to evolve (and most geneticists believe that this is the case), what kinds of changes do you think might occur?

Ethical Issues in Research with Animals Any time we use another species of animals for our own purposes, we should be sure that what we are doing is both humane and worthwhile. I believe that a good case can be made that research on the physiology of behavior qualifies on both counts. Humane treatment is a matter of procedure. We know how to maintain laboratory animals in good health in comfortable, sanitary conditions. We know how to administer anesthetics and analgesics so that animals do not suffer during or after surgery, and we know how to prevent infections with proper surgical procedures and the use of antibiotics. Most industrially developed societies have very strict regulations about the care of animals and require approval of the experimental procedures used on them. There is no excuse for mistreating animals in our care. In fact, the vast majority of laboratory animals are treated humanely. We use animals for many purposes. We eat their meat and eggs, and we drink their milk; we turn their hides into leather; we extract insulin and other hormones from their organs to treat people’s diseases; we train them to do useful work on farms or to entertain us. Even having a pet

Origins of Behavioral Neuroscience

is a form of exploitation; it is we—not they—who decide that they will live in our homes. The fact is, we have been using other animals throughout the history of our species. Pet owning causes much more suffering among animals than scientific research does. As Miller (1983) notes, pet owners are not required to receive permission from a board of experts that includes a veterinarian to house their pets, nor are they subject to periodic inspections to be sure that their homes are clean and sanitary, that their pets have enough space to exercise properly, or that their pets’ diets are appropriate. Scientific researchers are. Miller also notes that fifty times more dogs and cats are killed by humane societies each year because they have been abandoned by former pet owners than are used in scientific research. If a person believes that it is wrong to use another animal in any way, regardless of the benefits to humans, there is nothing anyone can say to convince him or her of the value of scientific research with animals. For this person the issue is closed from the very beginning. Moral absolutes cannot be settled logically; like religious beliefs, they can be accepted or rejected, but they cannot be proved or disproved. My arguments in support of scientific research with animals are based on an evaluation of the benefits the research has to humans. (We should also remember that research with animals often helps other animals; procedures used by veterinarians, as well as those used by physicians, come from such research.) Before describing the advantages of research with animals, let me point Unlike pet owners, scientists who use animals in their research out that the use of animals in research and teaching is a special target of animal must follow stringent regulations designed to ensure that the rights activists. Nicholl and Russell (1990) examined twenty-one books writ- animals are properly cared for. ten by such activists and counted the number of pages devoted to concern for Patrick Landmann/Science Source/Photo Researchers, Inc. different uses of animals. Next, they compared the relative concern the authors showed for these uses to the numbers of animals actually involved in each of these categories. The results indicate that the authors showed relatively little concern for animals used for food, hunting, or furs, or for those killed in pounds. In contrast, although only 0.3 percent of the animals were used for research and education, 63.3 percent of the pages were devoted to criticizing this use. In terms of pages per million animals used, the authors devoted 0.08 to food, 0.23 to hunting, 1.27 to furs, 1.44 to killing in pounds—and 53.2 to research and education. The authors showed 665 times more concern for research and education than for food and 231 times more than for hunting. Even the use of animals for furs (which consumes two-thirds as many animals as research and education) attracted 41.9 times less attention per animal. The disproportionate amount of concern that animal rights activists show toward the use of animals in research and education is puzzling, particularly because this is the one indispensable use of animals. We can survive without eating animals, we can live without hunting, we can do without furs. But without using animals for research and for training future researchers, we cannot make progress in understanding and treating diseases. In not too many years our scientists will probably have developed vaccines that will prevent the further spread of diseases such as malaria and AIDS. Some animal rights activists believe that preventing the deaths of laboratory animals in the pursuit of such vaccines is a more worthy goal than preventing the deaths of millions of humans that will occur as a result of these diseases if vaccines are not developed. Even diseases that we have already conquered would take new victims if drug companies could no longer use animals. If they were deprived of animals, these companies could no longer extract some of the hormones used to treat human diseases, and they could not prepare many of the vaccines that we now use to prevent them. Our species is beset by medical, mental, and behavioral problems, many of which can be solved only through biological research. Let us consider some of the major neurological disorders. Strokes, caused by bleeding or obstruction of a blood vessel within the brain, often leave people partially paralyzed, unable to read, write, or converse with their friends and family. Basic research on the means by which nerve cells communicate with each other has led to important discoveries about the causes of the death of brain cells. This research was not directed toward a specific practical goal; the potential benefits actually came as a surprise to the investigators.

Origins of Behavioral Neuroscience

Research with laboratory animals has produced important discoveries about the possible causes or potential treatments of neurological and mental disorders, including Parkinson’s disease, schizophrenia, manic-depressive illness, anxiety disorders, obsessive-compulsive disorders, anorexia nervosa, obesity, and drug addictions. Although much progress has been made, these problems are still with us, and they cause much human suffering. Unless we continue our research with laboratory animals, the problems will not be solved. Some people have suggested that instead of using laboratory animals in our research, we could use tissue cultures or computers. Unfortunately, neither tissue cultures nor computers are substitutes for living organisms. We have no way to study behavioral problems such as addictions in tissue cultures, nor can we program a computer to simulate the workings of an animal’s nervous system. (If we could, that would mean that we already had all the answers.) The easiest way to justify research with animals is to point to actual and potential benefits to human health, as I have just done. However, we can also justify this research with a less practical, but perhaps equally important, argument. One of the things that characterize our species is a quest for an understanding of our world. For example, astronomers study the universe and try to uncover its mysteries. Even if their discoveries never lead to practical benefits such as better drugs or faster methods of transportation, the fact that they enrich our understanding of the beginning and the fate of our universe justifies their efforts. The pursuit of knowledge is itself a worthwhile endeavor. Surely, the attempt to understand the universe within us—our nervous system, which is responsible for all that we are or can be—is also valuable.

Careers in Neuroscience

behavioral neuroscientist (Also called physiological psychologist) A scientist who studies the physiology of behavior, primarily by performing physiological and behavioral experiments with laboratory animals.

What is behavioral neuroscience, and what do behavioral neuroscientists do? It may be worthwhile for me to describe the field and careers that are open to those who specialize in it before we begin our study in earnest. Behavioral neuroscientists study all behavioral phenomena that can be observed in nonhuman animals. They attempt to understand the physiology of behavior: the nervous system’s role, through interacting with the rest of the body (especially the endocrine system, which secretes hormones), in controlling behavior. They study such topics as sensory processes, sleep, emotional behavior, ingestive behavior, aggressive behavior, sexual behavior, parental behavior, and learning and memory. They also study animal models of disorders that afflict humans, such as anxiety, depression, obsessions and compulsions, phobias, psychosomatic illnesses, and schizophrenia. Although the original name for the field was physiological psychology, several other terms are now in general use, such as biological psychology, biopsychology, psychobiology, and—the most common one—behavioral neuroscience. Most professional behavioral neuroscientists have received a Ph.D. from a graduate program in psychology or from an interdisciplinary program. (My own university awards a Ph.D. in neuroscience and behavior. The program includes faculty members from the departments of psychology, biology, biochemistry, and computer science.) Behavioral neuroscience belongs to a larger field that is simply called neuroscience. Neuroscientists concern themselves with all aspects of the nervous system: its anatomy, chemistry, physiology, development, and functioning. The research of neuroscientists ranges from the study of molecular genetics to the study of social behavior. The field has grown enormously in the last few years; the membership of the Society for Neuroscience is currently over thirty-eight thousand. Most professional behavioral neuroscientists are employed by colleges and universities, where they are engaged in teaching and research. Others are employed by institutions devoted to research—for example, laboratories owned and operated by national governments or by private philanthropic organizations. A few work in industry, usually for pharmaceutical companies that are interested in assessing the effects of drugs on behavior. To become a professor or independent researcher, one must receive a doctorate—usually a Ph.D., although some people turn to research after receiving an M.D. Nowadays, most behavioral neuroscientists spend two years in a temporary postdoctoral position, working in the laboratory of a senior scientist to gain more research experience. During this time, they write articles describing their research findings and submit them for publication in scientific journals. These articles and the publications they appear in are important factors in obtaining a permanent position.

Origins of Behavioral Neuroscience

Two other fields often overlap with behavioral neuroscience: neurology and cognitive neuroscience. Neurologists are physicians who are involved in the diagnosis and treatment of diseases of the nervous system. Most neurologists are solely involved in the practice of medicine, but a few engage in research devoted to advancing our understanding of the physiology of behavior. They study the behavior of people whose brains have been damaged by natural causes, using advanced brain-scanning devices to study the activity of various regions of the brain as a subject participates in various behaviors. This research is also carried out by cognitive neuroscientists—scientists with a Ph.D. and specialized training in the principles and procedures of neurology. Not all people who are engaged in neuroscience research have doctoral degrees. Many research technicians perform essential—and intellectually rewarding—services for the scientists with whom they work. Some of these technicians gain enough experience and education on the job to enable them to collaborate with their employers on their research projects rather than simply work for them.

SECTION SUMMARY Ethical Issues in Research with Animals and Careers in Neuroscience Research on the physiology of behavior necessarily involves the use of laboratory animals. It is incumbent on all scientists using these animals to see that they are housed comfortably and treated humanely, and laws have been enacted to ensure that they are. Such research has already produced many benefits to humankind and promises to continue to do so. Behavioral neuroscience (originally called physiological psychology and also called biological psychology, biopsychology, and psychobiology) is a field devoted to our understanding of the physiology of behavior. Behavioral neuroscientists are allied with other scientists in the

broader field of neuroscience. To pursue a career in behavioral neuroscience (or in the sister field of cognitive neuroscience), one must obtain a graduate degree and (usually) serve two years or more as a “postdoc”—a scientist working in the laboratory of an established scientist.

Thought Question 1. Why do you think some people are apparently more upset about using animals for research and teaching than about using them for other purposes?

Strategies for Learning The brain is a complicated organ. After all, it is responsible for all our abilities and all our complexities. Scientists have been studying this organ for a good many years and (especially in recent years) have been learning a lot about how it works. It is impossible to summarize this progress in a few simple sentences. Learning about the physiology of behavior involves much more than memorizing facts. Of course, there are facts to be memorized: names of parts of the nervous system, names of chemicals and drugs, scientific terms for particular phenomena and procedures used to investigate them, and so on. But the quest for information is nowhere near completed; we know only a small fraction of what we have to learn. And almost certainly, many of the “facts” that we now accept will someday be shown to be incorrect. If all you do is learn facts, where will you be when these facts are revised? The antidote to obsolescence is knowledge of the process by which facts are obtained. Scientific facts are the conclusions that scientists make about their observations. If you learn only the conclusions, obsolescence is almost guaranteed. You will have to remember which conclusions are overturned and what the new conclusions are, and that kind of rote learning is hard to do. But if you learn about the research strategies the scientists use, the observations they make, and the reasoning that leads to the conclusions, you will develop an understanding that is easily revised

Origins of Behavioral Neuroscience

when new observations are made and new “facts” emerge. If you understand what lies behind the conclusions, then you can incorporate new information into what you already know and revise these conclusions yourself. In recognition of these realities about learning, knowledge, and the scientific method, it is important to consider the procedures, experiments, and logical reasoning that scientists have used in their attempt to understand the physiology of behavior. If, in the interest of expediency, you focus on the conclusions and ignore the process that leads to them, you run the risk of acquiring information that will quickly become obsolete. On the other hand, if you try to understand the experiments and see how the conclusions follow from the results, you will acquire knowledge that lives and grows. Now let me offer some practical advice about studying. You have been studying throughout your academic career, and you have undoubtedly learned some useful strategies along the way. Even if you have developed efficient and effective study skills, at least consider the possibility that there might be some ways to improve them. If possible, the first reading of the assignment should be as uninterrupted as you can make it; that is, read the chapter without worrying much about remembering details. Next, after the first class meeting devoted to the topic, read the assignment again in earnest. Use a pen or pencil as you go, making notes. Don’t use a highlighter. Sweeping the felt tip of a highlighter across some words on a page provides some instant gratification; you can even imagine that the highlighted words are somehow being transferred to your knowledge base. You have selected what is important, and when you review the reading assignment you have only to read the highlighted words. But this is an illusion. Be active, not passive. Force yourself to write down whole words and phrases. The act of putting the information into your own words will not only give you something to study shortly before the next exam but also put something into your head (which is helpful at exam time). Using a highlighter puts off the learning until a later date; rephrasing the information in your own words starts the learning process right then. You will notice that some words in this chapter are italicized and others are printed in boldface. Italic type means one of two things: Either the word is being stressed for emphasis and is not a new term, or I am pointing out a new term that you probably do not need to learn. On the other hand, a word in boldface is a new term that you should try to learn. Most of the boldfaced terms in the text are part of the vocabulary of behavioral neuroscience. Okay, the preliminaries are over.

EPILOGUE

| Models of Brain Functions

René Descartes had no way to study the operations of the nervous system. He did, however, understand how the statues in the royal gardens at Saint-Germain were powered and controlled, which led him to view the body as a complicated piece of plumbing. Many scientists have followed Descartes’s example, using technological devices that were fashionable at the time to explain how the brain worked. What motivates people to use artificial devices to explain the workings of the brain? The most important reason, I suppose, is that the brain is enormously complicated. Even the most complex human inventions are many times simpler than the brain, and because they have been designed and made by people, people can understand them. If an artificial device can do some of the things that the brain does, then perhaps both the brain and the device accomplish their tasks in the same way. Most models of brain function developed in the last half of the twentieth century have been based on the modern, generalpurpose digital computer. Actually, they have been based not on the computers themselves but on computer programs. Computers can be programmed to store any kind of information that can be coded in numbers or words, can solve any logical problem that can be explicitly described, and can compute any mathematical equations that can be written. Therefore, in principle at least, they can be programmed to do the things we do: perceive, remember, make deductions, and solve problems. The construction of computer programs that simulate human brain functions can help to clarify the nature of these functions. For instance, to construct a program and simulate, say, perception and classification of certain types of patterns, the investigator is forced to specify precisely what is required by the task of pattern perception. If the program fails to recognize the patterns, then the investigator knows that something is wrong with the model or with the way it has been implemented in the program. The investigator revises the model, tries again, and keeps working until it finally works (or until he or she gives up the task as being too ambitious). Ideally, this task tells the investigator the kinds of processes the brain must perform. However, there is usually more than one way to accomplish a particular goal; critics of computer modeling have pointed out that it is possible to write a program that performs a task that the human brain performs and comes up with exactly the same results but does the task in an entirely different way. In fact,

some say, given the way that computers work and what we know about the structure of the human brain, the computer program is guaranteed to work differently. When we base a model of brain functions on a physical device with which we are familiar, we enjoy the advantage of being able to think concretely about something that is difficult to observe. However, if the brain does not work like a computer, then our models will not tell us very much about the brain. Such models are constrained (“restricted”) by the computer metaphor; they will be able to do things only the way that computers can do them. If the brain can actually do some different sorts of things that computers cannot do, the models will never contain these features. In fact, computers and brains are fundamentally different. Modern computers are serial devices; they work one step at a time. (Serial, from the Latin sererei “to join,” refers to events that occur in order, one after the other.) Programs consist of a set of instructions stored in the computer’s memory. The computer follows these instructions, one at a time. Because each of these steps takes time, a complicated program will take more time to execute. But we do some things extremely quickly that computers take a very long time to do. The best example is visual perception. We can recognize a complex figure about as quickly as a simple one; for example, it takes about the same amount of time to recognize a friend’s face as it does to identify a simple triangle. The same is not true at all for a serial computer. A computer must “examine” the scene through an input device like a video camera. Information about the brightness of each point of the picture must be converted into a number and stored in a memory location. Then the program examines each memory location, one at a time, and does calculations that determine the locations of lines, edges, textures, and shapes; finally, it tries to determine what these shapes represent. Recognizing a face takes much longer than recognizing a triangle. Unlike serial computers, the brain is a parallel processor, in which many different modules (collections of circuits of neurons) work simultaneously at different tasks. A complex task is broken down into many smaller ones, and separate modules work on each of them. Because the brain consists of many billions of neurons, it can afford to devote different clusters of neurons to different tasks. With so many things happening at the same time, the task gets done quickly.

Origins of Behavioral Neuroscience

KEY CONCEPTS UNDERSTANDING HUMAN CONSCIOUSNESS: A PHYSIOLOGICAL APPROACH

1. Behavioral neuroscientists believe that the mind is a function performed by the brain. 2. The study of human brain functions has helped us gain some insight into the nature of human consciousness, which appears to be related to the language functions of the brain. This chapter described one example, the effects of the split-brain operation. THE NATURE OF BEHAVIORAL NEUROSCIENCE

3. Scientists attempt to explain natural phenomena by means of generalization and reduction. Because behavioral neuroscientists use the methods of psychology and physiology, they employ both types of explanations. 4. Descartes developed the first model to explain how the brain controls movement, based on the animated statues in the royal gardens. Subsequently, investigators tested their ideas with scientific experiments. NATURAL SELECTION AND EVOLUTION

6. We owe our status as the dominant species to our bipedal stance, our agile hands, our excellent vision, and the behavioral and cognitive abilities provided by our large, complex brains, which enable us to adapt to a wide variety of environments, exploit a wide variety of resources, and, with the development of language, form large, complex communities. ETHICAL ISSUES IN RESEARCH WITH ANIMALS

7. Scientific research with animals has taught us most of what we know about the functions of the body, including that of the nervous system. This knowledge is essential in developing ways to prevent and treat neurological and mental disorders. CAREERS IN NEUROSCIENCE

8. Behavioral neuroscientists study the physiology of behavior by performing research with animals. They use the research methods and findings of other neuroscientists in pursuit of their particular interests.

5. Darwin’s theory of evolution, with its emphasis on function, helps behavioral neuroscientists discover the relations between brain mechanisms, behaviors, and an organism’s adaptation to its environment.

EXPLORE the Virtual Brain in The Virtual Brain is an interactive application in MyPsychLab. It contains a series of modules that cover the different subjects you will encounter in your course. Each module contains a tour of relevant neuroanatomy, physiological animations that help students visualize complex processes, case studies that connect biology to behavior, and assessments that allow you to review your understanding. The Brain is also available as a web application for iPad.

Origins of Behavioral Neuroscience

REFERENCES Blest, A. D. The function of eyespot patterns in insects. Behaviour, 1957, 11, 209–256. Finger, S. Origins of Neuroscience: A History of Explorations into Brain Function. New York: Oxford University Press, 1994. Galen. De Usu Partium. Translated by M. T. May. Ithaca, New York: Cornell University Press, 1968. Gazzaniga, M. Forty-five years of split-brain research and still going strong. Nature Reviews: Neuroscience, 2005, 6, 653–659. Gazzaniga, M. S., and LeDoux, J. E. The Integrated Mind. New York: Plenum Press, 1978. Gordon, H. W., and Sperry, R. Lateralization of olfactory perception in the surgically separated hemispheres in man. Neuropsychologia, 1969, 7, 111–120. Jaynes, J. The problem of animate motion in the seventeenth century. Journal of the History of Ideas, 1970, 6, 219–234. Miller, N. E. Understanding the use of animals in behavioral research: Some critical issues. Annals of the New York Academy of Sciences, 1983, 406, 113–118. Nicholl, C. S., and Russell, R. M. Analysis of animal rights literature reveals the underlying motives of the movement: Ammunition for counter offensive by scientists. Endocrinology, 1990, 127, 985–989. Sperry, R. W. Brain bisection and consciousness. In Brain and Conscious Experience, edited by J. Eccles. New York: Springer-Verlag, 1966.

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OUTLINE ■

Cells of the Nervous System Neurons

Structure and Functions of Cells of the Nervous System

Supporting Cells The Blood–Brain Barrier ■

Communication Within a Neuron Neural Communication: An Overview Measuring Electrical Potentials of Axons The Membrane Potential: Balance of Two Forces The Action Potential Conduction of the Action Potential

■

Communication Between Neurons Structure of Synapses Release of Neurotransmitter Activation of Receptors Postsynaptic Potentials Termination of Postsynaptic Potentials Effects of Postsynaptic Potentials: Neural Integration Autoreceptors

LEARNING OBJECTIVES 1. Name and describe the parts of a neuron and explain their functions. 2. Describe the supporting cells of the central and peripheral nervous systems and describe and explain the importance of the blood–brain barrier.

Thomas Deerinck, NCMIR / Photo Researchers, Inc.

Axoaxonic Synapses Nonsynaptic Chemical Communication

5. Describe the role of ion channels in action potentials and explain the all-or-none law and the rate law. 6. Describe the structure of synapses, the release of neurotransmitter, and the activation of postsynaptic receptors.

3. Brieﬂy describe the neural circuitry responsible for a withdrawal reﬂex and its inhibition by neurons in the brain.

7. Describe postsynaptic potentials: the ionic movements that cause them, the processes that terminate them, and their integration.

4. Describe the measurement of the action potential and explain how the balance between the forces of diﬀusion and electrostatic pressure is responsible for the membrane potential.

8. Describe the role of autoreceptors and axoaxonic synapses in synaptic communication and describe the role of neuromodulators and hormones in nonsynaptic communication.

PROLOGUE

| Unresponsive Muscles

Kathryn D. was getting desperate. All her life she had been healthy and active, eating wisely and keeping fit with sports and regular exercise. She went to her health club almost every day for a session of low-impact aerobics, followed by a swim. But several months ago, she began having trouble keeping up with her usual schedule. At first, she found herself getting tired toward the end of her aerobics class. Her arms, particularly, seemed to get heavy. Then when she entered the pool and started swimming, she found that it was hard to lift her arms over her head; she abandoned the crawl and the backstroke and did the sidestroke and breaststroke instead. She did not have any flulike symptoms, so she told herself that she needed more sleep and perhaps she should eat a little more. Over the next few weeks, however, things only got worse. Aerobics classes were becoming an ordeal. Her instructor became concerned and suggested that Kathryn see her doctor. She did so, but he could find nothing wrong with her. She was not anemic, showed no signs of an infection, and seemed to be well nourished. He asked how things were going at work. “Well, lately I’ve been under some pressure,” she said. “The head of my department quit a few weeks ago, and I’ve taken over his job temporarily. I think I have a chance of getting the job permanently, but I feel as if my bosses are watching me to see whether I’m good enough for the job.” Kathryn and her physician agreed that increased stress could be the cause of her problem. “I’d prefer not to give you any medication at this time,” he said, “but if you don’t feel better soon we’ll have a closer look at you.” She did feel better for a while, but then all of a sudden her symptoms got worse. She quit going to the health club and found that she even had difficulty finishing a day’s work. She was certain that

T sensory neuron A neuron that detects changes in the external or internal environment and sends information about these changes to the central nervous system. motor neuron A neuron located within the central nervous system that controls the contraction of a muscle or the secretion of a gland. interneuron A neuron located entirely within the central nervous system.

people were noticing that she was no longer her lively self, and she was afraid that her chances for the promotion were slipping away. One afternoon she tried to look up at the clock on the wall and realized that she could hardly see—her eyelids were drooping, and her head felt as if it weighed a hundred pounds. Just then, one of her supervisors came over to her desk, sat down, and asked her to fill him in on the progress she had been making on a new project. As she talked, she found herself getting weaker and weaker. Her jaw was getting tired, even her tongue was getting tired, and her voice was getting weaker. With a sudden feeling of fright she realized that the act of breathing seemed to take a lot of effort. She managed to finish the interview, but immediately afterwards she packed up her briefcase and left for home, saying that she had a bad headache. She telephoned her physician, who immediately arranged for her to go to the hospital to be seen by Dr. T., a neurologist. Dr. T. listened to a description of her symptoms and examined her briefly. She said to Kathryn, “I think I know what may be causing your symptoms. I’d like to give you an injection and watch your reaction.” She gave some orders to the nurse, who left the room and came back with a syringe. Dr. T. took it, swabbed Kathryn’s arm, and injected the drug. She started questioning Kathryn about her job. Kathryn answered slowly, her voice almost a whisper. As the questions continued, she realized that it was getting easier and easier to talk. She straightened her back and took a deep breath. Yes, she was sure. Her strength was returning! She stood up and raised her arms above her head. “Look,” she said, her excitement growing. “I can do this again. I’ve got my strength back! What was that you gave me? Am I cured?” (For an answer to her question, see the Epilogue at the end of this chapter.)

he brain is the organ that moves the muscles. That might sound simplistic, but ultimately, movement—or, more accurately, behavior—is the primary function of the nervous system. To make useful movements, the brain must know what is happening outside in the environment. Thus, the body also contains cells that are specialized for detecting environmental events. Of course, complex animals such as humans do not react automatically to events in our environment; our brains are flexible enough that we behave in different ways, according to present circumstances and those we experienced in the past. Besides perceiving and acting, we can remember and decide. All these abilities are made possible by the billions of cells found in the nervous system or controlled by them. This chapter describes the structure and functions of the most important cells of the nervous system. Information, in the form of light, sound waves, odors, tastes, or contact with objects, is gathered from the environment by specialized cells called sensory neurons. Movements are accomplished by the contraction of muscles, which are controlled by motor neurons. (The term motor is used here in its original sense to refer to movement, not to a mechanical engine.) And in between sensory neurons and motor neurons come the interneurons—neurons that lie entirely within the central nervous system. Local interneurons form circuits with nearby neurons and analyze small pieces of information. Relay interneurons connect circuits of local interneurons in one region of the brain with those in other regions. Through these connections, circuits of

Structure and Functions of Cells of the Nervous System

neurons throughout the brain perform functions essential to tasks such as perceiving, learning, remembering, deciding, and controlling complex behaviors. How many neurons are there in the human nervous system? The most common estimate is around 100 billion, but no one has counted them yet. To understand how the nervous system controls behavior, we must first understand its parts—the cells that compose it. Because this chapter deals with cells, you need not be familiar with the structure of the nervous system. However, you need to know that the nervous system consists of two basic divisions: the central nervous system and the peripheral nervous system. The central nervous system (CNS) consists of the parts that are encased by the bones of the skull and spinal column: the brain and the spinal cord. The peripheral nervous system (PNS) is found outside these bones and consists of the nerves and most of the sensory organs.

Cells of the Nervous System The first part of this chapter is devoted to a description of the most important cells of the nervous system—neurons and their supporting cells—and to the blood–brain barrier, which provides neurons in the central nervous system with chemical isolation from the rest of the body.

Neurons BASIC STRUCTURE The neuron (nerve cell) is the information-processing and information-transmitting element of the nervous system. Neurons come in many shapes and varieties, according to the specialized jobs they perform. Most neurons have, in one form or another, the following four structures or regions: (1) cell body, or soma; (2) dendrites; (3) axon; and (4) terminal buttons. Soma The soma (cell body) contains the nucleus and much of the machinery that provides for the cell’s life processes. (See Figure 1.) Its shape varies considerably in different kinds of neurons. Dendrites Dendron is the Greek word for tree, and the dendrites of the neuron do resemble trees. (See Figure 1.) Neurons “converse” with one another, and dendrites serve as important recipients of these messages. The messages that pass from neuron to neuron are transmitted across the synapse, a junction between the terminal buttons (described later) of the sending cell and a portion of the somatic or dendritic membrane of the receiving cell. (The word synapse derives from the Greek sunaptein, “to join together.”) Communication at a synapse proceeds in one direction: from the terminal button to the membrane of the other cell. (Like many general rules, this one has some exceptions. For example, some synapses pass information in both directions.) Axon The axon is a long, slender tube, often covered by a myelin sheath. (The myelin sheath is described later.) The axon carries information from the cell body to the terminal buttons. (See Figure 1.) The basic message it carries is called an action potential. This function is an important one and will be described in more detail later in the chapter. For now, it suffices to say that an action potential is a brief electrical/chemical event that starts at the end of the axon next to the cell body and travels toward the terminal buttons. The action potential is like a brief pulse; in a given axon, the action potential is always of the same size and duration. When it reaches a point where the axon branches, it splits but does not diminish in size. Each branch receives a full-strength action potential. Like dendrites, axons and their branches come in different shapes. In fact, the three principal types of neurons are classified according to the way in which their axons and dendrites

central nervous system (CNS) The brain and spinal cord. peripheral nervous system (PNS) The part of the nervous system outside the brain and spinal cord, including the nerves attached to the brain and spinal cord. soma The cell body of a neuron, which contains the nucleus. dendrite A branched, treelike structure attached to the soma of a neuron; receives information from the terminal buttons of other neurons. synapse A junction between the terminal button of an axon and the membrane of another neuron. axon The long, thin, cylindrical structure that conveys information from the soma of a neuron to its terminal buttons.

Structure and Functions of Cells of the Nervous System

Dendrites

Terminal buttons Soma (cell body)

multipolar neuron A neuron with one axon and many dendrites attached to its soma. bipolar neuron A neuron with one axon and one dendrite attached to its soma.

Myelin sheath

Axon (inside myelin sheath)

unipolar neuron A neuron with one axon attached to its soma; the axon divides, with one branch receiving sensory information and the other sending the information into the central nervous system.

FIGURE

Direction of messages

The Principal Parts of a Multipolar Neuron.

terminal button The bud at the end of a branch of an axon; forms synapses with another neuron; sends information to that neuron.

leave the soma. The neuron depicted in Figure 1 is the most common type found in the central nervous system; it is a multipolar neuron. In this type of neuron, the somatic membrane gives rise to one axon but to the trunks of many dendritic trees. Bipolar neurons give rise to one axon and one dendritic tree, at opposite ends of the soma. (See Figure 2a.) Bipolar neurons are usually sensory; that is, their dendrites detect events occurring in the environment and communicate information about these events to Dendrites are sensitive the central nervous system. to physical stimuli The third type of nerve cell is the unipolar neuron. It has only one stalk, which leaves the soma and divides into two branches a short distance away. (See Figure 2b.) Unipolar neurons, like bipolar neurons, transmit sensory information from the environment to the CNS. The arborizations (treelike branches) outside the CNS are dendrites; the arborizations within the CNS end in terminal buttons. The dendrites of most unipolar neurons detect touch, temperature changes, and other sensory events that affect the skin. Other unipolar neurons detect events in our joints, muscles, and internal Soma of organs. unipolar neuron The central nervous system communicates with the rest of the body Axon through nerves attached to the brain and to the spinal cord. Nerves are bundles of many thousands of individual fibers, all wrapped in a tough, protective membrane. Under a microscope, nerves look something like telephone cables, with their bundles of wires. (See Figure 3.) Like the To brain individual wires in a telephone cable, nerve fibers transmit messages through the nerve, from a sense organ to the brain or from the brain to a muscle or gland.

neurotransmitter A chemical that is released by a terminal button; has an excitatory or inhibitory effect on another neuron.

Cilia are sensitive to physical stimuli

Receptor Dendrite Soma of bipolar neuron

Axon

To brain

Terminal buttons

(a)

Terminal buttons

(b)

F I G U R E 2 Bipolar and Unipolar Neurons. Pictured here are (a) a bipolar neuron, primarily found in sensory systems (for example, vision and audition) and (b) a unipolar neuron, found in the somatosensory system (touch, pain, and the like).

Terminal Buttons Most axons divide and branch many times. The ends of the “twigs” feature little knobs called terminal buttons. (Some neuroscientists prefer the original French word bouton, whereas others simply refer to them as terminals.) Terminal buttons have a very special function: When an action potential traveling down the axon reaches them, they secrete a chemical called a neurotransmitter. This chemical (there are many different ones in the CNS) either excites or inhibits the receiving cell and thus helps to determine whether an action potential occurs in its axon. Details of this process will be described later in this chapter.

Structure and Functions of Cells of the Nervous System

An individual neuron receives information from the terminal buttons of axons of other neurons—and the terminal buttons of its axons form synapses with other neurons. A neuron may receive information from dozens or even hundreds of other neurons, each of which can form a large number of synaptic connections with it. Figure 4 illustrates the nature of these connections. As you can see, terminal buttons can form synapses on the membrane of the dendrites or the soma. (See Figure4.) INTERNAL STRUCTURE

Nerve Bundle of axons BV

Figure 5 illustrates the internal structure of a typical multipolar neuron. (See Figure 5.) The membrane defines the boundary of the cell and consists of a double layer of lipid (fatlike) molecules. Embedded in Blood Individual vessel the membrane are a variety of protein molecules that have special funcaxons tions. Some proteins detect substances outside the cell (such as hormones) and pass information about the presence of these substances F I G U R E 3 Nerves. A nerve consists of a sheath of tissue that to the cell’s interior. Other proteins control access to the interior of the encases a bundle of individual nerve fibers (also known as axons). cell, permitting some substances to enter but barring others. Still other membrane A structure consisting proteins act as transporters, actively carrying certain molecules into or out of the cell. Because principally of lipid molecules that defines the proteins that are found in the neuron’s membrane are especially important in the transmisthe outer boundaries of a cell and also sion of information, their characteristics will be discussed in more detail later in this chapter. constitutes many of the cell organelles. The cell is filled with cytoplasm, a jellylike substance that contains small specialized cytoplasm The viscous, semiliquid structures, just as the body contains specialized organs. Among these structures are mitosubstance contained in the interior of a cell. chondria, which break down nutrients such as glucose and provide the cell with energy to mitochondria An organelle that is responsible for extracting energy from perform its functions. Mitochondria produce a chemical called adenosine triphosphate nutrients. (ATP), which can be used throughout the cell as an energy source. Many eons ago mitoadenosine triphosphate (ATP) (ah den chondria were free-living organisms that came to “infect” larger cells. Because the mitoo seen) A molecule of prime importance chondria could extract energy more efficiently than their hosts, they became useful to them to cellular energy metabolism; its and eventually became a permanent part of them. Mitochondria still contain their own breakdown liberates energy. genetic information and multiply independently of the cells in which they live. We inherit nucleus A structure in the central region our mitochondria from our mothers; fathers’ sperms do not contribute any mitochondria of a cell, containing the chromosomes. to the ova they fertilize. chromosome A strand of DNA, with Deep inside the cell is the nucleus (from the Latin word for “nut”). The nucleus contains associated proteins, found in the nucleus; carries genetic information. the chromosomes. Chromosomes, as you have probably already learned, consist of long strands

Synapse on soma Cell body Myelin sheath

Synapse on dendrite

FIGURE

Axon

Terminal button

An Overview of the Synaptic Connections Between Neurons. The arrows represent the directions of the flow of information.

Structure and Functions of Cells of the Nervous System

of deoxyribonucleic acid (DNA). The chromosomes have an important function: They contain the recipes for making proteins. Portions of the chromosomes, called genes, contain the recipes for individual proteins. Proteins are important in cell functions. If a neuNucleus ron grown in a tissue culture is exposed to a detergent, the lipid membrane and much of the cell’s interior dissolve away, leaving a matrix of insoluble strands of Dendrite Cytoplasm protein. This matrix, called the cytoskeleton, gives the neuron its shape. The cytoskeleton is made of various Membrane kinds of protein strands, linked to each other and formMicrotubules ing a cohesive mass. Besides providing structure, proteins serve as enzymes. Enzymes are the cell’s marriage brokers or divorce judges: They cause particular molecules to join together or split apart. Thus, enzymes determine what gets made from the raw materials contained in the cell, Myelin Mitochondria and they determine which molecules remain intact. sheath Proteins are also involved in transporting substances within the cell. Axons can be extremely long, F I G U R E 5 The Principal Internal Structures of a Multipolar Neuron. relative to their diameter and the size of the soma. For example, the longest axon in a human stretches from the foot to a region located in the base of the brain. Because terminal buttons need some items that can be produced only in the soma, there must be a system that can transport these items rapidly and efficiently through the axoplasm (that is, the cytoplasm of the axon). This system, axoplasmic transport, is an active process that prodeoxyribonucleic acid (DNA) (dee ox pels substances from one end of the axon to the other. This transport is accomplished by long proee ry bo new clay ik) A long, complex tein strands called microtubules, bundles of thirteen filaments arranged around a hollow core. macromolecule consisting of two Microtubules serve as railroad tracks, guiding the progress of the substances being transported. interconnected helical strands; along Movement from the soma to the terminal buttons is called anterograde axoplasmic transport. with associated proteins, strands of DNA constitute the chromosomes. (Antero- means “toward the front.”) Retrograde axoplasmic transport carries substances from the terminal buttons back to the soma. (Retro- means “toward the back.”) Anterograde axoplasmic gene The functional unit of the chromosome, which directs synthesis of transport is remarkably fast: up to 500 mm per day. Retrograde axoplasmic transport is about half one or more proteins. as fast. Energy for both forms of transport is supplied by ATP, produced by the mitochondria. Dendritic spines

cytoskeleton Support structure formed of microtubules and other protein fibers that are linked to each other and form a cohesive mass that gives a cell its shape. enzyme A molecule that controls a chemical reaction, combining two substances or breaking a substance into two parts. axoplasmic transport An active process by which substances are propelled along microtubules that run the length of the axon. microtubule (my kro too byool) A long strand of bundles of protein filaments arranged around a hollow core; part of the cytoskeleton and involved in transporting substances from place to place within the cell. glia (glee ah) The supporting cells of the central nervous system. astrocyte A glial cell that provides support for neurons of the central nervous system, provides nutrients and other substances, and regulates the chemical composition of the extracellular fluid.

Supporting Cells Neurons constitute only about half the volume of the CNS. The rest consists of a variety of supporting cells. Because neurons have a very high rate of metabolism but have no means of storing nutrients, they must constantly be supplied with nutrients and oxygen or they will quickly die. Thus, the role played by the cells that support and protect neurons is very important to our existence. GLIA The most important supporting cells of the central nervous system are the neuroglia, or “nerve glue.” Glia (also called glial cells) are much more numerous than neurons. They constitute approximately 85 percent of the cells of the brain. Although they glue the CNS together, they do much more than that. Neurons lead a very sheltered existence; they are buffered physically and chemically from the rest of the body by the glial cells. Glial cells surround neurons and hold them in place, controlling their supply of nutrients and some of the chemicals they need to exchange messages with other neurons; they insulate neurons from one another so that neural messages do not get scrambled; and they even act as housekeepers, destroying and removing the carcasses of neurons that are killed by disease or injury. There are several types of glial cells, each of which plays a special role in the CNS. The three most important types are astrocytes, oligodendrocytes, and microglia. Astrocyte means “star cell,” and this name accurately describes the shape of these cells. Astrocytes (or astroglia) provide physical support to neurons and clean up debris within the brain. They produce some

Structure and Functions of Cells of the Nervous System

Energy

Blood vessel

Lactate Lactate

Astrocyte

Glucose Neuron

Glucose Lactate

Glycogen (storage)

F I G U R E 6 Structure and Location of Astrocytes. The processes of astrocytes surround capillaries and neurons of the central nervous system.

chemicals that neurons need to fulfill their functions. They help to control the chemical composition of the fluid surrounding neurons by actively taking up or releasing substances whose concentrations must be kept within critical levels. Finally, astrocytes are involved in providing nourishment to neurons. Some of the astrocyte’s processes (the arms of the star) are wrapped around blood vessels. Other processes are wrapped around parts of neurons, so the somatic and dendritic membranes of neurons are largely surrounded by astrocytes. Evidence suggests that astrocytes receive nutrients from the capillaries, store them, and release them to neurons when needed (Tsacopoulos and Magistretti, 1996; Brown, Tekkök, and Ransom, 2004). Besides having a role in transporting chemicals to neurons, astrocytes serve as the matrix that holds neurons in place. These cells also surround and isolate synapses, limiting the dispersion of neurotransmitters that are released by the terminal buttons. (See Figure 6.) When cells in the central nervous system die, certain kinds of astrocytes take up the task of cleaning away the debris. These cells are able to travel around the CNS; they extend and retract their processes (pseudopodia, or “false feet”) and glide about the way amoebas do. When these astrocytes contact a piece of debris from a dead neuron, they push themselves against it, finally engulfing and digesting it. We call this process phagocytosis (phagein, “to eat”; kutos, “cell”). If there is a considerable amount of injured tissue to be cleaned up, astrocytes will divide and produce enough new cells to do the task. Once the dead tissue is broken down, a framework of astrocytes will be left to fill in the vacant area, and a specialized kind of astrocyte will form scar tissue, walling off the area. The principal function of oligodendrocytes is to provide support to axons and to produce the myelin sheath, which insulates most axons from one another. (Very small axons are not myelinated and lack this sheath.) Myelin, which is 80 percent lipid and 20 percent protein, is produced by the oligodendrocytes in the form of a tube surrounding the axon. This tube does not form a continuous sheath; rather, it consists of a series of segments, each approximately 1 mm long, with a small (1–2 μm) portion of uncoated axon between the segments. (A micrometer, abbreviated μm, is one-millionth of a meter, or one-thousandth of a millimeter.) The bare portion of axon is called a node of Ranvier, after the person who discovered it. The myelinated axon, then, resembles a string of elongated beads. (Actually, the beads are very much elongated—their length is approximately eighty times their width.)

phagocytosis (fagg o sy toe sis) The process by which cells engulf and digest other cells or debris caused by cellular degeneration. oligodendrocyte (oh li go den droh site) A type of glial cell in the central nervous system that forms myelin sheaths. myelin sheath (my a lin) A sheath that surrounds axons and insulates them, preventing messages from spreading between adjacent axons. node of Ranvier (raw vee ay) A naked portion of a myelinated axon, between adjacent oligodendroglia or Schwann cells.

Structure and Functions of Cells of the Nervous System

A given oligodendrocyte produces up to fifty segments of myelin. During the development of the CNS, oligodendrocytes form processes shaped something like canoe paddles. Each of these paddle-shaped processes then wraps itself many times around a segment of an axon and, while doing so, produces layers of myelin. Each paddle thus becomes a segment of an axon’s myelin sheath. (See Figures 7 and 8a.)

Myelinated axons

Axons

Myelin sheath

Node of Ranvier Oligodendrocyte

Soma of oligodendrocyte

(a) Schwann cell

Mitochondrion in axoplasm

Microtubule

Node of Ranvier F I G U R E 7 Oligodendrocyte. An oligodendrocyte forms the myelin that surrounds many axons in the central nervous system. Each cell forms one segment of myelin for several adjacent axons.

(b) F I G U R E 8 Formation of Myelin. During development, a process of an oligodendrocyte or an entire Schwann cell tightly wraps itself many times around an individual axon and forms one segment of the myelin sheath. (a) Oligodendrocyte. (b) Schwann cell.

Dr. C., a retired neurologist, had been afflicted with multiple sclerosis for more than two decades when she died of a heart attack. One evening, twenty-three years previously, she and her husband had had dinner at their favorite restaurant. As they were leaving, she stumbled and almost fell. Her husband joked, “Hey, honey, you shouldn’t have had that last glass of wine.” She smiled at his attempt at humor, but she knew better—her clumsiness wasn’t brought on by the two glasses of wine she had drunk with dinner. She suddenly realized that she had been ignoring some symptoms that she should have recognized. The next day, she consulted with one of her colleagues, who agreed that her own tentative diagnosis was probably correct: Her symptoms fit those of multiple sclerosis. She had experienced fleeting problems with double vision, she sometimes felt unsteady on her feet, and she occasionally noticed tingling sensations in her right hand. None of these symptoms was serious, and they lasted for only a short while, so she ignored them—or perhaps denied to herself that they were important. A few weeks after Dr. C.’s death, a group of medical students and neurological residents gathered in an autopsy room at the medical school. Dr. D., the school’s neuropathologist, displayed a stainless-steel tray on which were lying a brain and a spinal cord. “These belonged to Dr. C.,” he said. “Several years ago she donated her organs to the medical school.” Everyone looked at the brain more intently, knowing that it had animated an esteemed clinician and teacher whom they all knew by reputation, if not personally. Dr. D. led his audience to a set of light boxes on the wall, to which several MRI scans had been clipped. He pointed out some white spots that appeared on one scan. “This scan clearly shows some white-matter lesions, but they are gone on the next one, taken six months later. And here is another one, but it’s gone on the next scan. The immune system attacked the myelin sheaths in a particular region, and then glial cells cleaned up the debris. MRI doesn’t show the lesions then, but the axons can no longer conduct their messages.” (continued )

Structure and Functions of Cells of the Nervous System

He put on a pair of surgical gloves, picked up Dr. C.’s brain, and cut it in several slices. He picked one up. “Here, see this?” He pointed out a spot of discoloration in a band of white matter. “This is a sclerotic plaque—a patch that feels harder than the surrounding tissue. There are many of them, located throughout the brain and spinal cord, which is why the disease is called multiple sclerosis.” He picked up the spinal cord, felt along its length with his thumb and forefinger, and then stopped and said, “Yes, I can feel a plaque right here.” Dr. D. put the spinal cord down and said, “Who can tell me the etiology of this disorder?” One of the students spoke up. “It’s an autoimmune disease. The immune system gets sensitized to the body’s own myelin protein and periodically attacks it, causing a variety of different neurological symptoms. Some say that a childhood viral illness somehow causes the immune system to start seeing the protein as foreign.” “That’s right,” said Dr. D. “The primary criterion for the diagnosis of multiple sclerosis is the presence of neurological symptoms disseminated in time and space. The symptoms don’t all occur at once, and they can be caused only by damage to several different parts of the nervous system, which means that they can’t be the result of a stroke.”

As their name indicates, microglia are the smallest of the glial cells. Like some types of astrocytes, they act as phagocytes, engulfing and breaking down dead and dying neurons. But in addition, they serve as one of the representatives of the immune system in the brain, protecting the brain from invading microorganisms. They are primarily responsible for the inflammatory reaction in response to brain damage. SCHWANN CELLS In the central nervous system the oligodendrocytes support axons and produce myelin. In the peripheral nervous system the Schwann cells perform the same functions. Most axons in the PNS are myelinated. The myelin sheath occurs in segments, as it does in the CNS; each segment consists of a single Schwann cell, wrapped many times around the axon. In the CNS the oligodendrocytes grow a number of paddleshaped processes that wrap around a number of axons. In the PNS a Schwann cell provides myelin for only one axon, and the entire Schwann cell—not merely a part of it—surrounds the axon. (See Figure 8b.) There is an important difference between oligodendrocytes of the CNS and Schwann cells of the PNS: the chemical composition of the myelin protein they produce. The immune system of people with multiple sclerosis attacks only the myelin protein produced by oligodendrocytes; thus, the myelin of the peripheral nervous system is spared.

The Blood–Brain Barrier Over one hundred years ago, Paul Ehrlich discovered that if a blue dye is injected into an animal’s bloodstream, all tissues except the brain and spinal cord will be Touch, temperature changes, pain, and other sensory tinted blue. However, if the same dye is injected into the fluid-filled ventricles of events that affect the skin are detected by the dendrites the brain, the blue color will spread throughout the CNS (Bradbury, 1979). This of unipolar neurons. experiment demonstrates that a barrier exists between the blood and the fluid that Jeff Greenberg/The Image Works. surrounds the cells of the brain: the blood–brain barrier. Some substances can cross the blood–brain barrier; others cannot. Thus, it is selectively permicroglia The smallest of glial cells; they meable (from the Latin per, “through,” and meare, “to pass”). In most of the body the cells that act as phagocytes and protect the brain from invading microorganisms. line the capillaries do not fit together absolutely tightly. Small gaps are found between them that Schwann cell A cell in the peripheral permit the free exchange of most substances between the blood plasma and the fluid outside the nervous system that is wrapped around a capillaries that surrounds the body’s cells. In the central nervous system the capillaries lack these myelinated axon, providing one segment gaps; therefore, many substances cannot leave the blood. Thus, the walls of the capillaries in the of its myelin sheath. brain constitute the blood–brain barrier. (See Figure 9.) Other substances must be actively transblood–brain barrier A semipermeable ported through the capillary walls by special proteins. For example, glucose transporters bring the barrier between the blood and the brain brain its fuel, and other transporters rid the brain of toxic waste products (Rubin and Staddon, produced by the cells in the walls of the 1999; Zlokovic, 2008). brain’s capillaries.

Structure and Functions of Cells of the Nervous System

Gaps that permit the free flow of substances into and out of the blood Capillary in all of body except brain

Capillary in brain (a)

(b)

F I G U R E 9 The Blood–Brain Barrier. This figure shows that (a) the cells that form the walls of the capillaries in the body outside the brain have gaps that permit the free passage of substances into and out of the blood and (b) the cells that form the walls of the capillaries in the brain are tightly joined.

What is the function of the blood–brain barrier? As we will see, transmission of messages from place to place in the brain depends on a delicate balance between substances within neurons and in the extracellular fluid that surrounds them. If the composition of the extracellular fluid is changed even slightly, the transmission of these messages will be disrupted, which means that brain functions will be disrupted. The presence of the blood–brain barrier makes it easier to regulate the composition of this fluid. In addition, many of the foods that we eat contain chemicals that would interfere with the transmission of information between neurons. The blood–brain barrier prevents these chemicals from reaching the brain. The blood–brain barrier is not uniform throughout the nervous system. In several places the barrier is relatively permeable, allowing substances that are excluded elsewhere to cross freely. For example, the area postrema is a part of the brain that controls vomiting. The blood–brain barrier is much weaker there, permitting neurons in this region to detect the presence of toxic substances in the blood. A poison that enters the circulatory system from the stomach can thus stimulate this area to initiate vomiting. If the organism is lucky, the poison can be expelled from the stomach before causing too much damage.

area postrema (poss tree ma) A region of the medulla where the blood–brain barrier is weak; poisons can be detected there and can initiate vomiting.

SECTION SUMMARY Cells of the Nervous System Neurons are the most important cells of the nervous system. The central nervous system (CNS) includes the brain and spinal cord; the peripheral nervous system (PNS) includes nerves and some sensory organs. Neurons have four principal parts: dendrites, soma (cell body), axon, and terminal buttons. They communicate by means of synapses, junctions between the terminal buttons of one neuron and the somatic or dendritic membrane of another. When an action potential travels down an axon, its terminal buttons secrete a chemical that has either an excitatory or an inhibitory effect on the neurons with which they communicate. Ultimately, the effects of these excitatory and inhibitory synapses cause behavior in the form of muscular contractions. Neurons contain a quantity of clear cytoplasm, enclosed in a membrane. Embedded in the membrane are protein molecules that have special functions, such as the transport of particular substances into and out of the cell. The nucleus contains the genetic information—the recipes for all the proteins that the body can make. Microtubules and other protein filaments compose the cytoskeleton and help to transport chemicals from place to place. Mitochondria serve as the location for most of the chemical reactions through which the cell extracts energy from nutrients. Neurons are supported by the glial cells of the central nervous system and the supporting cells of the peripheral nervous system. In the CNS

astrocytes provide support and nourishment, regulate the composition of the fluid that surrounds neurons, and remove debris and form scar tissue in the event of tissue damage. Microglia are phagocytes that serve as the representatives of the immune system. Oligodendrocytes form myelin, the substance that insulates axons, and also support unmyelinated axons. In the PNS, support and myelin are provided by the Schwann cells. In most organs molecules freely diffuse between the blood within the capillaries that serve them and the extracellular fluid that bathes their cells. The molecules pass through gaps between the cells that line the capillaries. The walls of the capillaries of the CNS lack these gaps; consequently, fewer substances can enter or leave the brain across the blood–brain barrier.

Thought Question The fact that the mitochondria in our cells were originally microorganisms that infected our very remote ancestors points out that evolution can involve interactions between two or more species. Most species have other organisms living inside them; in fact, the bacteria in our intestines are necessary for our good health. Some microorganisms can exchange genetic information, so adaptive mutations developed in one species can be adopted by another. Is it possible that some of the features of the cells of our nervous system were bequeathed to our ancestors by other species?

Communication Within a Neuron This section describes the nature of communication within a neuron—the way an action potential is sent from the cell body down the axon to the terminal buttons, informing them to release some neurotransmitter. The details of synaptic transmission—the communication between neurons— will be described in the next section. As we will see in this section, an action potential consists

Structure and Functions of Cells of the Nervous System

of aseries of alterations in the membrane of the axon that permit various substances to move between the interior of the axon and the fluid surrounding it. These exchanges produce electrical currents.

Neural Communication: An Overview Before I begin my discussion of the action potential, let’s step back and see how neurons can interact to produce a useful behavior. We begin by examining a simple assembly of three neurons and a muscle that controls a withdrawal reflex. In the next two figures (and in subsequent figures that illustrate simple neural circuits), multipolar neurons are depicted in shorthand fashion as several-sided stars. The points of these stars represent dendrites, and only one or two terminal buttons are shown at the end of the axon. The sensory neuron in this example detects painful stimuli. When its dendrites are stimulated by a noxious stimulus (such as contact with a hot object), it sends messages down the axon to the terminal buttons, which are located in the spinal cord. (You will recognize this cell as a unipolar neuron; see Figure 10.) The terminal buttons of the sensory neuron release a neurotransmitter that excites the interneuron, causing it to send messages down its axon. The terminal buttons of the interneuron release a neurotransmitter that excites the motor neuron, which then sends messages down its axon. The axon of the motor neuron joins a nerve and travels to a muscle. When the terminal buttons of the motor neuron release their neurotransmitter, the muscle cells contract, causing the hand to move away from the hot object. (See Figure 10.) So far, all of the synapses have had excitatory effects. Now let us complicate matters a bit to see the effect of inhibitory synapses. Suppose you have removed a hot casserole from the oven. As you start walking over to the table to put it down, the heat begins to penetrate the rather thin potholders you are using. The pain caused by the hot casserole triggers a withdrawal reflex that tends to make you drop it. Yet you manage to keep hold of it long enough to get to the table and put it down. What prevented your withdrawal reflex from making you drop the casserole on the floor? The pain from the hot casserole increases the activity of excitatory synapses on the motor neurons, which tends to cause the hand to pull away from the casserole. However, this excitation is counteracted by inhibition, supplied by another source: the brain. The brain contains neural circuits that recognize what a disaster it would be if you dropped the casserole on the floor. These neural circuits send information to the spinal cord that prevents the withdrawal reflex from making you drop the dish. Figure 11 shows how this information reaches the spinal cord. As you can see, an axon from a neuron in the brain reaches the spinal cord, where its terminal buttons form synapses with an inhibitory interneuron. When the neuron in the brain becomes active, its terminal buttons excite

This interneuron excites motor neuron, causing muscular contraction

Brain

Spinal cord

Motor neuron

This muscle causes withdrawal from Dendrites of source of pain sensory neuron detect painful stimulus Axon of sensory neuron (pain)

Cross section of spinal cord

F I G U R E 10 A Withdrawal Reflex. The figure shows a simple example of a useful function of the nervous system. The painful stimulus causes the hand to pull away from the hot iron.

Structure and Functions of Cells of the Nervous System

This interneuron excites motor neuron, causing muscular contraction

Neuron in brain Brain Axon of neuron in brain

This muscle causes withdrawal from source of pain

Axon from neuron in brain

Motor neuron

Axon of sensory neuron (pain)

Spinal cord

Cross section of spinal cord This interneuron inhibits motor neuron, preventing muscular contraction F I G U R E 11 The Role of Inhibition. Inhibitory signals arising from the brain can prevent the withdrawal reflex from causing the person to drop the casserole.

this inhibitory interneuron. The interneuron releases an inhibitory neurotransmitter, which decreases the activity of the motor neuron, blocking the withdrawal reflex. This circuit provides an example of a contest between two competing tendencies: to drop the casserole and to hold onto it. (See Figure 11.) Of course, reflexes are more complicated than this description, and the mechanisms that inhibit them are even more so. In addition, thousands of neurons are involved in this process. The five neurons shown in Figure 11 represent many others: Dozens of sensory neurons detect the hot object, hundreds of interneurons are stimulated by their activity, hundreds of motor neurons produce the contraction—and thousands of neurons in the brain must become active if the reflex is to be inhibited. Yet this simple model provides an overview of the process of neural communication, which is described in more detail later in this chapter.

Measuring Electrical Potentials of Axons

electrode A conductive medium that can be used to apply electrical stimulation or to record electrical potentials. microelectrode A very fine electrode, generally used to record activity of individual neurons. membrane potential The electrical charge across a cell membrane; the difference in electrical potential inside and outside the cell.

Let’s examine the nature of the message that is conducted along the axon. To do so, we obtain an axon that is large enough to work with. Fortunately, nature has provided the neuroscientist with the giant squid axon (the giant axon of a squid, not the axon of a giant squid!). This axon is about 0.5 mm in diameter, which is hundreds of times larger than the largest mammalian axon. (This large axon controls an emergency response: sudden contraction of the mantle, which squirts water through a jet and propels the squid away from a source of danger.) We place an isolated giant squid axon in a dish of seawater, in which it can exist for a day or two. To measure the electrical charges generated by an axon, we will need to use a pair of electrodes. Electrodes are electrical conductors that provide a path for electricity to enter or leave a medium. One of the electrodes is a simple wire that we place in the seawater. The other one, which we use to record the message from the axon, has to be special. Because even a giant squid axon is rather small, we must use a tiny electrode that will record the membrane potential without damaging the axon. To do so, we use a microelectrode. A microelectrode, which is simply a very small electrode, can be made of metal or glass. In this case we will use one made of thin glass tubing, which is heated and drawn down to an exceedingly fine point, less than a thousandth of a millimeter in diameter. Because glass will not conduct electricity, the glass microelectrode is filled with a liquid that conducts electricity, such as a solution of potassium chloride. We place the wire electrode in the seawater and insert the microelectrode into the axon. (See Figure 12a.) As soon as we do so, we discover that the inside of the axon is negatively charged with respect to the outside; the difference in charge being 70 mV (millivolts, or thousandths of a volt). Thus, the inside of the membrane is –70 mV. This electrical charge is called the membrane potential. The term potential refers to a stored-up source of energy—in this case, electrical energy. For example, a flashlight battery that is not connected to an electrical circuit has a potential charge of 1.5 V between its terminals. If we connect a light bulb to the terminals, the potential

Structure and Functions of Cells of the Nervous System

Electrical stimulator

Oscilloscope

Voltmeter FREQUENCY

MODE

Stimulator

Records of changes in membrane potential displayed here

Glass microelectrode filled with liquid that conducts electricity Wire electrode placed in seawater

Wire electrode placed in seawater

Giant squid axon

Battery (b)

(a) F I G U R E 12 Measuring Electrical Charge. This figure shows (a) a voltmeter detecting the charge across a membrane of an axon and (b) a light bulb lit by the charge across the terminals of a battery.

Glass microelectrodes

Giant squid axon

F I G U R E 13 Studying the Axon. The figure illustrates the means by which an axon can be stimulated while its membrane potential is being recorded.

energy is tapped and converted into radiant energy (light). (See Figure 12b.) Similarly, if we connect our electrodes—one inside the axon and one outside it—to a very sensitive voltmeter, we will convert the potential energy to movement of the meter’s needle. Of course, the potential electrical energy of the axonal membrane is very weak in comparison with that of a flashlight battery. As we will see, the message that is conducted down the axon consists of a brief change in the membrane potential. However, this change occurs very rapidly—too rapidly for us to see if we were using a voltmeter. Therefore, to study the message, we will use an oscilloscope. This device, like a voltmeter, measures voltages, but it also produces a record of these voltages, graphing them as a function of time. These graphs are displayed on a screen, much like the one found in a television. The vertical axis represents voltage, and the horizontal axis represents time, going from left to right. Once we insert our microelectrode into the axon, the oscilloscope draws a straight horizontal line at –70 mV, as long as the axon is not disturbed. This electrical charge across the membrane is called, quite appropriately, the resting potential. Now let us disturb the resting potential and see what happens. To do so, we will use another device: an electrical stimulator that allows us to alter the membrane potential at a specific location. (See Figure 13.) The stimulator can pass current through another microelectrode that we have inserted into the axon. Because the inside of the axon is negative, a positive charge applied to the inside of the membrane produces a depolarization. That is, it takes away some of the electrical charge across the membrane near the electrode, reducing the membrane potential. Let us see what happens to an axon when we artificially change the membrane potential at one point. Figure 14 shows a graph drawn by an oscilloscope that has been monitoring the effects of brief depolarizing stimuli. The graphs of the effects of these separate stimuli are superimposed on the same drawing so that we can compare them. We deliver a series of depolarizing stimuli, starting with a very weak stimulus (number 1) and gradually increasing their strength. Each stimulus briefly depolarizes the membrane potential a little more. Finally, after we present depolarization number 4, the membrane potential suddenly reverses itself, so that the inside becomes positive (and the outside becomes negative). The membrane potential quickly returns to normal, but first it overshoots the resting potential, becoming hyperpolarized—more polarized than normal—for a short time. The whole process takes about 2 msec (milliseconds). (See Figure 14.) This phenomenon, a very rapid reversal of the membrane potential, is called the action potential. It constitutes the message carried by the axon from the cell body to the terminal buttons. The voltage level that triggers an action potential—which was achieved only by depolarizing shock number 4—is called the threshold of excitation.

oscilloscope A laboratory instrument that is capable of displaying a graph of voltage as a function of time on the face of a cathode ray tube. resting potential The membrane potential of a neuron when it is not being altered by excitatory or inhibitory postsynaptic potentials; approximately –70 mV in the giant squid axon. depolarization Reduction (toward zero) of the membrane potential of a cell from its normal resting potential. hyperpolarization An increase in the membrane potential of a cell, relative to the normal resting potential. action potential The brief electrical impulse that provides the basis for conduction of information along an axon. threshold of excitation The value of the membrane potential that must be reached to produce an action potential.

Structure and Functions of Cells of the Nervous System

The Membrane Potential: Balance of Two Forces

+40

To understand what causes the action potential to occur, we must first understand the reasons for the existence of the membrane potential. As we will see, this electrical charge is the result of a balance between two opposing forces: diffusion and electrostatic pressure.

+30 +20

Action potential

Membrane potential (mV)

–10 –20 –30 –40 –50

Threshold of excitation

+10

THE FORCE OF DIFFUSION

4 3

–60

Depolarization 2

–70 –80 Hyperpolarization

–90 1

Stimulus applied

2 Time (msec)

F I G U R E 14 An Action Potential. These results would be seen on an oscilloscope screen if depolarizing stimuli of varying intensities were delivered to the axon shown in Figure 13.

When a spoonful of sugar is poured carefully into a container of water, it settles to the bottom. After a time the sugar dissolves, but it remains close to the bottom of the container. After a much longer time (probably several days), the molecules of sugar distribute themselves evenly throughout the water, even if no one stirs the liquid. The process whereby molecules distribute themselves evenly throughout the medium in which they are dissolved is called diffusion. When there are no forces or barriers to prevent them from doing so, molecules will diffuse from regions of high concentration to regions of low concentration. Molecules are constantly in motion, and their rate of movement is proportional to the temperature. Only at absolute zero [0 K (kelvin) = –273.15°C = –459.7°F] do molecules cease their random movement. At all other temperatures they move about, colliding and veering off in different directions, thus pushing one another away. The result of these collisions in the example of sugar and water is to force sugar molecules upward (and to force water molecules downward), away from the regions in which they are most concentrated.

THE FORCE OF ELECTROSTATIC PRESSURE When some substances are dissolved in water, they split into two parts, each with an opposing electrical charge. Substances with this property are called electrolytes; the charged particles into which they decompose are called ions. Ions are of two basic types: Cations have a positive charge, and anions have a negative charge. For example, when sodium chloride (NaCl, table salt) is dissolved in water, many of the molecules split into sodium cations (Na+) and chloride anions (Cl–). (I find that the easiest way to keep the terms cation and anion straight is to think of the cation’s plus sign as a cross and remember the superstition of a black cat crossing your path. A reader emailed another suggestion to me: “An anion is a negative ion.”) As you have undoubtedly learned, particles with the same kind of charge repel each other (+ repels +, and – repels –), but particles with different charges are attracted to each other (+ and – attract). Thus, anions repel anions, cations repel cations, but anions and cations attract each other. The force exerted by this attraction or repulsion is called electrostatic pressure. Just as the force of diffusion moves molecules from regions of high concentration to regions of low concentration, electrostatic pressure moves ions from place to place: Cations are pushed away from regions with an excess of cations, and anions are pushed away from regions with an excess of anions.

diffusion Movement of molecules from regions of high concentration to regions of low concentration. electrolyte An aqueous solution of a material that ionizes—namely, a soluble acid, base, or salt. ion A charged molecule. Cations are positively charged, and anions are negatively charged. electrostatic pressure The attractive force between atomic particles charged with opposite signs or the repulsive force between atomic particles charged with the same sign. intracellular fluid The fluid contained within cells. extracellular fluid Body fluids located outside of cells.

IONS IN THE EXTRACELLULAR AND INTRACELLULAR FLUID The fluid within cells (intracellular fluid) and the fluid surrounding them (extracellular fluid) contain different ions. The forces of diffusion and electrostatic pressure contributed by these ions give rise to the membrane potential. Because the membrane potential is produced by a balance between the forces of diffusion and electrostatic pressures, understanding what produces this potential requires that we know the concentration of the various ions in the extracellular and intracellular fluids. There are several important ions in these fluids. I will discuss four of them here: organic anions (symbolized by A–), chloride ions (Cl–), sodium ions (Na+), and potassium ions (K+). The Latin words for sodium and potassium are natrium and kalium; hence, they are abbreviated Na and K, respectively. Organic anions—negatively charged proteins and intermediate products of the cell’s metabolic processes—are found only in the intracellular fluid. Although the other three ions are found in both the intracellular and extracellular fluids, K+ is found predominantly in the intracellular fluid, whereas Na+ and Cl– are found predominantly in the extracellular fluid. The sizes of the boxes in Figure 15 indicate the relative concentrations of these four ions. (See Figure 15.) The easiest way to remember which ion is found where is to recall that the fluid

Structure and Functions of Cells of the Nervous System

High concentration Low concentration Force of diffusion

K+

Outside of Cell

–

Cannot leave cell

Inside of Cell

A–

Na+

Cl – Electrostatic pressure

–

Force of diffusion

Electrostatic pressure

– Cl –

Electrostatic pressure

Force of diffusion

–

– Na+

K+

F I G U R E 15 Control of the Membrane Potential. The figure shows the relative concentration of some important ions inside and outside the neuron and the forces acting on them.

that surrounds our cells is similar to seawater, which is predominantly a solution of salt, NaCl. The primitive ancestors of our cells lived in the ocean; thus, the seawater was their extracellular fluid. Our extracellular fluid thus resembles seawater, produced and maintained by regulatory mechanisms. Let’s consider the ions in Figure 15, examining the forces of diffusion and electrostatic pressodium–potassium transporter A sure exerted on each and reasoning why each is located where it is. A–, the organic anion, is unprotein found in the membrane of all able to pass through the axon’s membrane; therefore, although the presence of this ion within cells that extrudes sodium ions from and transports potassium ions into the cell. the cell contributes to the membrane potential, it is located where it is because the membrane is impermeable to it. The potassium ion K+ is concentrated within the axon; thus, the force of diffusion tends to push it out of the cell. However, the outside of the cell 3 sodium ions is charged positively with respect to the inside, so electrostatic pressure Sodium–potassium pumped out transporter tends to force this cation inside. Thus, the two opposing forces balance, + Na Na+ and potassium ions tend to remain where they are. (See Figure 15.) Membrane Na+ The chloride ion Cl– is in greatest concentration outside the axon. Outside of Cell The force of diffusion pushes this ion inward. However, because the inside of the axon is negatively charged, electrostatic pressure pushes this anion outward. Again, two opposing forces balance each other. (See Figure 15.) The sodium ion Na+ is also in greatest concentration outside the axon, so it, like Cl–, is pushed into the cell by the force of diffusion. But unlike chloride, the sodium ion is positively charged. Therefore, electrostatic pressure does not prevent Na+ from entering the cell; indeed, the negative charge inside the axon attracts Na+. (See Figure 15.) How can Na+ remain in greatest concentration in the extracellular fluid, despite the fact that both forces (diffusion and electrostatic presInside of Cell sure) tend to push it inside? The answer is this: Another force con+ tinuously pushes Na out of the axon. This force is provided by a large K+ number of protein molecules embedded in the membrane, driven by + 2 potassium ions K energy provided by molecules of ATP produced by the mitochondria. pumped in These molecules, known as sodium–potassium transporters, exchange + + Na for K , pushing three sodium ions out for every two potassium ions F I G U R E 16 A Sodium–Potassium Transporter. These transporters are found in the cell membrane. they push in. (See Figure 16.)

Structure and Functions of Cells of the Nervous System

Because the membrane is not very permeable to Na+, sodium– potassium transporters very effectively keep the intracellular concentration of Na+ low. By transporting K+ into the cell, they also increase the intracellular concentration of K+ a small amount. The membrane is approximately 100 times more permeable to K+ than to Na+, so the increase is slight; but as we will see when we study the process of neural inhibition later in this chapter, it is very important. Sodium–potassium transporters use considerable energy: Up to 40 percent of a neuron’s metabolic resources are used to operate them. Neurons, muscle cells, glia—in fact, most cells of the body— have sodium–potassium transporters in their membrane.

The Action Potential As we saw, the forces of both diffusion and electrostatic pressure tend to push Na+ into the cell. However, the membrane is not very permeable to this ion, and sodium–potassium transporters continuously pump out Na+, keeping the intracellular level of Na+ low. But imagine what would happen if the membrane suddenly became permeable to Na+. The forces of diffusion and electrostatic pressure would cause Na+ to rush into the cell. This sudden influx (inflow) of positively charged ions would drastically change the Using the giant axon of the squid, researchers discovered the nature membrane potential. Indeed, experiments have shown that this mechanism of the message carried by axons. is precisely what causes the action potential: A brief increase in the permeLisa Poole/AP Photo. ability of the membrane to Na+ (allowing these ions to rush into the cell) is immediately followed by a transient increase in the permeability of the membrane to K+ (allowing these ions to rush out of the cell). What is responsible for these transient increases in permeability? We already saw that one type of protein molecule embedded in the membrane—the sodium– potassium transporter—actively pumps sodium ions out of the cell and pumps potassium ions into it. Another type of protein molecule provides an opening that permits ions to enter or leave the cells. These molecules provide ion channels, which contain passages (“pores”) that can open or close. When an ion channel is open, a particular type of ion can flow through the pore and thus can enter or leave the cell. (See Figure 17.) Neural membranes contain many thousands of ion channels. For example, the giant squid axon contains several hundred sodium channels in each square micrometer of membrane. (There are one million square micrometers in a square millimeter; thus, a patch of axonal membrane the size of a lowercase letter “o” in this chapter would contain several hundred million sodium channels.) Each sodium channel can admit up to 100million ions per second when it is open. Thus, the permeability of a membrane to a particular ion at a given moment is determined by the number of ion channels that are open.

Protein subunits of ion channel

Ions

Closed ion channel

Pore of ion channel

Outside of Cell

Inside of Cell

Lipid molecules in membrane Open ion channel ion channel A specialized protein molecule that permits specific ions to enter or leave cells.

FIGURE the cell.

Ion Channels. When ion channels are open, ions can pass through them, entering or leaving

Structure and Functions of Cells of the Nervous System

The following numbered paragraphs describe the movements of ions through the membrane during the action potential. The numbers on the figure correspond to the numbers of the paragraphs that follow. (See Figure 18.)

1 +

–

Reset

Refractory

3 –

–

Sodium ions enter +40

Membrane potential (mV)

1. As soon as the threshold of excitation is reached, the sodium channels in the membrane open and Na+ rushes in, propelled by the forces of diffusion and electrostatic pressure. The opening of these channels is triggered by reduction of the membrane potential (depolarization); they open at the point at which an action potential begins: the threshold of excitation. Because these channels are opened by changes in the membrane potential, they are called voltage-dependent ion channels. The influx of positively charged sodium ions produces a rapid change in the membrane potential, from –70 mV to +40 mV.

Sodium channel Open

Closed

Na+ channels become refractory, no more Na+ enters cell

4 K+ continues to 0

leave cell,

2. The membrane of the axon contains voltage-dependent potassium causes membrane K+ channels potential to return channels, but these channels are less sensitive than voltage-dependent 2 open, K+ to resting level sodium channels. That is, they require a greater level of depolarizabegins to leave cell tion before they begin to open. Thus, they begin to open later than the sodium channels. Na+ channels 3. At about the time the action potential reaches its peak (in approxiopen, Na+ begins to enter mately 1 msec), the sodium channels become refractory—the chancell K+ channels close, nels become blocked and cannot open again until the membrane once 1 5 Na+ channels reset + more reaches the resting potential. At this time then, no more Na can –70 enter the cell. + Threshold of 4. By now, the voltage-dependent potassium channels in the membrane 6 Extra K outside excitation diffuses away are open, letting K+ ions move freely through the membrane. At this time, the inside of the axon is positively charged, so K+ is driven out F I G U R E 18 Ion Movements During the Action Potential. of the cell by diffusion and by electrostatic pressure. This outflow of The shaded box at the top shows the opening of sodium channels cations causes the membrane potential to return toward its normal at the threshold of excitation, their refractory condition at the peak of the action potential, and their resetting when the membrane value. As it does so, the potassium channels begin to close again. potential returns to normal. 5. Once the membrane potential returns to normal, the sodium channels reset so that another depolarization can cause them to open again. 6. The membrane actually overshoots its resting value (–70 mV) and only gradually returns to normal as the potassium channels finally close. Eventually, sodium–potassium transporters remove the Na+ ions that leaked in and retrieve the K+ ions that leaked out. Experiments have shown that an action potential temporarily increases the number of Na+ ions inside the giant squid axon by 0.0003 percent. Although the concentration just inside the membrane is high, the total number of ions entering the cell is very small relative to the number already there. This means that on a short-term basis, sodium–potassium transporters are not very important. The few Na+ ions that manage to leak in diffuse into the rest of the axoplasm, and the slight increase in Na+ concentration is hardly noticeable. However, sodium–potassium transporters are important on a long-term basis. Without the activity of sodium–potassium transporters the concentration of sodium ions in the axoplasm would eventually increase enough that the axon would no longer be able to function.

Conduction of the Action Potential Now that we have a basic understanding of the resting membrane potential and the production of the action potential, we can consider the movement of the message down the axon, or conduction of the action potential. To study this phenomenon, we again make use of the giant squid axon. We attach an electrical stimulator to an electrode at one end of the axon and place recording electrodes, attached to oscilloscopes, at different distances from the stimulating electrode. Then we apply a depolarizing stimulus to the end of the axon and trigger an action potential. We record the action potential from each of the electrodes, one after the other. Thus, we see that the action potential is conducted down the axon. As the action potential travels, it remains constant in size. (See Figure 19.)

voltage-dependent ion channel An ion channel that opens or closes according to the value of the membrane potential.

Structure and Functions of Cells of the Nervous System

This experiment establishes a basic law of axonal conduction: the all-or-none law. This law states that an action potential either occurs or does not occur; and once triggered, it is transmitted down the axon to its end. An action potential always remains the same size, without growing or diminishing. And when an action potential reaches a point where the axon branches, it splits but does not diminish in size. An axon will transDepolarizing stimulus mit an action potential in either direction, or even in both directions, if Oscilloscope it is started in the middle of the axon’s length. However, because action shows action potentials potentials in living animals start at the end attached to the soma, axons normally carry one-way traffic. Giant squid As you know, the strength of a muscular contraction can vary from axon very weak to very forceful, and the strength of a stimulus can vary from barely detectable to very intense. We know that the occurrence of action potentials in axons controls the strength of muscular contractions Direction of travel of action potential and represents the intensity of a physical stimulus. But if the action potential is an all-or-none event, how can it represent information that F I G U R E 19 Conduction of the Action Potential. When an action can vary in a continuous fashion? The answer is simple: A single acpotential is triggered, its size remains undiminished as it travels down tion potential is not the basic element of information; rather, variable the axon. The speed of conduction can be calculated from the delay between the stimulus and the action potential. information is represented by an axon’s rate of firing. (In this context, firing refers to the production of action potentials.) A high rate of firing causes a strong muscular contraction, and a strong stimulus (such as a bright light) causes a high rate of firing in axons that serve the eyes. Thus, the all-or-none law is supplemented by the rate law. (See Figure 20.) Recall that all but the smallest axons in mammalian nervous systems are myelinated; segments of the axons are covered by a myelin sheath produced by the oligodendrocytes of the CNS or the Schwann cells of the PNS. These segments are separated by portions of naked axon, the nodes of Ranvier. Conduction of an action potential in a myelinated axon is somewhat different from conduction in an unmyelinated axon. Schwann cells and the oligodendrocytes of the CNS wrap tightly around the axon, leaving no measurable extracellular fluid between them and the axon. The only place where a myelinated axon comes into contact with the extracellular fluid is at a node of Ranvier, where the axon is naked. In the myelinated areas there can be no inward flow of Na+ when the sodium channels open, because there is no extracellular sodium. The axon conducts the electrical disturbance from the action potential to the next node of Ranvier. The disturbance is conducted passively, the way an electrical signal is conducted through an insulated cable. The disturbance gets smaller as it passes down the axon, but it is still large enough to trigger a new action potential at the next all-or-none law The principle that node. (This decrease in the size of the disturbance is called decremental conduction.) The action once an action potential is triggered potential gets retriggered, or repeated, at each node of Ranvier, and the electrical disturbance that in an axon, it is propagated, without decrement, to the end of the fiber. results is conducted decrementally along the myelinated area to the next node. Transmission of this message, hopping from node to node, is called saltatory conduction, from the Latin saltare, rate law The principle that variations in the intensity of a stimulus or other “to dance.” (See Figure 21.) information being transmitted in an axon Saltatory conduction confers two advantages. The first is economic. Sodium ions enter axons are represented by variations in the rate during action potentials, and these ions must eventually be removed. Sodium–potassium transat which that axon fires. porters must be located along the entire length of unmyelinated axons because Na+ enters everysaltatory conduction Conduction of where. However, because Na+ can enter myelinated axons only at the nodes of Ranvier, much less action potentials by myelinated axons. gets in, and consequently, much less has to be pumped out again. Therefore, myelinated axons The action potential appears to jump from one node of Ranvier to the next. expend much less energy to maintain their sodium balance.

Strong stimulus

Weak stimulus Action potentials

Action potentials On

Off

Stimulus

Stimulus Time FIGURE

The Rate Law. The strength of a stimulus is represented by the rate of firing of an axon. The size of each action potential is always constant.

Structure and Functions of Cells of the Nervous System

The second advantage to myelin is speed. Conduction of an action potential is faster in a myelinated axon because the transmission between the nodes is very fast. Increased speed enables an animal to react faster and (undoubtedly) to think faster. One of the ways to increase the speed of conduction is to increase size. Because it is so large, the unmyelinated squid axon, with a diameter of 500 μm, achieves a conduction velocity of approximately 35 m/sec (meters per second). However, a myelinated cat axon achieves the same speed with a diameter of a mere 6 μm. The fastest myelinated axon, 20 μm in diameter, can conduct action potentials at a speedy 120 m/sec, or 432 km/h (kilometers per hour). At that speed a signal can get from one end of an axon to the other without much delay.

Depolarizing stimulus Myelin sheath

Decremental conduction under myelin sheath

Action potential is regenerated at nodes of Ranvier

F I G U R E 21 Saltatory Conduction. The figure shows propagation of an action potential down a myelinated axon.

SECTION SUMMARY Communication Within a Neuron The withdrawal reflex illustrates how neurons can be connected to accomplish useful behaviors. The circuit responsible for this reflex consists of three sets of neurons: sensory neurons, interneurons, and motor neurons. The reflex can be suppressed when neurons in the brain activate inhibitory interneurons that form synapses with the motor neurons. The message that is conducted down an axon is called an action potential. The membranes of all cells of the body are electrically charged, but only axons can produce action potentials. The resting membrane potential occurs because various ions are located in different concentrations in the fluid inside and outside the cell. The extracellular fluid (like seawater) is rich in Na+ and Cl–, and the intracellular fluid is rich in K+ and various organic anions, designated as A–. The cell membrane is freely permeable to water, but its permeability to various ions—in particular, Na+ and K+—is regulated by ion channels. When the membrane potential is at its resting value (–70 mV), the voltage-dependent sodium and potassium channels are closed. Some Na+ continuously leaks into the axon but is promptly forced out of the cell again by the sodium–potassium transporters (which also pump potassium into the axon). When an electrical stimulator depolarizes the axon’s membrane so that its potential reaches the threshold of excitation, voltage-dependent sodium channels open and Na+ rushes into the cell, driven by the force of diffusion and by electrostatic pressure. The entry of these positively charged ions further reduces the membrane potential and, indeed, causes it to reverse, so the inside becomes positive. The opening of the sodium channels is temporary; they soon close again. The depolarization caused by the influx of Na+ activates voltagedependent potassium channels, and K+ leaves the axon, traveling down

its concentration gradient. This efflux (outflow) of K+ quickly brings the membrane potential back to its resting value. Because an action potential of a given axon is an all-or-none phenomenon, neurons represent intensity by their rate of firing. The action potential normally begins at one end of the axon, where the axon attaches to the soma. The action potential then travels continuously down unmyelinated axons, remaining constant in size, until it reaches the terminal buttons. (If the axon divides, an action potential continues down each branch.) In myelinated axons ions can flow through the membrane only at the nodes of Ranvier, because the axons are covered everywhere else with myelin, which isolates them from the extracellular fluid. Thus, the action potential is conducted passively from one node of Ranvier to the next. When the electrical message reaches a node, voltage-dependent sodium channels open, and a new action potential is triggered. This mechanism saves a considerable amount of energy because sodium– potassium transporters are not needed along the myelinated portions of the axon. Saltatory conduction is also faster than conduction of action potentials in unmyelinated axons.

Thought Questions The evolution of the human brain, with all its complexity, depended on many apparently trivial mechanisms. For example, what if cells had not developed the ability to manufacture myelin? Unmyelinated axons must be very large if they are to transmit action potentials rapidly. How big would the human brain have to be if oligodendrocytes did not produce myelin? Could the human brain as we know it have evolved without myelin?

Communication Between Neurons Now that you know about the basic structure of neurons and the nature of the action potential, it is time to describe the ways in which neurons can communicate with each other. These communications make it possible for circuits of neurons to gather sensory information, make plans, and initiate behaviors.

Structure and Functions of Cells of the Nervous System

postsynaptic potential Alterations in the membrane potential of a postsynaptic neuron, produced by liberation of neurotransmitter at the synapse.

The primary means of communication between neurons is synaptic transmission—the transmission of messages from one neuron to another through a synapse. As we saw, these messages are carried by neurotransmitters and released by terminal buttons. These chemicals diffuse across the fluid-filled gap between the terminal buttons and the membranes of the neurons with which they form synapses. As we will see in this section, neurotransmitters produce postsynaptic potentials—brief depolarizations or hyperpolarizations—that increase or decrease the rate of firing of the axon of the postsynaptic neuron. Neurotransmitters exert their effects on cells by attaching to a particular region of a receptor molecule called the binding site. A molecule of the chemical fits into the binding site the way a key fits into a lock: The shape of the binding site and the shape of the molecule of the neurotransmitter are complementary. A chemical that attaches to a binding site is called a ligand, from ligare, “to bind.” Neurotransmitters are natural ligands, produced and released by neurons. But other chemicals found in nature (primarily in plants or in the poisonous venoms of animals) can serve as ligands too. In addition, artificial ligands can be produced in the laboratory.

binding site The location on a receptor protein to which a ligand binds.

Structure of Synapses

ligand (ligh gand or ligg and) A chemical that binds with the binding site of a receptor.

As you have already learned, synapses are junctions between the terminal buttons at the ends of the axonal branches of one neuron and the membrane of another. Synapses can occur in three places: on dendrites, on the soma, and on other axons. These synapses are referred to as axodendritic, axosomatic, and axoaxonic. Axodendritic synapses can occur on the smooth surface of a dendrite or on dendritic spines—small protrusions that stud the dendrites of several types of large neurons in the brain. (See Figure 22.) Figure 23 illustrates a synapse. The presynaptic membrane, located at the end of the terminal button, faces the postsynaptic membrane, located on the neuron that receives the message (the postsynaptic neuron). These two membranes face each other across the synaptic cleft, a gap that varies in size from synapse to synapse but is usually around 20 nm wide. (A nanometer (nm) is one-billionth of a meter.) The synaptic cleft contains extracellular fluid, through which the neurotransmitter diffuses. (See Figure 23.) As you may have noticed in Figure 23, two prominent structures are located in the cytoplasm of the terminal button: mitochondria and synaptic vesicles. We also see microtubules, which are responsible for transporting material between the soma and terminal button. The presence of mitochondria implies that the terminal button needs energy to perform its functions. Synaptic vesicles are small, rounded objects in the shape of spheres or ovoids. They are filled with molecules of the neurotransmitter that is released by the terminal button. (The term vesicle means “little bladder.”) A given terminal button can contain from a few hundred to nearly a million

dendritic spine A small bud on the surface of a dendrite, with which a terminal button of another neuron forms a synapse. presynaptic membrane The membrane of a terminal button that lies adjacent to the postsynaptic membrane and through which the neurotransmitter is released. postsynaptic membrane The cell membrane opposite the terminal button in a synapse; the membrane of the cell that receives the message. synaptic cleft The space between the presynaptic membrane and the postsynaptic membrane. synaptic vesicle (vess i kul) A small, hollow, beadlike structure found in terminal buttons; contains molecules of a neurotransmitter.

Smooth dendrite

Somatic membrane

Terminal button

(a)

Presynaptic terminal button Postsynaptic terminal button

Dendritic spine

(b)

(c)

(d)

F I G U R E 22 Types of Synapses. Axodendritic synapses can occur on the smooth surface of a dendrite (a) or on dendritic spines (b). Axosomatic synapses occur on somatic membrane (c). Axoaxonic synapses consist of synapses between two terminal buttons (d).

Structure and Functions of Cells of the Nervous System

Detail of Synapse Mitochondrion Microtubule

Synaptic vesicle

Synaptic vesicle being transported from soma

Terminal button Synaptic cleft

Neuron FIGURE

Synaptic vesicle located at release zone Postsynaptic density

Presynaptic membrane

Postsynaptic membrane

Details of a Synapse.

synaptic vesicles. These vesicles are found in greatest numbers around the part of the presynaptic membrane that faces the synaptic cleft—near the release zone, the region from which the neurotransmitter is released. (See Figure 23.) In an electron micrograph the postsynaptic membrane under the terminal button appears somewhat thicker and more dense than the membrane elsewhere. This postsynaptic density is caused by the presence of receptors—specialized protein molecules that detect the presence of neurotransmitters in the synaptic cleft—and protein filaments that hold the receptors in place. (See Figure 23.)

Release of Neurotransmitter When action potentials are conducted down an axon (and down all of its branches), something happens inside all of the terminal buttons: Several synaptic vesicles located just inside the presynaptic membrane fuse with the membrane and then break open, spilling their contents into the synaptic cleft. Heuser and colleagues (Heuser, 1977; Heuser et al., 1979) obtained photomicrographs that illustrate this process. Because the release of neurotransmitter is a very rapid event, taking only a few milliseconds to occur, special procedures are needed to stop the action so that the details can be studied. The experimenters electrically stimulated the nerve attached to an isolated frog muscle and then dropped the muscle against a block of pure copper that had been cooled to 4 K (approximately –453°F). Contact with the supercooled metal froze the outer layer of tissue in 2 msec or less. The ice held the components of the terminal buttons in place until they could be chemically stabilized and examined with an electron microscope.

Activation of Receptors How do molecules of the neurotransmitter produce a depolarization or hyperpolarization in the postsynaptic membrane? They do so by diffusing across the synaptic cleft and attaching to the binding sites of special protein molecules located in the postsynaptic membrane, called postsynaptic receptors. Once binding occurs, the postsynaptic receptors open neurotransmitterdependent ion channels, which permit the passage of specific ions into or out of the cell. Thus,

Simulate Synapses in MyPsychLab

release zone A region of the interior of the presynaptic membrane of a synapse to which synaptic vesicles attach and release their neurotransmitter into the synaptic cleft. postsynaptic receptor A receptor molecule in the postsynaptic membrane of a synapse that contains a binding site for a neurotransmitter. neurotransmitter-dependent ion channel An ion channel that opens when a molecule of a neurotransmitter binds with a postsynaptic receptor.

Structure and Functions of Cells of the Nervous System

Molecule of neurotransmitter attached to binding site

Binding site of receptor

Ions

This figure is intentionally omitted from this text.

Closed ion channel

Open ion channel

Inside of Cell

F I G U R E 25 Ionotropic Receptors. The ion channel opens when a molecule of neurotransmitter attaches to the binding site. For purposes of clarity the drawing is schematic; molecules of neurotransmitter are actually much larger than individual ions.

ionotropic receptor (eye on oh trow pik) A receptor that contains a binding site for a neurotransmitter and an ion channel that opens when a molecule of the neurotransmitter attaches to the binding site. metabotropic receptor (meh tab oh trow pik) A receptor that contains a binding site for a neurotransmitter; activates an enzyme that begins a series of events that opens an ion channel elsewhere in the cell’s membrane when a molecule of the neurotransmitter attaches to the binding site. G protein A protein coupled to a metabotropic receptor; conveys messages to other molecules when a ligand binds with and activates the receptor. second messenger A chemical produced when a G protein activates an enzyme; carries a signal that results in the opening of the ion channel or causes other events to occur in the cell.

the presence of the neurotransmitter in the synaptic cleft allows particular ions to pass through the membrane, changing the local membrane potential. Neurotransmitters open ion channels by at least two different methods, direct and indirect. The direct method is simpler, so I will describe it first. Figure 25 illustrates a neurotransmitterdependent ion channel that is equipped with its own binding site. When a molecule of the appropriate neurotransmitter attaches to it, the ion channel opens. The formal name for this combination receptor/ion channel is an ionotropic receptor. (See Figure 25.) Ionotropic receptors were first discovered in the organ that produces electrical current in Torpedo, the electric ray, where they occur in great number. (The electric ray is a fish that generates a powerful electrical current, not some kind of Star Wars weapon.) These receptors, which are sensitive to a neurotransmitter called acetylcholine, contain sodium channels. When these channels are open, sodium ions enter the cell and depolarize the membrane. The indirect method is more complicated. Some receptors do not open ion channels directly but instead start a chain of chemical events. These receptors are called metabotropic receptors because they involve steps that require the cell to expend metabolic energy. Metabotropic receptors are located in close proximity to another protein attached to the membrane—a G protein. When a molecule of the neurotransmitter binds with the receptor, the receptor activates a G protein situated inside the membrane next to the receptor. When activated, the G protein activates an enzyme that stimulates the production of a chemical called a second messenger. (The neurotransmitter is the first messenger.) Molecules of the second messenger travel through the cytoplasm, attach themselves to nearby ion channels, and cause them to open. Compared with postsynaptic potentials produced by ionotropic receptors, those produced by metabotropic receptors take longer to begin and last longer. (See Figure 26.) The first second messenger to be discovered was cyclic AMP, a chemical that is synthesized from ATP. Since then, several other second messengers have been discovered. Second messengers play an important role in both synaptic and nonsynaptic communication. And they can do more than open ion channels. For example, they can travel to the nucleus or other regions of the neuron and initiate biochemical changes that affect the cell’s functions. They can even turn

Structure and Functions of Cells of the Nervous System

specific genes on or off, thus initiating or terminating production of particular proteins.

Molecule of neurotransmitter

Surface of membrane

Metabotropic receptor

Postsynaptic Potentials As I mentioned earlier, postsynaptic potentials can be either depolarizing (excitatory) or hyperpolarizing (inhibitory). What determines the nature of the postsynaptic potential at a particular synapse is not the neurotransmitter itself. Instead, it is determined by the characteristics of the postsynaptic receptors—in particular, by the particular type of ion channel they open. As Figure 27 shows, three major types of neurotransmitter-dependent ion channels are found in the postsynaptic membrane: sodium (Na+), potassium (K+), and chloride (Cl–). Although the figure depicts only directly activated (ionotropic) ion channels, you should realize that many ion channels are activated indirectly, by metabotropic receptors coupled to G proteins. The neurotransmitter-dependent sodium channel is the most important source of excitatory postsynaptic potentials. As we saw, sodium–potassium transporters keep sodium outside the cell, waiting for the forces of diffusion and elecOpen ion Molecule of neurotransmitter Closed ion trostatic pressure to push it in. Obviously, when sodium channels are opened, channel channel attached to binding site of the result is a depolarization—an excitatory postsynaptic potential (EPSP). (See metabotropic receptor Figure 27a.) F I G U R E 26 Metabotropic Receptors. When a molecule We also saw that sodium–potassium transporters maintain a small surplus of of neurotransmitter binds with a receptor, a second potassium ions inside the cell. If potassium channels open, some of these cations messenger (represented by black arrows) is produced that will follow this gradient and leave the cell. Because K+ is positively charged, its opens nearby ion channels. efflux will hyperpolarize the membrane, producing an inhibitory postsynaptic potential (IPSP). (See Figure 27b.) At many synapses inhibitory neurotransmitters open the chloride channels instead of (or in addition to) potassium channels. The effect of opening chloride channels depends on the membrane potential of the neuron. If the membrane is at the resting potential, nothing happens, because (as we saw earlier) the forces of diffusion and electrostatic pressure balance perfectly for the chloride ion. However, if the membrane potential has already been depolarized by the activity of excitatory synapses located nearby, then the opening of chloride channels will

Molecule of neurotransmitter attached to binding site Membrane

Ion channel

K+

–

K+

Cl-

Na+

–

– Cl-

Na+

FIGURE

Inﬂow of Na+ causes depolarization (EPSP)

Outﬂow of K+ causes

b hyperpolarization (IPSP)

Ionic Movements During Postsynaptic Potentials.

Inﬂow of Cl- causes c hyperpolarization (IPSP)

excitatory postsynaptic potential (EPSP) An excitatory depolarization of the postsynaptic membrane of a synapse caused by the liberation of a neurotransmitter by the terminal button. inhibitory postsynaptic potential (IPSP) An inhibitory hyperpolarization of the postsynaptic membrane of a synapse caused by the liberation of a neurotransmitter by the terminal button.

Structure and Functions of Cells of the Nervous System

permit Cl– to enter the cell. The influx of anions will bring the membrane potential back to its normal resting condition. Thus, the opening of chloride channels serves to neutralize EPSPs. (See Figure 27c.)

Termination of Postsynaptic Potentials Postsynaptic potentials are brief depolarizations or hyperpolarizations caused by the activation of postsynaptic receptors with molecules of a neurotransmitter. They are kept brief by two mechanisms: reuptake and enzymatic deactivation. The postsynaptic potentials produced by most neurotransmitters are terminated by reuptake. This process is simply an extremely rapid removal of neurotransmitter from the synaptic cleft by the terminal button. The neurotransmitter does not return in the vesicles that get pinched off the membrane of the terminal button. Instead, the membrane contains special transporter molecules that draw on the cell’s energy reserves to force molecules of the neurotransmitter from the synaptic cleft directly into the cytoplasm—just as sodium–potassium transporters move Na+ and K+ across the membrane. When an action potential arrives, the terminal button releases a small amount of neurotransmitter into the synaptic cleft and then takes it back, giving the postsynaptic receptors only a brief exposure to the neurotransmitter. (See Figure 28.) Enzymatic deactivation is accomplished by an enzyme that destroys molecules of the neurotransmitter. Postsynaptic potentials are terminated in this way for acetylcholine (ACh). Transmission at synapses on muscle fibers and at some synapses between neurons in the central nervous system is mediated by ACh. Postsynaptic potentials produced by ACh are short-lived because the postsynaptic membrane at these synapses contains an enzyme called

Molecules of neurotransmitter returned to terminal button

“Omega ﬁgure”– remnants of synaptic vesicle that has released its neurotransmitter

Transporter

Presynaptic membrane reuptake The reentry of a neurotransmitter just liberated by a terminal button back through its membrane, thus terminating the postsynaptic potential.

Postsynaptic membrane

Synaptic cleft

Postsynaptic receptor

enzymatic deactivation The destruction of a neurotransmitter by an enzyme after its release—for example, the destruction of acetylcholine by acetylcholinesterase. acetylcholine (ACh) (a see tul koh leen) A neurotransmitter found in the brain, spinal cord, and parts of the peripheral nervous system; responsible for muscular contraction.

F I G U R E 28 Reuptake. Molecules of a neurotransmitter that has been released into the synaptic cleft are transported back into the terminal button.

Structure and Functions of Cells of the Nervous System

acetylcholinesterase (AChE). AChE destroys ACh by cleaving it into its constituents: choline and acetate. Because neither of these substances is capable of activating postsynaptic receptors, the postsynaptic potential is terminated once the molecules of ACh are broken apart. AChE is an extremely energetic destroyer of ACh; one molecule of AChE will chop apart more than 5000 molecules of ACh each second.

Effects of Postsynaptic Potentials: Neural Integration We have seen how neurons are interconnected by means of synapses, how action potentials trigger the release of neurotransmitters, and how these chemicals initiate excitatory or inhibitory postsynaptic potentials. Excitatory postsynaptic potentials increase the likelihood that the postsynaptic neuron will fire; inhibitory postsynaptic potentials decrease this likelihood. (Remember, “firing” refers to the occurrence of an action potential.) Thus, the rate at which an axon fires is determined by the relative activity of the excitatory and inhibitory synapses on the soma and dendrites of that cell. If there are no active excitatory synapses or if the activity of inhibitory synapses is particularly high, that rate could be close to zero. Let’s look at the elements of this process. The interaction of the effects of excitatory and inhibitory synapses on a particular neuron is called neural integration. (Integration means “to make whole,” in the sense of combining two or more functions.) Figure29 illustrates the effects of excitatory and inhibitory synapses on a postsynaptic neuron. The top panel shows what happens when several excitatory synapses become active. The release of the neurotransmitter produces depolarizing EPSPs in the dendrites of the neuron. These EPSPs (represented in red) are then transmitted down the dendrites and across the soma to the axon hillock located at the base of the axon. If the depolarization is still strong enough when it reaches this point, the axon will fire. (See Figure 29a.)

acetylcholinesterase (AChE) (a see tul koh lin ess ter ace) The enzyme that destroys acetylcholine soon after it is liberated by the terminal buttons, thus terminating the postsynaptic potential. neural integration The process by which inhibitory and excitatory postsynaptic potentials summate and control the rate of firing of a neuron.

Activity of inhibitory synapses produces IPSPs (blue) in postsynaptic neuron

Activity of excitatory synapses produces EPSPs (red) in postsynaptic neuron

Axon hillock reaches threshold of excitation; action potential is triggered in axon (a)

IPSPs counteract EPSPs; action potential is not triggered in axon (b)

F I G U R E 29 Neural Integration. (a) If several excitatory synapses are active at the same time, the EPSPs they produce (shown in red) summate as they travel toward the axon, and the axon fires. (b) If several inhibitory synapses are active at the same time, the IPSPs they produce (shown in blue) diminish the size of the EPSPs and prevent the axon from firing.

Structure and Functions of Cells of the Nervous System

Now let’s consider what would happen if, at the same time, inhibitory synapses also become active. Inhibitory postsynaptic potentials are hyperpolarizing—they bring the membrane potential away from the threshold of excitation. Thus, they tend to cancel the effects of excitatory postsynaptic potentials. (See Figure 29b.) The rate at which a neuron fires is controlled by the relative activity of the excitatory and inhibitory synapses on its dendrites and soma. If the activity of excitatory synapses goes up, the rate of firing will go up. If the activity of inhibitory synapses goes up, the rate of firing will go down.

Autoreceptors

autoreceptor A receptor molecule located on a neuron that responds to the neurotransmitter released by that neuron. presynaptic inhibition The action of a presynaptic terminal button in an axoaxonic synapse; reduces the amount of neurotransmitter released by the postsynaptic terminal button. presynaptic facilitation The action of a presynaptic terminal button in an axoaxonic synapse; increases the amount of neurotransmitter released by the postsynaptic terminal button.

Postsynaptic receptors detect the presence of a neurotransmitter in the synaptic cleft and initiate excitatory or inhibitory postsynaptic potentials. But the postsynaptic membrane is not the only location of receptors that respond to neurotransmitters. Many neurons also possess receptors that respond to the neurotransmitter that they themselves release, called autoreceptors. Autoreceptors can be located on the membrane of any part of the cell, but in this discussion we will consider those located on the terminal button. In most cases these autoreceptors do not control ion channels. Thus, when stimulated by a molecule of the neurotransmitter, autoreceptors do not produce changes in the membrane potential of the terminal button. Instead, they regulate internal processes, including the synthesis and release of the neurotransmitter. (As you may have guessed, autoreceptors are metabotropic; the control they exert on these processes is accomplished through G proteins and second messengers.) In most cases the effects of autoreceptor activation are inhibitory; that is, the presence of the neurotransmitter in the extracellular fluid in the vicinity of the neuron causes a decrease in the rate of synthesis or release of the neurotransmitter. Most investigators believe that autoreceptors are part of a regulatory system that controls the amount of neurotransmitter that is released. If too much is released, the autoreceptors inhibit both production and release; if not enough is released, the rates of production and release go up.

Axoaxonic Synapses Terminal button A

Terminal button B

Axoaxonic synapse

Postsynaptic density

Axodendritic synapse Dendritic spine

F I G U R E 30 An Axoaxonic Synapse. The activity of terminal button A can increase or decrease the amount of neurotransmitter released by terminal button B.

As we saw in Figure 22, the central nervous system contains three types of synapses. Activity of the first two types, axodendritic and axosomatic synapses, causes postsynaptic excitation or inhibition. The third type, axoaxonic synapses, does not contribute directly to neural integration. Instead, the activity of these synapses alters the amount of neurotransmitter released by the terminal buttons of the postsynaptic axon. They can produce presynaptic modulation, presynaptic inhibition, or presynaptic facilitation. As you know, the release of a neurotransmitter by a terminal button is initiated by an action potential. Normally, a particular terminal button releases a fixed amount of neurotransmitter each time an action potential arrives. However, the release of neurotransmitter can be modulated by the activity of axoaxonic synapses. If the activity of the axoaxonic synapse decreases the release of the neurotransmitter, the effect is called presynaptic inhibition. If it increases the release, it is called presynaptic facilitation. (See Figure 30.) By the way, the active ingredient in marijuana exerts its effects on the brain by binding with presynaptic receptors.

Nonsynaptic Chemical Communication Neurotransmitters are released by terminal buttons of neurons and bind with receptors in the membrane of another cell located a very short

Structure and Functions of Cells of the Nervous System

distance away. The communication at each synapse is private. Neuromodulators are chemicals released by neurons that travel farther and are dispersed more widely than are neurotransmitters. Most neuromodulators are peptides, chains of amino acids that are linked together by chemical attachments called peptide bonds (hence their name). Neuromodulators are secreted in larger amounts and diffuse for longer distances, modulating the activity of many neurons in a particular part of the brain. For example, neuromodulators affect general behavioral states such as vigilance, fearfulness, and sensitivity to pain. Hormones are secreted by cells of endocrine glands (from the Greek endo-, “within,” and krinein, “to secrete”) or by cells located in various organs, such as the stomach, the intestines, the kidneys, and the brain. Cells that secrete hormones release these chemicals into the extracellular fluid. The hormones are then distributed to the rest of the body through the bloodstream. Hormones affect the activity of cells (including neurons) that contain specialized receptors located either on the surface of their membrane or deep within their nuclei. Cells that contain receptors for a particular hormone are referred to as target cells for that hormone; only these cells respond to its presence. Many neurons contain hormone receptors, and hormones are able to affect behavior by stimulating the receptors and changing the activity of these neurons. For example, a sex hormone, testosterone, increases the aggressiveness of most male mammals.

neuromodulator A naturally secreted substance that acts like a neurotransmitter except that it is not restricted to the synaptic cleft but diffuses through the extracellular fluid. peptide A chain of amino acids joined together by peptide bonds. Most neuromodulators, and some hormones, consist of peptide molecules. hormone A chemical substance that is released by an endocrine gland and that has effects on target cells in other organs. endocrine gland A gland that liberates its secretions into the extracellular fluid around capillaries and hence into the bloodstream. target cell The type of cell that contains receptors for a particular hormone and is affected by that hormone.

SECTION SUMMARY Communication Between Neurons Synapses consist of junctions between the terminal buttons of one neuron and the membrane of another neuron, a muscle cell, or a gland cell. When an action potential is transmitted down an axon, the terminal buttons at the end release a neurotransmitter, a chemical that produces either depolarizations (EPSPs) or hyperpolarizations (IPSPs) of the postsynaptic membrane. The rate of firing of the postsynaptic neuron’s axon is determined by the relative activity of the excitatory and inhibitory synapses on the membrane of its dendrites and soma—a phenomenon known as neural integration. Terminal buttons contain synaptic vesicles, filled with molecules of the neurotransmitter. When an action potential reaches a terminal button, it causes the release of the neurotransmitter: Some of the synaptic vesicles fuse with the presynaptic membrane of the terminal button, break open, and release their contents into the synaptic cleft. The activation of postsynaptic receptors by molecules of a neurotransmitter causes neurotransmitter-dependent ion channels to open, resulting in postsynaptic potentials. Ionotropic receptors contain ion channels, which are directly opened when a ligand attaches to the binding site. Metabotropic receptors are linked to G proteins, which, when activated, open ion channels—usually by producing a chemical called a second messenger. The nature of the postsynaptic potential depends on the type of ion channel that is opened by the postsynaptic receptors at a particular synapse. Excitatory postsynaptic potentials occur when Na+ enters the cell. Inhibitory postsynaptic potentials are produced when K+ leaves the cell or Cl– enters it. Postsynaptic potentials are normally brief. They are terminated by two means. The most common mechanism is reuptake: retrieval of

molecules of the neurotransmitter from the synaptic cleft by means of transporters located in the presynaptic membrane, which transport the molecules back into the cytoplasm. Acetylcholine is deactivated by the enzyme acetylcholinesterase. The presynaptic membrane, as well as the postsynaptic membrane, contains receptors that detect the presence of a neurotransmitter. Presynaptic receptors, also called autoreceptors, monitor the quantity of neurotransmitter that a neuron releases and, apparently, regulate the amount that is synthesized and released. Axoaxonic synapses produce presynaptic inhibition or presynaptic facilitation, reducing or enhancing the amount of neurotransmitter that is released. Neuromodulators and hormones, like neurotransmitters, act on cells by attaching to the binding sites of receptors and initiating electrical or chemical changes in these cells. However, whereas the action of neurotransmitters is localized, neuromodulators and hormones have much more widespread effects.

Thought Questions 1. Why does synaptic transmission involve the release of chemicals? Direct electrical coupling of neurons is far simpler, so why do our neurons not use it more extensively? (A tiny percentage of synaptic connections in the human brain do use electrical coupling.) Normally, nature uses the simplest means possible to a given end, so there must be some advantages to chemical transmission. What do you think they are? 2. Consider the control of the withdrawal reflex illustrated in Figure 11. Could you design a circuit using electrical synapses that would accomplish the same tasks?

EPILOGUE

| Myasthenia Gravis

“Am I cured?” asked Kathryn. Dr. T. smiled ruefully. “I wish it were so simple!” she said. “No, I’m afraid you aren’t cured, but now we know what is causing your weakness. There is a treatment,” she hastened to add, seeing Kathryn’s disappointment. “You have a condition called myasthenia gravis. The injection I gave you lasts only for a few minutes, but I can give you some pills that have effects that last much longer.” Indeed, as she was talking, Kathryn felt herself weakening, and she sat down again. Myasthenia gravis (MG) was first described in 1672 by Thomas Willis, an English physician. The term literally means “grave muscle weakness.” It is not a very common disorder, but most experts believe that many cases—much milder than Kathryn’s, of course— go undiagnosed. Kathryn’s disease involved her face, neck, arm, and trunk muscles, but sometimes only the eye muscles are involved. Before the 1930s, Kathryn would have become bedridden and almost certainly would have died within a few years, probably of pneumonia resulting from difficulty in breathing and coughing. Fortunately, Kathryn’s future is not so bleak. The cause of myasthenia gravis is well understood, and it can be treated, if not cured. The hallmark of myasthenia gravis is fatigability. That is, a patient has reasonable strength when rested but becomes very weak after moving for a little while. For many years, researchers have realized that the weakness occurs in the synapses on the muscles, not in the nervous system or the muscles themselves. In the late nineteenth century, a physician placed electrodes on the skin of a person with myasthenia gravis and electrically stimulated a nerve leading to a muscle. The muscle contracted each time he stimulated the nerve, but the contractions became progressively weaker. However, when he placed the electrodes above the muscle and stimulated it directly, the contractions showed no signs of fatigue. Later, with the development of techniques of electrical recording, researchers found that the action potentials in the nerves of people with myasthenia gravis were completely normal. If nerve conduction and muscular contraction were normal, then the problem had to lie in the synapses. In 1934, Dr. Mary Walker remarked that the symptoms of myasthenia gravis resembled the effects of curare, a poison that blocks neural transmission at the synapses on muscles. The antidote for curare poisoning was a drug called physostigmine, which deactivates acetylcholinesterase (AChE). As you learned in this chapter, AChE is an enzyme that destroys the neurotransmitter acetylcholine (ACh) and terminates the postsynaptic potentials it produces. By deactivating AChE, physostigmine greatly increases and prolongs the effects of ACh on the postsynaptic membrane. Thus, it increases the strength of synaptic transmission at the synapses on muscles and reverses the effects of curare. Dr. Walker reasoned that if physostigmine reversed the effects of curare poisoning, perhaps it would also reverse the symptoms of myasthenia gravis. She tried it, and it did within a matter of a

few minutes. Subsequently, pharmaceutical companies discovered drugs that could be taken orally and that produced longer-lasting effects. Nowadays, an injectable drug is used to make the diagnosis and an oral drug is used to treat it. Researchers turned their efforts to understanding the cause of myasthenia gravis. They discovered that MG is an autoimmune disease. Normally, the immune system protects us from infections by being alert for proteins that are present on invading microorganisms. The immune system produces antibodies that attack these foreign proteins, and the microorganisms are killed. However, sometimes the immune system makes a mistake and becomes sensitized against one of the proteins normally present in our bodies. As researchers have found, the blood of patients with MG contains antibodies against the protein that makes up acetylcholine receptors. Thus, myasthenia gravis is an autoimmune disease in which the immune system attacks and destroys many of the person’s ACh receptors, which are necessary for synaptic transmission. Recently, researchers have succeeded in developing an animal model of MG. An animal model is a disease that can be produced in laboratory animals and that closely resembles a human disease. The course of the disease can then be studied, and possible treatments or cures can be tested. In this case, the disease is produced by extracting ACh-receptor protein from electric rays (Torpedo) and injecting it into laboratory animals. The animals’ immune systems become sensitized to the protein and develop antibodies that attack their own ACh receptors. The animals exhibit the same muscular fatigability shown by people with MG, and they become stronger after receiving an injection of a drug such as physostigmine. One promising result that has emerged from studies with the animal model of MG is the finding that an animal’s immune system can be desensitized so that it will not produce antibodies that destroy ACh receptors. If ACh-receptor proteins are modified and then injected into laboratory animals, their immune systems develop an antibody against the altered protein. This antibody does not attack the animals’ own ACh receptors. Later, if they are given the pure ACh-receptor protein, they do not develop MG. Apparently, the pure protein is so similar to the one to which the animals were previously sensitized that the immune system does not bother to produce another antibody. Perhaps a vaccine can be developed to arrest MG in its early stages by inducing the person’s immune system to produce the harmless antibody rather than the one that attacks acetylcholine receptors. Even with the drugs that are available to physicians today, myasthenia gravis remains a serious disease. The drugs do not restore a person’s strength to normal, and they can have serious side effects. But the progress made in the laboratory in recent years gives us hope for a brighter future for people like Kathryn.

Structure and Functions of Cells of the Nervous System

KEY CONCEPTS CELLS OF THE NERVOUS SYSTEM

1. Neurons have a soma, dendrites, an axon, and terminal buttons. Circuits of interconnected neurons are responsible for the functions performed by the nervous system. Neurons are supported by glia and by Schwann cells, which provide myelin sheaths, housekeeping services, and physical support. The blood–brain barrier helps to regulate the chemicals that reach the brain. COMMUNICATION WITHIN A NEURON

2. The action potential occurs when the membrane potential of an axon reaches the threshold of excitation. Although the action potential is electrical, it is caused by the flow of sodium and potassium ions through voltage-dependent ion channels in the membrane. Saltatory conduction, which takes place in myelinated axons, is faster and more efficient than conduction in unmyelinated axons. COMMUNICATION BETWEEN NEURONS

3. Neurons communicate by means of synapses, which enable the presynaptic neuron to produce excitatory or inhibitory effects on the postsynaptic neuron. These effects increase or decrease the rate at which the axon of the postsynaptic neuron sends action potentials down to its terminal buttons.

4. When an action potential reaches the end of an axon, it causes some synaptic vesicles to release a neurotransmitter into the synaptic cleft. Molecules of the neurotransmitter attach themselves to receptors in the postsynaptic membrane. 5. When they become activated by molecules of the neurotransmitters, postsynaptic receptors produce either excitatory or inhibitory postsynaptic potentials by opening neurotransmitter-dependent sodium, potassium, or chloride ion channels. 6. The postsynaptic potential is terminated by the destruction of the neurotransmitter or by its reuptake into the terminal button. 7. Autoreceptors help to regulate the amount of neurotransmitter that is released. 8. Axoaxonic synapses consist of junctions between two terminal buttons. Release of neurotransmitter by the first terminal button increases or decreases the amount of neurotransmitter released by the second. 9. Neuromodulators and hormones have actions similar to those of neurotransmitters: They bind with and activate receptors on or in their target cells.

EXPLORE the Virtual Brain in NEURAL CONDUCTION This module reveals the key components of the neural communication system, as well as the processes of electrical intra-neural and chemical inter-nerual communication. See membrane potentials, synaptic communication, and neurotransmitters in action in detailed animations.

Structure and Functions of Cells of the Nervous System

REFERENCES Bradbury, M. W. B. The Concept of a Blood-Brain Barrier. New York: John Wiley & Sons, 1979. Brown, A. M., Tekkök, S. B., and Ransom, B. R. Energy transfer from astrocytes to axons: The role of CNS glycogen. Neurochemistry International, 2004, 45, 529–536. Heuser, J. E. Synaptic vesicle exocytosis revealed in quick-frozen frog neuromuscular junctions treated with 4-aminopyridine and given a single electrical shock. In Society for Neuroscience Symposia, Vol. II, edited by W. M. Cowan and J. A. Ferrendelli. Bethesda, Md.: Society for Neuroscience, 1977. Heuser, J. E., Reese, T. S., Dennis, M. J., et al. Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. Journal of Cell Biology, 1979, 81, 275–300. Rubin, L. L., and Staddon, J. M. The cell biology of the blood–brain barrier. Annual Review of Neuroscience, 1999, 22, 11–28. Tsacopoulos, M., and Magistretti, P. J. Metabolic coupling between glia and neurons. Journal of Neuroscience, 1996, 16, 877–885. Zlokovic, B. V. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron, 2008, 57, 178–201.

Structure of the Nervous System

OUTLINE ■

Structure of the Nervous System

Basic Features of the Nervous System An Overview Meninges The Ventricular System and Production of Cerebrospinal Fluid

■

The Central Nervous System Development of the Central Nervous System The Forebrain The Midbrain The Hindbrain The Spinal Cord

■

The Peripheral Nervous System Spinal Nerves Cranial Nerves

LEARNING OBJECTIVES 1. Describe the appearance of the brain and identify the terms used to indicate directions and planes of section. 2. Describe the divisions of the nervous system, the meninges, the ventricular system, and the production of cerebrospinal ﬂuid and its ﬂow through the brain. 3. Outline the development of the central nervous system. 4. Describe the telencephalon, one of the two major structures of the forebrain.

Science Photo Library/Getty Images

The Autonomic Nervous System

5. Describe the two major structures of the diencephalon. 6. Describe the major structures of the midbrain, the hindbrain, and the spinal cord. 7. Describe the peripheral nervous system, including the two divisions of the autonomic nervous system.

PROLOGUE

| The Left Is Gone

Ms. S. was a 60-year-old woman with a history of high blood pressure, which was not responding well to the medication she was taking. One evening she was sitting in her reclining chair reading the newspaper when the phone rang. She got out of her chair and walked to the phone. As she did, she began feeling giddy and stopped to hold onto the kitchen table. She has no memory of what happened after that. The next morning, a neighbor, who usually stopped by to have coffee with Ms. S., found her lying on the floor, mumbling incoherently. The neighbor called an ambulance, which took Ms. S. to a hospital. Two days after her admission, I visited Ms. S. in her room, accompanied by a group of people being led by the chief of neurology. The neurological resident in charge of her case had already told us that she had had a stroke in the back part of the right side of the brain. He had attached a CT scan to an illuminated viewer mounted on the wall and had showed us a white spot caused by the accumulation of blood in a particular region of her brain. About a dozen of us entered Ms. S.’s room. She was awake but seemed a little confused. The resident greeted her and asked how she was feeling. “Fine, I guess,” she said. “I still don’t know why I’m here.” “Can you see the other people in the room?” “Why, sure.” “How many are there?” She turned her head to the right and began counting. She stopped when she had counted the people at the foot of her bed. “Seven,” she reported. “What about us?” asked a voice from the left of her bed. “What?” she said, looking at the people she had already counted. “Here, to your left. No, toward your left!” the voice

repeated. Slowly, rather reluctantly, she began turning her head to the left. The voice kept insisting, and finally, she saw who was talking. “Oh,” she said, “I guess there are more of you.” The resident approached the left side of her bed and touched her left arm. “What is this?” he asked. “Where?” she said. “Here,” he answered, holding up her arm and moving it gently in front of her face. “Oh, that’s an arm.” “An arm? Whose arm?” “I don’t know. . . . I guess it must be yours.” “No, it’s yours. Look, it’s a part of you.” He traced with his fingers from her arm to her shoulder. “Well, if you say so,” she said, still sounding unconvinced. When we returned to the residents’ lounge, the chief of neurology said that we had seen a classic example of unilateral neglect, caused by damage to a particular part of the brain. “I’ve seen many cases like this,” he explained. “People can still perceive sensations from the left side of their body, but they just don’t pay attention to them. A woman will put makeup on only the right side of her face, and a man will shave only half of his beard. When they put on a shirt or a coat, they will use their left hand to slip it over their right arm and shoulder, but then they’ll just forget about their left arm and let the garment hang from one shoulder. They also don’t look at things located toward the left or even the left halves of things. Once I saw a man who had just finished eating breakfast. He was sitting in his bed, with a tray in front of him. There was half of a pancake on his plate. ‘Are you all done?’ I asked. ‘Sure,’ he said. I turned the plate around so that the uneaten part was on his right. He gave a startled look and said, ‘Where the hell did that come from?’”

he goal of neuroscience research is to understand how the brain works. To understand the results of this research, you must be acquainted with the basic structure of the nervous system. The number of terms introduced in this chapter is kept to a minimum (but as you will see, the minimum is still a rather large number). With the framework you will receive from this chapter, you should have no trouble continuing your studies on the subject in the future.

Basic Features of the Nervous System Before beginning a description of the nervous system, I want to discuss the terms that are used to describe it. The gross anatomy of the brain was described long ago, and everything that could be seen without the aid of a microscope was given a name. Early anatomists named most brain structures according to their similarity to commonplace objects: amygdala, or “almond-shaped object”; hippocampus, or “sea horse”; genu, or “knee”; cortex, or “bark”; pons, or “bridge”; uncus, or “hook,” to give a few examples.

Structure of the Nervous System

anterior With respect to the central nervous system, located near or toward the head. posterior With respect to the central nervous system, located near or toward the tail. rostral “Toward the beak”; with respect to the central nervous system, in a direction along the neuraxis toward the front of the face.

dorsal “Toward the back”; with respect to the central nervous system, in a direction perpendicular to the neuraxis toward the top of the head or the back.

Caudal or posterior Lateral Medial

Neuraxis

Ventral

Dorsal Lateral Medial Ventral

Dorsal

Rostral or anterior Neuraxis

Lateral Medial

Dorsal

caudal “Toward the tail”; with respect to the central nervous system, in a direction along the neuraxis away from the front of the face.

Dorsal Rostral or anterior

Ventral

neuraxis An imaginary line drawn through the center of the length of the central nervous system, from the bottom of the spinal cord to the front of the forebrain.

Knowing the translation makes the terms more memorable. For example, knowing that cortex means “bark” (like the bark of a tree) will help you to remember that the cortex is the outer layer of the brain. When describing features of a structure as complex as the brain, we need to use terms denoting directions. Directions in the nervous system are normally described relative to the neuraxis, an imaginary line drawn through the length of the central nervous system, from the lower end of the spinal cord up to the front of the brain. For simplicity’s sake, let’s consider an animal with a straight neuraxis. Figure 1 shows an alligator and two humans. This alligator is certainly laid out in a linear fashion; we can draw a straight line that starts between its eyes and continues down the center of its spinal cord. (See Figure 1.) The front end is anterior, and the tail is posterior. The terms rostral (toward the beak) and caudal (toward the tail) are also employed, especially when referring specifically to the brain. The top of the head and the back are part of the dorsal surface, while the ventral (front) surface faces the ground. (Dorsum means “back,” and ventrum means “belly.”) These directions are somewhat more complicated in the human; because we stand upright, our neuraxis bends, so the top of the head is perpendicular to the back. (You will also encounter the terms superior and inferior. In referring to the brain, these terms do not denote value judgments. Superior simply means “above,” and inferior means “below.” For example, the superior colliculi are located above the inferior colliculi.) The frontal views of both the alligator and the human illustrate the terms lateral and medial: toward the side and toward the middle, respectively. (See Figure 1.) Two other useful terms are ipsilateral and contralateral. Ipsilateral refers to structures on the same side of the body. (Ipsi means “same.”) If we say that the olfactory bulb sends axons to the ipsilateral hemisphere, we mean that the left olfactory bulb sends axons to the left hemisphere and the right olfactory bulb sends axons to the right hemisphere. Contralateral refers to structures on opposite sides of the body. If we say that a particular region of the left cerebral cortex controls movements of the contralateral hand, we mean that the region controls movements of the right hand.

ventral “Toward the belly”; with respect to the central nervous system, in a direction perpendicular to the neuraxis toward the bottom of the skull or the front surface of the body. lateral Toward the side of the body, away from the middle. medial Toward the middle of the body, away from the side. ipsilateral Located on the same side of the body. contralateral Located on the opposite side of the body.

Caudal or posterior Caudal or posterior F I G U R E 1 Views of Alligator and Human. These side and frontal views show the terms used to denote anatomical directions.

Structure of the Nervous System

Dorsal

Transverse plane (frontal section) Horizontal plane

Sagittal plane Ventral

Caudal

Rostral

Ventral

Transverse plane (cross section)

Dorsal Rostral

Caudal

Ventral FIGURE

Brain Slices and Planes. Planes of section as they pertain to the human central nervous system.

To see what is in the nervous system, we have to cut it open; to be able to convey information about what we find, we slice it in a standard way. Figure 2 shows a human nervous system. We can slice the nervous system in three ways: 1. Transversely, like a salami, giving us cross sections (also known as frontal sections when referring to the brain) 2. Parallel to the ground, giving us horizontal sections 3. Perpendicular to the ground and parallel to the neuraxis, giving us sagittal sections. The midsagittal plane divides the brain into two symmetrical halves. The sagittal section in Figure 2 lies in the midsagittal plane. Note that because of our upright posture, cross sections of the spinal cord are parallel to the ground. (See Figure 2.)

An Overview The nervous system consists of the brain and spinal cord, which make up the central nervous system (CNS), and the cranial nerves, spinal nerves, and peripheral ganglia, which constitute the peripheral nervous system (PNS). The CNS is encased in bone: The brain is covered by the skull, and the spinal cord is encased by the vertebral column. (See Table 1.) TABLE

1 The Major Divisions of the Nervous System

Central Nervous System (CNS)

Peripheral Nervous System (PNS)

Brain

Nerves

Spinal cord

Peripheral ganglia

cross section With respect to the central nervous system, a slice taken at right angles to the neuraxis. frontal section A slice through the brain parallel to the forehead. horizontal section A slice through the brain parallel to the ground. sagittal section (sadj i tul) A slice through the brain parallel to the neuraxis and perpendicular to the ground. midsagittal plane The plane through the neuraxis perpendicular to the ground; divides the brain into two symmetrical halves.

Structure of the Nervous System

Meninges Dura mater Arachnoid membrane

Opening cut in meninges to show brain

Layers of meninges

Central Nervous System:

Subarachnoid space (filled with cerebrospinal fluid) Arachnoid trabeculae

Cranial nerves

Brain

Pia mater

Spinal cord (b) Surface of brain

Spinal nerves

Spinal cord Pia mater (adheres to spinal cord) Spinal nerve Arachnoid membrane

Lung

Ribs

Dura mater Kidney Vertebra Cauda equina Edge of dura mater (cut open) Spinal nerves

(c)

(a) F I G U R E 3 The Nervous System. The figures show (a) the relation of the nervous system to the rest of the body, (b) detail of the meninges that cover the central nervous system, and (c) a closer view of the lower spinal cord and cauda equina.

Figure 3 shows the relation of the brain and spinal cord to the rest of the body. Do not be concerned with unfamiliar labels on this figure; these structures will be described later. (See Figure 3.) The brain is a large mass of neurons, glia, and other supporting cells. It is the most protected organ of the body, encased in a tough, bony skull and floating in a pool of cerebrospinal fluid. The brain receives a copious supply of blood and is chemically guarded by the blood–brain barrier.

Structure of the Nervous System

Meninges The entire nervous system—brain, spinal cord, cranial and spinal nerves, and peripheral ganglia—is covered by tough connective tissue. The protective sheaths around the brain and spinal cord are referred to as the meninges (singular: meninx, the Greek word for “membrane”). The meninges consist of three layers, which are shown in Figure 3. The outer layer is thick, tough, and flexible but unstretchable; its name, dura mater, means “hard mother.” The middle layer of the meninges, the arachnoid membrane, gets its name from the weblike appearance of the arachnoid trabeculae that protrude from it (from the Greek arachne, meaning “spider”; trabecula means “track”). The arachnoid membrane, soft and spongy, lies beneath the dura mater. Closely attached to the brain and spinal cord, and following every surface convolution, is the pia mater (“pious mother”). The smaller surface blood vessels of the brain and spinal cord are contained within this layer. Between the pia mater and the arachnoid membrane is a gap called the subarachnoid space. This space is filled with a liquid called cerebrospinal fluid (CSF). (See Figure 3.) The peripheral nervous system (PNS) is covered with two layers of meninges. The middle layer (arachnoid membrane), with its associated pool of CSF, covers only the brain and spinal cord. Outside the central nervous system, the outer and inner layers (dura mater and pia mater) fuse and form a sheath that covers the spinal and cranial nerves and the peripheral ganglia.

The Ventricular System and Production of Cerebrospinal Fluid The brain is very soft and jellylike. The considerable weight of a human brain (approximately 1400g), along with its delicate construction, necessitates that it be protected from shock. Fortunately, the brain is well protected. It floats in a bath of CSF contained within the subarachnoid space. Because the brain is completely immersed in liquid, its net weight is reduced to approximately 80 g; thus, pressure on the base of the brain is considerably diminished. The CSF surrounding the brain and spinal cord also reduces the shock to the central nervous system that would be caused by sudden head movement. The brain contains a series of hollow, interconnected chambers called ventricles (“little bellies”), which are filled with CSF. (See Figure 4.) The largest chambers are the two lateral ventricles, which are connected to the third ventricle. The third ventricle is located at the midline of the brain; its walls divide the surrounding part of the brain into symmetrical halves. A bridge of neural tissue called the massa intermedia crosses through the middle of the third ventricle and serves as a convenient reference point. The cerebral aqueduct, a long tube, connects the third ventricle to the fourth ventricle. The lateral ventricles constitute the first and second ventricles, but they are never referred to as such. (See Figure 4.) Cerebrospinal fluid is extracted from the blood and resembles blood plasma in its composition. It is manufactured by special tissue with an especially rich blood supply called the choroid plexus, which protrudes into all four of the ventricles. CSF is produced continuously; the total volume of CSF is approximately 125 ml, and the half-life (the time it takes for half of the CSF present in the ventricular system to be replaced by fresh fluid) is about 3 hours. Therefore, several times this amount is produced by the choroid plexus each day. Cerebrospinal fluid is produced by the choroid plexus of the lateral ventricles and flows into the third ventricle. More CSF is produced by the choroid plexus located in this ventricle, which then flows through the cerebral aqueduct to the fourth ventricle, where still more CSF is produced. The CSF leaves the fourth ventricle through small openings that connect with the subarachnoid space surrounding the brain. The CSF then flows through the subarachnoid space around the central nervous system, where it is reabsorbed into the blood supply.

meninges (singular: meninx) (men in jees) The three layers of tissue that encase the central nervous system: the dura mater, arachnoid membrane, and pia mater. dura mater The outermost of the meninges; tough and flexible. arachnoid membrane (a rak noyd) The middle layer of the meninges, located between the outer dura mater and inner pia mater. pia mater The layer of the meninges that clings to the surface of the brain; thin and delicate. subarachnoid space The fluid-filled space that cushions the brain; located between the arachnoid membrane and the pia mater. cerebrospinal fluid (CSF) A clear fluid, similar to blood plasma, that fills the ventricular system of the brain and the subarachnoid space surrounding the brain and spinal cord. ventricle (ven trik ul) One of the hollow spaces within the brain, filled with cerebrospinal fluid. lateral ventricle One of the two ventricles located in the center of the telencephalon. third ventricle The ventricle located in the center of the diencephalon. cerebral aqueduct A narrow tube interconnecting the third and fourth ventricles of the brain, located in the center of the mesencephalon. fourth ventricle The ventricle located between the cerebellum and the dorsal pons, in the center of the metencephalon. choroid plexus The highly vascular tissue that protrudes into the ventricles and produces cerebrospinal fluid.

Structure of the Nervous System

Lateral ventricle

Third ventricle Massa intermedia Cerebral aqueduct

Fourth ventricle

Fourth ventricle (b)

(a)

Third ventricle

Cerebral aqueduct

Arachnoid granulation

Choroid plexus of lateral ventricle

Lateral ventricle

Fourth ventricle

Superior sagittal sinus Choroid plexus of third ventricle Cerebral aqueduct

Subarachnoid space Third ventricle Cerebral aqueduct (c) FIGURE

Subarachnoid space

Choroid plexus of fourth ventricle

Opening into subarachnoid space

(d)

The Ventricular System of the Brain. The figure shows (a) a lateral view of the brain, (b) a frontal view, (c) a dorsal view, and (d) a midsagittal view.

SECTION SUMMARY Basic Features of the Nervous System Anatomists have adopted a set of terms to describe the locations of parts of the body. Anterior is toward the head, posterior is toward the tail, lateral is toward the side, medial is toward the middle, dorsal is toward the back, and ventral is toward the front surface of the body. In the special case of the nervous system, rostral means toward the beak (or nose), and caudal means toward the tail. Ipsilateral means “same side,” and contralateral means “other side.” A cross section (or, in the case of the brain, a frontal section) slices the nervous system at right angles to the neuraxis, a horizontal section slices the brain parallel to the ground, and a sagittal section slices it perpendicular to the ground, parallel to the neuraxis.

The central nervous system (CNS) consists of the brain and spinal cord, and the peripheral nervous system (PNS) consists of the spinal and cranial nerves and peripheral ganglia. The CNS is covered with the meninges: dura mater, arachnoid membrane, and pia mater. The space under the arachnoid membrane is filled with cerebrospinal fluid (CSF), in which the brain floats. The PNS is covered with only the dura mater and pia mater. CSF is produced in the choroid plexus of the lateral, third, and fourth ventricles. It flows from the two lateral ventricles into the third ventricle, through the cerebral aqueduct into the fourth ventricle, then into the subarachnoid space, and finally back into the blood supply.

The Central Nervous System Although the brain is exceedingly complicated, an understanding of the basic features of brain development makes it easier to learn and remember the location of the most important structures. With that end in mind, I introduce these features here in the context of development of the central nervous system.

Structure of the Nervous System

Development of the Central Nervous System The central nervous system begins early in embryonic life as a hollow tube, and it maintains this basic shape even after it is fully developed. During development, parts of the tube elongate, pockets and folds form, and the tissue around the tube thickens until the brain reaches its final form. AN OVERVIEW OF BRAIN DEVELOPMENT Development of the human nervous system begins around the eighteenth day after conception. Part of the ectoderm (outer layer) of the back of the embryo thickens and forms a plate. The edges of this plate form ridges that curl toward each other along a longitudinal line, running in a rostral–caudal direction. By the twenty-first day these ridges touch each other and fuse together, forming a tube—the neural tube—that gives rise to the brain and spinal cord. By the twenty-eighth day of development the neural tube is closed, and its rostral end has developed three interconnected chambers. These chambers become ventricles, and the tissue that surrounds them becomes the three major parts of the brain: the forebrain, the midbrain, and the hindbrain. (See Figures 5a and 5c.) As development progresses, the rostral chamber (the forebrain) divides into three separate parts, which become the two lateral ventricles and the third ventricle. The region around the lateral ventricles becomes the telencephalon (“end brain”), and the region around the third ventricle becomes the diencephalon (“interbrain”). (See Figures 5b and 5d.) In its final form, the chamber inside the midbrain (mesencephalon) becomes narrow, forming the cerebral aqueduct, and two structures develop in the hindbrain: the metencephalon (“afterbrain”) and the myelencephalon (“marrowbrain”). (See Figure 5e.) Table 2 summarizes the terms I have introduced here and mentions some of the major structures found in each part of the brain. The colors in the table match those in Figure 5. These structures will be described in the remainder of the chapter, in the order in which they are listed in Table 2. (See Table 2.) PRENATAL BRAIN DEVELOPMENT Brain development begins with a thin tube and ends with a structure weighing approximately 1400 g (about 3 lb) and consisting of several hundreds of billions of cells. Where do these cells come from, and what controls their growth? Let’s consider the development of the cerebral cortex, about which most is known. The principles described here are similar to the ones that apply to development of other regions of the brain. (For details of this process, see Cooper, 2008, and Rakic, 2009.) Cortex means “bark,” and the cerebral cortex, approximately 3 mm thick, surrounds the cerebral hemispheres like the bark of a tree. Corrected for body size, the cerebral cortex is larger in humans than in any other species. Circuits of neurons in the cerebral cortex play a vital role in perception, cognition, and the control of movement. Stem cells that line the inside of the neural tube give rise to the cells of the central nervous system. The cerebral cortex develops from the inside out. That is, the first cells to be produced migrate a short distance and establish the first—and deepest—layer. The next wave of newborn cells passes through the first layer and forms the second one—and so on, until all six layers of the cerebral cortex are laid down. The last cells to be produced must pass through all the ones born before them. The stem cells that give rise to the cells of the brain are known as progenitor cells. (A progenitor is a direct ancestor of a line of descendants.) During the first phase of development, progenitor cells in the ventricular zone (VZ), located just outside the wall of the neural tube, divide, making new progenitor cells and increasing the size of the ventricular zone. This phase is referred to as symmetrical division, because the division of each progenitor cell produces two new progenitor cells. Then, seven weeks after conception, progenitor cells receive a signal to begin a period of asymmetrical division. During this phase, progenitor cells form two different kinds of cells as they divide: another progenitor cell and a brain cell. The first brain cells produced through asymmetrical division are radial glia. The cell bodies of radial glia remain in the ventricular zone, but they extend fibers radially outward from the ventricular zone, like spokes in a wheel. These fibers end in cuplike feet that attach to the pia mater, located at the outer surface of what becomes the cerebral cortex. As the cortex becomes

neural tube A hollow tube, closed at the rostral end, that forms from ectodermal tissue early in embryonic development; serves as the origin of the central nervous system. cerebral cortex The outermost layer of gray matter of the cerebral hemispheres. progenitor cells Cells of the ventricular zone that divide and give rise to cells of the central nervous system. ventricular zone (VZ) A layer of cells that line the inside of the neural tube; contains progenitor cells that divide and give rise to cells of the central nervous system. symmetrical division Division of a progenitor cell that gives rise to two identical progenitor cells; increases the size of the ventricular zone and hence the brain that develops from it. asymmetrical division Division of a progenitor cell that gives rise to another progenitor cell and a neuron, which migrates away from the ventricular zone toward its final resting place in the brain. radial glia Special glia with fibers that grow radially outward from the ventricular zone to the surface of the cortex; provide guidance for neurons migrating outward during brain development.

Structure of the Nervous System

Forebrain

Midbrain Hindbrain

Telencephalon Mesencephalon

Cerebral hemisphere

Metencephalon

Thalamus

Rostral

Myelencephalon

Caudal (a)

Diencephalon Hypothalamus (b)

Dorsal

Pituitary gland

Basal Thalamus ganglia Tectum Cerebellum Medulla

Cerebral cortex

Brain Stem

Midbrain Pons Medulla

Cerebellum

Spinal cord (e)

Ventral (c) Hypothalamus

Tegmentum

Spinal Pons cord

(d) F I G U R E 5 Brain Development. This schematic outline of brain development shows its relation to the ventricles. Views (a) and (c) show early development. Views (b) and (d) show later development. View (e) shows a lateral view of the left side of a semitransparent human brain with the brain stem “ghosted in.” The colors of all figures denote corresponding regions.

thicker, the fibers of the radial glia grow longer and maintain their connections with the pia mater. (See Figure 6.) The period of asymmetrical division lasts about three months. Because the human cerebral cortex contains about 100 billion neurons, there are about one billion neurons migrating along radial glial fibers on a given day. The migration path of the earliest neurons is the shortest and takes about one day. The neurons that produce the last, outermost layer have to pass through five layers of neurons, and their migration takes about two weeks. The end of cortical development occurs when the progenitor cells receive a chemical signal that causes them to die—a phenomenon known as apoptosis (literally, a “falling away”). Molecules of the chemical that conveys this signal bind with receptors that activate killer genes within the cells. (All cells have these genes, but only certain cells possess the receptors that respond to the chemical signals that turn them on.) At this time, some radial glia appear to undergo apoptosis, but many are transformed into astrocytes or neurons. Once neurons have migrated to their final locations, they begin forming connections with other neurons. They grow dendrites, which receive the terminal buttons from the axons of other neurons, and they grow axons of their own. Some neurons extend their dendrites and axons laterally, connecting adjacent columns of neurons or even establishing connections with other neurons in distant regions of the brain. TABLE

2 Anatomical Subdivisions of the Brain

Major Division

Ventricle

Subdivision

Principal Structures Cerebral cortex

Lateral

Telencephalon

Forebrain

Limbic system Third

Midbrain apoptosis (ay po toe sis) Death of a cell caused by a chemical signal that activates a genetic mechanism inside the cell.

Basal ganglia

Cerebral aqueduct Fourth

Diencephalon Mesencephalon

Metencephalon

Hindbrain Myelencephalon

Thalamus Hypothalamus Tectum Tegmentum Cerebellum Pons Medulla oblongata

Structure of the Nervous System

6 Cortex

5 Pia mater 4

2 Migrating neuron 1

Radial glial fiber

1 Radial glial cell Ventricular zone

Early

Late

F I G U R E 6 Cortical Development. This cross section through the cerebral cortex shows the area early in its development. The radially oriented fibers of glial cells help to guide the migration of newly formed neurons from the ventricular zone to their final resting place in the cerebral cortex. Each successive wave of neurons passes neurons that migrated earlier, so the most recently formed neurons occupy layers closer to the cortical surface. Based on Rakic, P., A Small Step for the cell, a giant leap for mankind: A hypothesis of necortical expansion during evolution. Trends in Neuroscience, 1995, 18, 383–388.

During development, thousands of different pathways—groups of axons that connect one brain region with another—develop in the brain. Within many of these pathways the connections are orderly and systematic. For example, the axons of sensory neurons from the skin form orderly connections in the brain; axons from the little finger form synapses in one region, those of the ring finger form synapses in a neighboring region, and so on. In fact, the surface of the body is neurogenesis The production of new “mapped” on the brain’s surface. Similarly, the surface of the retina of the eye is “mapped” on neurons within the brain. another region of the brain’s surface. For many years, researchers have believed that neurogenesis— production of new neurons—cannot take place in the fully developed brain. However, more recent studies have shown this belief to be incorrect—the adult brain contains some stem cells (similar to the progenitor cells that give rise to the cells of the developing brain) that can divide and produce neurons. Detection of newly produced cells is done by administering a small amount of a radioactive form of one of This figure is intentionally omitted from this text. the nucleotide bases that cells use to produce the DNA that is needed for neurogenesis. The next day, the animals’ brains are removed and examined. Such studies have found evidence for neurogenesis in just two parts of the adult brain: the hippocampus, primarily involved in learning, and the olfactory bulb, involved in the sense of smell (Doetsch and Hen, 2005). Evidence indicates that exposure to new odors can increase the survival rate of new neurons in the olfactory bulbs, and training on a learning task can enhance neurogenesis in the hippocampus.

Structure of the Nervous System

In addition, depression or exposure to stress can suppress neurogenesis in the hippocampus, and drugs that reduce stress and depression can reinstate neurogenesis. Unfortunately, there is no evidence so far that indicates that growth of new neurons can repair the effects of brain damage, such as that caused by head injury or strokes.

The Forebrain As we saw, the forebrain surrounds the rostral end of the neural tube. Its two major components are the telencephalon and the diencephalon. TELENCEPHALON The telencephalon includes most of the two symmetrical cerebral hemispheres that make up the cerebrum. The cerebral hemispheres are covered by the cerebral cortex and contain the limbic system and the basal ganglia. The latter two sets of structures are primarily in the subcortical regions of the brain—those located deep within it, beneath the cerebral cortex.

forebrain The most rostral of the three major divisions of the brain; includes the telencephalon and diencephalon. cerebral hemisphere (sa ree brul) One of the two major portions of the forebrain, covered by the cerebral cortex. subcortical region The region located within the brain, beneath the cortical surface. sulcus (plural: sulci) (sul kus, sul sigh) A groove, smaller than a fissure, in the surface of the cerebral hemisphere. fissure A major groove in the surface of the brain; it is larger than a sulcus. gyrus (plural: gyri) (jye russ, jye rye) A convolution of the cortex of the cerebral hemispheres, separated by sulci or fissures. primary visual cortex The region of the posterior occipital lobe whose primary input is from the visual system.

Cerebral Cortex As we saw, cortex means “bark,” and the cerebral cortex surrounds the cerebral hemispheres like the bark of a tree. In humans the cerebral cortex is greatly convoluted. These convolutions, consisting of sulci (small grooves), fissures (large grooves), and gyri (bulges between adjacent sulci or fissures), greatly enlarge the surface area of the cortex, compared with a smooth brain of the same size. In fact, two-thirds of the surface of the cortex is hidden in the grooves; thus, the presence of gyri and sulci triples the area of the cerebral cortex. The total surface area is approximately 2360 cm2 (2.5 ft2), and the thickness is approximately 3 mm. The cerebral cortex consists mostly of glia and the cell bodies, dendrites, and interconnecting axons of neurons. Because cells predominate, the cerebral cortex has a grayish tan appearance, and is called gray matter. (See Figure 8.) Millions of axons run beneath the cerebral cortex and connect its neurons with those located elsewhere in the brain. The large concentration of myelin around these axons gives this tissue an opaque white appearance—hence the term white matter. Different regions of the cerebral cortex perform different functions. Three regions receive information from the sensory organs. The primary visual cortex, which receives visual information, is located at the back of the brain, on the inner surfaces of the cerebral hemispheres—primarily on the upper and lower banks of the calcarine fissure. (Calcarine means “spur-shaped.” See Figure 9.) The primary auditory cortex, which receives auditory information, is located on the upper surface of a deep fissure in the side of the brain—the lateral fissure. (See inset, Figure 9.) The primary somatosensory cortex, a vertical strip of cortex just caudal to the central sulcus, receives information Dorsal White matter

Cerebral cortex (gray matter) Gyrus

Sulcus

calcarine fissure (kal ka rine) A fissure located in the occipital lobe on the medial surface of the brain; most of the primary visual cortex is located along its upper and lower banks. primary auditory cortex The region of the superior temporal lobe whose primary input is from the auditory system. lateral fissure The fissure that separates the temporal lobe from the overlying frontal and parietal lobes. primary somatosensory cortex The region of the anterior parietal lobe whose primary input is from the somatosensory system. central sulcus (sul kus) The sulcus that separates the frontal lobe from the parietal lobe.

Fissure

Ventral F I G U R E 8 Cross Section of the Human Brain. The brain slice shows fissures and gyri and the layer of cerebral cortex that follows these convolutions.

Structure of the Nervous System

from the body senses. As Figure 9 shows, different regions of the primary somatosensory cortex receive information from different regions of the body. In addition, the base of the somatosensory cortex receives information concerning taste. (Look again at Figure 9.) With the exception of olfaction and gustation (taste), sensory information from the body or the environment is sent to the primary sensory cortex of the contralateral hemisphere. Thus, the primary somatosensory cortex of the left hemisphere learns what the right hand is holding, the left primary visual cortex learns what is happening toward the person’s right, and so on. The region of the cerebral cortex that is most directly involved in the control of movement is the primary motor cortex, located just in front of the primary somatosensory cortex. Neurons in different parts of the primary motor cortex are connected to muscles in different parts of the body. The connections, like those of the sensory regions of the cerebral cortex, are contralateral; the left primary motor cortex controls the right side of the body and vice versa. Thus, if a surgeon places an electrode on the surface of the primary motor cortex and stimulates the neurons there with a weak electrical current, the result will be movement of a particular part of the body. Moving the electrode to a different spot will cause a different part of the body to move. (Look again at Figure 9.) I like to think of the strip of primary motor cortex as the keyboard of a piano, with each key controlling a different movement. (We will see shortly who the “player” of this piano is.) The regions of primary sensory and motor cortex occupy only a small part of the cerebral cortex. The rest of the cerebral cortex accomplishes what is done between sensation and action: perceiving, learning and remembering, planning, and acting. These processes take place in the association areas of the cerebral cortex. The central sulcus provides an important dividing line between the rostral and caudal regions of the cerebral cortex. (Look once more at Figure 9.) The rostral region is involved in movement-related activities, such as planning and executing behaviors. The caudal region is involved in perceiving and learning. Discussing the various regions of the cerebral cortex is easier if we have names for them. In fact, the cerebral cortex is divided into four areas, or lobes, named for the bones of the skull that cover them: the frontal lobe, parietal lobe, temporal lobe, and occipital lobe. Of course, the brain contains two of each lobe, one in each hemisphere. The frontal lobe (the “front”) includes everything in front of the central sulcus. The parietal lobe (the “wall”) is located on the side of the cerebral hemisphere,

Insular cortex

Primary auditory cortex

primary motor cortex The region of the posterior frontal lobe that contains neurons that control movements of skeletal muscles. frontal lobe The anterior portion of the cerebral cortex, rostral to the parietal lobe and dorsal to the temporal lobe. parietal lobe (pa rye i tul) The region of the cerebral cortex caudal to the frontal lobe and dorsal to the temporal lobe. Primary somatosensory cortex

Primary motor cortex

Right Hemisphere

Central sulcus

Calcarine fissure

Feet Feet Trunk Trunk Hands

Fi Fingers

Hands Fingers

Face Face Lips Lips Portion of Left Hemisphere Primary visual cortex Lateral fissure

Primary auditory cortex

Left Hemisphere

F I G U R E 9 The Primary Sensory Regions of the Brain. The figure shows a lateral view of the left hemisphere of the brain and part of the inner surface of the right hemisphere. The inset shows a cutaway of part of the frontal lobe of the left hemisphere, permitting us to see the primary auditory cortex on the dorsal surface of the temporal lobe, which forms the ventral bank of the lateral fissure.

Structure of the Nervous System

temporal lobe (tem por ul) The region of the cerebral cortex rostral to the occipital lobe and ventral to the parietal and frontal lobes. occipital lobe (ok sip i tul) The region of the cerebral cortex caudal to the parietal and temporal lobes. sensory association cortex Those regions of the cerebral cortex that receive information from the regions of primary sensory cortex. motor association cortex The region of the frontal lobe rostral to the primary motor cortex; also known as the premotor cortex. prefrontal cortex The region of the frontal lobe rostral to the motor association cortex. corpus callosum (ka loh sum) A large bundle of axons that interconnects corresponding regions of the association cortex on each side of the brain. neocortex The phylogenetically newest cortex, including the primary sensory cortex, primary motor cortex, and association cortex. limbic cortex Phylogenetically old cortex, located at the medial edge (“limbus”) of the cerebral hemispheres; part of the limbic system. cingulate gyrus (sing yew lett) A strip of limbic cortex lying along the lateral walls of the groove separating the cerebral hemispheres, just above the corpus callosum.

just behind the central sulcus, caudal to the frontal lobe. The temporal lobe (the “temple”) juts forward from the base of the brain, ventral to the frontal and parietal lobes. The occipital lobe (from the Latin ob, “in back of,” and caput, “head”) lies at the very back of the brain, caudal to the parietal and temporal lobes. Figure 10 shows these lobes in three views of the cerebral hemispheres: a ventral view (a view from the bottom), a midsagittal view (a view of the inner surface of the right hemisphere after the left hemisphere has been removed), and a lateral view. (See Figure 10.) Each primary sensory area of the cerebral cortex sends information to adjacent regions, called the sensory association cortex. Circuits of neurons in the sensory association cortex analyze the information received from the primary sensory cortex; perception takes place there, and memories are stored there. The regions of the sensory association cortex located closest to the primary sensory areas receive information from only one sensory system. For example, the region closest to the primary visual cortex analyzes visual information and stores visual memories. Regions of the sensory association cortex located far from the primary sensory areas receive information from more than one sensory system; thus, they are involved in several kinds of perceptions and memories. These regions make it possible to integrate information from more than one sensory system. For example, we can learn the connection between the sight of a particular face and the sound of a particular voice. (Look again at Figure 10.) If people sustain damage to the somatosensory association cortex, their deficits are related to somatosensation and to the environment in general; for example, they may have difficulty perceiving the shapes of objects that they can touch but not see, they may be unable to name parts of their bodies (see the following case), or they may have trouble drawing maps or following them. Destruction of the primary visual cortex causes blindness. However, although people who sustain damage to the visual association cortex will not become blind, they may be unable to recognize objects by sight. People who sustain damage to the auditory association cortex may have difficulty perceiving speech or even producing meaningful speech of their own. People who sustain damage to regions of the association cortex at the junction of the three posterior lobes, where the somatosensory, visual, and auditory functions overlap, may have difficulty reading or writing. Just as regions of the sensory association cortex of the posterior part of the brain are involved in perceiving and remembering, the frontal association cortex is involved in the planning and

Mr. M., a city bus driver, stopped to let a passenger climb aboard. The passenger asked him a question, and Mr. M. suddenly realized that he didn’t understand what she was saying. He could hear her, but her words made no sense. He opened his mouth to reply. He made some sounds, but the look on the woman’s face told him that she couldn’t understand what he was trying to say. He turned off the engine and looked around at the passengers and tried to tell them to get some help. Although he was unable to say anything, they understood that something was wrong, and one of them called an ambulance. An MRI scan showed that Mr. M. had sustained an intracerebral hemorrhage—a kind of stroke caused by rupture of blood vessels in the brain. The stroke had damaged his left parietal lobe. Mr. M. gradually regained the ability to talk and understand the speech of others, but some deficits remained. A colleague, Dr. D., and I studied Mr. M. several weeks after his stroke. The dialogue went something like this: “Show me your hand.” “My hand . . . my hand.” Looks at his arms, then touches his left forearm. “Show me your chin.” “My chin.” Looks at his arms, looks down, puts his hand on his abdomen. “Show me your right elbow.” “My right . . .” (points to the right with his right thumb) “elbow.” Looks up and down his right arm, finally touches his right shoulder. As you can see, Mr. M. could understand that we were asking him to point out parts of his body and could repeat the names of the body parts when we spoke them, but he could not identify which body parts these names referred to. This strange deficit, which sometimes follows damage to the left parietal lobe, is called autotopagnosia, or “poor knowledge of one’s own topography.” (A better term would be autotopanomia, or “poor knowledge of the names of one’s own topography,” but, then, no one asked me to choose the term.) The parietal lobes are involved with space: the right primarily with external space and the left with one’s body and personal space.

Structure of the Nervous System

Cross section through midbrain

Temporal Lobe

Limbic cortex

Frontal Lobe

Occipital Lobe

(a) Cingulate gyrus (limbic cortex)

Parietal Lobe

Frontal Lobe

Occipital Lobe Temporal Lobe

Primary auditory cortex (mostly hidden from view)

(b)

Primary Primary motor cortex somatosensory cortex Parietal Lobe Primary visual Somatosensory cortex association cortex

motor cor tex Pre

Frontal Lobe

ntal cor tex efro Pr

execution of movements. The motor association cortex (also known as the premotor cortex) is located just rostral to the primary motor cortex. This region controls the primary motor cortex; thus, it directly controls behavior. If the primary motor cortex is the keyboard of the piano, then the motor association cortex is the piano player. The rest of the frontal lobe, rostral to the motor association cortex, is known as the prefrontal cortex. This region of the brain is less involved with the control of movement and more involved in formulating plans and strategies. Although the two cerebral hemispheres cooperate with each other, they do not perform identical functions. Some functions are lateralized— located primarily on one side of the brain. In general, the left hemisphere participates in the analysis of information—the extraction of the elements that make up the whole of an experience. This ability makes the left hemisphere particularly good at recognizing serial events—events whose elements occur one after the other—and controlling sequences of behavior. (In a few people the functions of the left and right hemispheres are reversed.) The serial functions that are performed by the left hemisphere include verbal activities, such as talking, understanding the speech of other people, reading, and writing. These abilities are disrupted by damage to the various regions of the left hemisphere. In contrast, the right hemisphere is specialized for synthesis; it is particularly good at putting isolated elements together to perceive things as a whole. For example, our ability to draw sketches (especially of three-dimensional objects), read maps, and construct complex objects out of smaller elements depends heavily on circuits of neurons that are located in the right hemisphere. Damage to the right hemisphere disrupts these abilities. We are not aware of the fact that each hemisphere perceives the world differently. Although the two cerebral hemispheres perform somewhat different functions, our perceptions and our memories are unified. This unity is accomplished by the corpus callosum, a large band of axons that connects corresponding parts of the association cortex of the left and right hemispheres: The left and right temporal lobes are connected, the left and right parietal lobes are connected, and so on. Because of the corpus callosum, each region of the association cortex knows what is happening in the corresponding region of the opposite side of the brain. The corpus callosum also makes a few asymmetrical connections that link different regions of the two hemispheres. Figure 11 shows the bundles of axons that constitute the corpus callosum, obtained by means of diffusion tensor imaging, a special scanning method. (See Figure 11.) Figure 12 shows a midsagittal view of the brain. The brain (and part of the spinal cord) has been sliced down the middle, dividing it into its two symmetrical halves. The left half has been removed, so we see the inner surface of the right half. The cerebral cortex that covers most of the surface of the cerebral hemispheres (including the frontal, parietal, occipital, and temporal lobes) is called the neocortex (“new” cortex, because it is of relatively recent evolutionary origin). Another form of cerebral cortex, the limbic cortex, is located around the medial edge of the cerebral hemispheres (limbus means “border”). The cingulate gyrus, an important region of the limbic cortex, can be seen in this figure. (See Figure 12.) In addition, if you look back at Figures 10a and 10b, you will see that the limbic cortex occupies the regions that have not been colored in. (Refer to Figures 10a and 10b.) Figure 12 also shows the corpus callosum. To slice the brain into its two symmetrical halves, one must slice through the middle of the corpus callosum. (See Figure 12.)

r dito Au

ocia a ss

ua Vis

co tion

so c l as

r tex

n co iatio

Visual association cortex

r tex

Occipital Lobe Temporal Lobe (c)

Rostral

Caudal

F I G U R E 10 The Four Lobes of the Cerebral Cortex. This figure shows the location of the four lobes, the primary sensory and motor areas, and the association areas of the cerebral cortex. (a) Ventral view, from the base of the brain. (b) Midsagittal view, with the cerebellum and brain stem removed. (c) Lateral view.

Structure of the Nervous System

F I G U R E 11 Bundles of Axons in the Corpus Callosum. This figure, obtained by means of diffusion tensor imaging, shows bundles of axons in the corpus callosum that serve different regions of the cerebral cortex that constitute the corpus callosum.

Limbic System A neuroanatomist, Papez (1937), suggested that a set of interconnected brain structures formed a circuit whose primary function was motivation and emotion. This system included several regions of the limbic cortex (already described) and a set of interconnected structures surrounding the core of the forebrain. A physiologist, MacLean (1949), expanded the system to include other structures and coined the term limbic system. Besides the limbic cortex, the most important parts of the limbic system are the hippocampus (“sea horse”) and the amygdala (“almond”), located next to the lateral ventricle in the temporal lobe. The fornix (“arch”) is a bundle of axons that connects the hippocampus with other regions of the brain, including the mammillary (“breast-shaped”) bodies, protrusions on the base of the brain that contain parts of the hypothalamus. (See Figure 13.) MacLean noted that the evolution of this system, which includes the first and simplest form of cerebral cortex, appears to have coincided with the development of emotional responses. We now know that parts of the limbic system (notably, the hippocampal formation and the region of limbic cortex that surrounds it) are involved in learning and memory. The amygdala and some regions of the limbic cortex are specifically involved in emotions: feelings and expressions of emotions, emotional memories, and recognition of the signs of emotions in other people.

Basal Ganglia The basal ganglia are a collection of subcortical nuclei in the forebrain, which lie beneath the anterior portion of the lateral ventricles. Nuclei are NeuroImage, 32, Hofer, S., and Frahm, J., Topography of the Human groups of neurons of similar shape. (The word nucleus, from the Greek word for Corpus Callosum Revisited—Comprehensive Fiber Tractography “nut,” can refer to the inner portion of an atom, to the structure of a cell that contains Using Diffusion Tensor Magnetic Resonance Imaging, 989–994, the chromosomes, and—as in this case—to a collection of neurons located within the Copyright 2006, with permission from Elsevier. brain.) The major parts of the basal ganglia are the caudate nucleus, the putamen, and the globus pallidus (the “nucleus with a tail,” the “shell,” and the “pale globe”). (See Figure 14). The basal ganglia are involved in the control of movement. For example, Parkinson’s disease is caused by degeneration of certain neurons located in the midbrain that send axons to the caudate nucleus and the putamen. The symptoms of this disease are weakness, tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements.

limbic system A group of brain regions including the anterior thalamic nuclei, amygdala, hippocampus, limbic cortex, and parts of the hypothalamus, as well as their interconnecting fiber bundles.

Cingulate gyrus (region of limbic cortex)

hippocampus A forebrain structure of the medial temporal lobe, constituting an important part of the limbic system; involved in learning and memory.

Scalp

Skull

Choroid plexus

Massa intermedia

Layers of meninges (includes blood vessels)

amygdala (a mig da la) A structure in the interior of the rostral temporal lobe, containing a set of nuclei; part of the limbic system.

Midbrain Tentorium Fourth ventricle

Pituitary gland

mammillary bodies (mam i lair ee) A protrusion of the bottom of the brain at the posterior end of the hypothalamus, containing some hypothalamic nuclei; part of the limbic system.

Pons Cerebellum Choroid plexus

basal ganglia A group of subcortical nuclei in the telencephalon, the caudate nucleus, the globus pallidus, and the putamen; important parts of the motor system.

Thalamus

Third ventricle

fornix A fiber bundle that connects the hippocampus with other parts of the brain, including the mammillary bodies of the hypothalamus; part of the limbic system.

nucleus (plural: nuclei) An identifiable group of neural cell bodies in the central nervous system.

Corpus callosum

Medulla Spinal cord FIGURE

A Midsagittal View of the Brain and Part of the Spinal Cord.

Structure of the Nervous System

Massa intermedia

Basal ganglia

Limbic cortex

Corpus callosum

Fornix

Mammillary body

Thalamus Hypothalamus

Amygdala Hippocampus Hippocampus of right hemisphere (ghosted in)

Cerebellum

F I G U R E 13 The Major Components of the Limbic System. All of the left hemisphere except for the limbic system has been removed.

Thalamus

F I G U R E 14 The Basal Ganglia and Diencephalon. The basal ganglia and diencephalon (thalamus and hypothalamus) are ghosted into a semitransparent brain.

DIENCEPHALON The second major division of the forebrain, the diencephalon, is situated between the telencephalon and the mesencephalon; it surrounds the third ventricle. Its two most important structures are the thalamus and the hypothalamus. (See Figure 15.) Thalamus. The thalamus (from the Greek thalamos, “inner chamber”) makes up the dorsal part of the diencephalon. It is situated near the middle of the cerebral hemispheres, immediately medial and caudal to the basal ganglia. The thalamus has two lobes, connected by a bridge of gray matter called the massa intermedia, which pierces the middle of the third ventricle. (Look again at Figure 15.) The massa intermedia is probably not an important structure, because it is absent in the brains of many people. However, it serves as a useful reference point in looking at diagrams of the brain; it appears in Figures 4, 12, 13, and 15. Most neural input to the cerebral cortex is received from the thalamus; indeed, much of the cortical surface can be divided into regions that receive projections from specific parts of the thalamus. Projection fibers are sets of axons that arise from cell bodies located in one region of the brain and synapse on neurons located within another region (that is, they project to these regions). The thalamus is divided into several nuclei. Some thalamic nuclei receive sensory information from the sensory systems. The neurons in these nuclei then relay the sensory information to specific sensory projection areas of the cerebral cortex. For example, the lateral geniculate nucleus receives information from the eye and sends axons to the primary visual cortex, and the medial geniculate nucleus receives information from the inner ear and sends axons to the primary auditory cortex. Other thalamic nuclei project to specific regions of the cerebral cortex, but they do not relay sensory information. For example, the ventrolateral nucleus receives information from the cerebellum and projects it to the primary motor cortex. And several nuclei are involved in controlling the general excitability of the cerebral cortex. To accomplish this task, these nuclei have widespread projections to all cortical regions. Hypothalamus. As its name implies, the hypothalamus lies at the base of the brain, under the thalamus. Although the hypothalamus is a relatively small structure, it is an important one. It controls the autonomic nervous system and the endocrine system and organizes behaviors related to survival of the species—the so-called four F’s: fighting, feeding, fleeing, and mating. The hypothalamus, which is situated on both sides of the ventral portion of the third ventricle, is a complex structure containing many nuclei and fiber tracts. Figure 15 indicates its location and size. Note that the pituitary gland is attached to the base of the hypothalamus via the pituitary stalk. Just in front of the pituitary stalk is the optic chiasm, where half of the axons in the optic nerves (from the eyes) cross from one side of the brain to the other. (See Figure 15.)

diencephalon (dy en seff a lahn) A region of the forebrain surrounding the third ventricle; includes the thalamus and the hypothalamus. thalamus The largest portion of the diencephalon, located above the hypothalamus; contains nuclei that project information to specific regions of the cerebral cortex and receive information from it. projection fiber An axon of a neuron in one region of the brain whose terminals form synapses with neurons in another region. lateral geniculate nucleus A group of cell bodies within the lateral geniculate body of the thalamus that receives fibers from the retina and projects fibers to the primary visual cortex. medial geniculate nucleus A group of cell bodies within the medial geniculate body of the thalamus; receives fibers from the auditory system and projects fibers to the primary auditory cortex. ventrolateral nucleus A nucleus of the thalamus that receives inputs from the cerebellum and sends axons to the primary motor cortex. hypothalamus The group of nuclei of the diencephalon situated beneath the thalamus; involved in regulation of the autonomic nervous system, control of the anterior and posterior pituitary glands, and integration of species-typical behaviors. optic chiasm (kye az’m) An X-shaped connection between the optic nerves, located below the base of the brain, just anterior to the pituitary gland.

Structure of the Nervous System

Corpus callosum Fornix

Massa intermedia

Wall of third ventricle

anterior pituitary gland The anterior part of the pituitary gland; an endocrine gland whose secretions are controlled by the hypothalamic hormones. neurosecretory cell A neuron that secretes a hormone or hormonelike substance. posterior pituitary gland The posterior part of the pituitary gland; an endocrine gland that contains hormone-secreting terminal buttons of axons whose cell bodies lie within the hypothalamus.

Hypothalamic nuclei Optic chiasm

midbrain The mesencephalon; the central of the three major divisions of the brain.

Pituitary gland

Mammillary body

mesencephalon (mezz en seff a lahn) The midbrain; a region of the brain that surrounds the cerebral aqueduct; includes the tectum and the tegmentum.

F I G U R E 15 A Midsagittal View of Part of the Brain. This view shows some of the nuclei of the hypothalamus. The nuclei are situated on the far side of the wall of the third ventricle, inside the right hemisphere.

tectum The dorsal part of the midbrain; includes the superior and inferior colliculi.

Much of the endocrine system is controlled by hormones produced by cells in the hypothalamus. A special system of blood vessels directly connects the hypothalamus with the anterior pituitary gland. (See Figure 16.) The hypothalamic hormones are secreted by specialized neurons called neurosecretory cells, located near the base of the pituitary stalk. These hormones stimulate the anterior pituitary gland to secrete its hormones. For example, gonadotropin-releasing hormone causes the anterior pituitary gland to secrete the gonadotropic hormones, which play a role in reproductive physiology and behavior. Most of the hormones secreted by the anterior pituitary gland control other endocrine glands. Because of this function, the anterior pituitary gland has been called the body’s “master gland.” For example, the gonadotropic hormones stimulate the gonads (ovaries and testes) to release male or female sex hormones. These hormones affect cells throughout the body, including some in the brain. Two other anterior pituitary hormones—prolactin and somatotropic hormone (growth hormone)—do not control other glands but act as the final messenger. The posterior pituitary gland is in many ways an extension of the hypothalamus. The hypothalamus produces the posterior pituitary hormones and directly controls their secretion. These hormones include oxytocin, which stimulates ejection of milk and uterine contractions at the time of childbirth, and vasopressin, which regulates urine output by the kidneys. They are produced by two different sets of neurons in the hypothalamus whose axons travel down the pituitary stalk and terminate in the posterior pituitary gland. The hormones are carried in vesicles through the axoplasm of these neurons and collect in the terminal buttons in the posterior pituitary gland. When these axons fire, the hormone contained within their terminal buttons is liberated and enters the circulatory system.

superior colliculi (ka lik yew lee) Protrusions on top of the midbrain; part of the visual system. inferior colliculi Protrusions on top of the midbrain; part of the auditory system. brain stem The “stem” of the brain, from the medulla to the diencephalon, excluding the cerebellum.

The Midbrain The midbrain (also called the mesencephalon) surrounds the cerebral aqueduct and consists of two major parts: the tectum and the tegmentum.

Prolactin, a hormone produced by the anterior pituitary gland, stimulates milk production in a nursing mother. Oxytocin, a hormone released by the posterior pituitary gland, stimulates the ejection of milk when the baby sucks on a nipple. David Parker/Photo Researchers, Inc.

TECTUM The tectum (“roof”) is located in the dorsal portion of the mesencephalon. Its principal structures are the superior colliculi and the inferior colliculi, which appear as four bumps on the dorsal surface of the brain stem. The brain stem includes the

Structure of the Nervous System

Neurosecretory cells in the hypothalamus For posterior pituitary gland

For anterior pituitary gland

Mammillary body

Artery Pituitary stalk Anterior pituitary gland

Secretory cells; release anterior pituitary hormones

Capillary bed around terminals of neurosecretory cells; hypothalamic hormones released here Artery Posterior pituitary gland

Terminals release posterior pituitary hormones

F I G U R E 16 The Pituitary Gland. Hormones released by the neurosecretory cells in the hypothalamus enter capillaries and are conveyed to the anterior pituitary gland, where they control its secretion of hormones. The hormones of the posterior pituitary gland are produced in the hypothalamus and carried there in vesicles by means of axoplasmic transport.

diencephalon, midbrain, and hindbrain; it is so called because it looks just like that—a stem. Figure 17 shows several views of the brain stem: lateral and posterior views of the brain stem inside a semitransparent brain, an enlarged view of the brain stem with part of the cerebellum cut away to reveal the inside of the fourth ventricle, and a cross section through the midbrain. (See Figure 17.) The inferior colliculi are a part of the auditory system. The superior colliculi are part of the visual system. In mammals they are primarily involved in visual reflexes and reactions to moving stimuli. TEGMENTUM The tegmentum (“covering”) consists of the portion of the mesencephalon beneath the tectum. It includes the rostral end of the reticular formation, several nuclei controlling eye movements, the periaqueductal gray matter, the red nucleus, the substantia nigra, and the ventral tegmental area. (See Figure 17d.) The reticular formation is a large structure consisting of many nuclei (over ninety in all). It is also characterized by a diffuse, interconnected network of neurons with complex dendritic and axonal processes. (Indeed, reticulum means “little net”; early anatomists were struck by the netlike appearance of the reticular formation.) The reticular formation occupies the core of the brain stem, from the lower border of the medulla to the upper border of the midbrain. (Look again at Figure 17d.) The reticular formation receives sensory information by means of various pathways and projects axons to the cerebral cortex, thalamus, and spinal cord. It plays a role in sleep and arousal, attention, muscle tonus, movement, and various vital reflexes. The periaqueductal gray matter is so called because it consists mostly of cell bodies of neurons (“gray matter,” as contrasted with the “white matter” of axon bundles) that surround the cerebral aqueduct as it travels from the third to the fourth ventricle. The periaqueductal gray matter contains neural circuits that control sequences of movements that constitute species-typical behaviors, such as fighting and mating. Opiates such as morphine decrease an organism’s sensitivity to pain by stimulating receptors on neurons located in this region. The red nucleus and substantia nigra (“black substance”) are important components of the motor system. A bundle of axons that arises from the red nucleus constitutes one of the two major fiber systems that bring motor information from the cerebral cortex and cerebellum to the spinal cord.

tegmentum The ventral part of the midbrain; includes the periaqueductal gray matter, reticular formation, red nucleus, and substantia nigra. reticular formation A large network of neural tissue located in the central region of the brain stem, from the medulla to the diencephalon. periaqueductal gray matter The region of the midbrain surrounding the cerebral aqueduct; contains neural circuits involved in species-typical behaviors. red nucleus A large nucleus of the midbrain that receives inputs from the cerebellum and motor cortex and sends axons to motor neurons in the spinal cord. substantia nigra A darkly stained region of the tegmentum that contains neurons that communicate with the caudate nucleus and putamen in the basal ganglia.

Structure of the Nervous System

Thalamus Thalamus Midbrain Pons Medulla

Cerebellum

Medulla

Cerebellum

(a)

(b)

Thalamus Pineal body Superior colliculus Superior colliculus

Dorsal

Periaqueductal gray matter Cerebral aqueduct

Inferior colliculus Reticular formation

Red nucleus

Cerebellum

Cerebellar peduncles Medulla Floor of fourth ventricle

Substantia nigra

Ventral (d)

(c) F I G U R E 17 The Cerebellum and Brain Stem. The figure shows (a) a lateral view of a semitransparent brain, showing the cerebellum and brain stem ghosted in, (b) a view from the back of the brain, and (c) a dorsal view of the brain stem. The left hemisphere of the cerebellum and part of the right hemisphere have been removed to show the inside of the fourth ventricle and the cerebellar peduncles. Part (d) shows a cross section of the midbrain.

hindbrain The most caudal of the three major divisions of the brain; includes the metencephalon and myelencephalon. cerebellum (sair a bell um) A major part of the brain located dorsal to the pons, containing the two cerebellar hemispheres, covered with the cerebellar cortex; an important component of the motor system. cerebellar cortex The cortex that covers the surface of the cerebellum. deep cerebellar nuclei Nuclei located within the cerebellar hemispheres; receive projections from the cerebellar cortex and send projections out of the cerebellum to other parts of the brain. cerebellar peduncle (pee dun kul) One of three bundles of axons that attach each cerebellar hemisphere to the dorsal pons.

The substantia nigra contains neurons whose axons project to the caudate nucleus and putamen, parts of the basal ganglia. Degeneration of these neurons causes Parkinson’s disease.

The Hindbrain The hindbrain, which surrounds the fourth ventricle, consists of two major divisions: the metencephalon and the myelencephalon. METENCEPHALON The metencephalon consists of the cerebellum and the pons. Cerebellum. The cerebellum (“little brain”), with its two hemispheres, resembles a miniature version of the cerebrum. It is covered by the cerebellar cortex and has a set of deep cerebellar nuclei. These nuclei receive projections from the cerebellar cortex and then send projections out of the cerebellum to other parts of the brain. Each hemisphere of the cerebellum is attached to the dorsal surface of the pons by bundles of axons: the superior, middle, and inferior cerebellar peduncles (“little feet”). (See Figure 17c.)

Structure of the Nervous System

Damage to the cerebellum impairs one’s ability to stand, walk, or perform coordinated movements. (A virtuoso pianist or other performing musician owes much to his or her cerebellum.) The cerebellum receives visual, auditory, vestibular, and somatosensory information, and it also receives information about individual muscle movements being directed by the brain. The cerebellum integrates this information and modifies the motor outflow, exerting a coordinating and smoothing effect on the movements. Cerebellar damage results in jerky, poorly coordinated, exaggerated movements; extensive cerebellar damage makes it impossible even to stand.

Cervical vertebrae Spinal foramen (spinal cord passes through this opening)

Thoracic vertebrae

Pons. The pons, a large bulge in the brain stem, lies between the mesencephalon and medulla oblongata, immediately ventral to the cerebellum. Pons means “bridge,” but it does not really look like one. (Refer to Figures 12 and 17a.) The pons contains, in its core, a portion of the reticular formation, including some nuclei that appear to be important in sleep and arousal. It also contains a large nucleus that relays information from the cerebral cortex to the cerebellum. MYELENCEPHALON The myelencephalon contains one major structure, the medulla oblongata (literally, “oblong marrow”), usually just called the medulla. This structure is the most caudal portion of the brain stem; its lower border is the rostral end of the spinal cord. (Refer again to Figures 12 and 17a.) The medulla contains part of the reticular formation, including nuclei that control vital functions such as regulation of the cardiovascular system, respiration, and skeletal muscle tonus.

Ventral

Dorsal

Ventral Lumbar vertebrae

Sacral vertebrae (fused)

Dorsal

Coccyx

The Spinal Cord

F I G U R E 18 Ventral View of the Spinal Column. Details show the anatomy of the bony vertebrae.

The spinal cord is a long, conical structure, approximately as thick as an adult’s little finger. The principal function of the spinal cord is to distribute motor fibers to the body’s effector organs (glands and muscles) and to collect somatosensory information to be passed on to the brain. The spinal cord also has a certain degree of autonomy from the brain; various reflexive control circuits are located there. The spinal cord is protected by the vertebral column, which is composed of twenty-four individual vertebrae of the cervical (neck), thoracic (chest), and lumbar (lower back) regions and the fused vertebrae making up the sacral and coccygeal portions of the column (located in the pelvic region). The spinal cord passes through a hole in each of the vertebrae (the spinal foramens). Figure 18 illustrates the divisions and structures of the spinal cord and vertebral column. (See Figure 18.) The spinal cord is only about two-thirds as long as the vertebral column; the rest of the space is filled by a mass of spinal roots composing the cauda equina (“horse’s tail”). (Refer to Figure 3c.) Early in embryological development the vertebral column and spinal cord are the same length. As development progresses, the vertebral column grows faster than the spinal cord. This differential growth rate causes the spinal roots to be displaced downward; the most caudal roots travel the farthest before they emerge through openings between the vertebrae and thus compose the cauda equina. To produce the caudal block that is sometimes used in pelvic surgery or childbirth, a local anesthetic can be injected into the CSF contained within the sac of dura mater surrounding the cauda equina. The drug blocks conduction in the axons of the cauda equina. Figure 19a shows a portion of the spinal cord, with the layers of the meninges that wrap it. Small bundles of fibers emerge from each side of the spinal cord in two straight lines along its dorsolateral and ventrolateral surfaces. Groups of these bundles fuse together and become the thirty-one paired sets of dorsal roots and ventral roots. The dorsal and ventral roots join together as they pass through the intervertebral foramens and become spinal nerves. (See Figure 19.) Figure 19b shows a cross section of the spinal cord. Like the brain, the spinal cord consists ofwhite matter and gray matter. Unlike the white matter of the brain, the white matter of the

pons The region of the metencephalon rostral to the medulla, caudal to the midbrain, and ventral to the cerebellum. medulla oblongata (me doo la) The most caudal portion of the brain; located in the myelencephalon, immediately rostral to the spinal cord. spinal cord The cord of nervous tissue that extends caudally from the medulla. spinal root A bundle of axons surrounded by connective tissue that occurs in pairs, which fuse and form a spinal nerve. cauda equina (ee kwye na) A bundle of spinal roots located caudal to the end of the spinal cord. caudal block The anesthesia and paralysis of the lower part of the body produced by injection of a local anesthetic into the cerebrospinal fluid surrounding the cauda equina. dorsal root The spinal root that contains incoming (afferent) sensory fibers. ventral root The spinal root that contains outgoing (efferent) motor fibers.

Structure of the Nervous System

White matter

Dorsal

Gray matter

Subarachnoid space Pia mater (adheres to spinal cord)

Dorsal root ganglion Ventral root

Arachnoid membrane

Dorsal root Spinal nerve

Ventral Dura mater

(b)

Vertebra

(a) F I G U R E 19 Ventral View of the Spinal Cord. The figure shows (a) a portion of the spinal cord, showing the layers of the meninges and the relation of the spinal cord to the vertebral column, and (b) a cross section through the spinal cord. Ascending tracts are shown in blue; descending tracts are shown in red.

spinal cord (consisting of ascending and descending bundles of myelinated axons) is on the outside; the gray matter (mostly neural cell bodies and short, unmyelinated axons) is on the inside. In Figure 19b, ascending tracts are indicated in blue; descending tracts are indicated in red. (See Figure 19b.)

SECTION SUMMARY The Central Nervous System The brain consists of three major divisions, organized around the three chambers of the tube that develops early in embryonic life: the forebrain, the midbrain, and the hindbrain. The development of the neural tube into the mature central nervous system is illustrated in Figure 5, and Table 2 outlines the brain’s major divisions and subdivisions. During the first phase of brain development, symmetrical division of the progenitor cells of the ventricular zone, which lines the neural tube, increases in size. During the second phase, asymmetrical division of these cells gives rise to neurons, which migrate up the fibers of radial glial cells to their final resting places. There, neurons develop dendrites and axons and establish synaptic connections with other neurons. Later, neurons that fail to develop a sufficient number of synaptic connections are killed through apoptosis. The large size of the human brain, relative to the brains of other primates, appears to be accomplished primarily by lengthening the first and second periods of brain development.

The forebrain, which surrounds the lateral and third ventricles, consists of the telencephalon and diencephalon. The telencephalon contains the cerebral cortex, the limbic system, and the basal ganglia. The cerebral cortex is organized into the frontal, parietal, temporal, and occipital lobes. The central sulcus divides the frontal lobe, which deals specifically with movement and the planning of movement, from the other three lobes, which deal primarily with perceiving and learning. The limbic system, which includes the limbic cortex, the hippocampus, and the amygdala, is involved in emotion, motivation, and learning. The basal ganglia participate in the control of movement. The diencephalon consists of the thalamus, which directs information to and from the cerebral cortex, and the hypothalamus, which controls the endocrine system and modulates species-typical behaviors. The midbrain, which surrounds the cerebral aqueduct, consists of the tectum and tegmentum. The tectum is involved in audition and

Structure of the Nervous System

Section Summary (continued) the control of visual reflexes and reactions to moving stimuli. The tegmentum contains the reticular formation, which is important in sleep, arousal, and movement; the periaqueductal gray matter, which controls various species-typical behaviors; and the red nucleus and the substantia nigra, both of which are parts of the motor system. The hindbrain, which surrounds the fourth ventricle, contains the cerebellum, the pons, and the medulla. The cerebellum plays an important role in integrating and

coordinating movements. The pons contains some nuclei that are important in sleep and arousal. The medulla oblongata, too, is involved in sleep and arousal, but it also plays a role in control of movement and in control of vital functions such as heart rate, breathing, and blood pressure. The outer part of the spinal cord consists of white matter: axons conveying information up or down. The central gray matter contains cell bodies.

The Peripheral Nervous System The brain and spinal cord communicate with the rest of the body via the cranial nerves and spinal nerves. These nerves are part of the peripheral nervous system, which conveys sensory information to the central nervous system and conveys messages from the central nervous system to the body’s muscles and glands.

Spinal Nerves The spinal nerves begin at the junction of the dorsal and ventral roots of the spinal cord. The nerves leave the vertebral column and travel to the muscles or sensory receptors they innervate, branching repeatedly as they go. Branches of spinal nerves often follow blood vessels, especially those branches that innervate skeletal muscles. (Refer to Figure 3.) Now let us consider the pathways by which sensory information enters the spinal cord and motor information leaves it. The cell bodies of all axons that bring sensory information into the brain and spinal cord are located outside the CNS. (The sole exception is the visual system; the retina of the eye is actually a part of the brain.) These incoming axons are referred to as afferent axons because they “bear toward” the CNS. The cell bodies that give rise to the axons that bring somatosensory information to the spinal cord reside in the dorsal root ganglia, rounded swellings of the dorsal root. (See Figure 20.) These neurons are of the unipolar type (one stalk, which To brain Dorsal root Dorsal root ganglion

Dura mater

Afferent axon

Arachnoid membrane Pia mater

Spinal nerve

Ventral root

Efferent axon

Motor neuron

Spinal cord

Subarachnoid space

Fat tissue Vertebra (for cushioning)

F I G U R E 20 A Cross Section of the Spinal Cord. The figure shows the routes taken by afferent and efferent axons through the dorsal and ventral roots.

spinal nerve A peripheral nerve attached to the spinal cord. afferent axon An axon directed toward the central nervous system, conveying sensory information. dorsal root ganglion A nodule on a dorsal root that contains cell bodies of afferent spinal nerve neurons.

Structure of the Nervous System

leaves the soma and divides into two branches a short distance away). The axonal stalk divides close to the cell body, sending one limb into the spinal cord and the other limb out to the sensory organ. Note that all of the axons in the dorsal root convey somatosensory information. Cell bodies that give rise to the ventral root are located within the gray matter of the spinal cord. The axons of these multipolar neurons leave the spinal cord via a ventral root, which joins a dorsal root to make a spinal nerve. The axons that leave the spinal cord through the ventral roots control muscles and glands. They are referred to as efferent axons because they “bear away from” the CNS. (See Figure 20.)

Cranial Nerves

efferent axon (eff ur ent) An axon directed away from the central nervous system, conveying motor commands to muscles and glands. cranial nerve A peripheral nerve attached directly to the brain. vagus nerve The largest of the cranial nerves, conveying efferent fibers of the parasympathetic division of the autonomic nervous system to organs of the thoracic and abdominal cavities. olfactory bulb The protrusion at the end of the olfactory nerve; receives input from the olfactory receptors. somatic nervous system The part of the peripheral nervous system that controls the movement of skeletal muscles or transmits somatosensory information to the central nervous system. autonomic nervous system (ANS) The portion of the peripheral nervous system that controls the body’s vegetative functions. sympathetic division The portion of the autonomic nervous system that controls functions that accompany arousal and expenditure of energy. sympathetic ganglia Nodules that contain synapses between preganglionic and postganglionic neurons of the sympathetic nervous system. sympathetic ganglion chain One of a pair of groups of sympathetic ganglia that lie ventrolateral to the vertebral column.

Twelve pairs of cranial nerves are attached to the ventral surface of the brain. Most of these nerves serve sensory and motor functions of the head and neck region. One of them, the tenth, or vagus nerve, regulates the functions of organs in the thoracic and abdominal cavities. It is called the vagus (“wandering”) nerve because its branches wander throughout the thoracic and abdominal cavities. (The word vagabond has the same root.) Figure 21 presents a view of the base of the brain and illustrates the cranial nerves and the structures they serve. Note that efferent (motor) fibers are drawn in red and that afferent (sensory) fibers are drawn in blue. (See Figure 21.) As I mentioned in the previous section, cell bodies of sensory nerve fibers that enter the brain and spinal cord (except for the visual system) are located outside the central nervous system. Somatosensory information (and the sense of taste) is received, via the cranial nerves, from unipolar neurons. Auditory, vestibular, and visual information is received via fibers of bipolar neurons. Olfactory information is received via the olfactory bulbs, which receive information from the olfactory receptors in the nose. The olfactory bulbs are complex structures containing a considerable amount of neural circuitry; actually, they are part of the brain.

The Autonomic Nervous System The part of the peripheral nervous system that I have discussed so far—which receives sensory information from the sensory organs and controls movements of the skeletal muscles—is called the somatic nervous system. The other branch of the peripheral nervous system—the autonomic nervous system (ANS)—is concerned with regulation of smooth muscle, cardiac muscle, and glands. (Autonomic means “self-governing.”) Smooth muscle is found in the skin (associated with hair follicles), in blood vessels, in the eyes (controlling pupil size and accommodation of the lens), and in the walls and sphincters of the gut, gallbladder, and urinary bladder. Merely describing the organs that are innervated by the autonomic nervous system suggests the function of this system: regulation of “vegetative processes” in the body. The ANS consists of two anatomically separate systems: the sympathetic division and the parasympathetic division. With few exceptions organs of the body are innervated by both of these subdivisions, and each has a different effect. For example, the sympathetic division speeds the heart rate, whereas the parasympathetic division slows it. SYMPATHETIC DIVISION OF THE ANS The sympathetic division is most involved in activities associated with the expenditure of energy from reserves that are stored in the body. For example, when an organism is excited, the sympathetic nervous system increases blood flow to skeletal muscles, stimulates the secretion of epinephrine (resulting in increased heart rate and a rise in blood sugar level), and causes piloerection (erection of fur in mammals that have it and production of “goose bumps” in humans). The cell bodies of sympathetic motor neurons are located in the gray matter of the thoracic and lumbar regions of the spinal cord (hence the sympathetic nervous system is also known as the thoracolumbar system). The fibers of these neurons exit via the ventral roots. After joining the spinal nerves, the fibers branch off and pass into sympathetic ganglia (not to be confused with the dorsal root ganglia). Figure 22 shows the relation of these ganglia to the spinal cord. Note that individual sympathetic ganglia are connected to the neighboring ganglia above and below, thus forming the sympathetic ganglion chain. (See Figure 22.)

Structure of the Nervous System

2. Optic

3. Oculomotor 4. Trochlear 6. Abducens Touch, pain

Vision 1. Olfactory

Jaw muscles

Eye movements

Smell

5. Trigeminal

Face muscles

Tongue movements 7. Facial 12. Hypoglossal

Neck muscles

Taste

11. Spinal accessory

8. Auditory Hearing

9. Glossopharyngeal

Balance

10. Vagus

Internal organs

Muscles of throat and larynx

Taste

F I G U R E 21 The Cranial Nerves. The figure shows the twelve pairs of cranial nerves and the regions and functions they serve. Red lines denote axons that control muscles or glands; blue lines denote sensory axons.

The axons that leave the spinal cord through the ventral root belong to the preganglionic neurons. With one exception, all sympathetic preganglionic axons enter the ganglia of the sympathetic chain, but not all of them form synapses there. (The exception is the medulla of the adrenal gland.) Some axons leave and travel to one of the other sympathetic ganglia, located among the internal organs. All sympathetic preganglionic axons form synapses with neurons located in one of the ganglia. The neurons with which they form synapses are called postganglionic neurons. In turn, the postganglionic neurons send axons to the target organs, such as the intestines, stomach, kidneys, or sweat glands. (See Figure 22.) PARASYMPATHETIC DIVISION OF THE ANS The parasympathetic division of the autonomic nervous system supports activities that are involved with increases in the body’s supply of stored energy. These activities include salivation, gastric and intestinal motility, secretion of digestive juices, and increased blood flow to the gastrointestinal system. Cell bodies that give rise to preganglionic axons in the parasympathetic nervous system are located in two regions: the nuclei of some of the cranial nerves (especially the vagus nerve) and the

preganglionic neuron The efferent neuron of the autonomic nervous system whose cell body is located in a cranial nerve nucleus or in the intermediate horn of the spinal gray matter and whose terminal buttons synapse upon postganglionic neurons in the autonomic ganglia. postganglionic neuron Neurons of the autonomic nervous system that form synapses directly with their target organ. parasympathetic division The portion of the autonomic nervous system that controls functions that occur during a relaxed state.

Structure of the Nervous System

Constricts pupil, produces tears

Dilates pupil, inhibits tears

Inhibits salivation

Stimulates salivation

Constricts airways

Lungs

Speeds heartbeat

Slows heartbeat

Stimulates glucose release

Constricts blood vessels in skin

Parasympathetic: Cranial and Sacral

Sympathetic: Thoracic and Lumbar

Stimulates sweating

Liver

Pancreas

Inhibits digestive system Stomach Stimulates secretion of epinephrine and norepinephrine by adrenal medulla

Stimulates digestive system

Large intestine Small intestine Rectum Relaxes bladder

Contracts bladder

Parasympathetic: Preganglionic neuron Postganglionic neuron Sympathetic: Preganglionic neuron Postganglionic neuron

Stimulates orgasm

Stimulates sexual arousal

F I G U R E 22 The Autonomic Nervous System. The schematic figure shows the target organs and functions served by the sympathetic and parasympathetic branches of the autonomic nervous system.

TABLE

3 The Major Divisions of the Peripheral Nervous System

Somatic Nervous System

Autonomic Nervous System (ANS)

Spinal nerves

Sympathetic branch

Afferents from sense organs

Spinal nerves (from thoracic and lumbar regions)

Efferents to muscles

Sympathetic ganglia

Cranial nerves

Parasympathetic branch

Afferents from sense organs

Cranial nerves (3rd, 7th, 9th, and 10th)

Efferents to muscles

Spinal nerves (from sacral region) Parasympathetic ganglia (adjacent to target organs)

intermediate horn of the gray matter in the sacral region of the spinal cord. Thus, the parasympathetic division of the ANS has often been referred to as the craniosacral system. Parasympathetic ganglia are located in the immediate vicinity of the target organs; the postganglionic fibers are therefore relatively short. The terminal buttons of both preganglionic and postganglionic neurons in the parasympathetic nervous system secrete acetylcholine. Table 3 summarizes the major divisions of the peripheral nervous system. (See Table 3.)

SECTION SUMMARY The Peripheral Nervous System The spinal nerves and the cranial nerves convey sensory axons into the central nervous system and motor axons out from it. Spinal nerves are formed by the junctions of the dorsal roots, which contain incoming (afferent) axons, and the ventral roots, which contain outgoing (efferent) axons. The autonomic nervous system consists of two divisions: the sympathetic division, which controls activities that occur during excitement

EPILOGUE

or exertion, such as increased heart rate; and the parasympathetic division, which controls activities that occur during relaxation, such as decreased heart rate and increased activity of the digestive system. The pathways of the autonomic nervous system contain preganglionic axons, from the brain or spinal cord to the sympathetic or parasympathetic ganglia, and postganglionic axons, from the ganglia to the target organ.

| Unilateral Neglect

When we see people like Miss S., the woman with unilateral neglect described in the prologue to this chapter, we realize that perception and attention are somewhat independent. The perceptual mechanisms of our brain provide the information, and the mechanisms involved in attention determine whether we become conscious of this information. Unilateral (“one-sided”) neglect occurs when the right parietal lobe is damaged. The parietal lobe contains the primary somatosensory cortex. It receives information from the skin, the muscles, the joints, the internal organs, and the part of the inner ear that is concerned with balance. Thus, it is concerned with the body and its position. But that is not all; the association cortex of the parietal lobe also receives auditory and visual information from the association cortex of the occipital and temporal lobes. Its most important

function seems to be to put together information about the movements and location of the parts of the body with the locations of objects in space around us. If unilateral neglect simply consisted of blindness in the left side of the visual field and anesthesia of the left side of the body, it would not be nearly as interesting. But individuals with unilateral neglect are neither half blind nor half numb. Under the proper circumstances, they can see things located to their left, and they can tell when someone touches the left side of their bodies. But normally, they ignore such stimuli and act as if the left side of the world and of their bodies did not exist. Volpe, LeDoux, and Gazzaniga (1979) presented pairs of visual stimuli to people with unilateral neglect—one stimulus in the left visual field and one stimulus in the right. Invariably, the people

Structure of the Nervous System

reported seeing only the right-hand stimulus. But when the investigators asked the people to say whether or not the two stimuli were identical, they answered correctly even though they said that they were unaware of the left-hand stimulus. If you think about the story that the chief of neurology told about the man who ate only the right half of a pancake, you will realize that people with unilateral neglect must be able to perceive more than the right visual field. Remember that people with unilateral neglect fail to notice not only things to their left but also the left halves of things. But to distinguish between the left and right halves of an object, you first have to perceive the entire object— otherwise, how would you know where the middle was? People with unilateral neglect also demonstrate their unawareness of the left half of things when they draw pictures. For example, when asked to draw a clock, they almost always successfully draw a circle; but then when they fill in the numbers, they scrunch them all in on the right side. Sometimes they simply stop after reaching 6 or 7, and sometimes they write the rest of the numbers underneath the circle. When asked to draw a daisy, they begin with a stem and a leaf or two and then draw all the petals to the right. (See Figure 23.) Bisiach and Luzzatti (1978) demonstrated a similar phenomenon, which suggests that unilateral neglect extends even to a person’s own visual imagery. The investigators asked two patients with unilateral neglect to describe the Piazza del Duomo, a wellknown landmark in Milan, the city in which they and the patients lived. They asked the patients to imagine that they were standing at the north end of the piazza and to tell them what they saw. The patients duly named the buildings, but only those on the west, to their right. Then the investigators asked the patients to imagine themselves at the south end of the piazza. This time, they named the buildings on the east—again, to their right. Obviously, they knew about all of the buildings and their locations, but they visualized them only when the buildings were located in the right side of their (imaginary) visual field.

Although neglect of the left side of one’s own body can be studied only in people with brain abnormalities, an interesting phenomenon seen in people with undamaged brains confirms the importance of the parietal lobe (and another region of the brain) in feelings of body ownership. Ehrsson, Spence, and Passingham (2004) studied the rubber hand illusion. Normal subjects were positioned with their left hand hidden out of sight. They saw a lifelike rubber left hand in front of them. The experimenters stroked both the subject’s hidden left hand and the visible rubber hand with a small paintbrush. If the two hands were stroked synchronously and in the same direction, the subjects began to experience the rubber hand as their own. In fact, if they were then asked to use their right hand to point to their left hand, they tended to point toward the rubber hand. However, if the real and artificial hands were stroked in different directions or at different times, the subjects did not experience the rubber hand as their own. (See Figure 24.) While the subjects were participating in the experiment, the experimenters recorded the activity of their brains with a functional MRI scanner. The scans showed increased activity in the parietal lobe, and then, as the subjects began to experience the rubber hand as belonging to their body, in the premotor cortex, a region of the brain involved in planning movements. When the stroking of the real and artificial hands was uncoordinated and the subjects did not experience the rubber hand as their own, the premotor cortex did not become activated. The experimenters concluded that the parietal cortex analyzed the sight and the feeling of brush strokes. When the parietal cortex detected that they were congruent, this information was transmitted to the premotor cortex, which gave rise to the feeling of ownership of the rubber hand.

Brushes move in synchrony Hand and brush hidden from view

Rubber hand

F I G U R E 23 Unilateral Neglect. When people with unilateral neglect attempt to draw simple objects, they demonstrate their unawareness of the left half of things by drawing only those features that appear on the right.

F I G U R E 24 The Rubber Hand Illusion. If the subject’s hidden left hand and the visible rubber hand are stroked synchronously in the same direction, the subject will come to experience the artificial hand as his or her own. If the hands are stroked asynchronously or in different directions, this illusion will not occur. Based on Botwinick, M. Science, 2004, 305, 782–783.

Structure of the Nervous System

A second study from the same laboratory provided a particularly convincing demonstration that people experience a genuine feeling of ownership of the rubber hand (Ehrsson et al., 2007). The investigators used the previously described procedure to establish a feeling of ownership and then threatened the rubber hand by making a stabbing movement toward the hand with a needle. (They did not actually touch the hand with the needle.) Brain scans showed increased activity in a region of the brain (the anterior

cingulate cortex) that is normally activated when a person anticipates pain, and also in a region (the supplementary motor area) that is normally activated when a person feels the urge to move his or her arm (Fried et al., 1991; Peyron and Garcia-Larrea, 2000). So the impression that the rubber hand was about to receive a painful stab from a needle made people react as they would if their own hand were the target of the threat.

KEY CONCEPTS BASIC FEATURES OF THE NERVOUS SYSTEM

1. The central nervous system consists of the brain and spinal cord; it is covered with the meninges and floats in cerebrospinal fluid. THE CENTRAL NERVOUS SYSTEM

2. The nervous system develops first as a tube, which thickens and forms pockets and folds as cells are produced. The tube becomes the ventricular system. 3. The primary cause of the difference between the human brain and that of other primates is a slightly extended period of symmetrical and asymmetrical division of progenitor cells located in the ventricular zone. 4. The forebrain, surrounding the lateral and third ventricles, consists of the telencephalon (cerebral cortex, limbic

system, and basal ganglia) and diencephalon (thalamus and hypothalamus). 5. The midbrain, which surrounds the cerebral aqueduct, consists of the tectum and tegmentum. 6. The hindbrain, which surrounds the fourth ventricle, contains the cerebellum, the pons, and the medulla. THE PERIPHERAL NERVOUS SYSTEM

7. The spinal and cranial nerves connect the central nervous system with the rest of the body. The autonomic nervous system consists of two divisions: sympathetic and parasympathetic.

EXPLORE the Virtual Brain in THE NERVOUS SYSTEM Learn about the anatomy of the nervous system from the micro-level of the neuron to the macro level of the Central and Peripheral Nervous Systems. Hear about the research methods scientists use to learn about neuroanatomy.

Structure of the Nervous System

REFERENCES Bisiach, E., and Luzzatti, C. Unilateral neglect of representational space. Cortex, 1978, 14, 129–133. Cooper, J. A. A mechanism for inside-out lamination in the neocortex. Trends in Neurosciences, 2008, 32, 113–119. Doetsch, F., and Hen, R. Young and excitable: The function of new neurons in the adult mammalian brain. Current Opinion in Neuroscience, 2005, 15, 121–128. Ehrsson, H. H., Spence, C., and Passingham, R. E. That’s my hand! Activity in premotor cortex reflects feeling of ownership of a limb. Science, 2004, 305, 875–877. Ehrsson, H. H., Wiech, K., Weiskopf, N., Dolan, R. J., and Passingham, R. E. Threatening a rubber hand that you feel is yours elicits a cortical anxiety response. Proceedings of the National Academy of Sciences, USA, 2007, 104, 9828–9833. Fried, I., Katz, A., McCarthy, G., Sass, K. J., et al. Functional organization of human supplementary motor cortex studied by electrical stimulation. Journal of Neuroscience, 1991, 11, 3656–3666. MacLean, P. D. Psychosomatic disease and the “visceral brain”: Recent developments bearing on the Papez theory of emotion. Psychosomatic Medicine, 1949, 11, 338–353. Papez, J. W. A proposed mechanism of emotion. Archives of Neurology and Psychiatry, 1937, 38, 725–744. Peyron, R., Laurent, B., and Garcia-Larrea, L. Functional imaging of brain responses to pain: A review and meta-analysis. Neurophysiology Clinics, 2000, 30, 263–288. Rakic, P. Evolution of the neocortex: A perspective from developmental biology. Nature Reviews Neuroscience, 2009, 10, 724–735. Volpe, B. T., LeDoux, J. E., and Gazzaniga, M. S. Information processing of visual stimuli in an “extinguished” field. Nature, 1979, 282, 722–724.

Psychopharmacology

OUTLINE ■

Principles of Psychopharmacology Pharmacokinetics

Psychopharmacology

Drug Effectiveness Effects of Repeated Administration Placebo Effects ■

Sites of Drug Action Effects on Production of Neurotransmitters Effects on Storage and Release of Neurotransmitters Effects on Receptors Effects on Reuptake or Destruction of Neurotransmitters

■

Neurotransmitters and Neuromodulators Acetylcholine The Monoamines Amino Acids Peptides Lipids Nucleosides

LEARNING OBJECTIVES 1. Describe the routes of administration of drugs and their subsequent distribution within the body.

5. Describe the monoaminergic pathways in the brain and the drugs that aﬀect these neurons.

2. Describe drug eﬀectiveness, the eﬀects of repeated administration of drugs, and the placebo eﬀect.

6. Review the role of neurons that release amino acid neurotransmitters and describe drugs that aﬀect these neurons.

3. Describe the eﬀects of drugs on synaptic activity.

7. Describe the eﬀects of peptides, lipids, nucleosides, and soluble gases released by neurons.

4. Review the general role of neurotransmitters and neuromodulators, and describe the acetylcholinergic pathways in the brain and the drugs that aﬀect these neurons.

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Soluble Gases

PROLOGUE

| A Contaminated Drug

In July 1982, some people in northern California began showing up at neurology clinics displaying dramatic, severe symptoms (Langston, Ballard, Tetrud, and Irwin, 1983). The most severely affected patients were almost totally paralyzed. They were unable to speak intelligibly, they drooled constantly, and their eyes were open with a fixed stare. Others, who were less severely affected, walked with a slow, shuffling gait and moved slowly and with great difficulty. The symptoms looked like those of Parkinson’s disease, but that disorder has a very gradual onset. In addition, it rarely strikes people before late middle age, and these patients were all in their twenties or early thirties. The common factor linking these patients was intravenous drug use; all of them had been taking a “new heroin,” a synthetic opiate related to meperidine (Demerol). Because the symptoms looked like those of Parkinson’s disease, the patients were given L-DOPA, the drug used to treat this disease, and they all showed significant improvement in their symptoms. But even with this treatment the

symptoms were debilitating. In normal cases of Parkinson’s disease L-DOPA therapy works for a time, but as the degeneration of dopamine-secreting neurons continues, the drug loses its effectiveness. This pattern of response also appears to have occurred in the young patients (Langston and Ballard, 1984). After some detective work, researchers discovered that the chemical that caused the neurological symptoms was not the synthetic opiate itself but another chemical, MPTP, with which it was contaminated. According to researcher William Langston, the mini-epidemic appeared to have started “when a young man in Silicon Valley was sloppy in his synthesis of synthetic heroin. That sloppiness led to the presence of MPTP, which by an extraordinary trick of fate is highly toxic to the very same neurons that are lost in Parkinson’s disease” (Lewin, 1989, p. 467). As we will see, this discovery led to the discovery of a drug that is now commonly used to treat the symptoms of Parkinson’s disease.

Psychopharmacology is the study of the effects of drugs on the nervous system and (of course) on behavior. (Pharmakon is the Greek word for “drug.”) As we will see in this chapter, drugs have effects and sites of action. Drug effects are the changes we can observe in an animal’s physiological processes and behavior. For example, the effects of morphine, heroin, and other opiates include decreased sensitivity to pain, slowing of the digestive system, sedation, muscular relaxation, constriction of the pupils, and euphoria. The sites of action of drugs are the points at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells. For example, the sites of action of the opiates are specialized receptors situated in the membrane of certain neurons. When molecules of opiates attach to and activate these receptors, the drugs alter the activity of these neurons and produce their effects. This chapter considers both the effects of drugs and their sites of action. Psychopharmacology is an important field of neuroscience. It has been responsible for the development of psychotherapeutic drugs, which are used to treat psychological and behavioral disorders. It has also provided tools that have enabled other investigators to study the functions of cells of the nervous system and the behaviors controlled by particular neural circuits.

Principles of Psychopharmacology This chapter begins with a description of the basic principles of psychopharmacology: the routes of administration of drugs and their fate in the body. The second section discusses the sites of drug actions. The final section discusses specific neurotransmitters and neuromodulators and the physiological and behavioral effects of specific drugs that interact with them.

psychopharmacology The study of the effects of drugs on the nervous system and on behavior.

Pharmacokinetics

drug effect The changes a drug produces in an animal’s physiological processes and behavior.

To be effective, a drug must reach its sites of action. To do so, molecules of the drug must enter the body and then enter the bloodstream so that they can be carried to the organ (or organs) they act on. Once there, they must leave the bloodstream and come into contact with the molecules with which they interact. For almost all of the drugs we are interested in, this means that the molecules

site of action A location at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells.

Psychopharmacology

of the drug must enter the central nervous system. Some behaviorally active drugs exert their effects on the peripheral nervous system, but these drugs are less important to neuroscientists than those that affect cells of the CNS. Molecules of drugs must cross several barriers to enter the body and find their way to their sites of action. Some molecules pass through these barriers easily and quickly; others do so very slowly. And once molecules of drugs enter the body, they begin to be metabolized—broken down by enzymes—or excreted in the urine (or both). In time, the molecules either disappear or are transformed into inactive fragments. The process by which drugs are absorbed, distributed within the body, metabolized, and excreted is referred to as pharmacokinetics (“movements of drugs”). ROUTES OF ADMINISTRATION

pharmacokinetics The process by which drugs are absorbed, distributed within the body, metabolized, and excreted. intravenous (IV) injection Injection of a substance directly into a vein. intraperitoneal (IP) injection (in tra pair i toe nee ul) Injection of a substance into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs. intramuscular (IM) injection Injection of a substance into a muscle. subcutaneous (SC) injection Injection of a substance into the space beneath the skin. oral administration Administration of a substance into the mouth, so that it is swallowed. sublingual administration (sub ling wul) Administration of a substance by placing it beneath the tongue. intrarectal administration Administration of a substance into the rectum. inhalation Administration of a vaporous substance into the lungs.

First, let’s consider the routes by which drugs can be administered. For laboratory animals the most common route is injection. The drug is dissolved in a liquid (or, in some cases, suspended in a liquid in the form of fine particles) and injected through a hypodermic needle. The fastest route is intravenous (IV) injection—injection into a vein. The drug immediately enters the bloodstream, and it reaches the brain within a few seconds. The disadvantages of IV injections are the increased care and skill they require in comparison to most other forms of injection and the fact that the entire dose reaches the bloodstream at once. If an animal is especially sensitive to the drug, there may be little time to administer another drug to counteract its effects. An intraperitoneal (IP) injection is rapid, but not as rapid as an IV injection. The drug is injected through the abdominal wall into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs. Intraperitoneal injections are the most common route for administering drugs to small laboratory animals. An intramuscular (IM) injection is made directly into a large muscle, such as the ones found in the upper arm, thigh, or buttocks. The drug is absorbed into the bloodstream through the capillaries that supply the muscle. If very slow absorption is desirable, the drug can be mixed with another drug (such as ephedrine) that constricts blood vessels and retards the flow of blood through the muscle. A drug can also be injected into the space beneath the skin, by means of a subcutaneous (SC) injection. A subcutaneous injection is useful only if small amounts of the drug need to be administered, because large amounts would be painful. Some fat-soluble drugs can be dissolved in vegetable oil and administered subcutaneously. In this case, molecules of the drug will slowly leave the deposit of oil over a period of several days. If very slow and prolonged absorption of a drug is desired, the drug can be formed into a dry pellet or placed in a sealed silicone rubber capsule and implanted beneath the skin. Oral administration is the most common form of administering medicinal drugs to humans. Because of the difficulty of getting laboratory animals to eat something that does not taste good to them, researchers seldom use this route. Some chemicals cannot be administered orally because they will be destroyed by stomach acid or digestive enzymes or because they are not absorbed from the digestive system into the bloodstream. For example, insulin, a peptide hormone, must be injected. Sublingual administration of certain drugs can be accomplished by placing them beneath the tongue. The drug is absorbed into the bloodstream by the capillaries that supply the mucous membrane that lines the mouth. (Obviously, this method works only with humans, who can cooperate and leave the capsule beneath their tongue.) Nitroglycerine, a drug that causes blood vessels to dilate, is taken sublingually by people who suffer the pains of angina pectoris, caused by obstructions in the coronary arteries. Drugs can also be administered at the opposite end of the digestive tract, in the form of suppositories. Intrarectal administration is rarely used to give drugs to experimental animals. For obvious reasons, this process would be difficult with a small animal. In addition, when agitated, small animals such as rats tend to defecate, which would mean that the drug would not remain in place long enough to be absorbed. And I’m not sure I would want to try to administer a rectal suppository to a large animal. Rectal suppositories are most commonly used to administer drugs that might upset a person’s stomach. The lungs provide another route for drug administration: inhalation. Nicotine, freebase cocaine, and marijuana are usually smoked. In addition, drugs used to treat lung disorders are often inhaled in the form of a vapor or fine mist, and many general anesthetics are gases that are administered through inhalation. The route from the lungs to the brain is very short, and drugs administered this way have very rapid effects.

Psychopharmacology

Plasma cocaine concentration (ng/ml)

Some drugs can be absorbed directly through the skin, so they can 600 be given by means of topical administration, usually in the form of creams, ointments, or patches. Natural or artificial steroid hormones 500 Intravenous (0.6 mg/kg) can be administered this way, as can nicotine (as a treatment to make 400 it easier for a person to stop smoking). The mucous membrane lining Smoked (100 mg base) the nasal passages also provides a route for topical administration. 300 Commonly abused drugs such as cocaine hydrochloride are often sniffed Oral (2 mg/kg) so that they come into contact with the nasal mucosa. This route delivers 200 the drug to the brain very rapidly. (The technical, rarely used name for Intranasal (2 mg/kg) this route is insufflation. Note that sniffing is not the same as inhalation; 100 when powdered cocaine is sniffed, it ends up in the mucous membrane of the nasal passages, not in the lungs.) 0 Finally, drugs can be administered directly into the brain. The 0 120 180 240 300 360 420 480 60 blood–brain barrier prevents certain chemicals from leaving capillaries and entering the brain. Some drugs cannot cross the blood–brain barTime (min) rier. If these drugs are to reach the brain, they must be injected directly F I G U R E 1 Cocaine in Blood Plasma. The graph shows the into the brain or into the cerebrospinal fluid in the brain’s ventricular concentration of cocaine in blood plasma after intravenous injection, system. To study the effects of a drug in a specific region of the brain inhalation, sniffing, and oral administration. (for example, in a particular nucleus of the hypothalamus), a researcher Based on data from Jones, R. T. NIDA Research Monographs, 1990, 99, 30–41. will inject a very small amount of the drug directly into the brain. This procedure is known as intracerebral administration. To achieve a widespread distribution of a drug in the brain, a researcher will get past the blood–brain barrier by injecting the drug into a cerebral ventricle. The drug is then absorbed into the brain tissue, where it can exert its effects. This route, intracerebroventricular (ICV) administration, is very rarely used in humans—primarily just to deliver antibiotics directly to the brain to treat certain types of infections. Figure 1 shows the time course of blood levels of a commonly abused drug, cocaine, after intravenous injection, inhalation, sniffing, and oral administration. The amounts received were not identical, but the graph illustrates the relative rapidity with which the drug reaches the blood. (See Figure 1.) ENTRY OF DRUGS INTO THE BRAIN As we saw, drugs exert their effects only when they reach their sites of action. In the case of drugs that affect behavior, most of these sites are located on or in particular cells in the central nervous system. The previous section described the routes by which drugs can be introduced into the body. With the exception of intracerebral or intracerebroventricular administration, the differences in the routes of drug administration vary only in the rate at which a drug reaches the blood plasma (that is, the liquid part of the blood). But what happens next? All the sites of action of drugs that are of interest to psychopharmacologists lie outside the blood vessels. The most important factor that determines the rate at which a drug in the bloodstream reaches sites of action within the brain is lipid solubility. The blood–brain barrier is a barrier only for watersoluble molecules. Molecules that are soluble in lipids pass through the cells that line the capillaries in the central nervous system, and they rapidly distribute themselves throughout the brain. For example, diacetylmorphine (more commonly known as heroin) is more lipid soluble than morphine is. Thus, an intravenous injection of heroin produces more rapid effects than does one of morphine. Even though the molecules of the two drugs are equally effective when they reach their sites of action in the brain, the fact that heroin molecules get there faster means that they produce a more intense “rush” and thus explains why drug addicts prefer heroin to morphine. INACTIVATION AND EXCRETION Drugs do not remain in the body indefinitely. Many are deactivated by enzymes, and all are eventually excreted, primarily by the kidneys. The liver plays an especially active role in enzymatic deactivation of drugs, but some deactivating enzymes are also found in the blood. The brain also contains enzymes that destroy some drugs. In some cases enzymes transform molecules of a drug into other forms that themselves are biologically active. Occasionally, the transformed molecule is even more active than the one that is administered. In such cases the effects of a drug can have a very long duration.

topical administration Administration of a substance directly onto the skin or mucous membrane. intracerebral administration Administration of a substance directly into the brain. intracerebroventricular (ICV) administration Administration of a substance into one of the cerebral ventricles.

Psychopharmacology

Drug Effectiveness

dose-response curve A graph of the magnitude of an effect of a drug as a function of the amount of drug administered. therapeutic index The ratio between the dose that produces the desired effect in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals.

Drugs vary widely in their effectiveness. The effects of a small dose of a relatively effective drug can equal or exceed the effects of larger amounts of a relatively ineffective drug. The best way to measure the effectiveness of a drug is to plot a dose-response curve. To do this, subjects are given various doses of a drug, usually defined as milligrams of drug per kilogram of a subject’s body weight, and the effects of the drug are plotted. Because the molecules of most drugs distribute themselves throughout the blood and then throughout the rest of the body, a heavier subject (human or laboratory animal) will require a larger quantity of a drug to achieve the same concentration as that in a smaller subject. As Figure 2 shows, increasingly stronger doses of a drug cause increasingly larger effects, until the point of maximum effect is reached. At this point, increasing the dose of the drug does not produce any more effect. (See Figure 2.) Most drugs have more than one effect. Opiates such as morphine and codeine produce analgesia (reduced sensitivity to pain), but they also depress the activity of neurons in the medulla that control heart rate and respiration. A physician who prescribes an opiate to relieve a patient’s pain wants to administer a dose that is large enough to produce analgesia but not enough to depress heart rate and respiration—effects that could be fatal. Figure 3 shows two dose-response curves, one for the analgesic effects of a painkiller and one for the drug’s depressant effects on respiration. The difference between these curves indicates the drug’s margin of safety. Obviously, the most desirable drugs have a large margin of safety. (See Figure 3.) One measure of a drug’s margin of safety is its therapeutic index. This measure is obtained by administering varying doses of the drug to a group of laboratory animals such as mice. Two numbers are obtained: the dose that produces the desired effects in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. The therapeutic index is the ratio of these two numbers. For example, if the toxic dose is five times higher than the effective dose, then the therapeutic index is 5.0. The lower the therapeutic index, the more care must be taken in prescribing the drug. For example, barbiturates have relatively low therapeutic indexes—as low as 2 or 3. In contrast, tranquilizers such as Valium have therapeutic indexes of well over 100. As a consequence, an accidental overdose of a barbiturate is much more likely to have tragic effects than a similar overdose of Valium. Why do drugs vary in their effectiveness? There are two reasons. First, different drugs—even those with the same behavioral effects—may have different sites of action. For example, both morphine and aspirin have analgesic effects, but morphine suppresses the activity of neurons in the spinal cord and brain that are involved in pain perception, whereas aspirin reduces the

Effect of drug

After this point, increasing the dose does not produce a stronger effect

low

Margin of safety

Dose-response curve for the depressive effect of morphine on respiration

low low

Dose of drug

high

F I G U R E 2 A Dose-Response Curve. Increasingly stronger doses of the drug produce increasingly larger effects until the maximum effect is reached. After that point, increments in the dose do not produce any increments in the drug’s effect. However, the risk of adverse side effects increases.

Dose-response curve for the analgesic effect of morphine

Effect of drug

high

low

Dose of drug

high

F I G U R E 3 Dose-Response Curves for Morphine. The hypothetical dose-response curve on the left shows the analgesic effect of morphine, and the curve on the right shows one of the drug’s adverse side effects: its depressant effect on respiration. A drug’s margin of safety is reflected by the difference between the dose-response curve for its therapeutic effects and that for its adverse side effects.

Psychopharmacology

production of a chemical involved in transmitting information from damaged tissue to painsensitive neurons. Because the drugs act very differently, a given dose of morphine (expressed in terms of milligrams of drug per kilogram of body weight) produces much more pain reduction than does the same dose of aspirin. The second reason that drugs vary in their effectiveness has to do with the drug’s affinity with its site of action. As we will see in the next major section of this chapter, most drugs of interest to psychopharmacologists exert their effects by binding with other molecules located in the central nervous system—with presynaptic or postsynaptic receptors, with transporter molecules, or with enzymes involved in the production or deactivation of neurotransmitters. Drugs vary widely in their affinity for the molecules to which they attach—the readiness with which the two molecules join together. A drug with a high affinity will produce effects at a relatively low concentration, whereas one with a low affinity must be administered in relatively high doses. Thus, even two drugs with identical sites of action can vary widely in their effectiveness if they have different affinities for their binding sites. In addition, because most drugs have multiple effects, a drug can have high affinities for some of its sites of action and low affinities for others. The most desirable drug has a high affinity for sites of action that produce therapeutic effects and a low affinity for sites of action that produce toxic side effects. One of the goals of research by drug companies is to find chemicals with just this pattern of effects.

Effects of Repeated Administration Often, when a drug is administered repeatedly, its effects will not remain constant. In most cases its effects will diminish—a phenomenon known as tolerance. In other cases a drug becomes more and more effective—a phenomenon known as sensitization. Let’s consider tolerance first. Tolerance is seen in many drugs that are commonly abused. For example, a regular user of heroin must take larger and larger amounts of the drug for it to be effective. And once a person has taken an opiate regularly enough to develop tolerance, that individual will suffer withdrawal symptoms if he or she suddenly stops taking the drug. Withdrawal symptoms are primarily the opposite of the effects of the drug itself. For example, heroin produces euphoria; withdrawal from it produces dysphoria—a feeling of anxious misery. (Euphoria and dysphoria mean “easy to bear” and “hard to bear,” respectively.) Heroin produces constipation; withdrawal from heroin produces nausea and cramping. Heroin produces relaxation; withdrawal from it produces agitation. Withdrawal symptoms are caused by the same mechanisms that are responsible for tolerance. Tolerance is the result of the body’s attempt to compensate for the effects of the drug. That is, most systems of the body, including those controlled by the brain, are regulated so that they stay at an optimal value. When the effects of a drug alter these systems for a prolonged time, compensatory mechanisms begin to produce the opposite reaction, at least partially compensating for the disturbance from the optimal value. These mechanisms account for the fact that more and more of the drug must be taken to achieve a given level of effects. Then, when the person stops taking the drug, the compensatory mechanisms make themselves felt, unopposed by the action of the drug. Research suggests that there are several types of compensatory mechanisms. As we will see, many drugs that affect the brain do so by binding with receptors and activating them. The first compensatory mechanism involves a decrease in the effectiveness of such binding. Either the receptors become less sensitive to the drug (that is, their affinity for the drug decreases) or the receptors decrease in number. The second compensatory mechanism involves the process that couples the receptors to ion channels in the membrane or to the production of second messengers. After prolonged stimulation of the receptors, one or more steps in the coupling process become less effective. (Of course, both effects can occur.) As we have just seen, many drugs have several different sites of action and thus produce several different effects. This means that some of the effects of a drug may show tolerance but others may not. For example, barbiturates cause sedation and also depress neurons that control respiration. The sedative effects show tolerance, but the respiratory depression does not. This means that if larger and larger doses of a barbiturate are taken to achieve the same level of sedation, the person begins to run the risk of taking a dangerously large dose of the drug. Sensitization is, of course, the exact opposite of tolerance: Repeated doses of a drug produce larger and larger effects. Because compensatory mechanisms tend to correct for deviations away from the optimal values of physiological processes, sensitization is less common than tolerance.

affinity The readiness with which two molecules join together. tolerance A decrease in the effectiveness of a drug that is administered repeatedly. sensitization An increase in the effectiveness of a drug that is administered repeatedly. withdrawal symptom The appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken.

Psychopharmacology

In addition, some of the effects of a drug may show sensitization while others show tolerance. For example, repeated injections of cocaine become more and more likely to produce movement disorders and convulsions, whereas the euphoric effects of the drug do not show sensitization— and may even show tolerance.

Placebo Effects

placebo (pla see boh) An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug.

A placebo is an innocuous substance that has no specific physiological effect. The word comes from the Latin placere, “to please.” A physician may sometimes give a placebo to anxious patients to placate them. (You can see that the word placate also has the same root.) But although placebos have no specific physiological effect, it is incorrect to say that they have no effect. If a person thinks that a placebo has a physiological effect, then administration of the placebo may actually produce that effect. In fact, a study by Kaptchuk et al. (2010) found evidence of a placebo effect even when the subjects knew that they were receiving a placebo. The subjects were given placebo pills “made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement . . . through mind-body self-healing processes” (p. e15591). In other words, if the subjects expected a placebo effect, such an effect did indeed occur. When experimenters want to investigate the behavioral effects of drugs in humans, they must use control groups whose members receive placebos, or they cannot be sure that the behavioral effects they observe were caused by specific effects of the drug. Studies with laboratory animals must also use placebos, even though we need not worry about the animals’ “beliefs” about the effects of the drugs we give them. Consider what you must do to give a rat an intraperitoneal injection of a drug: You reach into the animal’s cage, pick the animal up, hold it in such a way that its abdomen is exposed and its head is positioned to prevent it from biting you, insert a hypodermic needle through its abdominal wall, press the plunger of the syringe, and replace the animal in its cage, being sure to let go of it quickly so that it cannot turn and bite you. Even if the substance you inject is innocuous, the experience of receiving the injection would activate the animal’s autonomic nervous system, cause the secretion of stress hormones, and have other physiological effects. If we want to know what the behavioral effects of a drug are, we must compare the drugtreated animals with other animals who receive a placebo, administered in exactly the same way as the drug. (By the way, a skilled and experienced researcher can handle a rat so gently that it shows very little reaction to a hypodermic injection.)

SECTION SUMMARY Principles of Psychopharmacology Psychopharmacology is the study of the effects of drugs on the nervous system and behavior. Drugs are exogenous chemicals that are not necessary for normal cellular functioning that significantly alter the functions of certain cells of the body when taken in relatively low doses. Drugs have effects, physiological and behavioral, and they have sites of action—molecules located somewhere in the body with which they interact to produce these effects. Pharmacokinetics is the fate of a drug as it is absorbed into the body, circulates throughout the body, and reaches its sites of action. Drugs may be administered by intravenous, intraperitoneal, intramuscular, and subcutaneous injection; they may be administered orally, sublingually, intrarectally, by inhalation, and topically (on skin or mucous membrane); and they may be injected intracerebrally or intracerebroventricularly. Lipid-soluble drugs easily pass through the blood–brain barrier, whereas others pass this barrier slowly or not at all. The dose-response curve represents a drug’s effectiveness; it relates the amount administered (usually in milligrams per kilogram of the subject’s body weight) to the resulting effect. Most drugs have more than

one site of action and therefore more than one effect. The safety of a drug is measured by the difference between doses that produce desirable effects and those that produce toxic side effects. Drugs vary in their effectiveness because of the nature of their sites of actions and the affinity between molecules of the drug and these sites of action. Repeated administration of a drug can cause either tolerance, often resulting in withdrawal symptoms, or sensitization. Tolerance can be caused by decreased affinity of a drug with its receptors, by decreased numbers of receptors, or by decreased coupling of receptors with the biochemical steps it controls. Some of the effects of a drug may show tolerance, while others may not—or may even show sensitization.

Thought Questions 1. Choose a drug whose effects you are familiar with, and suggest where in the body the sites of action of that drug might be. 2. Some drugs can cause liver damage if large doses are taken for an extended period of time. What aspect of the pharmacokinetics of these drugs might cause the liver damage?

Psychopharmacology

Sites of Drug Action Throughout the history of our species, people have discovered that plants—and some animals— produce chemicals that act on the nervous system. (Of course, the people who discovered these chemicals knew nothing about neurons and synapses.) Some of these chemicals have been used for their pleasurable effects; others have been used to treat illness, reduce pain, or poison other animals (or enemies). More recently, scientists have learned to produce completely artificial drugs, some with potencies far greater than those of the naturally occurring ones. The traditional uses of drugs remain; in addition, however, they can be used in research laboratories to investigate the operations of the nervous system. Most drugs that affect behavior do so by affecting synaptic transmission. These drugs are classified into two general categories: antagonists, those that block or inhibit the postsynaptic effects, and agonists, those that facilitate them. (The Greek word agon means “contest.” Thus, an agonist is one who takes part in the contest.) This section will describe the basic effects of drugs on synaptic activity. The sequence of synaptic activity goes like this: Neurotransmitters are synthesized and stored in synaptic vesicles. The synaptic vesicles travel to the presynaptic membrane. When an axon fires, voltage-dependent calcium channels in the presynaptic membrane open, permitting the entry of calcium ions. The calcium ions interact with proteins in the synaptic vesicles and presynaptic membrane and initiate the release of the neurotransmitters into the synaptic cleft. Molecules of the neurotransmitter bind with postsynaptic receptors, causing particular ion channels to open, which produces excitatory or inhibitory postsynaptic potentials. The effects of the neurotransmitter are kept relatively brief by their reuptake by transporter molecules in the presynaptic membrane or by their destruction by enzymes. In addition, the stimulation of presynaptic autoreceptors on the terminal buttons regulates the synthesis and release of the neurotransmitter. The discussion of the effects of drugs in this section follows the same basic sequence. All of the effects I will describe are summarized in Figure 4, with some details shown in additional figures. I should warn you that some of the effects are complex, so the discussion that follows bears careful reading.

Drug serves as precursor AGO (e.g., L-DOPA—dopamine)

antagonist A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell. agonist A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell.

Drug inactivates synthetic enzyme; inhibits synthesis of NT ANT (e.g., PCPA—serotonin)

Precursor

Enzyme 3

Drug prevents storage of NT in vesicles ANT (e.g., reserpine—monoamines)

Drug stimulates autoreceptors; inhibits synthesis/release of NT ANT (e.g., apomorphine—dopamine)

Neurotransmitter

Drug stimulates release of NT AGO (e.g., black widow spider venom—ACh) 9

Inhibition

Drug inhibits release of NT ANT (e.g., botulinum toxin—ACh)

Drug stimulates postsynaptic receptors AGO (e.g., nicotine, muscarine—ACh)

Choline + acetate ACh

Drug blocks postsynaptic receptors ANT (e.g., curare, atropine—ACh)

Drug blocks autoreceptors; increases synthesis/release of NT AGO (e.g., idazoxan—norepinephrine)

Molecules of drugs

AChE

Drug blocks reuptake AGO (e.g., cocaine—dopamine) Drug inactivates acetylcholinesterase AGO (e.g., physostigmine—ACh)

F I G U R E 4 Drug Effects on Synaptic Transmission. The figure summarizes the ways in which drugs can affect the synaptic transmission (AGO = agonist; ANT = antagonist; NT = neurotransmitter). Drugs that act as agonists are marked in blue; drugs that act as antagonists are marked in red.

Psychopharmacology

Effects on Production of Neurotransmitters The first step is the synthesis of the neurotransmitter from its precursors. In some cases the rate of synthesis and release of a neurotransmitter is increased when a precursor is administered; in these cases the precursor itself serves as an agonist. (See step 1 in Figure 4.) The steps in the synthesis of neurotransmitters are controlled by enzymes. Therefore, if a drug inactivates one of these enzymes, it will prevent the neurotransmitter from being produced. Such a drug serves as an antagonist. (See step 2 in Figure 4.)

Effects on Storage and Release of Neurotransmitters Neurotransmitters are stored in synaptic vesicles, which are transported to the presynaptic membrane where the chemicals are released. The storage of neurotransmitters in vesicles is accomplished by the same kind of transporter molecules that are responsible for reuptake of a neurotransmitter into a terminal button. The transporter molecules are located in the membrane of synaptic vesicles, and their action is to pump molecules of the neurotransmitter across the membrane, filling the vesicles. Some of the transporter molecules that fill synaptic vesicles are capable of being blocked by a drug. Molecules of the drug bind with a particular site on the transporter and inactivate it. Because the synaptic vesicles remain empty, nothing is released when the vesicles eventually rupture against the presynaptic membrane. The drug serves as an antagonist. (See step 3 in Figure 4.) Some drugs act as antagonists by preventing the release of neurotransmitters from the terminal button. They do so by deactivating the proteins that cause synaptic vesicles to fuse with the presynaptic membrane and expel their contents into the synaptic cleft. Other drugs have just the opposite effect: They act as agonists by binding with these proteins and directly triggering release of the neurotransmitter. (See steps 4 and 5 in Figure 4.)

Effects on Receptors

direct agonist A drug that binds with and activates a receptor. receptor blocker A drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor. direct antagonist A synonym for receptor blocker. noncompetitive binding Binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand. indirect antagonist A drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding site for the principal ligand.

The most important—and most complex—site of action of drugs in the nervous system is on receptors, both presynaptic and postsynaptic. Let’s consider postsynaptic receptors first. (Here is where the careful reading should begin.) Once a neurotransmitter has been released, it must stimulate the postsynaptic receptors. Some drugs bind with these receptors, just as the neurotransmitter does. Once a drug has bound with the receptor, it can serve as either an agonist or an antagonist. A drug that mimics the effects of a neurotransmitter acts as a direct agonist. Molecules of the drug attach to the binding site to which the neurotransmitter normally attaches. This binding causes ion channels controlled by the receptor to open, just as they do when the neurotransmitter is present. Ions then pass through these channels and produce postsynaptic potentials. (See step 6 in Figure 4.) Drugs that bind with postsynaptic receptors can also serve as antagonists. Molecules of such drugs bind with the receptors but do not open the ion channel. Because they occupy the receptor’s binding site, they prevent the neurotransmitter from opening the ion channel. These drugs are called receptor blockers or direct antagonists. (See step 7 in Figure 4.) Some receptors have multiple binding sites, to which different ligands can attach. Molecules of the neurotransmitter bind with one site, and other substances (such as neuromodulators and various drugs) bind with the others. Binding of a molecule with one of these alternative sites is referred to as noncompetitive binding, because the molecule does not compete with molecules of the neurotransmitter for the same binding site. If a drug attaches to one of these alternative sites and prevents the ion channel from opening, the drug is said to be an indirect antagonist. The ultimate effect of an indirect antagonist is similar to that of a direct antagonist, but its site of

Psychopharmacology

Drug

Neurotransmitter binding site Drug

Neurotransmitter

Drug

Neurotransmitter

Drug

Competitive Binding

Direct agonist

Direct antagonist

Neuromodulator binding site

Noncompetitive Binding

Indirect agonist

(a)

Indirect antagonist (b)

F I G U R E 5 Drug Actions as Binding Sites. (a) Competitive binding: Direct agonists and antagonists act directly on the neurotransmitter binding site. (b) Noncompetitive binding: Indirect agonists and antagonists act on an alternative binding site and modify the effects of the neurotransmitter on opening of the ion channel.

action is different. If a drug attaches to one of the alternative sites and facilitates the opening of the ion channel, it is said to be an indirect agonist. (See Figure 5.) The presynaptic membranes of some neurons contain autoreceptors that regulate the amount of neurotransmitter that is released. Because stimulation of these receptors causes less neurotransmitter to be released, drugs that selectively activate presynaptic receptors act as antagonists. Drugs that block presynaptic autoreceptors have the opposite effect: They increase the release of the neurotransmitter, acting as agonists. (Refer to steps 8 and 9 in Figure 4.)

Effects on Reuptake or Destruction of Neurotransmitters The next step after stimulation of the postsynaptic receptor is termination of the postsynaptic potential. Two processes accomplish this task: Molecules of the neurotransmitter are taken back into the terminal button through the process of reuptake, or they are destroyed by an enzyme. Drugs can interfere with either of these processes. In the first case molecules of the drug attach to the transporter molecules that are responsible for reuptake and inactivate them, thus blocking reuptake. In the second case molecules of the drug bind with the enzyme that normally destroys the neurotransmitter and prevents the enzymes from working. The most important example of such an enzyme is acetylcholinesterase, which destroys acetylcholine. Because both types of drugs prolong the presence of the neurotransmitter in the synaptic cleft (and hence in a location where they can stimulate postsynaptic receptors), they serve as agonists. (Refer to steps 10 and 11 in Figure 4.)

indirect agonist A drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site for the principal ligand.

SECTION SUMMARY Sites of Drug Action The process of synaptic transmission entails the synthesis of the neurotransmitter, its storage in synaptic vesicles, its release into the synaptic cleft, its interaction with postsynaptic receptors, and the consequent opening of ion channels in the postsynaptic membrane. The effects of the neurotransmitter are then terminated by reuptake into the terminal button or by enzymatic deactivation. Each of the steps necessary for synaptic transmission can be interfered with by drugs that serve as antagonists, and a few of these steps can be stimulated by drugs that serve as agonists. In particular, drugs

can increase the pool of available precursor, block a biosynthetic enzyme, prevent the storage of neurotransmitter in the synaptic vesicles, stimulate or block the release of the neurotransmitter, stimulate or block presynaptic or postsynaptic receptors, retard reuptake, or deactivate enzymes that destroy the neurotransmitter postsynaptically or presynaptically. A drug that activates postsynaptic receptors serves as an agonist, whereas one that activates presynaptic autoreceptors serves as an antagonist. A drug that blocks postsynaptic receptors serves as an antagonist, whereas one that blocks autoreceptors serves as an agonist.

Psychopharmacology

Neurotransmitters and Neuromodulators Because neurotransmitters have two general effects on postsynaptic membranes—depolarization (EPSP) and hyperpolarization (IPSP)—one might expect that there would be two kinds of neurotransmitters: excitatory and inhibitory. Instead, there are many different kinds—several dozen, at least. In the brain most synaptic communication is accomplished by two neurotransmitters: one with excitatory effects (glutamate) and one with inhibitory effects (GABA). (Another inhibitory neurotransmitter, glycine, is found in the spinal cord and lower brain stem.) Most of the activity of local circuits of neurons involves balances between the excitatory and inhibitory effects of these chemicals, which are responsible for most of the information transmitted from place to place within the brain. In fact, there are probably no neurons in the brain that do not receive excitatory input from glutamate-secreting terminal buttons and inhibitory input from neurons that secrete either GABA or glycine. And with the exception of neurons that detect painful stimuli, all sensory organs transmit information to the brain through axons whose terminals release glutamate. (Pain-detecting neurons secrete a peptide.) What do all the other neurotransmitters do? In general, they have modulating effects rather than information-transmitting effects. That is, the release of neurotransmitters other than glutamate and GABA tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions. For example, secretion of acetylcholine activates the cerebral cortex and facilitates learning, but the information that is learned and remembered is transmitted by neurons that secrete glutamate and GABA. Secretion of norepinephrine increases vigilance and enhances readiness to act when a signal is detected. Secretion of histamine enhances wakefulness. Secretion of serotonin suppresses certain categories of species-typical behaviors and reduces the likelihood that the animal acts impulsively. Secretion of dopamine in some regions of the brain generally activates voluntary movements but does not specify which movements will occur. In other regions secretion of dopamine reinforces ongoing behaviors and makes them more likely to occur at a later time. Because particular drugs can selectively affect neurons that secrete particular neurotransmitters, they can have specific effects on behavior. This section introduces the most important neurotransmitters, discusses some of their behavioral functions, and describes the drugs that interact with them. As we saw in the previous section of this chapter, drugs have many different sites of action. Fortunately for your information-processing capacity (and perhaps your sanity), not all types of neurons are affected by all types of drugs. As you will see, that still leaves a good number of drugs to be mentioned by name. Obviously, some are more important than others. Those whose effects I describe in some detail are more important than those I mention in passing.

Acetylcholine

The venom of the black widow spider is much less toxic than botulinum toxin, but both toxins affect the release of acetylcholine. Scott Camazine / Photo Researchers, Inc.

Acetylcholine (ACh) is the primary neurotransmitter secreted by efferent axons of the central nervous system. All muscular movement is accomplished by the release of acetylcholine, and ACh is also found in the ganglia of the autonomic nervous system and at the target organs of the parasympathetic branch of the ANS. Because ACh is found outside the central nervous system in locations that are easy to study, this neurotransmitter was the first to be discovered, and it has received much attention from neuroscientists. Some terminology: These synapses are said to be acetylcholinergic. Ergon is the Greek word for “work.” Thus, dopaminergic synapses release dopamine, serotonergic synapses release serotonin, and so on. (The suffix -ergic is pronounced “ur jik.”) The axons and terminal buttons of acetylcholinergic neurons are distributed widely throughout the brain. Three systems have received the most attention from neuroscientists: those originating in the dorsolateral pons, the basal forebrain, and the medial septum. The effects of ACh release in the brain are generally facilitatory. The acetylcholinergic neurons located in the dorsolateral pons play a role in REM sleep (the phase of sleep during which dreaming occurs). Those located in the basal forebrain are involved in activating the cerebral cortex and facilitating learning, especially perceptual learning. Those located in the medial septum control the electrical rhythms of the hippocampus and modulate its functions, which include the formation of particular kinds of memories. Acetylcholine is composed of two components: choline, a substance derived from the breakdown of lipids, and acetate, the anion found in vinegar, also called acetic acid. Acetate cannot be

Psychopharmacology

attached directly to choline; instead, it is transferred from a molecule of Coenzyme A Acetyl coenzyme A acetyl-CoA. CoA (coenzyme A) is a complex molecule, consisting in part (CoA) (acetyl-CoA) of the vitamin pantothenic acid (one of the B vitamins). CoA is produced by the mitochondria, and it takes part in many reactions in the body. Acetyl-CoA is simply CoA with an acetate ion attached to it. ACh is proAcetylcholine (ACh) duced by the following reaction: In the presence of the enzyme choline acetyltransferase (ChAT), the acetate ion is transferred from the acetyl-CoA ChAT transfers molecule to the choline molecule, yielding a molecule of ACh and one of acetate ion from acetyl-CoA to ordinary CoA. (See Figure 6.) Choline choline Choline A simple analogy will illustrate the role of coenzymes in chemical acetyltransferase reactions. Think of acetate as a hot dog and choline as a bun. The task of (ChAT) the person (enzyme) who operates the hot dog vending stand is to put a hot dog into the bun (make acetylcholine). To do so, the vendor needs a fork (coenzyme) to remove the hot dog from the boiling water. The FI G U R E 6 Biosynthesis of Acetylcholine. vendor inserts the fork into the hot dog (attaches acetate to CoA) and transfers the hot dog from fork to bun. Two drugs, botulinum toxin and the venom of the black widow spider, affect the release of acetylcholine. Botulinum toxin is produced by clostridium botulinum, a bacterium that can grow acetyl-CoA (a see tul) A cofactor that in improperly canned food. This drug prevents the release of ACh (step 5 of Figure 4). The drug is supplies acetate for the synthesis of an extremely potent poison; someone once calculated that a teaspoonful of pure botulinum toxin acetylcholine. could kill the world’s entire human population. You undoubtedly know that botox treatment has choline acetyltransferase (ChAT) (koh become fashionable. In these treatments, a very dilute (obviously!) solution of botulinum toxin leen a see tul trans fer ace) The enzyme is injected into people’s facial muscles to stop muscular contractions that are causing wrinkles in that transfers the acetate ion from acetyl the skin. In contrast, black widow spider venom has the opposite effect: It stimulates the release coenzyme A to choline, producing the neurotransmitter acetylcholine. of ACh (step 4 of Figure 4). Although the effects of black widow spider venom can also be fatal, the venom is much less toxic than botulinum toxin. In fact, most healthy adults have to receive botulinum toxin (bot you lin um) An acetylcholine antagonist; prevents several bites for a fatal reaction; however, infants and frail, elderly people are more susceptible. release by terminal buttons. After being released by the terminal button, ACh is deactivated by the enzyme acetylcholinblack widow spider venom A poison esterase (AChE), which is present in the postsynaptic membrane. (See Figure 7.) produced by the black widow spider that Drugs that deactivate AChE (step 11 of Figure 4) are used for several purposes. Some are used triggers the release of acetylcholine. as insecticides. These drugs readily kill insects but not humans and other mammals, because our neostigmine (nee o stig meen) A blood contains enzymes that destroy them. (Insects lack the enzyme.) Other AChE inhibitors are drug that inhibits the activity of used medically. For example, a hereditary disorder called myasthenia gravis is caused by an attack acetylcholinesterase. of a person’s immune system against acetylcholine receptors located on skeletal muscles. The pernicotinic receptor An ionotropic son becomes weaker and weaker as the muscles become less responsive to the neurotransmitter. If acetylcholine receptor that is stimulated the person is given an AChE inhibitor such as neostigmine, the person will regain some strength, by nicotine and blocked by curare. because the acetylcholine that is released has a more prolonged effect on the remaining receptors. muscarinic receptor (muss ka rin ic) (Fortunately, neostigmine cannot cross the blood–brain barrier, so it does not affect the AChE A metabotropic acetylcholine receptor found in the central nervous system.) that is stimulated by muscarine and blocked by atropine. There are two types of ACh receptors—one ionotropic and one metabotropic. These receptors were identified when investigators discovered that different drugs activated them (step 6 of Figure 4). The ionotropic ACh receptor is stimulated by nicotine, a drug found in tobacco leaves. (The Latin name of the plant is Nicotiana tabacum.) The metabotropic ACh receptor is stimulated by muscarine, a drug found in the poison mushroom Amanita muscaria. Consequently, these two ACh receptors Acetylcholine are referred to as nicotinic receptors and muscarinic receptors, respectively. molecule Acetate ion Because muscle fibers must be able to contract rapidly, they contain the rapid, ionotropic nicotinic receptors. Because muscarinic receptors are metabotropic Choline molecule in nature and thus control ion channels through the production of second messengers, their actions are slower and more prolonged than those of nicoAction of AChE tinic receptors. The central nervous system contains both kinds of ACh recepbreaks apart tors, but muscarinic receptors predominate. Some nicotinic receptors are found Acetylcholinacetylcholine esterase at axoaxonic synapses in the brain, where they produce presynaptic facilitation. molecule (AChE) Activation of these receptors is responsible for the addictive effect of the nicotine found in tobacco smoke. FI G U R E 7 Destruction of Acetylcholine (ACh) by Acetylcholinesterase (AChE).

Psychopharmacology

Just as two different drugs stimulate the two classes of acetylcholine receptors, two different drugs block them (step 7 of Figure 4). Both drugs were discovered in nature long ago, and both are still used by modern medicine. The first, atropine, blocks muscarinic receptors. The drug is named after Atropos, the Greek fate who cut the thread of life (which a sufficient dose of atropine will certainly do). Atropine is one of several belladonna alkaloids extracted from a plant called the deadly nightshade, and therein lies a tale. Many years ago, women who wanted to increase their attractiveness to men put drops containing belladonna alkaloids into their eyes. In fact, belladonna means “pretty lady.” Why was the drug used this way? One of the unconscious responses that occurs when we are interested in something is dilation of our pupils. By blocking the effects of acetylcholine on the pupil, belladonna alkaloids such as atropine make the pupils dilate. This change makes a woman appear more interested in a man when she looks at him, and, of course, this apparent sign of interest makes him regard her as more attractive. Another drug, curare, blocks nicotinic receptors. Because these receptors are the ones found on muscles, curare, like botulinum toxin, causes paralysis. However, the effects of curare are much faster. The drug is extracted from several different species of plants found in South America, where it was discovered long ago by people who used it to coat the tips of arrows and darts. Within minutes of being struck by one of these points, an animal collapses, ceases breathing, and dies. Nowadays, curare (and other drugs with the same site of action) are used to paralyze patients who are to undergo surgery so that their muscles will relax completely and not contract when they are cut with a scalpel. An anesthetic must also be used, because a person who receives only curare will remain perfectly conscious and sensitive to pain, even though paralyzed. And, of course, a respirator must be used to supply air to the lungs.

The Monoamines Dopamine, norepinephrine, epinephrine, and serotonin are four chemicals that belong to a family of compounds called monoamines. Because the molecular structures of these substances are similar, some drugs affect the activity of all of them to some degree. The first three—dopamine, norepinephrine, and epinephrine—belong to a subclass of monoamines called catecholamines. (See Table 1.) The monoamines are produced by several systems of neurons in the brain. Most of these systems consist of a relatively small number of cell bodies located in the brain stem, whose axons branch repeatedly and give rise to an enormous number of terminal buttons distributed throughout many regions of the brain. Monoaminergic neurons thus serve to modulate the function of widespread regions of the brain, increasing or decreasing the activities of particular brain functions. DOPAMINE

atropine (a tro peen) A drug that blocks muscarinic acetylcholine receptors. curare (kew rahr ee) A drug that blocks nicotinic acetylcholine receptors. monoamine (mahn o a meen) A class of amines that includes indolamines such as serotonin and catecholamines such as dopamine, norepinephrine, and epinephrine. catecholamine (cat a kohl a meen) A class of amines that includes the neurotransmitters dopamine, norepinephrine, and epinephrine. dopamine (DA) (dope a meen) A neurotransmitter; one of the catecholamines.

The first catecholamine in Table 1, dopamine (DA), produces both excitatory and inhibitory postsynaptic potentials, depending on the postsynaptic receptor. Dopamine is one of the more interesting neurotransmitters because it has been implicated in several important functions, including movement, attention, learning, and the reinforcing effects of drugs that people tend to abuse.

TABLE

1 Classification of the Monoamine Transmitter Substances

Catecholamines

Indolamines

Dopamine

Serotonin

Norepinephrine Epinephrine

Psychopharmacology

The synthesis of the catecholamines is somewhat more complicated than that of ACh, but each step is a simple one. The precursor molecule is modified slightly, step by step, until it achieves its final shape. Each step is controlled by a different enzyme, which causes a small part to be added or taken off. The precursor for the two major catecholamine neurotransmitters (dopamine and norepinephrine) is tyrosine, an essential amino acid that we must obtain from our diet. An enzyme converts tyrosine into l-DOPA. Another enzyme converts l-DOPA into dopamine. In dopaminergic neurons, that conversion is the last step; however, in noradrenergic neurons dopamine is converted into norepinephrine. (See Figure 8.) The brain contains several systems of dopaminergic neurons. The three most important of these originate in the midbrain. The cell bodies of neurons of the nigrostriatal system are located in the substantia nigra and project their axons to the neostriatum: the caudate nucleus and the putamen. The neostriatum, an important part of the basal ganglia, is involved in the control of movement. The cell bodies of neurons of the mesolimbic system are located in the ventral tegmental area and project their axons to several parts of the limbic system, including the nucleus accumbens, amygdala, and hippocampus. (The term meso- refers to the midbrain, or mesencephalon.) The nucleus accumbens plays an important role in the reinforcing (rewarding) effects of certain categories of stimuli, including those of drugs that people abuse. The cell bodies of neurons of the mesocortical system are also located in the ventral tegmental area. Their axons project to the prefrontal cortex. These neurons have an excitatory effect on the frontal cortex and thus affect such functions as formation of short-term memories, planning, and strategy preparation for problem solving. (See Table 2.) Degeneration of dopaminergic neurons that connect the substantia nigra with the caudate nucleus causes Parkinson’s disease, a movement disorder characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements. The cell bodies of these neurons are located in a region of the brain called the substantia nigra (“black substance”). This region is normally stained black with melanin, the substance that gives color to skin. This compound is produced by the breakdown of dopamine. (The brain damage that causes Parkinson’s disease was discovered by pathologists who observed that the substantia nigra of a deceased person who had had this disorder was pale rather than black.) People with Parkinson’s disease are given l-DOPA, the precursor to dopamine. Although dopamine cannot cross the blood–brain barrier, l-DOPA can. Once l-DOPA reaches the brain, it is taken up by dopaminergic neurons and is converted to dopamine (step 1 of Figure 4). The increased synthesis of dopamine causes more dopamine to be released by the surviving dopaminergic neurons in patients with Parkinson’s disease. As a consequence, the patients’ symptoms are alleviated. Another drug, AMPT (or α-methyl-p-tyrosine), inactivates tyrosine hydroxylase, the enzyme that converts tyrosine to l-DOPA (step 2 of Figure 4). Because this drug interferes with the synthesis of dopamine (and of norepinephrine, as well), it serves as a catecholamine antagonist. The drug is not normally used medically, but it has been used as a research tool in laboratory animals. The drug reserpine prevents the storage of monoamines in synaptic vesicles by blocking the transporters in the membrane of vesicles in the terminals of monoaminergic neurons (step 3 of Figure 4). Because the synaptic vesicles remain empty, no neurotransmitter is released when an action potential reaches the terminal button. Reserpine, then, is a monoamine antagonist.

TABLE

Tyrosine Enzyme L-DOPA

Enzyme Dopamine Enzyme Norepinephrine F I G U R E 8 Biosynthesis of the Catecholamines.

L-DOPA (ell dope a)

The levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson’s disease because of its effect as a dopamine agonist. nigrostriatal system (nigh grow stry ay tul) A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen).

mesolimbic system (mee zo lim bik) A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus. mesocortical system (mee zo kor ti kul) A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex.

2 The Three Major Dopaminergic Pathways

Name

Origin (Location of Cell Bodies)

Location of Terminal Buttons

Nigrostriatal system

Substantia nigra

Neostriatum (caudate nucleus and putamen)

Control of movement

Mesolimbic system

Ventral tegmental area

Nucleus accumbens and amygdala

Reinforcement, effects of addictive drugs

Mesocortical system

Ventral tegmental area

Prefrontal cortex

Short-term memories, planning, strategies for problem solving

Behavioral Effects

Parkinson’s disease A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system. AMPT A drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines. reserpine (ree sur peen) A drug that interferes with the storage of monoamines in synaptic vesicles.

Psychopharmacology

methylphenidate (meth ul fen i date) A drug that inhibits the reuptake of dopamine. monoamine oxidase (MAO) (mahn o a meen) A class of enzymes that destroy the monoamines: dopamine, norepinephrine, and serotonin. deprenyl (depp ra nil) A drug that blocks the activity of MAO-B; acts as a dopamine agonist. chlorpromazine (klor proh ma zeen) A drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors.

MAO converts dopamine to an inactive substance Dopamine

The drug, which comes from the root of a shrub, was discovered over three thousand years ago in India, where it was found to be useful in treating snakebite and seemed to have a calming effect. Pieces of the root are still sold in markets in rural areas of India. In Western medicine reserpine was previously used to treat high blood pressure, but it has been replaced by drugs that have fewer side effects. Several different types of dopamine receptors have been identified, all metabotropic. Of these, two are the most common: D1 dopamine receptors and D2 dopamine receptors. It appears that D1 receptors are exclusively postsynaptic, whereas D2 receptors are found both presynaptically and postsynaptically in the brain. Several drugs stimulate or block specific types of dopamine receptors. Several drugs inhibit the reuptake of dopamine, thus serving as potent dopamine agonists (step 10 of Figure 4). The best known of these drugs are amphetamine, cocaine, and methylphenidate. Amphetamine has an interesting effect: It causes the release of both dopamine and norepinephrine by causing the transporters for these neurotransmitters to run in reverse, propelling DA and NE into the synaptic cleft. Of course, this action also blocks reuptake of these neurotransmitters. Cocaine and methylphenidate simply block dopamine reuptake. Because cocaine also blocks voltage-dependent sodium channels, it is sometimes used as a topical anesthetic, especially in the form of eye drops for eye surgery. Methylphenidate (Ritalin) is used to treat children with attention deficit disorder. The production of the catecholamines is regulated by an enzyme called monoamine oxidase (MAO). This enzyme is found within monoaminergic terminal buttons, where it destroys excessive amounts of neurotransmitter. A drug called deprenyl destroys the particular form of monoamine oxidase (MAO-B) that is found in dopaminergic terminal buttons. Because deprenyl prevents the destruction of dopamine, more dopamine is released when an action potential reaches the terminal button. Thus, deprenyl serves as a dopamine agonist. (See Figure 9.) MAO is also found in the blood, where it deactivates amines that are present in foods such as chocolate and cheese; without such deactivation these amines could cause dangerous increases in blood pressure. Dopamine has been implicated as a neurotransmitter that might be involved in schizophrenia, a serious mental disorder whose symptoms include hallucinations, delusions, and disruption of normal, logical thought processes. Drugs such as chlorpromazine, which block D2 receptors, alleviate these symptoms (step 7 of Figure 4). Hence, investigators have speculated that schizophrenia is produced by overactivity of dopaminergic neurons. More recently discovered drugs— the so-called atypical antipsychotics—have more complicated actions.

Because of the higher concentration of dopamine, more dopamine is stored in synaptic vesicles

Deprenyl, an MAO inhibitor, blocks the destruction of dopamine MAO

MAO Inactive substance

Dopamine is stored in synaptic vesicles

F I G U R E 9 Role of Monoamine Oxidase (MAO). This schematic illustration shows the role of monoamine oxidase in dopaminergic terminal buttons and the action of deprenyl.

Psychopharmacology

NOREPINEPHRINE Because norepinephrine (NE), like ACh, is found in neurons in the autonomic nervous system, this neurotransmitter has received much experimental attention. I should note that the terms Adrenalin and epinephrine are synonymous, as are noradrenalin and norepinephrine. Let me explain why. Epinephrine is a hormone produced by the adrenal medulla, the central core of the adrenal glands, located just above the kidneys. Epinephrine also serves as a neurotransmitter in the brain, but it is of minor importance compared with norepinephrine. Ad renal is Latin for “toward kidney.” In Greek, one would say epi nephron (“upon the kidney”), hence the term epinephrine. The latter term has been adopted by pharmacologists, probably because the word Adrenalin was appropriated by a drug company as a proprietary name; therefore, to be consistent with general usage, I will refer to the neurotransmitter as norepinephrine. The accepted adjectival form is noradrenergic; I suppose that norepinephrinergic never caught on because it takes so long to pronounce. We have already seen the biosynthetic pathway for norepinephrine in Figure 8. The drug fusaric acid, which prevents the conversion of dopamine to norepinephrine, blocks the production of NE. Almost every region of the brain receives input from noradrenergic neurons. The cell bodies of most of these neurons are located in seven regions of the pons and medulla and one region of the thalamus. The cell bodies of the most important noradrenergic system begin in the locus coeruleus, a nucleus located in the dorsal pons. The axons of these neurons project to widespread regions of the brain. One effect of activation of these neurons is an increase in vigilance—attentiveness to events in the environment. There are several types of noradrenergic receptors, identified by their differing sensitivities to various drugs. Actually, these receptors are usually called adrenergic receptors rather than noradrenergic receptors, because they are sensitive to epinephrine (Adrenalin) as well as norepinephrine. Neurons in the central nervous system contain β1- and β2-adrenergic receptors and α1- and α2adrenergic receptors. All four kinds of receptors are also found in various organs of the body besides the brain and are responsible for the effects of the catecholamines when they act as hormones outside the central nervous system. In the brain all autoreceptors appear to be of the α2 type. The drug idazoxan blocks α2 autoreceptors and hence acts as an agonist. All adrenergic receptors are metabotropic, coupled to G proteins that control the production of second messengers. SEROTONIN The third monoamine neurotransmitter, serotonin (also called 5-HT, or 5-hydroxytryptamine), has also received much experimental attention. Its behavioral effects are complex. Serotonin plays a role in the regulation of mood; in the control of eating, sleep, and arousal; and in the regulation of pain. Serotonergic neurons are involved somehow in the control of dreaming. The precursor for serotonin is the amino acid tryptophan. An enzyme converts tryptophan to 5-HTP (5-hydroxytryptophan). Another enzyme converts 5-HTP to 5-HT (serotonin). (See Figure 10.) The drug PCPA (p-chlorophenylalanine) blocks the conversion of tryptophan to 5-HTP and thus serves as a serotonergic antagonist. The cell bodies of serotonergic neurons are found in nine clusters, most of which are located in the raphe nuclei of the midbrain, pons, and medulla. The two most important clusters are found in the dorsal and medial raphe nuclei, and I will restrict my discussion to these clusters. The word raphe means “seam” or “crease” and refers to the fact that most of the raphe nuclei are found at or near the midline of the brain stem. Both the dorsal and median raphe nuclei project axons to the cerebral cortex. In addition, neurons in the dorsal raphe innervate the basal ganglia, and those in the median raphe innervate the dentate gyrus, a part of the hippocampal formation. Investigators have identified at least nine different types of serotonin receptors, and pharmacologists have discovered drugs that serve as agonists or antagonists for many of these types of 5-HT receptors. Drugs that inhibit the reuptake of serotonin have found a very important place in the treatment of mental disorders. The best known of these, fluoxetine (Prozac), is used to treat depression, some forms of anxiety disorders, and obsessive-compulsive disorder. Another drug, fenfluramine, which causes the release of serotonin as well as inhibits its reuptake, was formerly used as an appetite suppressant in the treatment of obesity.

norepinephrine (NE) (nor epp i neff rin) One of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the autonomic nervous system. epinephrine (epp i neff rin) One of the catecholamines; a hormone secreted by the adrenal medulla; serves also as a neurotransmitter in the brain. fusaric acid (few sahr ik) A drug that inhibits the activity of the enzyme dopamine-β-hydroxylase and thus blocks the production of norepinephrine. locus coeruleus (sur oo lee us) A darkcolored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle. idazoxan A drug that blocks presynaptic noradrenergic α2 receptors and hence acts as an agonist, stimulating the synthesis and release of NE. serotonin (5-HT) (sair a toe nin) An indolamine neurotransmitter; also called 5-hydroxytryptamine. PCPA A drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT. fluoxetine (floo ox i teen) A drug that inhibits the reuptake of 5-HT. fenfluramine (fen fluor i meen) A drug that stimulates the release of 5-HT.

Tryptophan Enzyme 5-hydroxytryptophan (5-HTP) Enzyme 5-hydroxytryptamine (5-HT, or serotonin) F I G U R E 10 Biosynthesis of Serotonin (5-hydroxytryptamine, or 5-HT).

Psychopharmacology

Several hallucinogenic drugs produce their effects by interacting with serotonergic transmission. LSD (lysergic acid diethylamide) produces distortions of visual perceptions that some people find awesome and fascinating but that simply frighten other people. This drug, which is effective in extremely small doses, is a direct agonist for postsynaptic 5-HT2A receptors in the forebrain. Another drug, MDMA (methylenedioxymethamphetamine), is both a noradrenergic and serotonergic agonist and has both excitatory and hallucinogenic effects. Like its relative amphetamine, MDMA (popularly called “ecstasy”) causes noradrenergic transporters to run backwards, thus causing the release of NE and inhibiting its reuptake. This site of action is apparently responsible for the drug’s excitatory effect. MDMA also causes serotonergic transporters to run backwards, and this site of action is apparently responsible for the drug’s hallucinogenic effects. Unfortunately, research indicates that MDMA can damage serotonergic neurons and cause cognitive deficits. HISTAMINE Histamine is produced from histidine—an amino acid—by the action of the enzyme histidine decarboxylase. The cell bodies of histaminergic neurons are found in only one place in the brain: the tuberomammillary nucleus, located in the posterior hypothalamus. Histaminergic neurons send their axons to widespread regions of the cerebral cortex and brain stem. Histamine plays an important role in wakefulness. In fact, the activity of histaminergic neurons is strongly correlated with the states of sleep and wakefulness, and drugs that block histamine receptors cause drowsiness. Histamine also plays a role in control of the digestive system and immune system and is essential for the development of allergic symptoms. Histaminergic H1 receptors are responsible for the itching produced by histamine and for the constriction of the bronchi seen in asthma attacks, H2 receptors stimulate gastric secretions, and both H2 and H4 receptors are involved in immune reactions. Cimetidine, an H2 antagonist, blocks gastric acid secretion. H3 receptors serve as autoreceptors on the terminals of histaminergic neurons in the brain; thus, the drug ciproxifan, an H3 antagonist, increases the release of histamine. All types of histamine receptors are found in the central nervous system. The older antihistamines (H1 antagonists) such as diphenhydramine produced drowsiness. In fact, some over-the-counter sleep aids contain these drugs for that very reason. Modern antihistamines that are used to treat the symptoms of allergies do not cross the blood–brain barrier, so they have no direct effects on the brain.

Amino Acids

LSD A drug that stimulates 5-HT2A receptors. MDMA A drug that serves as a noradrenergic and serotonergic agonist, also known as “ecstasy”; has excitatory and hallucinogenic effects. histamine A neurotransmitter that plays an important role in stimulating wakefulness. glutamate An amino acid; the most important excitatory neurotransmitter in the brain.

So far, all of the neurotransmitters I have described are synthesized within neurons: acetylcholine from choline, the catecholamines from the amino acid tyrosine, and serotonin from the amino acid tryptophan. Some neurons secrete simple amino acids as neurotransmitters. Because amino acids are used for protein synthesis by all cells of the brain, it is difficult to prove that a particular amino acid is a neurotransmitter. However, investigators suspect that at least eight amino acids may serve as neurotransmitters in the mammalian central nervous system. As we saw in the introduction to this section, three of them are especially important because they are the most common neurotransmitters in the CNS: glutamate, gamma-aminobutyric acid (GABA), and glycine. GLUTAMATE Because glutamate (also called glutamic acid) and GABA are found in very simple organisms, many investigators believe that these neurotransmitters are the first to have evolved. Besides producing postsynaptic potentials by activating postsynaptic receptors, they also have direct excitatory effects (glutamic acid) and inhibitory effects (GABA) on axons; they raise or lower the threshold of excitation, thus affecting the rate at which action potentials occur. These direct effects suggest that these substances had a general modulating role even before the evolutionary development of specific receptor molecules.

Psychopharmacology

Glutamate, the principal excitatory neurotransmitter in the brain and spinal cord, is produced in abundance by the cells’ metabolic processes. There is no effective way to prevent its synthesis without disrupting other activities of the cell. Investigators have discovered four major types of glutamate receptors. Three of these receptors are ionotropic and are named after the artificial ligands that stimulate them: the NMDA receptor, the AMPA receptor, and the kainate receptor. The other glutamate receptor—the metabotropic glutamate receptor—is (obviously!) metabotropic. Actually, there appear to be at least seven subtypes of metabotropic glutamate receptors, but little is known about their functions except that some of them serve as presynaptic autoreceptors. The AMPA receptor is the most common glutamate receptor. It controls a sodium channel, so when glutamate attaches to the binding site, it produces EPSPs. The kainate receptor, which is stimulated by the drug kainic NMDA receptor A specialized acid, has similar effects. ionotropic glutamate receptor that The NMDA receptor has some special—and very important—characteristics. It contains at controls a calcium channel that is normally blocked by Mg2+ ions; has least six different binding sites: four located on the exterior of the receptor and two located deep several other binding sites. within the ion channel. When it is open, the ion channel controlled by the NMDA receptor AMPA receptor An ionotropic permits both sodium and calcium ions to enter the cell. The influx of both of these ions causes a glutamate receptor that controls a depolarization, of course, but the entry of calcium (Ca2+) is especially important. Calcium serves sodium channel; stimulated by AMPA. as a second messenger, binding with—and activating—various enzymes within the cell. These kainate receptor (kay in ate) An enzymes have profound effects on the cell’s biochemical and structural properties. As we shall ionotropic glutamate receptor that see, one important result is alteration in the characteristics of the synapse that provide one of the controls a sodium channel; stimulated building blocks of a newly formed memory. The drug AP5 (2-amino-5-phosphonopentanoate) by kainic acid. blocks the glutamate binding site on the NMDA receptor and impairs synaptic plasticity and metabotropic glutamate receptor certain forms of learning. (meh tab a troh pik) A category of Figure 11 presents a schematic diagram of an NMDA receptor and its binding sites. Obmetabotropic receptors that are sensitive to glutamate. viously, glutamate binds with one of these sites, or we would not call it a glutamate receptor. However, glutamate by itself cannot open the calcium channel. For that to happen, a molecule AP5 (2-amino-5-phosphonopentanoate) A drug that blocks the glutamate binding of glycine must be attached to the glycine binding site, located on the outside of the receptor. site on NMDA receptors. (We do not yet understand why glycine—which also serves as an inhibitory neurotransmitPCP Phencyclidine; a drug that binds ter in some parts of the central nervous system—is required for this ion channel to open.) with the PCP binding site of the NMDA (See Figure 11.) receptor and serves as an indirect One of the six binding sites on the NMDA receptor is sensitive to alcohol. In fact, researchantagonist. ers believe that this binding site is responsible for the dangerous convulsions that can be caused GABA An amino acid; the most by sudden withdrawal from heavy, long-term alcohol abuse. Another binding site is sensitive important inhibitory neurotransmitter to a hallucinogenic drug, PCP (phencyclidine, also known as “angel dust”). PCP serves as an in the brain. indirect antagonist; when it attaches to its binding site, calcium ions cannot pass through the allylglycine A drug that inhibits the ion channel. PCP is a synthetic drug and is not produced by the brain. Thus, it is not the natural activity of GAD and thus blocks the ligand of the PCP binding site. What that ligand is and what useful functions it serves are not synthesis of GABA. yet known. Several drugs affect glutamatergic synapses. As we have just seen, NMDA, AMPA, and kainate (more precisely, kainic acid) serve as direct agonists at the Zn2+ Calcium receptors named after them. Glutamate channel Polyamine

GABA GABA (gamma-aminobutyric acid) is produced from glutamic acid by the action of an enzyme (glutamic acid decarboxylase, or GAD) that removes a carboxyl group. The drug allylglycine inactivates GAD and thus prevents the synthesis of GABA (step 2 of Figure 4). GABA is an inhibitory neurotransmitter, and it appears to have a widespread distribution throughout the brain and spinal cord. Two GABA receptors have been identified: GABAA and GABAB. The GABAA receptor is ionotropic and controls a chloride channel; the GABAB receptor is metabotropic and controls a potassium channel. As you know, neurons in the brain are greatly interconnected. Without the activity of inhibitory synapses these interconnections would make the brain unstable. That is, through excitatory synapses neurons would excite their neighbors, which would then excite their neighbors, which would then

Glycine

Mg2+

PCP

F I G U R E 11 NMDA Receptor. This schematic illustration of an NMDA receptor shows its binding sites.

Psychopharmacology

excite the originally active neurons, and so on, until most of the neurons in the brain would be firing uncontrollably. In fact, this event does sometimes occur, Picrotoxin and we refer to it as a seizure. (Epilepsy is a neurological disorder characterized site by the presence of seizures.) Normally, an inhibitory influence is supplied by Benzodiazepine Barbiturate GABA-secreting neurons, which are present in large numbers in the brain. site (and alcohol?) Some investigators believe that one of the causes of epilepsy is an abnormality site in the biochemistry of GABA-secreting neurons or in GABA receptors. + + Like NMDA receptors, GABAA receptors are complex; they contain at least five different binding sites. The primary binding site is, of course, for GABA. The drug muscimol (derived from the ACh agonist, muscarine) serves as a direct agonist for this site (step 6 of Figure 4). Another drug, bicuculline, blocks this GABA binding site, serving as a direct antagonist (step 7 of Figure 4). A second site on the GABAA receptor binds with a class of tranquilizing drugs called the benzodiazepines. These drugs include diazepam (Valium) and chlordiazepoxide (Librium), which are used to reduce anxiety, promote sleep, reduce seizure activity, and produce muscle relaxation. The third site binds with barbiturates. The fourth site binds with various steroids, including some steroids used to produce general anesthesia. The fifth site binds with F I G U R E 12 GABAA Receptor. This schematic illustration of a picrotoxin, a poison found in an East Indian shrub. In addition, alcohol binds GABAA receptor shows its binding sites. with an as yet unknown site on the GABAA receptor. (See Figure 12.) Barbiturates, drugs that bind to the steroid site, and benzodiazepines all promote the activity of the GABAA receptor; thus, all these drugs serve as indirect agonists. The benzodiazepines are very effective anxiolytics, or “anxiety-dissolving” drugs. They are often used to treat people with anxiety disorders. In addition, some benzodiazepines serve as effective sleep medications, and others are used to treat some types of seizure disorder. Picrotoxin has effects opposite to those of benzodiazepines and barbiturates: It inhibits the activity of the GABAA receptor, thus serving as an indirect antagonist. In high enough doses, this drug causes convulsions. Various steroid hormones are normally produced in the body, and some hormones related to progesterone (the principal pregnancy hormone) act on the steroid binding site of the GABAA receptor, producing a relaxing, anxiolytic effect. However, the brain does not produce Valium, barbiturates, or picrotoxin. The natural ligands for these binding sites have not yet been identified. What about the GABAB receptor? This metabotropic receptor, coupled to a G protein, serves as both a postsynaptic receptor and a presynaptic autoreceptor. A GABAB agonist, baclofen, serves as a muscle relaxant. Another drug, CGP 335348, serves as an antagonist. The activation of GABAB receptors opens potassium channels, producing hyperpolarizing inhibitory postsynaptic potentials. GABA site

Chloride channel Steroid site

muscimol (musk i mawl) A direct agonist for the GABA binding site on the GABAA receptor. bicuculline (by kew kew leen) A direct antagonist for the GABA binding site on the GABAA receptor. benzodiazepine (ben zoe dy azz a peen) A category of anxiolytic drugs; an indirect agonist for the GABAA receptor. anxiolytic (angz ee oh lit ik) An anxietyreducing effect. glycine (gly seen) An amino acid; an important inhibitory neurotransmitter in the lower brain stem and spinal cord. strychnine (strik neen) A direct antagonist for the glycine receptor.

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GLYCINE The amino acid glycine appears to be the inhibitory neurotransmitter in the spinal cord and lower portions of the brain. Little is known about its biosynthetic pathway; there are several possible routes, but not enough is known to decide how neurons produce glycine. The bacteria that cause tetanus (lockjaw) release a chemical that prevents the release of glycine (and GABA as well); the removal of the inhibitory effect of these synapses causes muscles to contract continuously. The glycine receptor is ionotropic, and it controls a chloride channel. Thus, when it is active, it produces inhibitory postsynaptic potentials. The drug strychnine, an alkaloid found in the seeds of the Strychnos nux vomica, a tree found in India, serves as a glycine antagonist. Strychnine is very toxic, and even relatively small doses cause convulsions and death. No drugs have yet been found that serve as specific glycine agonists.

Peptides Recent studies have discovered that the neurons of the central nervous system release a large variety of peptides. Peptides consist of two or more amino acids linked together by peptide bonds. All the peptides that have been studied so far are produced from precursor molecules. These precursors are large polypeptides that are broken into pieces by special enzymes. Neurons manufacture

Psychopharmacology

both the polypeptides and the enzymes needed to break them apart in the right places. The appropriate sections of the polypeptides are retained, and the rest are destroyed. Because the synthesis of peptides takes place in the soma, vesicles containing these chemicals must be delivered to the terminal buttons by axoplasmic transport. Peptides are released from all parts of the terminal button, not just from the presynaptic membrane; thus, only a portion of the molecules are released into the synaptic cleft. The rest presumably act on receptors belonging to other cells in the vicinity. Once released, peptides are destroyed by enzymes. There is no mechanism for reuptake and recycling of peptides. Several different peptides are released by neurons. Although most peptides appear to serve as neuromodulators, some act as neurotransmitters. One of the best-known families of peptides is the endogenous opioids. (Endogenous means “produced from within”; opioid means “like opium.”) Research has revealed that opiates (drugs such as opium, morphine, and heroin) reduce pain because they have direct effects on the brain. (Please note that the term opioid refers to endogenous chemicals, and opiate refers to drugs.) Pert, Snowman, and Snyder (1974) discovered that neurons in a localized region of the brain contain specialized receptors that respond to opiates. Then, soon after the discovery of the opiate receptor, other neuroscientists discovered the natural ligands for these receptors (Hughes et al., 1975; Terenius and Wahlström, 1975), which they called enkephalins (from the Greek word enkephalos, “in the head”). We now know that the enkephalins are only two members of a family of endogenous opioids, all of which are synthesized from one of three large peptides that serve as precursors. In addition, we know that there are at least three different types of opiate receptors: μ (mu), δ (delta), and κ (kappa). Several different neural systems are activated when opiate receptors are stimulated. One type produces analgesia, another inhibits species-typical defensive responses such as fleeing and hiding, and another stimulates a system of neurons involved in reinforcement (“reward”). The last effect explains why opiates are often abused. So far, pharmacologists have developed only two types of drugs that affect neural communication by means of opioids: direct agonists and antagonists. Many synthetic opiates, including heroin (dihydromorphine) and Percodan (levorphanol), have been developed and some are used clinically as analgesics (step 6 of Figure 4). Several opiate receptor blockers have also been developed (step 7 of Figure 4). One of them, naloxone, is used clinically to reverse opiate intoxication. This drug has saved the lives of many drug abusers who would otherwise have died of an overdose of heroin. Several peptide hormones released by endocrine glands are also produced in the brain, where they serve as neuromodulators. In some cases the peripheral and central peptides perform related functions. For example, outside the nervous system the hormone angiotensin acts directly on the kidneys and blood vessels to produce effects that help the body cope with the loss of fluid, and inside the nervous system circuits of neurons that use angiotensin as a neurotransmitter perform complementary functions, including the activation of Cx neural circuits that produce thirst. The existence of the blood–brain barrier keeps most peptide hormones in the general circulation separate from the CP extracellular fluid in the brain, which means that the same peptide molecule can have different effects in these two regions. Many peptides produced in the brain have interesting behavioral effects.

endogenous opioid (en dodge en us oh pee oyd) A class of peptides secreted by the brain that act as opiates. enkephalin (en keff a lin) One of the endogenous opioids. naloxone (na lox own) A drug that blocks opiate receptors. endocannabinoid (can ob in oid) A lipid; an endogenous ligand for receptors that bind with THC, the active ingredient of marijuana.

Lipids Various substances derived from lipids can serve to transmit messages within or between cells. The best known, and probably the most important, are the two endocannabinoids (“endogenous cannabis-like substances”)—natural ligands for the receptors that are responsible for the physiological effects of the active ingredient in marijuana. Matsuda et al. (1990) discovered that THC (tetrahydrocannabinol, the active ingredient of marijuana) stimulates cannabinoid receptors located in specific regions of the brain. (See Figure 13.) Two types of cannabinoid receptors, CB1 and CB2, both metabotropic, have

F I G U R E 13 Cannabinoid Receptors in a Rat Brain. To produce this autoradiogram, the brain was incubated in a solution containing a radioactive ligand for THC receptors. The receptors are indicated by dark areas. (Br St = brain stem, Cer = cerebellum, CP = caudate nucleus/putamen, Cx = cortex, EP = entopeduncular nucleus, GP = globus pallidus, Hipp = hippocampus, SNr = substantia nigra.) Miles Herkenham/ National Institute of Mental Health.

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sincebeen discovered. Devane et al. (1992) discovered the first endocannabinoid: a lipidlike substance that they named anandamide, from the Sanskrit word ananda, or “bliss.” Anandamide seems to be synthesized on demand; that is, it is produced and released as it is needed and is not stored in synaptic vesicles. CB1 receptors are found in the brain, especially in the frontal cortex, anterior cingulate cortex, basal ganglia, cerebellum, hypothalamus, and hippocampus. They are located on terminal buttons of glutamatergic, GABAergic, acetylcholinergic, noradrenergic, dopaminergic, and serotonergic neurons, where they serve to regulate neurotransmitter release (Iversen, 2003). Very low levels of CB1 receptors are found in the brain stem, which accounts for the low toxicity of THC. CB1 receptors are blocked by the drug rimonabant. CB2 receptors are found outside the brain, especially in cells of the immune system. THC produces analgesia and sedation, stimulates appetite, reduces nausea caused by drugs used to treat cancer, relieves asthma attacks, decreases pressure within the eyes in patients with glaucoma, and reduces the symptoms of certain motor disorders. On the other hand, THC interferes with concentration and memory, alters visual and auditory perception, and distorts perceptions of the passage of time (Iversen, 2003). The short-term memory impairment that accompanies marijuana use appears to be caused by the action of THC on CB1 receptors in the hippocampus. Endocannabinoids appear to play an essential role in the reinforcing effects of opiates: A targeted mutation that prevents the production of CB1 receptors abolishes the reinforcing effects of morphine but not of cocaine, amphetamine, or nicotine (Cossu et al., 2001). I just mentioned that THC (and, of course, the endocannabinoids) has an analgesic effect. Agarwal et al. (2007) found that THC exerts its analgesic effects by stimulating CB1 receptors in the peripheral nervous system. In addition, a commonly used over-the-counter analgesic, acetaminophen (known as paracetamol in many countries), also acts on these receptors. Once it enters the blood, acetaminophen is converted into another compound that then joins with arachidonic acid, the precursor of anandamide. Because this compound does not cross the blood–brain barrier, it does not produce effects like those of THC. Administration of a CB1 antagonist completely blocks the analgesic effect of acetaminophen (Bertolini et al., 2006).

Nucleosides

anandamide (a nan da mide) The first cannabinoid to be discovered and probably the most important one. rimonabant A drug that blocks cannabinoid CB1 receptors. adenosine (a den oh seen) A nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain. caffeine A drug that blocks adenosine receptors. nitric oxide (NO) A gas produced by cells in the nervous system; used as a means of communication between cells.

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A nucleoside is a compound that consists of a sugar molecule bound with a purine or pyrimidine base. One of these compounds, adenosine (a combination of ribose and adenine), serves as a neuromodulator in the brain. Adenosine is known to be released by astrocytes when cells are short of fuel or oxygen. The release of adenosine activates receptors on nearby blood vessels and causes them to dilate, increasing the flow of blood and helping bring more of the needed substances to the region. Adenosine also acts as a neuromodulator, through its action on at least three different types of adenosine receptors. Adenosine receptors are coupled to G proteins, and their effect is to open potassium channels, producing inhibitory postsynaptic potentials. Because adenosine receptors suppress neural activity, adenosine and other adenosine receptor agonists have generally inhibitory effects on behavior. In fact, good evidence suggests that adenosine receptors play an important role in the control of sleep. For example, the amount of adenosine in the brain increases during wakefulness and decreases during sleep. In fact, the accumulation of adenosine after prolonged wakefulness may be the most important cause of the sleepiness that ensues. A very common drug, caffeine, blocks adenosine receptors (step 7 of Figure 4) and hence produces excitatory effects. Caffeine is a bitter-tasting alkaloid found in coffee, tea, cocoa beans, and other plants. In much of the world a majority of the adult population ingests caffeine every day—fortunately, without apparent harm.

Soluble Gases Recently, investigators have discovered that neurons use at least two simple, soluble gases—nitric oxide and carbon monoxide—to communicate with one another. One of these, nitric oxide (NO), has received the most attention. Nitric oxide (not to be confused with nitrous oxide, or laughing gas) is a soluble gas that is produced by the activity of an enzyme found in certain neurons. Researchers have found that NO is used as a messenger in many parts of the body; for example,

Psychopharmacology

it is involved in the control of the muscles in the wall of the intestines, it dilates blood vessels in regions of the brain that become metabolically active, and it stimulates the changes in blood vessels that produce penile erections (Culotta and Koshland, 1992). It may also play a role in the establishment of neural changes that are produced by learning. All of the neurotransmitters and neuromodulators discussed so far (with the exception of anandamide and adenosine) are stored in synaptic vesicles and released by terminal buttons. Nitric oxide is produced in several regions of a nerve cell—including dendrites—and is released as soon as it is produced. More accurately, it diffuses out of the cell as soon as it is produced. It does not activate membrane-bound receptors but enters neighboring cells, where it activates an enzyme responsible for the production of a second messenger, cyclic GMP. Within a few seconds of being produced, nitric oxide is converted into biologically inactive compounds. Nitric oxide is produced from arginine, an amino acid, by the activation of an enzyme known as nitric oxide synthase. This enzyme can be inactivated (step 2 of Figure 4) by a drug called l-NAME (nitro-l-arginine methyl ester). You have undoubtedly heard of a drug called sildenafil (more commonly known as Viagra), which is used to treat men with erectile dysfunction—difficulty maintaining a penile erection. As we just saw, nitric oxide produces its physiological effects by stimulating the production of cyclic GMP. Although nitric oxide lasts only for a few seconds, cyclic GMP lasts somewhat longer but is ultimately destroyed by an enzyme. Molecules of sildenafil bind with this enzyme and thus cause cyclic GMP to be destroyed at a much slower rate. As a consequence, an erection is maintained for a longer time. (By the way, sildenafil has effects on other parts of the body and is used to treat altitude sickness and other vascular disorders.)

nitric oxide synthase The enzyme responsible for the production of nitric oxide.

SECTION SUMMARY Neurotransmitters and Neuromodulators The nervous system contains a variety of neurotransmitters, each of which interacts with a specialized receptor. Those that have received the most study are acetylcholine and the monoamines: dopamine, norepinephrine, and 5-hydroxytryptamine (serotonin). The synthesis of these neurotransmitters is controlled by a series of enzymes. Several amino acids also serve as neurotransmitters, the most important of which are glutamate (glutamic acid), GABA, and glycine. Glutamate serves as an excitatory neurotransmitter; the others serve as inhibitory neurotransmitters. Peptide neurotransmitters consist of chains of amino acids. Like proteins, peptides are synthesized at the ribosomes according to sequences coded for by the chromosomes. The best-known class of peptides in the nervous system includes the endogenous opioids, whose effects

are mimicked by drugs such as opium and heroin. Two lipids serve as a chemical messenger: Anandamide and 2-AG are endogenous ligands for cannabinoid receptors. CB1 receptors are found in the central nervous system, and CB2 receptors are found outside the blood–brain barrier. Adenosine, a nucleoside that has inhibitory effects on synaptic transmission, is released by neurons and glial cells in the brain. In addition, two soluble gases—nitric oxide and carbon monoxide—can diffuse out of the cell in which they are produced and trigger the production of a second messenger in adjacent cells. This chapter has mentioned many drugs and their effects. It would be beneficial to review them, as they will appear throughout your studies. (See Table 3.)

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TABLE

3 Drugs Mentioned in This Chapter

Neurotransmitter Acetylcholine (ACh)

Dopamine (DA)

Norepinephrine (NE)

Serotonin (5-HT)

Glutamate

Effect of Drug

Effect on Synaptic Transmission

Botulinum toxin

Blocks release of ACh

Antagonist

Black widow spider venom

Stimulates release of ACh

Agonist

Nicotine

Stimulates nicotinic receptors

Agonist

Curare

Blocks nicotinic receptors

Antagonist

Muscarine

Stimulates muscarinic receptors

Agonist

Atropine

Blocks muscarinic receptors

Antagonist

Neostigmine

Inhibits acetylcholinesterase

Agonist

L-DOPA

Facilitates synthesis of DA

Agonist

AMPT

Inhibits synthesis of DA

Antagonist

Reserpine

Inhibits storage of DA in synaptic vesicles

Antagonist

Chlorpromazine

Blocks D2 receptors

Antagonist

Cocaine, methylphenidate

Blocks DA reuptake

Agonist

Amphetamine

Stimulates release of DA

Agonist

Deprenyl

Blocks MAO-B

Agonist

Fusaric acid

Inhibits synthesis of NE

Antagonist

Reserpine

Inhibits storage of NE in synaptic vesicles

Antagonist

Idazoxan

Blocks α2 autoreceptors

Agonist

MDMA, amphetamine

Stimulates release of NE

Agonist

PCPA

Inhibits synthesis of 5-HT

Antagonist

Reserpine

Inhibits storage of 5-HT in synaptic vesicles

Antagonist

Fenfluramine

Stimulates release of 5-HT

Agonist

Fluoxetine

Inhibits reuptake of 5-HT

Agonist

LSD

Stimulates 5-HT2A receptors

Agonist

MDMA

Stimulates release of 5-HT

Agonist

AMPA

Stimulates AMPA receptor

Agonist

Kainic acid

Stimulates kainate receptor

Agonist

NMDA

Stimulates NMDA receptor

Agonist

AP5

Blocks NMDA receptor

Antagonist

Allylglycine

Inhibits synthesis of GABA

Antagonist

Muscimol

Stimulates GABA receptors

Agonist

Bicuculline

Blocks GABA receptors

Antagonist

Benzodiazepines

Serve as indirect GABA agonist

Agonist

Glycine

Strychnine

Blocks glycine receptors

Antagonist

Opioids

Opiates (morphine, heroin, etc.)

Stimulates opiate receptors

Agonist

Naloxone

Blocks opiate receptors

Antagonist

GABA

Anandamide

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Name of Drug

Rimonabant

Blocks cannabinoid CB1 receptors

Antagonist

THC

Stimulates cannabinoid CB1 receptors

Agonist

Adenosine

Caffeine

Blocks adenosine receptors

Antagonist

Nitric oxide (NO)

L-NAME

Inhibits synthesis of NO

Antagonist

EPILOGUE

| Helpful Hints from a Tragedy

The discovery that MPTP damages the brain and causes the symptoms of Parkinson’s disease galvanized researchers interested in the disease. (I recently checked PubMed, a web site maintained by the U.S. National Institutes of Health, and found that 5452 scientific publications referred to MPTP.) The first step was to find out whether the drug would have the same effect in laboratory animals so that the details of the process could be studied. It did; Langston and Ballard (1984) found that injections of MPTP produced parkinsonian symptoms in squirrel monkeys and that these symptoms could be reduced by L-DOPA therapy. And just as the investigators had hoped, examination of the animals’ brains showed a selective loss of dopamine-secreting neurons in the substantia nigra. It turns out that MPTP itself does not cause neural damage; instead, the drug is converted by an enzyme present in glial cells into another substance, MPP+. That chemical is taken up by dopaminesecreting neurons by means of the reuptake mechanism that normally retrieves dopamine; this is released by terminal buttons. MPP+ accumulates in mitochondria in these cells and blocks their ability to metabolize nutrients, thus killing the cells (Maret et al., 1990). The enzyme that converts MPTP into MPP+ is none other than monoamine oxidase (MAO), which, as you now know, is responsible for deactivating excess amounts of monoamines present in terminal buttons. Because pharmacologists had already developed

MAO inhibitors, Langston and his colleagues decided to find out whether one of these drugs (pargyline) would protect squirrel monkeys from the toxic effects of MPTP by preventing its conversion into MPP+ (Langston and Ballard, 1984). It worked; when MAO was inhibited by pargyline, MPTP injections had no effects. These results made researchers wonder whether MAO inhibitors might possibly protect against the degeneration of dopaminesecreting neurons in patients with Parkinson’s disease. No one thought that Parkinson’s disease was caused by MPP+, but perhaps some other toxins were involved. Epidemiologists have found that Parkinson’s disease is more common in highly industrialized countries, which suggests that environmental toxins produced in these societies may be responsible for the brain damage (Tanner, 1989; Veldman et al., 1998). Fortunately, several MAO inhibitors have been tested and approved for use in humans. One of them, deprenyl, was tested and appeared to slow down the progression of neurological symptoms (Tetrud and Langston, 1989). As a result of this study, many neurologists are now treating their Parkinson’s patients with deprenyl, especially during the early stages of the disease. More recent studies found that deprenyl does not protect dopaminergic neurons indefinitely (Shoulson et al., 2002), but researchers are trying to develop other drugs with more sustained neuroprotective effects.

KEY CONCEPTS PRINCIPLES OF PSYCHOPHARMACOLOGY

1. Pharmacokinetics is the process by which drugs are absorbed, distributed within the body, metabolized, and excreted. 2. Drugs can act at several different sites and have several different effects. The effectiveness of a drug is the magnitude of the effects of a given quantity of the drug. 3. A drug’s therapeutic index is its margin of safety: the difference between an effective dose and a dose that produces toxic side effects. 4. When a drug is administered repeatedly, it often produces tolerance, and withdrawal effects often occur when the drug is discontinued. Sometimes, repeated administration of a drug causes sensitization. 5. Researchers must control for placebo effects in both humans and laboratory animals.

SITES OF DRUG ACTION

6. Each of the steps involved in synaptic transmission can be interfered with by drugs, and some can be facilitated. These steps include synthesis of the neurotransmitter, storage in synaptic vesicles, release, activation of postsynaptic and presynaptic receptors, and termination of postsynaptic potentials through reuptake or enzymatic deactivation. NEUROTRANSMITTERS AND NEUROMODULATORS

7. Neurons use a variety of chemicals as neurotransmitters, including acetylcholine, the monoamines (dopamine, norepinephrine, and 5-HT), the amino acids (glutamic acid, GABA, and glycine), various peptides, lipids, nucleosides, and soluble gases.

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EXPLORE the Virtual Brain in DRUG ADDICTION Learn about dopaminergic pathways and brain pleasure centers in depth. In the physiology section, see how psychoactive drugs interact with the neurotransmission processes.

REFERENCES Langston, J. W., Ballard, P., Tetrud, J., and Irwin, I. Chronic parkinsonism in humans due to a product of meperidineanalog synthesis. Science, 1983, 219, 979–980.

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OUTLINE ■

Experimental Ablation Evaluating the Behavioral Effects of Brain Damage

Methods and Strategies of Research

Producing Brain Lesions Stereotaxic Surgery Histological Methods Tracing Neural Connections Studying the Structure of the Living Human Brain ■

Recording and Stimulating Neural Activity Recording Neural Activity Recording the Brain’s Metabolic and Synaptic Activity Stimulating Neural Activity

■

Neurochemical Methods Finding Neurons That Produce Particular Neurochemicals Localizing Particular Receptors

LEARNING OBJECTIVES 1. Discuss the research method of experimental ablation: the rationale for this procedure, the distinction between brain function and behavior, and the production of brain lesions. 2. Describe stereotaxic surgery and its uses. 3. Describe research methods for preserving, sectioning, and staining the brain and for studying its parts. 4. Describe research methods for tracing eﬀerent and aﬀerent axons and for studying the structure of the living human brain. 5. Describe how the neural and metabolic activity of the brain is recorded.

Lawrence Migdale/Science Source/Photo Researchers, Inc.

Measuring Chemicals Secreted in the Brain ■

Genetic Methods Twin Studies Adoption Studies Genomic Studies Targeted Mutations Antisense Oligonucleotides

6. Describe how neural activity in the brain is stimulated, both electrically and chemically. 7. Describe research methods for locating particular neurochemicals, the neurons that produce them, and the receptors that respond to them. 8. Describe research techniques to identify genetic factors that may aﬀect the development of the nervous system and inﬂuence behavior. 9. Describe the use of targeted mutations and the administration of antisense oligonucleotides in the study of functions of particular sets of neurons in the brain.

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PROLOGUE

| Heart Repaired, Brain Damaged

All her life, Mrs. H. had been active. She had never been particularly athletic, but she and her husband often went hiking and camping with their children when they were young, and they continued to hike and go for bicycle rides after their children left home. Her husband died when she was 60, and even though she no longer rode her bicycle, she enjoyed gardening and walking around the neighborhood with her friends. A few years later, Mrs. H. was digging in her garden when a sudden pain gripped her chest. She felt as if a hand were squeezing her heart. She gasped and dropped her spade. The pain crept toward her left shoulder and then traveled down her left arm. The sensation was terrifying; she was sure that she was having a heart attack and was going to die. But after a few minutes the pain melted away, and she walked slowly back to her house. Her physician examined her, performed some tests, and later told her that she had not had a heart attack. Her pain was that of angina pectoris, caused by insufficient flow of blood to the heart. Some of her coronary arteries had become partially obstructed with atherosclerotic plaque—cholesterol-containing deposits on the walls of the blood vessels. Her efforts in her garden had increased her heart rate, and as a consequence, the metabolic activity of her heart muscle had also increased. Her clogged coronary arteries simply could not keep up with the demand, and the accumulation of metabolic by-products caused intense pain. Her physician cautioned her to avoid unnecessary exertion and prescribed nitroglycerine tablets to place under her tongue if another attack occurred. Mrs. H. stopped working in her garden but continued to walk around the neighborhood with her friends. Then one evening, while climbing the stairs to get ready for bed, she felt another attack grip her heart. With difficulty, she made her way to her bathroom cabinet, where she found her nitroglycerine tablets. Fumbling with the childproof cap, she extracted a tablet and placed it under her

tongue. As the tablet dissolved and the nitroglycerine entered her bloodstream, she felt the tightness in her chest loosen, and she stumbled to her bed. Over the next year the frequency and intensity of Mrs. H.’s attacks increased. Finally, the specialist to whom the physician had referred her recommended that she consider having a coronary artery bypass performed. She readily agreed. The surgeon, Dr. G., replaced two of her coronary arteries with sections of vein that he had removed from her leg. During the procedure, an artificial heart took over the pumping of her blood so that the surgeon could cut out the diseased section of the arteries and delicately sew in the replacements. Several days later, Dr. G. visited Mrs. H. in her hospital room. “How are you feeling, Mrs. H?” “I’m feeling fine,” she said, “but I’m having trouble with my vision. Everything looks so confusing, and I feel disoriented. I can’t. . . .” “Don’t worry,” he cut in. “It’s normal to feel confused after such serious surgery. Your tests look fine, and we don’t expect a recurrence of your angina. You should be good for many years!” He flashed a broad smile at her and left the room. But Mrs. H.’s visual problems and her confusion did not get better. Although the surgeon’s notes indicated a successful outcome, her family physician saw that something was wrong and asked Dr. J., a neuropsychologist, to evaluate her. Dr. J.’s report confirmed the physician’s fears: Mrs. H. had Balint’s syndrome. She could still see, but she could not control her eye movements. The world confused her because she saw only fleeting, fragmentary images. She could no longer read, and she could no longer locate and grasp objects in front of her. In short, her vision was almost useless. Her heart was fine, but she would henceforth have to live in a nursing home, where others could care for her.

tudy of the physiology of behavior involves the efforts of scientists in many disciplines, including physiology, neuroanatomy, biochemistry, psychology, endocrinology, and histology. Pursuing a research project in behavioral neuroscience requires competence in many experimental techniques. Because different procedures often produce contradictory results, investigators must be familiar with the advantages and limitations of the methods they employ. Scientific investigation entails a process of asking questions of nature. The method that is used frames the question. Often we receive a puzzling answer, only to realize later that we were not asking the question we thought we were. As we will see, the best conclusions about the physiology of behavior are made not by any single experiment, but by a program of research that enables us to compare the results of studies that approach the problem with different methods. An enormous—and bewildering—array of research methods is available to the investigator. If I merely presented a catalog of them, it would not be surprising if you got lost—or simply lost interest. Instead, I will present only the most important and commonly used procedures, organized around a few problems that researchers have studied. This way, it should be easier to see the types of information provided by various research methods and to understand their advantages and disadvantages. It will also permit me to describe the strategies that researchers employ as they follow up the results of one experiment by designing and executing another one.

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Methods and Strategies of Research

Experimental Ablation One of the most important research methods used to investigate brain functions involves destroying part of the brain and evaluating the animal’s subsequent behavior. This method is called experimental ablation (from the Latin word ablatus, a “carrying away”). In most cases experimental ablation does not involve the removal of brain tissue; instead, the researcher destroys some tissue and leaves it in place. Experimental ablation is the oldest method used in neuroscience, and it remains in common use today.

Evaluating the Behavioral Effects of Brain Damage A lesion is a wound or injury; a researcher who destroys part of the brain usually refers to the damage as a brain lesion. Experiments in which part of the brain is damaged and the animal’s behavior is subsequently observed are called lesion studies. The rationale for lesion studies is that the function of an area of the brain can be inferred from the behaviors that the animal can no longer perform after the area has been damaged. For example, if, after part of the brain is destroyed, an animal can no longer perform tasks that require vision, we can conclude that the animal is blind—and that the damaged area plays some role in vision. Just what can we learn from lesion studies? Our goal is to discover what functions are performed by different regions of the brain and then to understand how these functions are combined to accomplish particular behaviors. The distinction between brain function and behavior is an important one. Circuits within the brain perform functions, not behaviors. No one brain region or neural circuit is solely responsible for a behavior; each region performs a function (or set of functions) that contributes to performance of the behavior. For example, the act of reading involves functions required for controlling eye movements, focusing the lens of the eye, perceiving and recognizing words and letters, comprehending the meaning of the words, and so on. Some of these functions also participate in other behaviors; for example, controlling eye movement and focusing are required for any task that involves looking, and brain mechanisms used for comprehending the meanings of words also participate in comprehending speech. The researcher’s task is to understand the functions that are required for performing a particular behavior and to determine what circuits of neurons in the brain are responsible for each of these functions.

experimental ablation The removal or destruction of a portion of the brain of a laboratory animal; presumably, the functions that can no longer be performed are the ones the region previously controlled. lesion study A synonym for experimental ablation. excitotoxic lesion (ek sigh tow tok sik) A brain lesion produced by intracerebral injection of an excitatory amino acid, such as kainic acid.

Producing Brain Lesions How do we produce brain lesions? Usually, we want to destroy regions that are hidden away in the depths of the brain. Brain lesions of subcortical regions (regions located beneath the cortex) are usually produced by passing electrical current through a stainless steel wire that is coated with an insulating varnish except for the very tip. We guide the wire stereotaxically so that its end reaches the appropriate location. (Stereotaxic surgery is described in the next subsection.) Then we turn on a lesion-making device, which produces radio frequency (RF) current—alternating current of a very high frequency. The passage of the current through the brain tissue produces heat that kills cells in the region surrounding the tip of the electrode. (See Figure 1.) Lesions produced by these means destroy everything in the vicinity of the electrode tip, including neural cell bodies and the axons of neurons that pass through the region. A more selective method of producing brain lesions employs an excitatory amino acid such as kainic acid, which kills neurons by stimulating them to death. (Kainic acid stimulates glutamate receptors.) Lesions produced this way are referred to as excitotoxic lesions. When an excitatory amino acid is injected through a cannula (a small metal tube) into a region of the brain, the chemical destroys neural cell bodies in the vicinity but spares axons that belong to different neurons that happen to pass nearby. (See Figure 2.) This selectivity permits the investigator to determine whether the behavioral effects of destroying a particular brain structure are caused by the death of neurons located there or by the destruction of axons that pass nearby.

F I G U R E 1 Radio Frequency Lesion. The arrows point to very small lesions produced by passing radio frequency current through the tips of stainless steel electrodes placed in the medial preoptic nucleus of a rat brain. The oblong hole in the middle of the photograph is the third ventricle. (Frontal section, cell-body stain.) Turkenburg, J. L., Swaab, D. F., Endert, E., et al. Brain Research Bulletin, 1988, 21, 215–224.

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Even more specific methods of targeting and killing particular types of neurons are available. For example, molecular biologists have devised ways to attach toxic chemicals to antibodies that will bind with particular proteins found only on certain types of neurons in the brain. The antibodies target these proteins, and the toxic chemicals kill the cells to which the proteins are attached. Note that when we produce subcortical lesions by passing RF current through an electrode or infusing a chemical through a cannula, we always cause additional damage to the brain. When we pass an electrode or a cannula through the brain to get to our target, we inevitably cause a small amount of damage even before turning on the lesion maker or starting the infusion. Therefore, we cannot simply compare the behavior of brain-lesioned animals with that of unoperated control animals; the incidental damage to the brain regions above the lesion may actually (a) be responsible for some of the behavioral deficits we see. What we do is operate on a group of animals and produce sham lesions. To do so, we anesthetize each animal, put it in the stereotaxic apparatus (described in the following text), cut open the scalp, drill the holes, insert the electrode or cannula, and lower it to the proper depth. In other words, we do everything we would do to produce the lesion except turn on the lesion maker or start the infusion. This group of animals serves as a control group; if the behavior of the animals with brain lesions is different from that of the sham-operated control animals, we can conclude that the lesions caused the behavioral deficits. (As you can see, a sham lesion serves the same purpose as a placebo does in a pharmacology study.) Most of the time, investigators produce permanent brain lesions, but sometimes it is advantageous to disrupt the activity of a particular (b) region of the brain temporarily. The easiest way to do so is to inject a loF I G U R E 2 Excitotoxic Lesion. Slices through the hippocampus of cal anesthetic or a drug called muscimol into the appropriate part of the a rat brain. (a) Normal hippocampus. (b) Hippocampus with a lesion brain. The anesthetic blocks action potentials in axons from entering or produced by infusion of an excitatory amino acid. Arrowheads mark the leaving that region, thus effectively producing a temporary lesion (usuends of the region in which neurons have been destroyed. ally called a reversible brain lesion). Muscimol, a drug that stimulates Based on research from Benno Roozendaal/University of Groningen. GABA receptors, inactivates a region of the brain by inhibiting the neurons located there. (You will recall that GABA is the most important inhibitory neurotransmitter in the brain.)

Stereotaxic Surgery So how do we get the tip of an electrode or cannula to a precise location in the depths of an animal’s brain? The answer is stereotaxic surgery. Stereotaxis literally means “solid arrangement”; more specifically, it refers to the ability to locate objects in space. A stereotaxic apparatus contains a holder that fixes the animal’s head in a standard position and a carrier that moves an electrode or a cannula through measured distances in all three axes of space. However, to perform stereotaxic surgery, one must first study a stereotaxic atlas. sham lesion A “placebo” procedure that duplicates all the steps of producing a brain lesion except for the one that actually causes the brain damage. stereotaxic surgery (stair ee oh tak sik) Brain surgery using a stereotaxic apparatus to position an electrode or cannula in a specified position of the brain. bregma The junction of the sagittal and coronal sutures of the skull; often used as a reference point for stereotaxic brain surgery.

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THE STEREOTAXIC ATLAS No two brains of animals of a given species are completely identical, but there is enough similarity among individuals to predict the location of particular brain structures relative to external features of the head. For instance, a subcortical nucleus of a rat might be so many millimeters ventral, anterior, and lateral to a point formed by the junction of several bones of the skull. Figure3 shows two views of a rat skull: a drawing of the dorsal surface and, beneath it, a midsagittal view. (See Figure 3.) The skull is composed of several bones that grow together and form sutures (seams). The heads of newborn babies contain a soft spot at the junction of the coronal and sagittal sutures called the fontanelle. Once this gap closes, the junction is called bregma, from the Greek word meaning “front of head.” We can find bregma on a rat’s skull, too, and it serves as a convenient reference point. If the animal’s skull is oriented as shown in the illustration, a particular region of the brain is found in a fairly constant position relative to bregma.

Methods and Strategies of Research

A stereotaxic atlas contains photographs or drawings that correspond to frontal sections taken at various distances rostral and caudal to bregma. For example, the page shown in Figure 4 is a drawing of a slice of the brain that contains a brain structure (shown in red) that we are interested in. If we wanted to place the tip of a wire in this structure (the fornix), we would have to drill a hole through the skull immediately above it. (See Figure 4.) Each page of the stereotaxic atlas is labeled according to the distance of the section anterior or posterior to bregma. The grid on each page indicates distances of brain structures ventral to the top of the skull and lateral to the midline. To place the tip of a wire in the fornix, we would drill a hole above the target and then lower the electrode through the hole until the tip was at the correct depth, relative to the skull height at bregma. (Compare Figures 3 and 4.) Thus, by finding a neural structure (which we cannot see in our animal) on one of the pages of a stereotaxic atlas, we can determine the structure’s location relative to bregma (which we can see). Note that because of variations in different strains and ages of animals, the atlas gives only an approximate location. We always have to try out a new set of coordinates, slice and stain the animal’s brain, see the actual location of the lesion, correct the numbers, and try again. (Slicing and staining of brains are described later.)

Edge of incision in skin Coronal suture

Sagittal suture

Bregma

Hole will be drilled here above target of lesion (Figure 5.4)

Target of lesion

THE STEREOTAXIC APPARATUS A stereotaxic apparatus operates on simple principles. The device includes a head F I G U R E 3 Rat Brain and Skull. The figure shows the holder, which maintains the animal’s skull in the proper orientation; a holder for relation of the skull sutures to a rat’s brain, and the location the electrode; and a calibrated mechanism that moves the electrode holder in of a target for an electrode placement. Top: Dorsal view. measured distances along the three axes: anterior–posterior, dorsal–ventral, and Bottom: Midsagittal view. lateral–medial. Figure 5 illustrates a stereotaxic apparatus designed for small animals; various head holders can be used to outfit this device for such diverse species as rats, mice, hamsters, pigeons, and turtles. (See Figure 5.) stereotaxic atlas A collection of drawings of sections of the brain of a Once we obtain the coordinates from a stereotaxic atlas, we anesthetize the animal, place it particular animal with measurements in the apparatus, and cut the scalp open. We locate bregma, dial in the appropriate numbers on that provide coordinates for stereotaxic the stereotaxic apparatus, drill a hole through the skull, and lower the device into the brain by surgery. the correct amount. Now the tip of the cannula or electrode is where we want it to be, and we are stereotaxic apparatus A device ready to produce the lesion. that permits a surgeon to position an Of course, stereotaxic surgery may be used for purposes other than lesion production. Wires electrode or cannula into a specific part placed in the brain may be used to stimulate neurons as well as destroy them, and drugs can be of the brain.

Target of lesion Dorsal

Adjusting knobs

Ventral Skull F I G U R E 4 Stereotaxic Atlas. This sample page from a stereotaxic atlas shows a drawing of a frontal section through the rat brain. The target (the fornix) is indicated in red. Labels have been removed for the sake of clarity. Adapted from Swanson, L. W. Brain Maps: Structure of the Rat Brain. New York: Elsevier, 1992.

Electrode in brain F I G U R E 5 Stereotaxic Apparatus. This apparatus is used for performing brain surgery on rats.

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injected that stimulate neurons or block specific receptors. We can attach cannulas or wires permanently by following a procedure that will be described later in this chapter. In all cases, once surgery is complete, the wound is sewn together, and the animal is taken out of the stereotaxic apparatus and allowed to recover from the anesthetic. Stereotaxic apparatuses are also made for humans, by the way. Sometimes a neurosurgeon produces subcortical lesions—for example, to reduce the symptoms of Parkinson’s disease. Usually, the surgeon uses multiple landmarks and verifies the location of the wire (or other device) inserted into the brain by taking brain scans or recording the activity of the neurons in that region before producing a brain lesion. (See Figure 6.)

Histological Methods FIGURE

Stereotaxic Surgery on a Human Patient.

John W. Snell, University of Virginia Health System.

FIGURE

A Microtome.

fixative A chemical such as formalin; used to prepare and preserve body tissue. formalin (for ma lin) The aqueous solution of formaldehyde gas; the most commonly used tissue fixative. microtome (my krow tome) An instrument that produces very thin slices of body tissues.

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After producing a brain lesion and observing its effects on an animal’s behavior, we must slice and stain the brain so that we can observe it under a microscope and see the location of the lesion. Brain lesions often miss the mark, so we have to verify the precise location of the brain damage after testing the animal behaviorally. To do so, we must fix, slice, stain, and examine the brain. Together, these procedures are referred to as histological methods. (The prefix histo- refers to body tissue.) FIXATION AND SECTIONING If we hope to study the tissue in the form it had at the time of the organism’s death, we must destroy the autolytic enzymes (autolytic means “self-dissolving”), which will otherwise turn the tissue into mush. The tissue must also be preserved to prevent its decomposition by bacteria or molds. To achieve both of these objectives, we place the neural tissue in a fixative. The most commonly used fixative is formalin, an aqueous solution of formaldehyde, a gas. Formalin halts autolysis, hardens the very soft and fragile brain, and kills any microorganisms that might destroy it. Once the brain has been fixed, we must slice it into thin sections and stain various cellular structures to see anatomical details. Slicing is done with a microtome (literally, “that which slices small”). (See Figure 7.) Slices prepared for examination under a light microscope are typically 10 to 80 μm in thickness; those prepared for the electron microscope are generally cut at less than l μm. (A μm, or micrometer, is one-millionth of a meter, or one-thousandth of a millimeter.) For some reason, slices of brain tissue are usually referred to as sections. After the tissue is cut, we attach the slices to glass microscope slides. We can then stain the tissue by putting the entire slide into various chemical solutions. Finally, we cover the stained sections with a small amount of a transparent liquid known as a mounting medium and place a very thin glass coverslip over the sections. The mounting medium keeps the coverslip in position.

STAINING If you looked at an unstained section of brain tissue under a microscope, you would be able to see the outlines of some large cellular masses and the more prominent fiber bundles. However, no fine details would be revealed. For this reason the study of microscopic neuroanatomy requires special histological stains. Researchers have developed many different stains to identify specific substances within and outside of cells. For verifying the location of a brain lesion, we will use one of the simplest: a cell-body stain. In the late nineteenth century Franz Nissl, a German neurologist, discovered that a dye known as methylene blue would stain the cell bodies of brain tissue. The material that takes up the dye, known as the Nissl substance, consists of RNA, DNA, and associated proteins located in the nucleus and scattered, in the form of granules, in the cytoplasm. Many dyes besides methylene blue can be used to stain cell bodies found in slices of the brain, but the

Methods and Strategies of Research

most frequently used is cresyl violet. Incidentally, the dyes were not developed specifically for histological purposes but were originally formulated for use in dyeing cloth. The discovery of cell-body stains made it possible to identify nuclear masses in the brain. Figure 8 shows a frontal section of a cat brain stained with cresyl violet. Note that you can observe fiber bundles by their lighter appearance; they do not take up the stain. (See Figure 8.) The stain is not selective for neural cell bodies; all cells are stained, neurons and glia alike. It is up to the investigator to determine which is which—by size, shape, and location. ELECTRON MICROSCOPY The light microscope is limited in its ability to resolve extremely small details. Because of the nature of light itself, magnification of more than approximately 1500 times does not add any detail. To see such small anatomical structures as F I G U R E 8 Cell-Body Stain. The photomicrograph shows a frontal section through a cat brain, stained with cresyl synaptic vesicles and details of cell organelles, investigators must use an electron violet, a cell-body stain. The arrowheads point to nuclei, or microscope. A beam of electrons is passed through the tissue to be examined. groups of cell bodies. A shadow of the tissue is then cast onto a sheet of photographic film, which is Mary Carlson. exposed by the electrons. Electron photomicrographs produced in this way can provide information about structural details on the order of a few tens of nanometers. (See Figure 9.) A scanning electron microscope provides less magnification than a standard transmission electron microscope, which transmits the electron beam through the tissue. However, it shows objects in three dimensions. The microscope scans the tissue with a moving beam of electrons. The information received from the reflection of the beam is used to produce a remarkably detailed three-dimensional view.

Tracing Neural Connections Let’s suppose that we were interested in discovering the neural mechanisms responsible for reproductive behavior. To start out, we wanted to study the physiology of sexual behavior of female rats. On the basis of some hints we received by reading reports of experiments by other researchers published in scientific journals, we performed stereotaxic surgery on two groups of female rats. We made a lesion in the ventromedial nucleus of the hypothalamus (VMH) of the rats in the experimental group and performed sham surgery on the rats in the control group. After a few days’ recovery we placed each animal with a male rat. We found that the females in the control group responded positively to the males’ attention; they engaged in courting behavior followed by copulation. However, the females with the VMH lesions rejected the males’ attention and refused to copulate with them. We confirmed with histology that the VMH was indeed destroyed in the brains of the experimental animals. (One experimental rat did copulate, but we discovered later that the lesion had missed the VMH in that animal, so we discarded the data from that animal.) F I G U R E 9 Electron Photomicrograph. The results of our experiment indicate that neurons in the VMH appear to play a role The electron photomicrograph shows a section in functions required for copulatory behavior in females. (By the way, it turns out that these through an axodendritic synapse. Two synaptic lesions do not affect copulatory behavior in males.) So where do we go from here? What is regions are pointed out by arrows, and a circle the next step? In fact, there are many questions that we could pursue. One question concerns indicates a region of pinocytosis in an adjacent terminal button, presumably representing the system of brain structures that participate in female copulatory behavior. Certainly, the recycling of vesicular membrane. T = terminal VMH does not stand alone; it receives inputs from other structures and sends outputs to still button; f = microfilaments; M = mitochondrion. others. Copulation requires the integration of visual, tactile, and olfactory information and Rockel, A. J., and Jones, E. G. Journal of Comparative the organization of patterns of movements in response to those of the partner. In addition, Neurology, 1973, 147, 61–92. John Wiley & Sons, Inc., the entire network must be activated by the appropriate sex hormones. What is the precise Journals. role of the VMH in this complicated system? Before we can hope to answer this question, we must know more about the connections of scanning electron microscope A the VMH with the rest of the brain. What structures send their axons to the VMH, and to what microscope that provides threestructures does the VMH, in turn, send its axons? Once we know what the connections are, we can dimensional information about the investigate the role of these structures and the nature of their interactions. (See Figure 10.) shape of the surface of a small object.

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Methods and Strategies of Research

? VMH

How do we investigate the connections of the VMH? The question cannot be answered by means of histological procedures that stain all neurons, such as cell-body stains. If we look closely at a brain that has been prepared by these means, we see only a tangled mass of neurons. But in recent years researchers have developed very precise methods that make specific neurons stand out from all of the others.

? TRACING EFFERENT AXONS Because neurons in the VMH are not directly connected to muscles, they canF I G U R E 10 Tracing Neural Connections. Once we know not affect behavior directly. Neurons in the VMH must send axons to parts of that a particular brain region is involved in a particular function, the brain that contain neurons that are responsible for muscular movements. we may ask what structures provide inputs to the region and what structures receive outputs from it. The pathway is probably not direct; more likely, neurons in the VMH affect neurons in other structures, which influence those in yet other structures until, eventually, the appropriate motor neurons are stimulated. To discover this system, we want to be able to identify the paths followed by axons leaving the VMH. In other words, we want to trace the efferent axons of this structure. We will use an anterograde labeling method to trace these axons. (Anterograde means “moving forward.”) Anterograde labeling methods employ chemicals that are taken up by dendrites or cell bodies and are then transported through the axons toward the terminal buttons. Over the years neuroscientists have developed several different methods for tracing the pathways followed by efferent axons. For example, to discover the destination of the efferent axons of neurons located within the VMH, we inject a minute quantity of PHA-L (a protein found in kidney beans) into that nucleus. (We would use a stereotaxic apparatus to do so, of course.) The molecules of PHA-L are taken up by dendrites and are transported through the soma to the axon, where they PHA-L is injected into a region of the brain and taken up by dendrites and cell bodies travel by means of fast axoplasmic transport to the terminal buttons. Within a few days the cells are filled in their PHA-L is transported by axoplasmic flow entirety with molecules of PHA-L: dendrites, soma, axons and all their branches, and terminal buttons. Then we kill the animal, slice the brain, and mount the sections on microscope slides. A special immunocytochemical method is used to make the molecules of PHA-L visible, and the slides are examined under a microscope. (See Figure 11.) Immunocytochemical methods take advantage of the immune reaction. The body’s immune system has the Axons and terminal ability to produce antibodies in response to antigens. Anbuttons can be seen under the microscope tigens are proteins (or peptides), such as those found on the surface of bacteria or viruses. Antibodies, which are F I G U R E 11 Tracing Efferent Axons. The diagram illustrates the use of PHA-L to also proteins, are produced by white blood cells to destroy trace efferent axons. invading microorganisms. Antibodies either are secreted by white blood cells or are located on their surface, in the way neurotransmitter receptors are loanterograde labeling method (ann ter cated on the surface of neurons. When the antigens that are present on the surface of an invading oh grade) A histological method that microorganism come into contact with the antibodies that recognize them, the antibodies trigger labels the axons and terminal buttons of an attack on the invader by the white blood cells. neurons whose cell bodies are located in Molecular biologists have developed methods for producing antibodies to any peptide or proa particular region. tein. The antibody molecules are attached to various types of dye molecules. Some of these dyes PHA-L Phaseolus vulgaris react with other chemicals and stain the tissue a brown color. Others are fluorescent; they glow when leukoagglutinin; a protein derived from they are exposed to light of a particular wavelength. To determine where the peptide or protein (the kidney beans and used as an anterograde tracer; taken up by dendrites and cell antigen) is located in the brain, the investigator places fresh slices of brain tissue in a solution that bodies and carried to the ends of the contains the antibody/dye molecules. The antibodies attach themselves to their antigen. When the axons. investigator examines the slices with a microscope (under light of a particular wavelength in the case immunocytochemical method A of fluorescent dyes), he or she can see which parts of the brain—even which individual neurons— histological method that uses radioactive contain the antigen. antibodies or antibodies bound with a Figure 12 shows how PHA-L can be used to identify the efferents of a particular region of the dye molecule to indicate the presence of brain. Molecules of this chemical were injected into the VMH. Two days later, after the PHA-L particular proteins of peptides.

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had been taken up by the neurons in this region and transported to the ends of their axons, the animal was killed. Slices of the brain were treated with an antibody to PHA-L and then attached to a dye that stains the tissue a reddish brown color. Figure 12 shows a photomicrograph of the periaqueductal gray matter (PAG). As you can see, this region contains some labeled axons and terminal buttons (gold color), which proves that some of the efferent axons of the VMH terminate in the PAG. (See Figure 12.) To continue our study of the VMH’s role in female sexual behavior, we would find the structures that receive information from neurons in the VMH (such as the PAG) and see what happens when each of them is destroyed. Let’s suppose that damage to some of these structures also impairs female sexual behavior. We will inject these structures with PHA-L and see where their axons go. Eventually, we will discover the relevant pathways from the VMH to the motor neurons whose activity is necessary for copulatory behavior. (In fact, researchers have done so.)

F I G U R E 12 Anterograde Tracing Method. PHA-L was injected into the ventromedial nucleus of the hypothalamus (VMH), where it was taken up by dendrites and carried through the cells’ axons to their terminal buttons. Labeled axons and terminal buttons are seen in the periaqueductal gray matter (PAG).

TRACING AFFERENT AXONS Kirsten Nielsen Ricciardi and Jeffrey Blaustein, University of Massachusetts. Tracing efferent axons from the VMH will tell us only part of the story about the neural circuitry involved in female sexual behavior: the part between the VMH and the motor neurons. What about the circuits before the VMH? Is the VMH somehow involved in the analysis of sensory information (such as the sight, odor, or touch of the male)? Or perhaps the activating effect of a female’s sex hormones on her behavior act through the VMH or through neurons whose axons form synapses there. To discover the parts of the brain that are involved in the “upstream” components of the neural circuitry, we need to find the inputs of the VMH—its afferent connections. To do so, we will employ a retrograde labeling method. Retrograde means “moving backward.” Retrograde labeling methods employ chemicals that are taken up by terminal buttons and carried back through the axons toward the cell bodies. The method for identifying the afferent inputs to a particular region of the brain is similar to the method used for identifying its efferents. First, we inject a small F I G U R E 13 Retrograde Tracing Method. Fluorogold was injected quantity of a chemical called fluorogold into the VMH. The chemical in the VMH, where it was taken up by terminal buttons and transported is taken up by terminal buttons and is transported back by means of back through the axons to their cell bodies. The photograph shows retrograde axoplasmic transport to the cell bodies. A few days later we these cell bodies, located in the medial amygdala. kill the animal, slice its brain, and examine the tissue under light of the Yvon Delville, University of Texas. appropriate wavelength. The molecules of fluorogold fluoresce under this light. We discover that the medial amygdala is one of the regions that provides input to the VMH. (See Figure 13.) The anterograde and retrograde labeling methods that I have described identify a single link retrograde labeling method A histological method that labels cell in a chain of neurons—neurons whose axons enter or leave a particular brain region. Transneubodies that give rise to the terminal ronal tracing methods identify a series of neurons that form serial synaptic connections with buttons that form synapses with cells in a each other. The most effective transneuronal tracing method uses various strains of weakened particular region. rabies viruses or herpes viruses. The virus is injected directly into a brain region, is taken up fluorogold (flew roh gold) A dye that by neurons there, and infects them. The virus spreads throughout the infected neurons and is serves as a retrograde label; taken up by eventually released, passing on the infection to other neurons that form synaptic connections terminal buttons and carried back to the with them. Depending on the type and strain of the virus, the infection is preferentially transmitcell bodies. ted in an anterograde or a retrograde direction. After the animal is killed and the brain is sliced, transneuronal tracing method A immunocytochemical methods are used to localize a protein produced by the virus. tracing method that identifies a series of neurons that form serial synaptic Together, anterograde and retrograde labeling methods—including transneuronal methods— connections with each other, either in enable us to discover circuits of interconnected neurons. Thus, these methods help to provide us an anterograde or retrograde direction; with a “wiring diagram” of the brain. (See Figure 14.) Armed with other research methods (ininvolves infection of specific neurons cluding some to be described later in this chapter), we can try to discover the functions of each with weakened forms of rabies or herpes component of this circuit. viruses.

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1a Anterograde tracing: inject PHA-L in VMH

Studying the Structure of the Living Human Brain

There are many good reasons to investigate the functions of brains of animals other than humans. For one thing, we can compare the results of studies made with different species in order to make some inferences about the evolution of various neural systems. Even if our primary interest is in the functions of the human brain, we certainly cannot ask people to submit to brain surgery for the purposes of research. But diseases and accidents do occasionally damage the human brain, and if we know where the damage occurs, we can study the people’s behavior and try to make the same sorts of inferences we make with deliberately produced brain lesions in laboratory animals. The problem PAG is, where is the lesion? In past years a researcher might study the behavior of a person with brain VMH Medial damage and never find out exactly where the lesion was located. The only way Other amygdala structures? to be sure was to obtain the patient’s brain when he or she died and examine Sexual behavior slices of it under a microscope. But it was often impossible to do so. Sometimes the patient outlived the researcher. Sometimes the patient moved out of town. Sometimes (often, perhaps) the family refused permission for an autopsy. Be2a Retrograde tracing: inject fluorogold in VMH cause of these practical problems, study of the behavioral effects of damage to specific parts of the human brain made rather slow progress. 2b Then see cell bodies in medial amygdala Recent advances in X-ray techniques and computers have led to the develF I G U R E 14 Results of Tracing Methods. One of the inputs opment of several methods for studying the anatomy of the living brain. These to the VMH and one of the outputs, as revealed by anterograde advances permit researchers to study the location and extent of brain damage and retrograde labeling methods. while the patient is still living. The first method that was developed is called computerized tomography (CT) (from the Greek words tomos, “cut,” and graphein, “to write”). This procedure, usually referred to as a CT scan, works as follows: The patient’s head is placed in a large doughnutshaped ring. The ring contains an X-ray tube and, directly opposite it (on the other side of the patient’s head), an X-ray detector. The X-ray beam passes through the patient’s head, and the detector measures the amount of radioactivity that gets through it. The beam scans the head from all angles, and a computer translates the numbers it receives from the detector into pictures of the skull and its contents. (See Figure 15.) Figure 16 shows a series of these CT scans taken through the head of a patient who sustained a stroke. The stroke damaged a part of the brain involved in bodily awareness and perception of space. The patient lost her awareness of the left side of her body and of items located on her left. You can see the damage as a white spot in the lower left corner of scan 5. (See Figure 16.) An even more detailed, high-resolution picture of what is inside a F I G U R E 15 Computerized Tomography (CT) Scanner. person’s head is provided by a process called magnetic resonance imag© Steven Grover/age fotostock. ing (MRI). The MRI scanner resembles a CT scanner, but it does not use X-rays. Instead, it passes an extremely strong magnetic field through the patient’s head. When a person’s body is placed in a strong magnetic field, the nuclei of some atoms in molecules in the computerized tomography (CT) The use of a device that employs a computer body spin with a particular orientation. If a radio frequency wave is then passed through the body, to analyze data obtained by a scanning these nuclei emit radio waves of their own. Different molecules emit energy at different frequenbeam of X-rays to produce a twocies. The MRI scanner is tuned to detect the radiation from hydrogen atoms. Because these atoms dimensional picture of a “slice” through are present in different concentrations in different tissues, the scanner can use the information the body. to prepare pictures of slices of the brain. Unlike CT scans, which are generally limited to the magnetic resonance imaging (MRI) horizontal plane, MRI scans can be taken in the sagittal or frontal planes as well. (See Figure 17.) A technique whereby the interior of the As you can see in Figure 17, MRI scans distinguish between regions of gray matter and body can be accurately imaged; involves the interaction between radio waves and white matter, so major fiber bundles (such as the corpus callosum) can be seen. However, small a strong magnetic field. fiber bundles are not visible on these scans. A special modification of the MRI scanner permits diffusion tensor imaging (DTI) An the visualization of even small bundles of fibers and the tracing of fiber tracts. Above absolute imaging method that uses a modified zero, all molecules move in random directions because of thermal agitation: the higher the temMRI scanner to reveal bundles of perature, the faster the random movement. Diffusion tensor imaging (DTI) takes advantage of myelinated axons in the living human the fact that the movement of water molecules in bundles of white matter will not be random, brain. 1b Then see axons and terminals in PAG

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but will tend to be in a direction parallel to the axons that make up the bundles. The MRI scanner uses information about the movement of the water molecules to determine the location and orientation of bundles of axons in white matter. Figure 18 shows a sagittal view of some of the axons that project from the thalamus to the cerebral cortex in the human brain, as revealed by diffusion tensor imaging. The computer adds colors to distinguish different bundles of axons. (See Figure 18.)

(1)

(2)

(3)

(4)

(5)

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F I G U R E 16 CT Scans of a Lesion. The patient had a lesion in the right occipital-parietal area (scan 5). The lesion appears white because it was accompanied by bleeding; blood absorbs more radiation than does the surrounding brain tissue. Rostral is up, caudal is down; left and right are reversed. Scan 1 shows a section through the eyes and the base of the brain. J. McA. Jones.

Thalamus F I G U R E 17 Magnetic Resonance Imaging (MRI). The figure shows a midsagittal MRI scan of a human brain. Living Art Enterprises/Science Source/Photo Researchers, Inc.

F I G U R E 18 Diffusion Tensor Imaging (DTI). A sagittal view of some of the axons that project from the thalamus to the cerebral cortex in the human brain is revealed by diffusion tensor imaging. From Wakana, S., Jian, H., Nagae-Poetscher, L. M., van Zijl, P. C. M., and Mori, S. Radiology, 2004, 230, 77–87. Reprinted with permission.

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SECTION SUMMARY Experimental Ablation The goal of research in behavioral neuroscience is to understand the brain functions required for the performance of a particular behavior and then to learn the location of the neural circuits that perform these functions. The lesion method is the oldest one employed in such research, and it remains one of the most useful. A subcortical lesion is made under the guidance of a stereotaxic apparatus. The coordinates are obtained from a stereotaxic atlas, and the tip of an electrode or cannula is placed at the target. A lesion is made by passing radio frequency current through the electrode or infusing an excitatory amino acid through the cannula, producing an excitotoxic lesion. The advantage of excitotoxic lesions is that they destroy only neural cell bodies; axons passing through the region are not damaged. The location of a lesion must be determined after observation of the animal’s behavior. The animal is killed by humane means, and the brain is removed and placed in a fixative such as formalin. A microtome is used to slice the brain, which is usually frozen to make it hard enough to cut into thin sections. These sections are mounted on glass slides, stained with a cell-body stain, and examined under a microscope. Light microscopes enable us to see cells and their larger organelles, but an electron microscope is needed to see small details, such as individual mitochondria and synaptic vesicles. Scanning electron microscopes provide a three-dimensional view of tissue, but at a lower magnification than transmission electron microscopes. The next step in a research program often requires the investigator to discover the afferent and efferent connections of the region of interest with the rest of the brain. Efferent connections (those that carry information from the region in question to other parts of the brain) are revealed with

TABLE

Thought Questions 1. In the subsection “Tracing Neural Connections,” I wrote that “one experimental rat did copulate, but we discovered later that the lesion had missed the VMH in that animal, so we discarded the data from that animal.” Should the person who looks at the stained brain sections containing the lesions and decides whether the target was destroyed or missed know which animal each of these sections belonged to? Explain. 2. Would you like to see an MRI of your own brain? Why or why not?

1 Research Methods: Part I

Goal of Method

Method

Remarks

Destroy or inactivate specific brain region

Radio frequency lesion

Destroys all brain tissue near the tip of the electrode

Excitotoxic lesion; uses excitatory amino acid such as kainic acid

Destroys only cell bodies near the tip of the cannula; spares axons passing through the region

Infusion of local anesthetic or drug that produces local neural inhibition

Temporarily inactivates specific brain region; animal can serve as its own control

Infusion of a toxin attached to an antibody

Destroys neurons that contain the antibody; produces very precise brain lesions

Stereotaxic surgery

Consult stereotaxic atlas for coordinates

Place electrode or cannula in a specific region within the brain

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anterograde tracing methods, such as the one that uses PHA-L. Afferent connections (those that bring information to the region in question from other parts of the brain) are revealed with retrograde tracing methods, such as the one that uses fluorogold. Chains of neurons that form synaptic connections are revealed by anterograde or retrograde transneuronal tracing methods, which utilized weakened forms of rabies and herpes viruses. Although brain lesions are not deliberately made in the human brain for the purposes of research, diseases and accidents can cause brain damage, and if we know where the damage is located, we can study people’s behavior and make inferences about the location of the neural circuits that perform relevant functions. If the patient dies and the brain is available for examination, ordinary histological methods can be used. Otherwise, the living brain can be examined with CT scanners and MRI scanners. Diffusion tensor imaging (DTI) uses a modified MRI scanner to visualize bundles of myelinated axons in the living human brain. Table 1 summarizes the research methods presented in this section. (See Table 1.)

Find the location of the lesion

Fix brain; slice brain; stain sections

Identify axons leaving a particular region and the terminal buttons of these axons

Anterograde tracing method, such as PHA-L

Identify the location of neurons whose axons terminate in a particular region

Retrograde tracing method, such as fluorogold

Identify chain of neurons that are interconnected synaptically

Transneuronal tracing method; uses pseudorabies virus

Find location of lesion in living human brain

Computerized tomography (CT scanner)

Shows “slice” of brain; uses X-rays

Magnetic resonance imaging (MRI scanner)

Shows “slice” of brain; better detail than CT scan; uses a magnetic field and radio waves

Can be used for both anterograde and retrograde tracing

Methods and Strategies of Research

Recording and Stimulating Neural Activity The first section of this chapter dealt with the anatomy of the brain and the effects of damage to particular regions. This section considers a different approach: studying the brain by recording or stimulating the activity of particular regions. Brain functions involve activity of circuits of neurons; thus, different perceptions and behavioral responses involve different patterns of activity in the brain. Researchers have devised methods to record these patterns of activity or to artificially produce them.

Recording Neural Activity Axons produce action potentials, and terminal buttons elicit postsynaptic potentials in the membrane of the cells with which they form synapses. These electrical events can be recorded, and changes in the electrical activity of a particular region can be used to determine whether that region plays a role in various behaviors. For example, recordings can be made during stimulus presentations, decision making, or motor activities. Recordings can be made chronically, over an extended period of time after the animal recovers from surgery, or acutely, for a relatively short period of time during which the animal is kept anesthetized. Acute recordings, made while the animal is anesthetized, are usually restricted to studies of sensory pathways. Acute recordings seldom involve behavioral observations, since the behavioral capacity of an anesthetized animal is limited, to say the least. If we want to record the activity of a particular region of the brain of an animal that is awake and free to move about, we would implant the electrodes by means of stereotaxic surgery. We would attach the electrodes to miniaturized electrical sockets and bond the sockets to the animal’s skull, using plastics that were originally developed for the dental profession. Then, after recovery from surgery, the animal can be “plugged in” to the recording system. Laboratory animals pay no heed to the electrical sockets on their skulls and behave quite normally. (See Figure 19.)

Connecting socket Electrodes

Dental plastic

Skull

F I G U R E 19 Implantation of Electrodes. This schematic shows a permanently attached set of electrodes, with a connecting socket cemented to the skull.

RECORDINGS WITH MICROELECTRODES Drugs that affect serotonergic and noradrenergic neurons also affect REM sleep. Suppose that, knowing this fact, we wondered whether the activity of serotonergic and noradrenergic neurons would vary during different stages of sleep. To find out, we would record the activity of these neurons with microelectrodes. Microelectrodes have a very fine tip, small enough to record the electrical activity of individual neurons. This technique is usually called single-unit recording (a unit refers to an individual neuron). Because we want to record the activity of single neurons over a long period of time in unanesthetized animals, we want more durable electrodes. We can purchase arrays of very fine wires, gathered together in a bundle. The wires are insulated so that only their tips are bare. Researchers often attach rather complex devices to an animal’s skull when they implant microelectrodes. These devices include screw mechanisms that permit the experimenter to move the electrode—or array of electrodes—deeper into the brain so that they can record from several different parts of the brain during the course of their observations. The electrical signals detected by microelectrodes are quite small and must be amplified. Amplifiers used for this purpose work just like the amplifiers in a stereo system, converting the weak signals recorded at the brain into stronger ones. These signals can be displayed on an oscilloscope and stored in the memory of a computer for analysis at a later time. What about the results of our recordings from serotonergic and noradrenergic neurons? If we record the activity of these neurons during various stages of sleep, we will find that their firing rates fall almost to zero during REM sleep. This observation suggests that these neurons have an inhibitory effect on REM sleep. That is, REM sleep cannot occur until these neurons stop firing.

microelectrode A very fine electrode, generally used to record activity of individual neurons. single-unit recording Recording of the electrical activity of a single neuron.

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Paper moves

FIGURE

A Record from a Polygraph.

RECORDINGS WITH MACROELECTRODES Sometimes, we want to record the activity of a region of the brain as a whole, not the activity of individual neurons located there. To do this, we would use macroelectrodes. Macroelectrodes do not detect the activity of individual neurons; rather, the records that are obtained with these devices represent the postsynaptic potentials of many thousands—or millions—of cells in the area of the electrode. These electrodes can consist of unsharpened wires inserted into the brain, screws attached to the skull, or even metal disks attached to the human scalp with a special paste that conducts electricity. Recordings taken from the scalp, especially, represent the activity of an enormous number of neurons, whose electrical signals pass through the meninges, skull, and scalp before reaching the electrodes. Occasionally, neurosurgeons implant macroelectrodes directly into the human brain. The reason for doing so is to detect the source of abnormal electrical activity that is giving rise to frequent seizures. Once the source has been determined, the surgeon can open the skull and remove the source of the seizures—usually scar tissue caused by brain damage that occurred earlier in life. Usually, the electrical activity of a human brain is recorded through electrodes attached to the scalp and displayed on a polygraph. A polygraph contains a mechanism that moves a very long strip of paper past a series of pens. These pens are essentially the pointers of large voltmeters, moving up and down in response to the electrical signal sent to them by the biological amplifiers. Figure 20 illustrates a record of electrical activity recorded from macroelectrodes attached to various locations on a person’s scalp. (See Figure 20.) Such records are called electroencephalograms (EEGs), or “writings of electricity from the head.” They can be used to diagnose epilepsy or study the stages of sleep and wakefulness, which are associated with characteristic patterns of electrical activity. Another use of the EEG is to monitor the condition of the brain during surgical procedures that could potentially damage it, such as the one we encountered in the prologue to this chapter. The use of EEG monitoring during blood-vessel surgery is described in the epilogue to this chapter.

MAGNETOENCEPHALOGRAPHY As you undoubtedly know, when electrical current flows through a conductor, it induces a magnetic field. This means that as action potentials pass down axons or as postsynaptic potentials pass down dendrites or sweep across the somatic membrane of a neuron, magnetic fields are also produced. These fields are exceedingly small, but engineers have developed superconducting detectors (called superconducting quantum interference devices, or SQUIDs) that can detect magnetic fields that are approximately one-billionth of the size of the earth’s magnetic field. MagnetoenF I G U R E 21 Magnetoencephalography. An array cephalography (MEG) is performed with neuromagnetometers, devices that contain of SQUIDs in this neuromagnetometer detects regional changes in magnetic fields produced by electrical activity an array of several SQUIDs, oriented so that a computer can examine their output of the brain. and calculate the source of particular signals in the brain. The neuromagnetometer PHANIE/Science Source/Photo Researchers, Inc. shown in Figure 21 contains 275 SQUIDs. These devices can be used clinically—for example, to find the sources of seizures so that they can be removed surgically. They can also be used in experiments to measure regional brain activity that accompanies the perception of various stimuli or the performance of various behaviors or cognitive tasks. (See Figure 21.) macroelectrode An electrode used An important advantage of magnetoencephalography is its temporal resolution. Functional to record the electrical activity of large MRI (described later) provides excellent spatial resolution, but relatively poor temporal resolunumbers of neurons in a particular region of the brain; much larger than a tion. That is, the image can accurately measure differences in activity of closely spaced regions microelectrode. of the brain, but the acquisition of an fMRI image takes a relatively long time compared with electroencephalogram (EEG) An the rapid flow of information in the brain. The image produced by means of magnetoencephaelectrical brain potential recorded by lography is much more crude than an fMRI, but it can be acquired much more rapidly, and can placing electrodes on the scalp. consequently reveal fast-moving events. magnetoencephalography (MEG) A procedure that detects groups of synchronously activated neurons by means of the magnetic field induced by their electrical activity; uses an array of superconducting quantum interference devices (SQUIDs).

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Recording the Brain’s Metabolic and Synaptic Activity Electrical signals are not the only signs of neural activity. If the neural activity of a particular region of the brain increases, the metabolic rate of this region increases, too, largely as a result of increased operation of transporters in the membrane of the cells. This increased metabolic rate

Methods and Strategies of Research

can be measured. The experimenter injects radioactive 2-deoxyglucose (2-DG) into the animal’s bloodstream. Because this chemical resembles glucose (the principal food for the brain), it is taken into cells. Thus, the most active cells, which use glucose at the highest rate, will take up the highest concentrations of radioactive 2-DG. But unlike normal glucose, 2-DG cannot be metabolized, so it stays in the cell. The experimenter then kills the animal, removes the brain, slices it, and prepares it for autoradiography. Autoradiography can be translated roughly as “writing with one’s own radiation.” Sections of the brain are mounted on microscope slides. The slides are then taken into a darkroom, where they are coated with a photographic emulsion (the substance found on photographic film). Several weeks later, the slides, with their coatings of emulsion, are developed, just like photographic film. The molecules of radioactive 2-DG show themselves as spots of silver grains in the developed emulsion because the radioactivity exposes the F I G U R E 22 2-DG Autoradiography. This 2-DG emulsion, just as X-rays or light will do. The most active regions of the brain contain the most radioactiv- autoradiogram of a rat brain (frontal section, dorsal is at top) shows especially high regions of activity in the pair of nuclei in the ity, showing this radioactivity in the form of dark spots in the developed hypothalamus, at the base of the brain. emulsion. Figure 22 shows an autoradiograph of a slice of a rat brain; the American Association for the Advancement of Sciences. dark spots at the bottom (indicated by the arrow) are nuclei of the hypothalamus with an especially high metabolic rate. (See Figure 22.) Another method of identifying active regions of the brain capitalizes on the fact that when neurons are activated (for example, by the terminal buttons that form synapses with them), particular genes in the nucleus called immediate early genes are turned on and particular proteins are produced. These proteins then bind with the chromosomes in the nucleus. The presence of these proteins indicates that the neuron has just been activated. One of the nuclear proteins produced during neural activation is called Fos. You will remember that earlier in this chapter we began an imaginary research project on the neural circuitry involved in the sexual behavior of female rats. Suppose we want to use the Fos method in this project to see what neurons are activated during a female rat’s sexual activity. We place female rats with males and permit the animals to copulate. Then we remove the rats’ brains, slice them, and follow a procedure that stains Fos protein. Figure 23 shows the results: Neurons in the medial amygdala of a female rat that has just mated show the presence of dark spots, indicating the presence F I G U R E 23 Localization of Fos Protein. The of Fos protein. Thus, these neurons appear to be activated by copulatory acphotomicrograph shows a frontal section of the brain of a tivity—perhaps by the physical stimulation of the genitals that occurs then. female rat, taken through the medial amygdala. The dark spots As you will recall, when we injected a retrograde tracer (fluorogold) into the indicate the presence of Fos protein, localized by means of VMH, we found that this region receives input from the medial amygdala. immunocytochemistry. The synthesis of Fos protein was stimulated (See Figure23.) by permitting the animal to engage in copulatory behavior. The metabolic activity of specific brain regions can be measured in huDr. Marc Tetel, Wellesley College. man brains, too, by means of functional imaging—a computerized method 2-deoxyglucose (2-DG) (dee ox ee gloo of detecting metabolic or chemical changes within the brain. The first funckohss) A sugar that enters cells along tional imaging method to be developed was positron emission tomography (PET). First, the with glucose but is not metabolized. patient receives an injection of radioactive 2-DG. (The chemical soon breaks down and leaves the autoradiography A procedure that cells. The dose given to humans is harmless.) The person’s head is placed in a machine similar locates radioactive substances in a slice of tissue; the radiation exposes a to a CT scanner. When the radioactive molecules of 2-DG decay, they emit subatomic particles photographic emulsion or a piece of film called positrons, which meet nearby electrons. The particles annihilate each other and emit two that covers the tissue. photons, which travel in directly opposite paths. Sensors arrayed around the person’s head detect Fos (fahs) A protein produced in the these photons and the scanner plots the locations from which these photons are being emitted. nucleus of a neuron in response to From this information, the computer produces a picture of a slice of the brain, showing the activsynaptic stimulation. ity level of various regions in that slice. (See Figure 24.) functional imaging A computerized One of the disadvantages of PET scanners is their operating cost. For reasons of safety the method of detecting metabolic or chemical radioactive chemicals that are administered have very short half-lives; that is, they decay and lose changes in particular regions of the brain. positron emission tomography (PET) A functional imaging method that reveals the localization of a radioactive tracer in a living brain.

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their radioactivity very quickly. For example, the half-life of radioactive 2-DG is 110 minutes; the half-life of radioactive water (also used for PET scans) is only 2 minutes. Because these chemicals decay so quickly, they must be produced on site, in an atomic particle accelerator called a cyclotron. Therefore, the cost of the PET scanner must be added to the cost of the cyclotron and the salaries of the personnel who operate it. The functional brain imaging method with the best spatial and temporal resolution is known as functional MRI (fMRI). Engineers have devised modifications to existing MRI scanners and their software that permit the devices to acquire images that indicate regional metabolism. Brain activity is measured indirectly, by detecting levels of oxygen in the brain’s blood vessels. Increased activity of a brain region stimulates blood flow to that region, which increases the local blood oxygen level. The formal name of this type of imaging is BOLD—blood oxygen leveldependent signal. Functional MRI scans have a higher resolution than PET scans, and they can be acquired much faster. Thus, they reveal more detailed information about the activity of particular brain regions. (See Figure 25.)

Relaxed condition

Right fist clenched and unclenched 0

F I G U R E 24 PET Scans. In the top row of these human brain scans are three horizontal scans from a person at rest. The bottom row shows three scans from the same person while he was clenching and unclenching his right fist. The scans show increased uptake of radioactive 2-deoxyglucose in regions of the brain that are devoted to the control of movement, which indicates increased metabolic rate in these areas. Different computer-generated colors indicate different rates of uptake of 2-DG, as shown in the scale at the bottom. Brookhaven National Laboratory and the State University of New York, Stony Brook.

Stimulating Neural Activity So far, this section has been concerned with research methods that measure the activity of specific regions of the brain. But sometimes we may want to artificially change the activity of these regions to see what effects these changes have on the animal’s behavior. For example, female rats will copulate with males only if certain female sex hormones are present. If we remove the rats’ ovaries, the loss of these hormones will abolish their sexual behavior. We found in our earlier studies that VMH lesions disrupt this behavior. Perhaps if we activate the VMH, we will make up for the lack of female sex hormones and the rats will copulate again.

ELECTRICAL AND CHEMICAL STIMULATION How do we activate neurons? We can do so by electrical or chemical stimulation. Electrical stimulation simply involves passing an electrical current through a wire inserted into the brain, as you saw in Figure19. Chemical stimulation is usually accomplished by injecting a small amount of an excitatory amino acid, such as kainic acid or glutamic acid, into the brain. The principal excitatory neurotransmitter in the brain is glutamic acid (glutamate), and both of these chemicals stimulate glutamate receptors, thus activating the neurons on which these receptors are located. Injections of chemicals into the brain can be done through an apparatus that is permanently attached to the skull so that the aniF I G U R E 25 Functional MRI Scans. These scans of human brains mal’s behavior can be observed several times. We place a metal cannula show localized average increases in neural activity of males (left) and (aguide cannula) in an animal’s brain and cement its top to the skull. At a females (right) while they were judging whether pairs of written words later date we place a smaller cannula of measured length inside the guide rhymed. cannula and then inject a chemical into the brain. Because the aniShaywitz, B. A., et al., Nature, 1995, 373, 607–609. mal is free to move about, we can observe the effects of the injection on itsbehavior. (See Figure 26.) The principal disadvantage of chemical stimulation is that it is slightly more complicated than electrical stimulation; chemical stimulation requires cannulas, tubes, special pumps or syringes, functional MRI (fMRI) A functional and sterile solutions of excitatory amino acids. However, it has a distinct advantage over electrical imaging method; a modification of the MRI stimulation: It activates cell bodies but not axons. Because only cell bodies (and their dendrites, of procedure that permits the measurement course) contain glutamate receptors, we can be assured that an injection of an excitatory amino of regional metabolism in the brain.

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Outside of Cell

Chemical

ChR2

NpHR

Blue light

Yellow light

Ca2+

Cl-

Na+

Plastic tubing

Guide cannula

Dental plastic

Skull

Brain Ion channel

Ion transporter

(a) Depolarization Hyperpolarization

(b)

F I G U R E 26 Intracranial Cannula. A guide cannula is permanently attached to the skull (a), and at a later time a thinner cannula can be inserted through the guide cannula into the brain (b). Chemicals can be infused into the brain through this device.

acid into a particular region of the brain excites the cells there, but not the axons of other neurons that happen to pass through the region. Thus, the effects of chemical stimulation are more localized than the effects of electrical stimulation. You might have noticed that I just said that kainic acid, which I described earlier as a neurotoxin, can be used to stimulate neurons. These two uses are not really contradictory. Kainic acid produces excitotoxic lesions by stimulating neurons to death. Whereas large doses of a concentrated solution kill neurons, small doses of a dilute solution simply stimulate them. What about the results of our imaginary experiment? In fact, VMH stimulation does substitute for female sex hormones. Perhaps, then, the female sex hormones exert their effects in this nucleus. We will see how to test this hypothesis later in this chapter.

1.0 0.8 Activation

(a)

0.6

NpHR

ChR2

0.4 0.2 0 325

(b)

425

525

625

725

Wavelength (nm)

Action potentials

Yellow light applied

OPTOGENETIC METHODS When chemicals are injected into the brain through cannulas, molecules of the chemicals diffuse over a region that includes many different types of neurons: Time (c) excitatory neurons, inhibitory neurons, interneurons that participate in local circuits, projection neurons that communicate with different regions of the F I G U R E 27 Photostimulation. (a) Photosensitive proteins brain, and neurons that release or respond to a wide variety of neurotransmit- can be inserted into neural membranes by means of genetically modified viruses. Blue light causes ChR2 ion channels to ters and neuromodulators. Stimulating a particular brain region with electricity depolarize the membrane, and yellow light causes NpHR ion or an excitatory chemical affects all of these neurons, and the result is unlikely to transporters to hyperpolarize it. (b) The graph shows the effects resemble normal brain activity, which involves coordinated activation and inhi- on the membrane potential of different wavelengths of light bition of many different neurons. Ideally, we would like to be able to stimulate acting on ChR2 or NpHR proteins. (c) The graph shows action potentials elicited by pulses of blue light (blue arrows) and the or inhibit selected populations of neurons in a given brain region. inhibitory effects of the hyperpolarization caused by yellow light. Recent developments are providing the means to do just this. Optogenetic methPart (a) based on Hausser, M., and Smith, S. L. Nature, 2007, 446, ods can be used to stimulate or inhibit particular types of neurons in particular brain regions (Boyden et al., 2005; Zhang et al., 2007; Baker, 2011). Photosensitive proteins 617–619, and parts (b) and (c) based on Zhang, F., Wang, L. P., Brauner, M., et al. Nature, 2007, 446, 633–639. have evolved in many organisms—even single-celled organisms such as algae and bacteria. Researchers have discovered that when blue light strikes one of these proteins optogenetic methods The use of a genetically modified virus to insert (ChR2), the channel opens and the rush of positively charged sodium and calcium ions depolarizes the light-sensitive ion channels into the membrane, causing excitation. When yellow light strikes a second photosensitive protein, (NpHR), a membrane of particular neurons in the transporter moves chloride into the cell causing inhibition. The action of both of these photosensitive brain; can depolarize or hyperpolarize proteins begins and ends very rapidly when light of the appropriate wavelength is turned on and off. (See the neurons when light of the Figure 27.) appropriate wavelength is applied.

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F I G U R E 28 Transcranial Magnetic Stimulation (TMS). Pulses of electricity through the coil produce a magnetic field that stimulates a region of the cerebral cortex under the crossing point in the middle of the figure 8. The Kastner Lab/Princeton University.

transcranial magnetic stimulation (TMS) Stimulation of the cerebral cortex by means of magnetic fields produced by passing pulses of electricity through a coil of wire placed next to the skull; interferes with the functions of the brain region that is stimulated.

ChR2 and NpHR can be introduced into neurons by attaching the genes that code for them into the genetic material of harmless viruses. The viruses are then injected into the brain, where they infect neurons and begin expressing the proteins, which are inserted into the cell membrane. The genes can be modified so that the proteins will be expressed only in particular types of neurons. In this way, researchers can observe the effects of turning on or off particular types of neurons in a particular region of the brain. To activate photosensitive proteins in the membranes of neurons deep within the brain, optical fibers can be implanted by means of stereotaxic surgery, just like electrodes or cannulas, and light can be transmitted through these fibers. The development of these procedures has caused much excitement among neuroscientists because they promise ways to study the functions of particular neural circuits in the brain. Some investigators are also exploring possible clinical uses of photosensitive proteins. For example, retinitis pigmentosa is a genetic disease that causes blindness in humans. People with this disease are born with normal vision, but they gradually become blind as the photoreceptor cells in their retinas degenerate. The retina contains two major categories of photoreceptors: rods, which are responsible for night vision, and cones, which are responsible for daytime vision. The rods of people with retinitis pigmentosa die, but although the cones lose their sensitivity to light, their cell bodies survive. Busskamp et al. (2010) used anoptogenetic method to try to re-establish vision in mice with a genetic modification that caused them to develop retinitis pigmentosa. The investigators targeted the animals’ cones with NpHR. (Because the membranes of photoreceptors are normally hyperpolarized by light, they chose to use this protein.) Electrical recording and behavioral studies found that the treatment at least partially re-established the animals’ vision. Furthermore, the same treatment re-established light sensitivity in retinal tissue removed from deceased people who had suffered from retinitis pigmentosa. These findings provide hope that further research may develop a treatment for this form of blindness. TRANSCRANIAL MAGNETIC STIMULATION As we saw earlier in this chapter, neural activity induces magnetic fields that can be detected by means of magnetoencephalography. Similarly, magnetic fields can be used to stimulate neurons by inducing electrical currents in brain tissue. Transcranial magnetic stimulation (TMS) uses a coil of wires, usually arranged in the shape of the numeral 8, to stimulate neurons in the human cerebral cortex. The stimulating coil is placed on top of the skull so that the crossing point in the middle of the 8 is located immediately above the region to be stimulated. Pulses of electricity send magnetic fields that activate neurons in the cortex. Figure 28 shows an electromagnetic coil used in transcranial magnetic stimulation and its placement on a person’s head. (See Figure 28.) The effects of TMS are very similar to those of direct stimulation of the exposed brain. For example, stimulation of a particular region of the visual association cortex will disrupt a person’sability to detect movements in visual stimuli. In addition, TMS has been used to treat the symptoms of mental disorders such as depression. Depending on the strength and pattern of stimulation, TMS can either excite the region of the brain over which the coil is positioned or interfere with its functions.

SECTION SUMMARY Recording and Stimulating Neural Activity When circuits of neurons participate in their normal functions, their electrical activity and metabolic activity increase. Thus, by observing these processes as an animal perceives various stimuli or engages in various behaviors, we can make some inferences about the functions performed by various regions of the brain. Microelectrodes can be used to record the electrical activity of individual neurons. Chronic recordings require

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that the electrode be attached to an electrical socket, which is fastened to the skull with a plastic adhesive. Macroelectrodes record the activity of large groups of neurons. In rare cases macroelectrodes are placed in the depths of the human brain, but most often they are placed on the scalp and their activity is recorded on a polygraph or computer. Such records can be used in the diagnosis of epilepsy or the study of sleep.

g of Research Methods and Strategies

Section Summary (continued) Metabolic activity can be measured by giving an animal an injection of radioactive 2-DG, which accumulates in metabolically active neurons. The presence of the radioactivity is revealed through autoradiography: Slices of the brain are placed on microscope slides, covered with a photographic emulsion, left to sit a while, and then are developed like photographic negatives. When neurons are stimulated, they synthesize the nuclear protein Fos. The presence of Fos, revealed by a special staining method, provides another way to discover active regions of the brain. The metabolic activity of various regions of the living human brain can be revealed by the 2-DG method, but a PET scanner is used to detect the active regions. Other noninvasive methods of measuring regional brain activity are provided by functional MRI, which detects localized changes in oxygen levels, and magnetoencephalography (MEG), which detects magnetic fields produced by the electrical activity of neurons. Researchers can stimulate various regions of the brain by implanting a macroelectrode and applying mild electrical stimulation. Alternatively, they can implant a guide cannula in the brain; after the animal has recovered from the surgery, they insert a smaller cannula and inject a weak

TABLE

solution of an excitatory amino acid into the brain. The advantage of this procedure is that only neurons whose cell bodies are located nearby will be stimulated; axons passing through the region will not be affected. Viruses can be used to deliver genes for photosensitive proteins that produce depolarizations or hyperpolarizations of the membranes of specific neurons when the proteins are stimulated by light. Transcranial magnetic stimulation induces electrical activity in the human cerebral cortex, which temporarily disrupts the functioning of neural circuits located there. Table 2 summarizes the research methods presented in this section. (See Table 2.)

Thought Questions 1. Suppose that you had the opportunity to record an fMRI from a person (perhaps yourself) while the person was performing a behavior, thinking about something, or attending to a particular stimulus. Describe what you would have the person do. 2. Can you think of some ways that you could use optogenetic methods to investigate neural mechanisms involved in the control of a behavior or sensory system?

2 Research Methods: Part II

Goal of Method

Method

Remarks

Record electrical activity of single neurons

Glass or metal microelectrodes

Metal microelectrodes can be implanted permanently to record neural activity as animal moves

Record electrical activity of regions of the brain

Metal macroelectrodes

In humans, usually attached to the scalp with a special paste

Record magnetic fields induced by neural activity

Magnetoencephalography; uses a neuromagnetometer, which contains an array of SQUIDs

Can determine the location of a group of neurons firing synchronously

Record metabolic activity of regions of brain

2-DG autoradiography

Measures local glucose utilization

Measurement of Fos protein

Identifies neurons that have recently been stimulated

2-DG PET scan

Measures regional metabolic activity of the human brain

Functional magnetic resonance imaging (fMRI) scan

Measures regional metabolic activity of the human brain; better spatial and temporal resolution than PET scan

Electrical stimulation

Stimulates neurons near the tip of the electrode and axons passing through the region

Chemical stimulation with excitatory amino acid

Stimulates only neurons near the tip of the cannula, not axons passing through the region

Transcranial magnetic stimulation

Stimulates neurons in the human cerebral cortex with an electromagnet placed on the head

Stimulate neural activity

Neurochemical Methods Sometimes we are interested not in the general metabolic activity of particular regions of the brain, but in the location of neurons that possess particular types of receptors or produce particular types of neurotransmitters or neuromodulators. We might also want to measure the amount of these chemicals secreted by neurons in particular brain regions during particular circumstances.

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Finding Neurons That Produce Particular Neurochemicals Suppose we learn that a particular drug affects behavior. How would we go about discovering the neural circuits that are responsible for the drug’s effects? To answer this question, let’s take a specific example. Physicians discovered several years ago that farm workers who had been exposed to certain types of insecticides (the organophosphates) had particularly intense and bizarre dreams and even reported having hallucinations while awake. A plausible explanation for these symptoms is that the drug stimulates the neural circuits responsible for REM sleep—the phase of sleep during which dreaming occurs. (After all, dreams are hallucinations that we have while sleeping.) The first question to ask relates to how the organophosphate insecticides work. Pharmacologists have the answer: These drugs are acetylcholinesterase inhibitors. Acetylcholinesterase inhibitors are potent acetylcholine agonists. By inhibiting AChE, the drugs prevent the rapid destruction of ACh after it is released by terminal buttons and thus prolong the postsynaptic potentials at acetylcholinergic synapses. Now that we understand the action of the insecticides, we know that these drugs act at acetylcholinergic synapses. What neurochemical methods should we use to discover the sites of action of the drugs in the brain? First, let’s consider methods by which we can localize particular neurochemicals, such as neurotransmitters and neuromodulators. (In our case we are interested in acetylcholine.) There are at least two basic ways of localizing neurochemicals in the brain: localizing the chemicals F I G U R E 29 Localization of a Peptide. The peptide themselves or localizing the enzymes that produce them. is revealed by means of immunocytochemistry. The Peptides (or proteins) can be localized directly by means of immunocytochemiphotomicrograph shows a portion of a frontal section cal methods, which were described in the first section of this chapter. Slices of brain through the rat forebrain. The gold- and rust-colored tissue are exposed to an antibody for the peptide and linked to a dye (usually, a fibers are axons and terminal buttons that contain fluorescent dye). The slices are then examined under a microscope using light of vasopressin, a peptide neurotransmitter. a particular wavelength. For example, Figure 29 shows the location of axons in the Geert De Vries, Georgia State University. forebrain that contain vasopressin, a peptide neurotransmitter. Two sets of axons are shown. One set, which forms a cluster around the third ventricle at the base of the brain, shows up as a rusty color. The other set, scattered through the lateral septum, looks like strands of gold fibers. (As you can see, a properly stained brain section can be beautiful. See Figure 29.) But we are interested in acetylcholine, which is not a peptide. Therefore, we cannot use immunocytochemical methods to find this neurotransmitter. However, we can use these methods to localize the enzyme that produces it. The synthesis of acetylcholine is made possible by the enzyme choline acetyltransferase (ChAT). Thus, neurons that contain this enzyme almost certainly secrete ACh. Figure 30 shows acetylcholinergic neurons in the pons that have been identified by means of immunocytochemistry; the brain tissue was exposed to an antibody to ChAT attached to a fluorescent dye. In fact, research using many of the methods described in this chapter indicate that these neurons play a role in controlling REM sleep. (See Figure 30.)

Localizing Particular Receptors

F I G U R E 30 Localization of an Enzyme. An enzyme responsible for the synthesis of a neurotransmitter is revealed by immunocytochemistry. The photomicrograph shows a section through the pons. The orange neurons contain choline acetyltransferase, which implies that they produce (and thus secrete) acetylcholine. Courtesy of David Morilak, Ph.D. and Roland Ciaranello, M.D.

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Neurotransmitters, neuromodulators, and hormones convey their messages to their target cells by binding with receptors located on or in these cells. The location of these receptors can be determined by two different procedures. The first procedure uses autoradiography. We expose slices of brain tissue to a solution containing a radioactive ligand for a particular receptor. Next, we rinse the slices so that the only radioactivity remaining in them is that of the molecules of the ligand bound to

Methods and Strategies of Research

their receptors. Finally, we use autoradiographic methods to localize the radioactive ligand—and thus the receptors. The second procedure uses immunocytochemistry. Receptors are proteins; therefore, we can produce antibodies against them. We expose slices of brain tissue to the appropriate antibody (labeled with a fluorescent dye) and look at the slices with a microscope under light of a particular wavelength. Let’s apply the method for localizing receptors to the first line of investigation we considered in this chapter: the role of the ventromedial hypothalamus (VMH) in the sexual behavior of female rats. As we saw, lesions of the VMH abolish this behavior. We also saw that the behavior does not occur if the rat’s ovaries are removed but that it can be activated by stimulation of the VMH with electricity or an excitatory amino acid. These results suggest that the sex hormones produced by the ovaries act on neurons in the VMH. This hypothesis suggests two experiments. First, we could use the procedure shown in Figure 26 to place a small amount of the appropriate sex hormone directly into the VMH of female rats whose ovaries we had previously removed. This procedure works; the hormone does reactivate the animals’ sexual behavior. The second experiment would use autoradiography to look for the receptors for the sex hormone. We would expose slices of rat brain to the radioactive hormone, rinse them, and perform autoradiography. If we did so, we would indeed find radioactivity in the VMH. (And if we compared slices from the brains of female and male rats, we would find evidence of more hormone receptors in the females’ brains.) We could also use immunocytochemistry to localize the hormone receptors, and we would obtain the same results.

This figure is intentionally omitted from this text.

Measuring Chemicals Secreted in the Brain The previous two subsections described methods that permit researchers to identify the location of chemicals within cells or in cell membranes. But sometimes we might want to measure the concentration of particular chemicals secreted in particular regions of the brain. For example, we know that cocaine—a particularly addictive drug—blocks the reuptake of dopamine, which suggests that the extracellular concentration Fluid is pumped of dopamine increases in some parts of the brain when a person takes cothrough inner cannula caine. To measure the amount of dopamine in particular regions of an animal’s brain, we would use a procedure called microdialysis. Fluid is collected Dental and analyzed Dialysis is a process in which substances are separated by means of an plastic artificial membrane that is permeable to some molecules but not others. A microdialysis probe, as shown in Figure32, consists of a small metal Skull Brain tube that introduces a solution into a section of dialysis tubing—a piece of artificial membrane shaped in the form of a cylinder, sealed at the bottom. Another small metal tube leads the solution away after it has circulated through the pouch. (See Figure 32.) We use stereotaxic surgery to place a microdialysis probe in a rat’s brain so that the tip of the probe is located in the region we are interested in. We then pump a small amount of a solution similar to extracellular Dialysis tubing Substances in extracellular fluid through one of the small metal tubes into the dialysis tubing. The fluid diffuse through the fluid circulates through the dialysis tubing and passes through the secdialysis tubing ond metal tube, from which it is taken for analysis. As the fluid passes F I G U R E 32 Microdialysis. A dilute salt solution is slowly infused through the dialysis tubing, it collects molecules from the extracellular fluid of the brain, which are pushed across the membrane by the force into the microdialysis tube, where it picks up molecules that diffuse in from the extracellular fluid. The contents of the fluid are then analyzed. of diffusion. We analyze the contents of the fluid that has passed through the dialysis tubing by an extremely sensitive analytical method. This method is so sensitive that it can detect neurotransmitmicrodialysis A procedure for analyzing ters (and their breakdown products) that have been released by the terminal buttons and have chemicals present in the interstitial fluid through a small piece of tubing made of a semipermeable membrane that is implanted in the brain.

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escaped from the synaptic cleft into the rest of the extracellular fluid. We find that the amount of dopamine present in the extracellular fluid of the nucleus accumbens, located in the basal forebrain, does increase when we give a rat an injection of cocaine. In fact, we find that the amount of dopamine in this region increases when we administer any addictive drug, such as heroin, nicotine, or alcohol. We even see an increased dopamine secretion when the animal participates in a pleasurable activity such as eating when hungry, drinking when thirsty, or engaging in sexual activity. Such observations support the conclusion that the release of dopamine in the nucleus accumbens plays a role in reinforcement. In a few special cases (for example, in monitoring brain chemicals (a) (b) of people with intracranial hemorrhages or head trauma), the microdialysis procedure has been applied to study of the human brain, but F I G U R E 33 PET Scans of Patient with Parkinsonian Symptoms. The scans show uptake of radioactive L-DOPA in the basal ganglia of a patient ethical reasons prevent us from doing so for research purposes. Forwith parkinsonian symptoms induced by a toxic chemical before and after tunately, there is a noninvasive way to measure neurochemicals in the receiving a transplant of fetal dopaminergic neurons. (a) Preoperative scan. human brain. Although PET scanners are expensive machines, they are (b) Scan taken 13 months postoperatively. The increased uptake of L-DOPA also versatile. They can be used to localize any radioactive substance that indicates that the fetal transplant was secreting dopamine. emits positrons. Adapted from Widner, H., Tetrud, J., Rehncrona, S., Snow, B., Brundin, P., Several years ago, several people injected themselves with an ilGustavii, B., Björklund, A., Lindvall, O., and Langston, J. W. New England Journal of licit drug that was contaminated with a chemical that destroyed their Medicine, 1992, 327, 1556–1563. dopaminergic neurons. As a result they suffered from severe parkinsonism. Recently, neurosurgeons used stereotaxic procedures to transplant fetal dopaminergic neurons into the basal ganglia of some of these patients. Figure 33 shows PET scans of the brain of one of them. The patient was given an injection of radioactive l-DOPA one hour before each scan was made. l-DOPA is taken up by the terminals of dopaminergic neurons, where it is converted to dopamine; thus, the radioactivity shown in the scans indicates the presence of dopamine-secreting terminals in the basal ganglia. The scans show the amount of radioactivity before (part a) and after (part b) the patient received the transplant, which greatly diminished his symptoms. (See Figure 33.) I wish I could say that the fetal transplantation procedure has cured people stricken with Parkinson’s disease and those whose brains were damaged with the contaminated drug. Unfortunately, the therapeutic effects of the transplant are often temporary, and with time, serious side effects often emerge.

SECTION SUMMARY Neurochemical Methods Neurochemical methods can be used to determine the location of an enormous variety of substances in the brain. They can identify neurons that secrete a particular neurotransmitter or neuromodulator and those that possess receptors that respond to the presence of these substances. Peptides and proteins can be directly localized, through immunocytochemical methods; the tissue is exposed to an antibody that is linked to a molecule that fluoresces under light of a particular wavelength. Other substances can be detected by immunocytochemical localization of an enzyme that is required for their synthesis. Receptors for neurochemicals can be localized by two means. The first method uses autoradiography to reveal the distribution of a radioactive ligand to which the tissue has been exposed. The second method uses immunocytochemistry to detect the presence of the receptors themselves, which are proteins.

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The secretions of neurotransmitters and neuromodulators can be measured by implanting the tip of a microdialysis probe in a particular region of the brain. A PET scanner can be used to perform similar observations of the human brain. People are given an injection of a radioactive tracer such as a drug that binds with a particular receptor or a chemical that is incorporated into a particular neurotransmitter, and a PET scanner reveals the location of the tracer in the brain. Table 3 summarizes the research methods presented in this section. (See Table 3.)

Thought Question Using methods you learned about in this chapter so far, describe a behavior, cognitive process, or perceptual ability that you would like to study. Describe the kinds of experiments you would perform and say what kinds of information each method might provide.

Methods and Strategies of Research

TABLE

3 Research Methods: Part III

Goal of Method

Method

Remarks

Measure neurotransmitters and neuromodulators released by neurons

Microdialysis

A wide variety of substances can be analyzed

Measure neurochemicals in the living human brain

PET scan

Can localize any radioactive substance taken up in the human brain

Identify neurons producing a particular neurotransmitter or neuromodulator

Immunocytochemical localization of peptide or protein

Requires a specific antibody

Immunocytochemical localization of enzyme responsible for synthesis of substance

Useful if substance is not a peptide or protein

Identify neurons that contain a particular type of receptor

Autoradiographic localization of radioactive ligand Immunocytochemical localization of receptor

Requires a specific antibody

Genetic Methods All behavior is determined by interactions between an individual’s brain and his or her environment. Many behavioral characteristics—such as talents, personality variables, and mental disorders—seem to run in families. This fact suggests that genetic factors may play a role in the development of physiological differences that are ultimately responsible for these characteristics. In some cases the genetic link is very clear: A defective gene interferes with brain development, and a neurological abnormality causes behavioral deficits. In other cases the links between heredity and behavior are much more subtle, and special genetic methods must be used to reveal them.

Twin Studies A powerful method for estimating the influence of heredity on a particular trait is to compare the concordance rate for this trait in pairs of monozygotic and dizygotic twins. Monozygotic twins (identical twins) have identical genotypes—that is, their chromosomes, and the genes they contain, are identical. In contrast, the genetic similarity between dizygotic twins (fraternal twins) is, on the average, 50 percent. Investigators study records to identify pairs of twins in which at least one member has the trait—for example, a diagnosis of a particular mental disorder. If both twinshave been diagnosed with this disorder, they are said to be concordant. If only one has received this diagnosis, the twins are said to be discordant. Thus, if a disorder has a genetic basis, the percentage of monozygotic twins who are concordant for the diagnosis will be higher than the percentage of dizygotic twins. For example, the concordance rate for schizophrenia in twins is at least four times higher for monozygotic twins than for dizygotic twins, a finding that provides strong evidence that schizophrenia is a heritable trait. Twin studies have found that many individual characteristics, including personality traits, prevalence of obesity, incidence of alcoholism, and a wide variety of mental disorders, are influenced by genetic factors.

Twin studies provide a powerful method for estimating the relative roles of heredity and environment in the development of particular behavioral traits. Michael Schwartz/The Image Works.

Adoption Studies Another method for estimating the heritability of a particular behavioral trait is to compare people who were adopted early in life with their biological and adoptive parents. All behavioral traits are affected to some degree by hereditary factors, environmental factors, and an

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Methods and Strategies of Research

interaction between hereditary and environmental factors. Environmental factors are both social and biological in nature. For example, the mother’s health, nutrition, and drug-taking behaviors during pregnancy are prenatal environmental factors, and the child’s diet, medical care, and social environment (both inside and outside the home) are postnatal environmental factors. If a child is adopted soon after birth, the genetic factors will be associated with the biological parents, the prenatal environmental factors will be associated with the biological mother, and most of the postnatal environmental factors will be associated with the adoptive parents. Adoption studies require that the investigator know the identity of the parents of the people being studied and be able to measure the behavioral trait in the biological and adoptive parents. If the people being studied strongly resemble their biological parents, we conclude that the trait is probably influenced by genetic factors. To be certain, we will have to rule out possible differences in the prenatal environment of the adopted children. If, instead, the people resemble their adoptive parents, we conclude that the trait is influenced by environmental factors. (It would take further study to determine just what these environmental factors might be.) Of course, it is possible that both hereditary and environmental factors play a role, in which case the people being studied will resemble both their biological and adoptive parents.

Genomic Studies The human genome consists of the DNA that encodes our genetic information. Because of the accumulation of mutations over past generations of our species, no two people, with the exception of monozygotic twins, have identical genetic information. The particular form of an individual gene is called an allele (from the Greek allos, “other”). For example, different alleles of the gene responsible for the production of iris pigment produce pigments with different colors. Genomic studies attempt to determine the location in the genome of genes responsible for various physical and behavioral traits. Linkage studies identify families whose members vary with respect to a particular trait—for example, the presence or absence of a particular hereditary disease. A variety of markers, sequences of DNA whose locations are already known, are compared with the nature of an individual person’s trait. For example, the gene responsible for Huntington’s disease, a neurological disorder, was found to be located near a known marker on the short arm of chromosome 4. Researchers studied people in an extended family in Venezuela that contained many members with Huntington’s disease and found that the presence or absence of the disease correlated with the presence or absence of the marker. Genome-wide association studies have been made possible by the development of methods to obtain the DNA sequence of the entire human genome. These studies permit researchers to compare all or portions of the genomes of different individuals to determine whether differences in the people’s genomes correlate with the presence or absence of diseases (or other traits). These studies are beginning to reveal the location of genes that control characteristics that contribute to the development of various mental disorders.

Targeted Mutations genome The complete set of genes that compose the DNA of a particular species. allele The nature of the particular sequence of base pairs of DNA that constitutes a gene; for example, the genes that code for blue or brown iris pigment are different alleles of a particular gene. targeted mutation A mutated gene (also called a “knockout gene”) produced in the laboratory and inserted into the chromosomes of mice; fails to produce a functional protein.

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A genetic method developed by molecular biologists has put a powerful tool in the hands of neuroscientists. Targeted mutations are mutated genes produced in the laboratory and inserted into the chromosomes of mice. In some cases, the genes (also called knockout genes) are defective and fail to produce a functional protein. In many cases the target of the mutation is an enzyme that controls a particular chemical reaction. For example, the lack of a particular enzyme interferes with learning. This result suggests that the enzyme is partly responsible for changes in the structure of synapses required for learning to occur. In other cases the target of the mutation is a protein that itself serves useful functions in the cell. For example, a particular type of cannabinoid receptor is involved in the reinforcing and analgesic effects of opiates. Researchers can even produce conditional knockouts that cause the animal’s genes to stop expressing a particular gene when the animal is given a particular drug. This permits the targeted gene to express itself normally during the animal’s development and then be knocked out at a later time.

Methods and Strategies of Research

Investigators can also use methods of genetic engineering to insert new genes into the DNA of mice. These genes can cause increased production of proteins normally found in the host species, or they can produce entirely new proteins.

Antisense Oligonucleotides Another genetic method involves the production of molecules that block the production of proteins encoded by particular genes by injecting antisense oligonucleotides. The most common type of antisense oligonucleotide consists of modified strands of RNA or DNA that will bind with specific molecules of messenger RNA and prevent them from producing their protein. Once the molecules of mRNA are trapped this way, they are destroyed by enzymes present in the cell. The term antisense refers to the fact that the synthetic oligonucleotides contain a sequence of bases complementary to those contained by a particular gene or molecule of mRNA. Table 4 summarizes the research methods presented in this section. (See Table 4.)

TABLE

antisense oligonucleotide (oh li go new klee oh tide) A modified strand of RNA or DNA that binds with a specific molecule of messenger RNA and prevents it from producing its particular protein.

4 Research Methods: Part IV

Goal of Method

Method

Remarks

Genetic methods

Twin studies

Comparison of concordance rates of monozygotic and dizygotic twins estimates heritability of trait

Adoption studies

Similarity of offspring and adoptive and biological parents estimates heritability of trait

Genomic studies

Use of genomic analysis (linkage studies or genome-wide association studies) to identify genes that are associated with particular traits

Targeted mutations

Inactivation, insertion, or increased expression of a gene

Antisense oligonucleotides

Bind with messenger RNA; prevent synthesis of protein

SECTION SUMMARY Genetic Methods Because genes direct an organism’s development, genetic methods are very useful in studies of the physiology of behavior. Twin studies compare the concordance rates of monozygotic (identical) and dizygotic (fraternal) twins for a particular trait. A higher concordance rate for monozygotic twins provides evidence that the trait is influenced by heredity. Adoption studies compare people who were adopted during infancy with their biological and adoptive parents. If the people resemble their biological parents, evidence is seen for genetic factors. If the people resemble their adoptive parents, evidence is seen for a role of factors in the family environment. Linkage studies and genome-wide association studies make it possible to identify the locations of genes that are responsible for a variety of behavioral and physical traits. Targeted mutations permit neuroscientists to study the effects of the presence or absence of a particular protein—for example, an

enzyme, structural protein, or receptor—on an animal’s physiological and behavioral characteristics. Genes that cause the production of foreign proteins or increase production of native proteins can be inserted into the genome of strains of animals. Antisense oligonucleotides can be used to block the production of particular proteins.

Thought Questions 1. You have probably read news reports about studies of the genetics of human behavioral traits or seen them on television. What does it really mean when a laboratory reports the discovery of, say, a “gene for shyness”? 2. Most rats do not appear to like the taste of alcohol, but researchers have bred some rats that will drink alcohol in large quantities. Can you think of ways to use these animals to investigate the possible role of genetic factors in susceptibility to alcoholism?

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EPILOGUE

| Watch the Brain Waves

What went wrong? Why did Mrs. H.’s “successful” surgery cause a neurological problem? And can anything be done for her? First, let’s consider the cause of the problem. As you will recall, an artificial heart circulated Mrs. H.’s blood while the surgeon was removing two of her coronary arteries and replacing them with veins taken from her leg. The output of the machine is adjustable; that is, the person operating it can control the patient’s blood pressure. The surgeon tries to keep the blood pressure just high enough to sustain the patient but not so high as to interfere with the delicate surgery on the coronary arteries. Unfortunately, Mrs. H.’s coronary arteries were not the only blood vessels to be partially blocked; the arteries in her brain, too, contained atherosclerotic plaque. When the machine took over the circulation of her blood, some parts of her brain received an inadequate blood flow, and the cells in these regions were damaged. If Mrs. H.’s blood pressure had been maintained at a slightly higher level during the surgery, her brain damage might have been prevented. For most patients, the blood pressure would have been sufficient, but in her case it was not. Mrs. H.’s brain damage is irreversible. But are there steps that can be taken to prevent others from sharing her fate? The answer is yes. The solution is to use a method described in this chapter: electroencephalography. What we need is a warning system to indicate that the brain is not receiving a sufficient blood flow so that the surgeon can adjust the machine and increase the patient’s blood pressure. That warning can be provided by an EEG. For many years, clinical electroencephalographers (specialists who

perform EEGs to diagnose neurological disorders) have known that diffuse, widespread brain damage caused by various poisons, anoxia, or extremely low levels of blood glucose produces slowing of the regular rhythmic pattern of the EEG. Fortunately, this pattern begins right away, as soon as the damage commences. Thus, if EEG leads are attached to a patient undergoing cardiac surgery, an electroencephalographer can watch the record coming off the polygraph and warn the surgeon if the record shows slowing. If it does, the patient’s blood flow can be increased until the EEG reverts to normal, and brain damage can be averted. Mrs. H. was operated on over twenty years ago, at a time when only a few cardiac surgeons had their patient’s brain waves monitored. Today, the practice is common, and it is used during other surgical procedures that may reduce blood flow to the brain. For example, when the carotid arteries (the vessels that provide most of the brain’s blood supply) become obstructed by atherosclerotic plaque, a surgeon can cut open the arteries and remove the plaque. During this procedure, called carotid endarterectomy, clamps must be placed on the carotid artery, completely stopping the blood flow. Some patients can tolerate the temporary clamping of one carotid artery without damage; others cannot. If the EEG record shows no slowing while the artery is clamped, the surgeon can proceed. If it does, the surgeon must place the ends of a plastic tube into the artery above and below the clamped region to maintain a constant blood flow. This procedure introduces a certain amount of additional risk to the patient, so most surgeons would prefer to do it only if necessary. The EEG provides the essential information.

KEY CONCEPTS EXPERIMENTAL ABLATION

1. Neuroscientists produce brain lesions to try to infer the functions of the damaged region from changes in the animals’ behavior. 2. Brain lesions may be produced in the depths of the brain by passing electrical current through an electrode placed there or by infusing an excitatory amino acid; the latter method kills cells but spares axons that pass through the region. 3. The behavior of animals with brain lesions must be compared with that of a control group consisting of animals with sham lesions. 4. A stereotaxic apparatus is used to place electrodes or cannulas in particular locations in the brain. The coordinates are obtained from a stereotaxic atlas. 5. The location of a lesion is verified by means of histological methods, which include fixation, slicing, staining, and examination of the tissue under a microscope.

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6. Special histological methods have been devised to trace the afferent and efferent connections of a particular brain region. 7. The structure of the living human brain can be revealed through CT scans or MRI scans. RECORDING AND STIMULATING NEURAL ACTIVITY

8. The electrical activity of single neurons can be recorded with microelectrodes, and that of entire regions of the brain can be recorded with macroelectrodes. EEGs are recorded on polygraphs with data from macroelectrodes pasted on a person’s scalp. 9. Metabolic activity of particular parts of animals’ brains can be assessed by means of 2-DG autoradiography or by measurement of the production of Fos protein. The metabolic activity of specific regions of the human brain can be revealed through PET scans or functional MRI scans.

Methods and Strategies of Research

10. Neurons can be stimulated electrically, through electrodes, or chemically, by infusing dilute solutions of excitatory amino acids through cannulas. NEUROCHEMICAL METHODS

11. Immunocytochemical methods can be used to localize peptides in the brain or localize the enzymes that produce substances other than peptides. 12. Receptors can be localized by exposing the brain tissue to radioactive ligands and assessing the results with autoradiography or immunocytochemistry. 13. Microdialysis permits a researcher to measure the secretion of particular chemicals in specific regions of the brain. PET scans can be used to reveal the location of particular chemicals in the human brain.

GENETIC METHODS

14. Twin studies, adoption studies, and genomic studies enable investigators to estimate the role of hereditary factors in a particular physiological characteristic or behavior. 15. Targeted mutations are artificially produced mutations that interfere with the action of one or more genes, which enables investigators to study the effects of the lack of a particular gene product. 16. Genes that cause the production of foreign proteins or increase production of native proteins can be inserted into the genome of strains of animals, and antisense oligonucleotides can be used to block the production of particular proteins.

REFERENCES Baker, M. Light tools. Nature Methods, 2011, 8, 19–22. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., and Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience, 2005, 8, 1263–1268. Busskamp, V., Duebel, J., Balya, D., et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science, 2010, 329, 413–417.

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Vision

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OUTLINE ■

The Stimulus

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Anatomy of the Visual System The Eyes

Vision

Photoreceptors Connections Between Eye and Brain ■

Coding of Visual Information in the Retina Coding of Light and Dark Coding of Color

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Analysis of Visual Information: Role of the Striate Cortex Anatomy of the Striate Cortex Orientation and Movement Spatial Frequency Retinal Disparity Color Modular Organization of the Striate Cortex

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Analysis of Visual Information: Role of the Visual Association Cortex Two Streams of Visual Analysis Perception of Color Perception of Form Perception of Movement

LEARNING OBJECTIVES 1. Describe the characteristics of light and color, outline the anatomy of the eye and its connections with the brain, and describe the process of transduction of visual information. 2. Describe the coding of visual information by photoreceptors and ganglion cells in the retina. 3. Describe the striate cortex and discuss how its neurons respond to orientation, movement, spatial frequency, retinal disparity, and color. 4. Describe the anatomy of the visual association cortex and discuss the location and functions of the two streams of visual analysis that take place there.

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Perception of Spatial Location

5. Discuss the perception of color and the analysis of form by neurons in the ventral stream. 6. Describe the role of the visual association cortex in the perception of objects, faces, body parts, and places. 7. Describe the role of the visual association cortex in the perception of movement. 8. Describe the role of the visual association cortex in the perception of spatial location.

PROLOGUE

| Seeing Without Perceiving

Dr. L., a young neuropsychologist, was presenting the case of Mrs. R. to a group of medical students doing a rotation in the neurology department at the medical center. The chief of the department had shown them Mrs. R.’s MRI scans, and now Dr. L. was addressing the students. He told them that Mrs. R.’s stroke had not impaired her ability to talk or to move about, but it had affected her vision. A nurse ushered Mrs. R. into the room and helped her find a seat at the end of the table. “How are you, Mrs. R.?” asked Dr. L. “I’m fine. I’ve been home for a month now, and I can do just about everything that I did before I had my stroke.” “Good. How is your vision?” “Well, I’m afraid that’s still a problem.” “What seems to give you the most trouble?” “I just don’t seem to be able to recognize things. When I’m working in my kitchen, I know what everything is as long as no one moves anything. A few times my husband tried to help me by putting things away, and I couldn’t see them any more.” She laughed. “Well, I could see them, but I just couldn’t say what they were.” Dr. L. took some objects out of a paper bag and placed them on the table in front of her. “Can you tell me what these are?” he asked. “No,” he said, “please don’t touch them.” Mrs. R. stared intently at the objects. “No, I can’t rightly say what they are.” Dr. L. pointed to one of them, a wristwatch. “Tell me what you see here,” he said. Mrs. R. looked thoughtful, turning her head one way and then the other. “Well, I see something round, and it has two things attached to it, one on the top and one on the bottom.” She continued to stare at it. “There are some things inside the circle, I think, but I can’t make out what they are.” “Pick it up.”

She did so, made a wry face, and said, “Oh. It’s a wristwatch.” At Dr. L.’s request, she picked up the rest of the objects, one by one, and identified each of them correctly. “Do you have trouble recognizing people, too?” asked Dr. L. “Oh, yes!” she sighed. “While I was still in the hospital, my husband and my son both came in to see me, and I couldn’t tell who was who until my husband said something—then I could tell which direction his voice was coming from. Now I’ve trained myself to recognize my husband. I can usually see his glasses and his bald head, but I have to work at it. And I’ve been fooled a few times.” She laughed. “One of our neighbors is bald and wears glasses, too, and one day when he and his wife were visiting us, I thought he was my husband, so I called him ‘honey.’ It was a little embarrassing at first, but everyone understood.” “What does a face look like to you?” asked Dr. L. “Well, I know that it’s a face, because I can usually see the eyes, and it’s on top of a body. I can see a body pretty well, by how it moves.” She paused a moment. “Oh, yes, I forgot, sometimes I can recognize a person by how he moves. You know, you can often recognize friends by the way they walk, even when they’re far away. I can still do that. That’s funny, isn’t it? I can’t see people’s faces very well, but I can recognize the way they walk.” Dr. L. made some movements with his hands. “Can you tell what I’m pretending to do?” he asked. “Yes, you’re mixing something—like some cake batter.” He mimed the gestures of turning a key, writing, and dealing out playing cards, and Mrs. R. recognized them without any difficulty. “Do you have any trouble reading?” he asked. “Well, a little, but I don’t do too badly.” Dr. L. handed her a magazine, and she began to read the article aloud—somewhat hesitantly but accurately. “Why is it,” she asked, “that I can see the words all right but have so much trouble with things and with people’s faces?”

he brain performs two major functions: It controls the movements of the muscles, producing useful behaviors, and it regulates the body’s internal environment. To perform both these tasks, the brain must be informed about what is happening both in the external environment and within the body. Such information is received by the sensory systems. This chapter is devoted to a discussion of the ways in which sensory organs detect changes in the environment and the ways in which the brain interprets neural signals from these organs. We receive information about the environment from sensory receptors—specialized neurons that detect a variety of physical events. (Do not confuse sensory receptors with receptors for neurotransmitters, neuromodulators, and hormones. Sensory receptors are specialized neurons, and the other types of receptors are specialized proteins that bind with certain molecules.) Stimuli impinge on the receptors and alter their membrane potentials. This process is known as sensory transduction because sensory events are transduced (“transferred”) into changes in the cells’ membrane potential. These electrical changes, called receptor potentials, affect the release

sensory receptor A specialized neuron that detects a particular category of physical events. sensory transduction The process by which sensory stimuli are transduced into slow, graded receptor potentials. receptor potential A slow, graded electrical potential produced by a receptor cell in response to a physical stimulus.

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Some insects, such as this honeybee, can detect wavelengths of electromagnetic radiation that are invisible to people.

of neurotransmitters and hence modify the pattern of firing in neurons with which sensory receptors form synapses. Ultimately, the information reaches the brain. This chapter considers vision, the sensory modality that receives the most attention from psychologists, anatomists, and physiologists. One reason for this attention derives from the fascinating complexity of the sensory organs of vision and the relatively large proportion of the brain that is devoted to the analysis of visual information. Approximately 20 percent of the cerebral cortex plays a direct role in the analysis of visual information (Wandell, Dumoulin, and Brewer, 2007). Another reason, I am sure, is that vision is so important to us as individuals. A natural fascination with such a rich source of information about the world leads to curiosity about how this sensory modality works.

The Stimulus As we all know, our eyes detect the presence of light. For humans light is a narrow band of the spectrum of electromagnetic radiation. Electromagnetic radiation with a wavelength hue One of the perceptual dimensions of between 380 and 760 nm (a nanometer, nm, is one-billionth of a meter) is visible to us. of color; the dominant wavelength. (See Figure 1.) Other animals can detect different ranges of electromagnetic radiation. For brightness One of the perceptual example, honeybees can detect differences in ultraviolet radiation reflected by flowers that dimensions of color; intensity. appear white to us. The range of wavelengths we call light is not qualitatively different from saturation One of the perceptual the rest of the electromagnetic spectrum; it is simply the part of the continuum that we dimensions of color; purity. humans can see. The perceived color of light is determined by three dimensions: hue, saturation, and brightness. Light travels at a constant speed of approximately 300,000 Decreasing Increasing kilometers (186,000 miles) per second. Thus, if the frequency of oscillation of the saturation saturation wave varies, the distance between the peaks of the waves will vary similarly, but in Increasing inverse fashion. Slower oscillations lead to longer wavelengths, and faster ones lead brightness to shorter wavelengths. Wavelength determines the first of the three perceptual dimensions of light: hue. The visible spectrum displays the range of hues that our eyes can detect. Light can also vary in intensity, which corresponds to the second perceptual dimension of light: brightness. The third dimension, saturation, refers to the relative purity of the light that is being perceived. If all the radiation is of one wavelength, the perceived color is pure, or fully saturated. Conversely, if the radiation Decreasing contains all visible wavelengths, it produces no sensation of hue—it appears white. brightness Colors with intermediate amounts of saturation consist of different mixtures of F I G U R E 2 Saturation and Brightness. This figure wavelengths. Figure 2 shows some color samples, all with the same hue but with shows examples of colors with the same dominant different levels of brightness and saturation. (See Figure 2.) wavelength (hue) but different levels of saturations or brightness.

Wavelength in nanometers 400

500

600

700

The visible spectrum Gamma rays FIGURE

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X-rays

Ultraviolet rays

The Electromagnetic Spectrum.

Infrared rays

Radar

Television and radio broadcast bands

AC circuits

Vision

Anatomy of the Visual System For an individual to see, an image must be focused on the retina, the inner lining of the eye. This image causes changes in the electrical activity of millions of neurons in the retina, which results in messages being sent through the optic nerves to the rest of the brain. (I said “the rest” because the retina is actually part of the brain; it and the optic nerve are in the central—not peripheral—nervous system.) This section describes the anatomy of the eyes, the photoreceptors in the retina that detect the presence of light, and the connections between the retina and the brain.

The Eyes The eyes are suspended in the orbits, bony pockets in the front of the skull. They are held in place and moved by six extraocular muscles attached to the tough, white outer coat of the eye called the sclera. Normally, we cannot look behind our eyeballs and see these muscles, because their attachments to the eyes are hidden by the conjunctiva. These mucous membranes line the eyelid and fold back to attach to the eye (thus preventing a contact lens that has slipped off the cornea from “falling behind the eye”). Figure 3 illustrates the anatomy of the eye. (See Figure 3.) When you scan the scene in front of you, your gaze does not roam slowly and steadily across its features. Instead, your eyes make jerky saccadic movements—you shift your gaze abruptly from one point to another. (Saccade comes from the French word for “jerk.”) When you read a line in this chapter, your eyes stop several times, moving very quickly between each stop. You cannot consciously control the speed of movement between stops; during each saccade the eyes move as fast as they can. Only by performing a pursuit movement—say, by looking at your finger while you move it around—can you make your eyes move more slowly. The white outer layer of most of the eye, the sclera, is opaque and does not permit entry of light. However, the cornea, the outer layer at the front of the eye, is transparent. The amount of light that enters is regulated by the size of the pupil, which is an opening in the iris, the pigmented ring of muscles situated behind the cornea. The lens, situated immediately behind the iris, consists of a series of transparent, onionlike layers. Its shape can be altered by contraction of the ciliary muscles, a set of muscle fibers attached to the outer edge of the lens. These changes in shape permit the eye to focus images of near or distant objects on the retina—a process called accommodation. After passing through the lens, light traverses the main part of the eye, which is filled with vitreous humor (“glassy liquid”), a clear, gelatinous substance. Light then falls on the retina, the interior lining of the back of the eye. In the retina are located the receptor cells, the rods and cones (named for their shapes), collectively known as photoreceptors. Conjunctiva (merges with inside of The human retina contains approximately 120 million rods eyelids) and 6 million cones. Although they are greatly outnumbered by rods, cones provide us with most of the visual information about Cornea our environment. In particular, they are responsible for our dayIris time vision. They provide us with information about small features in the environment and thus are the source of vision of the highest sharpness, or acuity (from acus, “needle”). The fovea, or central region of the retina, which mediates our most acute vision, contains Lens only cones. Cones are also responsible for color vision—our ability to discriminate light of different wavelengths. Although rods do not detect different colors and provide vision of poor acuity, they are more sensitive to light. In a very dimly lighted environment we use our rod vision; therefore, in very dim light we are color-blind Pupil and lack foveal vision. (See Table 1.) (opening Another feature of the retina is the optic disk, where the axin iris) ons conveying visual information gather together and leave the F I G U R E 3 The Human Eye. eye through the optic nerve. The optic disk produces a blind spot

saccadic movement (suh kad ik) The rapid, jerky movement of the eyes used in scanning a visual scene. pursuit movement The movement that the eyes make to maintain an image of a moving object on the fovea. accommodation Changes in the thickness of the lens of the eye, accomplished by the ciliary muscles, that focus images of near or distant objects on the retina. retina The neural tissue and photoreceptive cells located on the inner surface of the posterior portion of the eye. rod One of the receptor cells of the retina; sensitive to light of low intensity. cone One of the receptor cells of the retina; maximally sensitive to one of three different wavelengths of light and hence encodes color vision. photoreceptor One of the receptor cells of the retina; transduces photic energy into electrical potentials. fovea (foe vee a) The region of the retina that mediates the most acute vision of birds and higher mammals. Colorsensitive cones constitute the only type of photoreceptor found in the fovea. optic disk The location of the exit point from the retina of the fibers of the ganglion cells that form the optic nerve; responsible for the blind spot. Layers of retina Vitreous humor (upper half has been removed) Optic nerve

Blood vessels

Sclera

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TABLE

bipolar cell A bipolar neuron located in the middle layer of the retina that conveys information from the photoreceptors to the ganglion cells. ganglion cell A neuron located in the retina that receives visual information from bipolar cells; its axons give rise to the optic nerve. horizontal cell A neuron in the retina that interconnects adjacent photoreceptors and the outer processes of the bipolar cells. amacrine cell (amm a krin) A neuron in the retina that interconnects adjacent ganglion cells and the inner processes of the bipolar cells. lamella A layer of membrane containing photopigments; found in rods and cones of the retina.

1 Locations and Response Characteristics of Photoreceptors

Cones

Rods

Most prevalent in the central retina; found in the fovea

Most prevalent in the peripheral retina; not found in the fovea

Sensitive to moderate-to-high levels of light

Sensitive to low levels of light

Provide information about hue

Provide only monochromatic information

Provide excellent acuity

Provide poor acuity

because no receptors are located there. We do not normally perceive our blind spots, but their presence can be demonstrated. If you have not found yours, you may want to try the exercise described in Figure 4 to discover it. (See Figure 4.) Close examination of the retina shows that it consists of several layers of neuron cell bodies, their axons and dendrites, and the photoreceptors. Figure 5 illustrates a cross section through the primate retina, which is divided into three main layers: the photoreceptive layer, the bipolar cell layer, and the ganglion cell layer. Note that the photoreceptors are at the back of the retina; light must pass through the overlying layers (which are transparent, of course) to get to them. (See Figure 5.) The photoreceptors form synapses with bipolar cells, neurons whose two arms connect the shallowest and deepest layers of the retina. In turn, bipolar cells form synapses with the ganglion cells, neurons whose axons travel through the optic nerves (the second cranial nerves) and carry visual information into the rest of the brain. In addition, the retina contains horizontal cells and amacrine cells, both of which transmit information in a direction parallel to the surface of the retina and thus combine messages from adjacent photoreceptors. (See Figure 5.) The primate retina contains approximately 55 different types of neurons: one type of rod, three types of cones, two types of horizontal cells, ten types of bipolar cells, twenty-four to twentynine types of amacrine cells, and ten to fifteen types of ganglion cells (Masland, 2001).

Photoreceptors Rods and cones consist of an outer segment connected by a cilium to an inner segment, which contains the nucleus. (See Figure 5.) The outer segment contains several hundred lamellae, or thin plates of membrane. (Lamella is the diminutive form of lamina, “thin layer.”) Let’s consider the nature of transduction of visual information. The first step in the chain of events that leads to visual perception involves a special chemical called a photopigment.

+ Optic disk (Blind spot)

Fovea

F I G U R E 4 A Test for the Blind Spot. With your left eye closed, look at the plus sign with your right eye and move the page nearer to and farther from you. When the page is about 20 cm from your face, the green circle disappears because its image falls on the blind spot of your right eye.

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Photoreceptor Layer

Bipolar Cell Layer Bipolar cell

Photoreceptors

Back of Eye

Ganglion Cell Layer

Ganglion cell Cone

Rod

Outer segment FIGURE

Inner segment

Light

Horizontal cell

Amacrine cell

Details of Retinal Circuitry.

Based on Dowling, J. E., and Boycott, B. B. Proceedings of the Royal Society of London, B, 1966, 166, 80–111.

Photopigments are special molecules embedded in the membrane of the lamellae; a single human rod contains approximately 10 million of them. The molecules consist of two parts: an opsin (a protein) and retinal (a lipid). There are several forms of opsin; for example, the photopigment of human rods, rhodopsin, consists of rod opsin plus retinal. (Rhod- refers to the Greek rhodon, “rose,” not to rod. Before it is bleached by the action of light, rhodopsin has a pinkish hue.) Retinal is synthesized from vitamin A, which explains why carrots, which are rich in this vitamin, are said to be good for your eyesight. When a molecule of rhodopsin is exposed to light, it breaks into its two constituents: rod opsin and retinal. When that happens, the opsin changes from its rosy color to a pale yellow; hence, we say that the light bleaches the photopigment. The splitting of the photopigment produces the receptor potential: a change in the membrane potential of the photoreceptor. The receptor potential affects the release of neurotransmitter by the photoreceptor, which alters the firing rate of the bipolar cells with which the photoreceptors communicate. This information is passed on to the ganglion cells. (See Figure 5.)

Connections Between Eye and Brain The axons of the retinal ganglion cells bring information to the rest of the brain. They ascend through the optic nerves and reach the dorsal lateral geniculate nucleus (LGN) of the thalamus. This nucleus receives its name from its resemblance to a bent knee (genu is Latin for “knee”). It contains six layers of neurons, each of which receives input from only one eye. The neurons in the two inner layers contain cell bodies that are larger than those in the outer four layers. For this reason, the inner two layers are called the magnocellular layers, and the outer four layers are called the parvocellular layers (parvo- refers to the small size of the cells). A third set of neurons in the koniocellular sublayers are found ventral to each of the magnocellular and parvocellular layers. (Konis is the Greek word for “dust.”) As we will see later, these three sets of layers belong to different systems, which are responsible for the analysis of different types of visual information. They receive input from different types of retinal ganglion cells. (See Figure 6.) The neurons in the dorsal lateral geniculate nucleus send their axons through a pathway known as the optic radiations to the primary visual cortex—the region surrounding the calcarine fissure (calcarine means “spur-shaped”), a horizontal fissure located in the medial and posterior occipital lobe. The primary visual cortex is often called the striate cortex because it contains a dark-staining layer (striation) of cells. (See Figure 6.)

photopigment A protein dye bonded to retinal, a substance derived from vitamin A; responsible for transduction of visual information. opsin (opp sin) A class of protein that, together with retinal, constitutes the photopigments. retinal (rett i nahl) A chemical synthesized from vitamin A; joins with an opsin to form a photopigment. rhodopsin (roh dopp sin) A particular opsin found in rods. dorsal lateral geniculate nucleus (LGN) A group of cell bodies within the lateral geniculate body of the thalamus; receives inputs from the retina and projects to the primary visual cortex. magnocellular layer One of the inner two layers of neurons in the dorsal lateral geniculate nucleus; transmits information necessary for the perception of form, movement, depth, and small differences in brightness to the primary visual cortex. parvocellular layer One of the four outer layers of neurons in the dorsal lateral geniculate nucleus; transmits information necessary for perception of color and fine details to the primary visual cortex. koniocellular sublayer (koh nee oh sell yew lur) One of the sublayers of neurons in the dorsal lateral geniculate nucleus found ventral to each of the magnocellular and parvocellular layers; transmits information from shortwavelength (“blue”) cones to the primary visual cortex. calcarine fissure (kal ka rine) A horizontal fissure on the inner surface of the posterior cerebral cortex; the location of the primary visual cortex. striate cortex (stry ate) The primary visual cortex.

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Striate cortex

Lateral geniculate nucleus

4 3

optic chiasm A cross-shaped connection between the optic nerves, located below the base of the brain, just anterior to the pituitary gland.

Region of overlap of two visual fields

F I G U R E 6 Lateral Geniculate Nucleus (LGN). The photomicrograph shows a section through the lateral geniculate nucleus and striate cortex of a rhesus monkey (cresyl violet stain). Layers 1, 4, and 6 of the lateral geniculate nucleus receive input from the contralateral eye, and layers 2, 3, and 5 receive input from the ipsilateral eye. Layers 1 and 2 are the magnocellular layers; layers 3–6 are the parvocellular layers. The koniocellular sublayers are found ventral to each of the parvocellular and magnocellular layers. The receptive fields of all six principal layers are in almost perfect registration; cells located along the line of the unlabeled arrow have receptive fields centered on the same point. The ends of the striate cortex are shown by arrows. Based on research from Hubel, D. H., Wiesel, T. N., and Le Vay, S. hilosophical Transactions of the Royal Society of London, B, 1977, 278, 131–163.

Visual field of right eye

Optic chiasm Information from left half of visual field (green) Visual field of left eye Optic nerve Lateral geniculate nucleus Information from right half of visual field (yellow)

FIGURE

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The Primary Visual Pathway.

Primary visual cortex

Figure 7 shows a diagrammatical view of a horizontal section of the human brain. The optic nerves join together at the base of the brain to form the X-shaped optic chiasm (khiasma means “cross”). There, axons from ganglion cells serving the inner halves of the retina (the nasal sides) cross through the chiasm and ascend to the dorsal lateral geniculate nucleus of the opposite side of the brain. The axons from the outer halves of the retina (the temporal sides) remain on the same side of the brain. (See Figure 7.) The lens inverts the image of the world projected on the retina (and similarly reverses left and right). Therefore, because the axons from the nasal halves of the retinas cross to the other side of the brain, each hemisphere receives information from the contralateral half (opposite side) of the visual scene. That is, if a person looks straight ahead, the right hemisphere receives information from the left half of the visual field, and the left hemisphere receives information from the right. It is not correct to say that each hemisphere receives visual information solely from the contralateral eye. (See Figure 7.) Besides the primary retino-geniculo-cortical pathway, several other pathways are taken by fibers from the retina. For example, one pathway to the hypothalamus synchronizes an animal’s activity cycles to the 24-hour rhythms of day and night. Other pathways, especially those that travel to the optic tectum and other midbrain nuclei, coordinate eye movements, control the muscles of the iris (and thus the size of the pupil) and the ciliary muscles (which control the lens), and help to direct our attention to sudden movements that occur in the periphery of our visual field.

Vision

SECTION SUMMARY The Stimulus and Anatomy of the Visual System Light consists of electromagnetic radiation, similar to radio waves but of a different frequency and wavelength. Color can vary in three perceptual dimensions: hue, brightness, and saturation, which correspond to the physical dimensions of wavelength, intensity, and purity. The photoreceptors in the retina—the rods and the cones—detect light. Muscles move the eyes so that images of particular parts of the environment fall on the retina. Accommodation is accomplished by the ciliary muscles, which change the shape of the lens. Photoreceptors communicate with bipolar cells, which communicate with ganglion cells whose axons send visual information to the rest of the brain. In addition, horizontal cells and amacrine cells combine messages from adjacent photoreceptors. When light strikes a molecule of photopigment in a photoreceptor, the retinal molecule detaches from the opsin molecule, a process known

as bleaching. This event causes a receptor potential, which changes the rate of firing of the ganglion cell, signaling the detection of light. Visual information from the retina reaches the striate cortex surrounding the calcarine fissure after being relayed through the magnocellular, parvocellular, and koniocellular layers of the LGN. Several other regions of the brain, including the hypothalamus and the tectum, also receive visual information. These regions help to regulate activity during the day–night cycle, coordinate eye and head movements, regulate the size of the pupils, and control attention to visual stimuli.

Thought Question People who try to see faint, distant lights at night are often advised to look just to the side of the location where they expect to see the lights. Can you explain the reason for this advice?

Coding of Visual Information in the Retina This section describes the way in which cells of the retina encode information they receive from the photoreceptors.

Coding of Light and Dark receptive field That portion of the

One of the methods for studying the physiology of the visual system is the use of microelectrodes visual field in which the presentation of to record the electrical activity of single neurons. As we saw in the previous section, some ganvisual stimuli will produce an alteration glion cells become excited when light falls on the photoreceptors that communicate with them. in the firing rate of a particular neuron. The receptive field of a neuron in the visual system is the part of the visual field that an individual neuron “sees”—that is, the place in which a Receptive field in center visual stimulus must be located to produce a response in that neuron. of retina (fovea) Obviously, the location of the receptive field of a particular neuron depends on the location of the photoreceptors that provide it with visual information. If a neuron receives information from photoreceptors located in the fovea, its receptive field will be at the fixation point—the Bipolar Photoreceptors point at which the eye is looking. If the neuron receives information from cells photoreceptors located in the periphery of the retina, its receptive field will be located off to one side. Ganglion At the periphery of the retina many individual receptors converge cells on a single ganglion cell, bringing information from a relatively large area of the retina—and hence a relatively large area of the visual field. However, the fovea contains approximately equal numbers of ganglion cells and cones. These receptor-to-axon relationships explain the fact that our foveal (central) vision is very acute but our peripheral vision is much less precise. (See Figure 8.) Kuffler (1952, 1953), recording from ganglion cells in the retina of the cat, discovered that their receptive field consists of a roughly circular center, surrounded by a ring. Stimulation of the center or surrounding Receptive field in fields had contrary effects: ON cells were excited by light falling in the periphery of retina central field (center) and were inhibited by light falling in the surroundF I G U R E 8 Foveal Versus Peripheral Acuity. Ganglion cells in the ing field (surround), whereas OFF cells responded in the opposite manfovea receive input from a smaller number of photoreceptors than in ner. ON/OFF ganglion cells were briefly excited when light was turned the periphery and hence provide more acute visual information.

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OFF Cell

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F I G U R E 9 ON and OFF Ganglion Cells. The figure shows responses of ON and OFF ganglion cells to stimuli presented in the center or the surround of the receptive field. Based on Kuffler, S. W. Cold Spring Harbor Symposium for Quantitative Biology, 1952, 17, 281–292.

on or off. In primates these ON/OFF cells project to the superior colliculus, which is primarily involved in visual reflexes in response to moving or suddenly appearing stimuli (Schiller and Malpeli, 1977), which suggests that they do not play a direct role in form perception. (See Figure 9.)

Coding of Color So far, we have been examining the monochromatic properties of ganglion cells—that is, their responses to light and dark. But, of course, objects in our environment selectively absorb some wavelengths of light and reflect others, which, to our eyes, gives them different colors. The retinas of humans and many species of nonhuman primates contain three different types of cones, which provide them (and us) with the most elaborate form of color vision (Jacobs, 1996; Hunt et al., 1998). Although monochromatic (black-and-white) vision is perfectly adequate for most purposes, color vision gave our primate ancestors the ability to distinguish ripe fruit from unripe fruit and made it more difficult for other animals to hide themselves by means of camouflage (Mollon, 1989). In fact, the photopigments of primates with three types of cones seem well suited for distinguishing red and yellow fruits against a background of green foliage (Regan et al., 2001). PHOTORECEPTORS: TRICHROMATIC CODING

Birds have full, three-cone color vision; thus, this bird’s green breast can be perceived by rival males of this hummingbird. © All Canada Photos/Alamy.

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Various theories of color vision have been proposed for many years—long before it was possible to disprove or validate them by physiological means. In 1802 Thomas Young, a British physicist and physician, proposed that the eye detected different colors because it contained three types of receptors, each sensitive to a single hue. His theory was referred to as the trichromatic (threecolor) theory. It was suggested by the fact that for a human observer any color can be reproduced by mixing various quantities of three colors judiciously selected from different points along the spectrum. I must emphasize that color mixing is different from pigment mixing. If we combine yellow and blue pigments (as when we mix paints), the resulting mixture is green. Color mixing refers to the addition of two or more light sources. However, if we shine a beam

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Relative absorbance

of red light and a beam of bluish green light together on a white screen, we 419 496 531 559 nm “Blue” will see yellow light. When white light appears on a color television screen or cone 1.0 computer monitor, it actually consists of a blend of tiny red, blue, and green Rod pixels. If you look closely at one of these screens with a strong magnifying glass, you will see these colored pixels. “Green” cone Physiological investigations of retinal photoreceptors in higher primates have found that Young was right: Three different types of photoreceptors “Red” (three different types of cones) are responsible for color vision. Investigators 0.5 cone have studied the absorption characteristics of individual photoreceptors, determining the amount of light of different wavelengths that is absorbed by the photopigments. These characteristics are controlled by the particular opsin a photoreceptor contains; different opsins absorb particular wavelengths more readily. The peak sensitivities of the three types of cones are approximately 420 nm (blue-violet), 530 nm (green), and 560 nm (yellow-green). 400 500 600 The peak sensitivity of the short-wavelength cone is actually 440 nm in the Wavelength (nm) intact eye because the lens absorbs some short-wavelength light. For conF I G U R E 10 Absorbance of Light by Rods and Cones. venience the short-, medium-, and long-wavelength cones are traditionally The graph shows the relative absorbance of light of various called “blue,” “green,” and “red” cones, respectively. (See Figure 10.) wavelengths by rods and the three types of cones in the human Genetic defects in color vision appear to result from anomalies in retina. one or more of the three types of cones (Boynton, 1979; Wissinger and Based on data from Dartnall, H. J. A., Bowmaker, J. K., and Mollon, J. D. Sharpe, 1998; Nathans, 1999). The first two kinds of defective color vi- Proceedings of the Royal Society of London, B, 1983, 220, 115–130. sion described here involve genes on the X chromosome; thus, because males have only one X chromosome, they are much more likely to have this disorder. (Females are likely to have a normal gene on one of their X chromosomes, which compensates for the defective one.) People with protanopia (“first-color defect”) confuse red and green. They see the world in shades of yellow and blue; both red and green look yellowish to them. Their visual acuity is normal, which suggests that their retinas do not lack “red” or “green” cones. This fact, and their sensitivity to lights of different wavelengths, suggests that their “red” cones are filled with “green” cone opsin. People with deuteranopia (“second-color defect”) also confuse red and green and also have normal visual acuity. Their “green” cones appear to be filled with “red” cone opsin. protanopia (pro tan owe pee a) An Mancuso et al. (2009) attempted to perform gene therapy on adult squirrel monkeys inherited form of defective color vision in whose retinas lacked the gene for “red” cone pigment. Although most female squirrel monwhich red and green hues are confused; keys have trichromatic color vision, males have only dichromatic (“two color”) vision, and “red” cones are filled with “green” cone cannot distinguish red from green. Mancuso and her colleagues used a genetically modified opsin. virus to insert a human gene for the pigment of that “red” cone into the retinas of male mondeuteranopia (dew ter an owe pee a) An keys. Color vision tests before and after surgery confirmed that the gene insertion converted inherited form of defective color vision in which red and green hues are confused; the monkeys from dichromats into trichromats: They could now distinguish between red “green” cones are filled with “red” cone and green. opsin. Tritanopia (“third-color defect”) is rare, affecting fewer than 1 in 10,000 people. This disortritanopia (try tan owe pee a) An der involves a faulty gene that is not located on an X chromosome; thus, it is equally prevalent in inherited form of defective color vision in males and females. People with tritanopia have difficulty with hues of short wavelengths and see which hues with short wavelengths are the world in greens and reds. To them a clear blue sky is a bright green, and yellow looks pink. confused; “blue” cones are either lacking Their retinas lack “blue” cones. Because the retina contains so few of these cones, their absence or faulty. does not noticeably affect visual acuity. RETINAL GANGLION CELLS: OPPONENTPROCESS CODING At the level of the retinal ganglion cell the three-color code gets translated into an opponent-color system. Daw (1968) and Gouras (1968) found that these neurons respond specifically to pairs of primary colors: red versus green and yellow versus blue. Thus, the retina contains two kinds of color-sensitive ganglion cells: red-green cells and yellow-blue cells. Some color-sensitive ganglion cells respond in a center-surround fashion. For example, a cell might be excited by red and inhibited by green in the center of their receptive field while showing the opposite response in the surrounding ring. (See Figure 11.) Other ganglion cells

Yellow on, blue off

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F I G U R E 11 Receptive Fields of Color-Sensitive Ganglion Cells. When a portion of the receptive field is illuminated with the color shown, the cell’s rate of firing increases. When a portion is illuminated with the complementary color, the cell’s rate of firing decreases.

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that receive input from cones do not respond differentially to different wavelengths but simply encode relative brightness in the center and surround. These cells serve as “black-and-white detectors.” The response characteristics of retinal ganglion cells to light of different wavelengths are obviously determined by the particular circuits that connect the three types of cones with the two types of ganglion cells. These circuits involve different types of bipolar cells, amacrine cells, and horizontal cells. For example, a red-green ganglion cell is excited by activation of “red” cones and inhibited by activation of “green” cones. The opponent-color system employed by the ganglion cells explains why we cannot perceive a reddish green or a bluish yellow: An axon that signals red or green (or yellow or blue) can either increase or decrease its rate of firing; it cannot do both at the same time. A reddish green would have to be signaled by a ganglion cell firing slowly and rapidly at the same time, which is obviously impossible.

SECTION SUMMARY Coding of Visual Information in the Retina Recordings of the electrical activity of single neurons in the retina indicate that each ganglion cell receives information from photoreceptors— just one in the fovea and many more in the periphery. The receptive field of most retinal ganglion cells consists of two concentric circles; the cells become excited when light falls in one region and become inhibited when it falls in the other. ON cells are excited by light in the center, and OFF cells are excited by light in the surround. ON/OFF cells play an important role in responding to movement. Color vision occurs as a result of information provided by three types of cones, each of which is sensitive to light of a certain wavelength: long, medium, or short. The absorption characteristics of the cones are determined by the particular opsin that their photopigment contains. Most forms of defective color vision appear to be caused by alterations in cone opsins. The “red” cones of people with protanopia are filled with “green”

II III IVa IVb IVc V VI

cone opsin, and the “green” cones of people with deuteranopia are filled with “red” cone opsin. The retinas of people with tritanopia appear to lack “blue” cones. An attempt at gene therapy successfully converted the dichromatic vision of male squirrel monkeys into trichromatic vision. Most color-sensitive ganglion cells respond in an opposing centersurround fashion to the pairs of primary colors: red and green, and blue and yellow. The responses of these neurons is determined by the retinal circuitry connecting them with the photoreceptors.

Thought Question Why is color vision useful? Birds, some fish, and some primates have full, three-cone color vision. Considering our own species, what other benefits (besides the ability to recognize ripe fruit, which I mentioned earlier in this section) might come from the evolution of color vision?

Analysis of Visual Information: Role of the Striate Cortex The retinal ganglion cells encode information about the relative amounts of light falling on the center and surround regions of their receptive field and, in many cases, about the wavelength of that light. The striate cortex performs additional processing of this information, which it then transmits to the visual association cortex.

Anatomy of the Striate Cortex VI V F I G U R E 12 The Six Layers of the Striate Cortex. This photomicrograph of a small section of striate cortex shows the six principal layers. The letter W refers to the white matter that underlies the visual cortex; beneath the white matter is layer VI of the striate cortex on the opposite side of the gyrus. Based on research from Hubel, D. H., and Wiesel, T. N. Proceedings of the Royal Society of London, B, 1977, 198, 1–59.

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The striate cortex consists of six principal layers (and several sublayers), arranged in bands parallel to the surface. These layers contain the nuclei of cell bodies and dendritic trees that show up as bands of light or dark in sections of tissue that have been dyed with a cell-body stain. (See Figure 12.) If we consider the striate cortex of one hemisphere as a whole—if we imagine that we remove it and spread it out on a flat surface—we find that it contains a map of the contralateral half of the visual field.

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(Remember that each side of the brain sees the opposite side of the visual field.) The map is distorted; approximately 25 percent of the striate cortex is devoted to the analysis of information from the fovea, which represents a small part of the visual field. (The area of the visual field seen by the fovea is approximately the size of a large grape held at arm’s length.) The pioneering studies of David Hubel and Torsten Wiesel at Harvard University during the 1960s began a revolution in the study of the physiology of visual perception (see Hubel and Wiesel, 1977, 1979). Hubel and Wiesel discovered that neurons in the visual cortex did not simply respond to spots of light; they selectively responded to specific features of the visual world. That is, the neural circuitry within the visual cortex combines information from several sources (for example, from axons carrying information received from several different ganglion cells) in such a way as to detect features that are larger than the receptive field of a single ganglion cell or a single cell in the LGN. The following subsections describe the visual characteristics that researchers have studied so far: orientation and movement, spatial frequency, retinal disparity, and color.

Stimulus On

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Orientation and Movement Most neurons in the striate cortex are sensitive to orientation. That is, if a line or an edge (the border of a light and a dark region) is positioned in the cell’s receptive field and rotated around its center, the cell will respond best when the line is in a particular position—a particular orientation. Some neurons respond best to a vertical line, some to a horizontal line, and some to a line oriented somewhere in between. Figure 13 shows the responses of a neuron in the striate cortex when lines were presented at various orientations. As you can see, this neuron responded best when a vertical line was presented in its receptive field. (See Figure 13.) Some orientation-sensitive neurons have receptive fields organized in an opponent fashion. Hubel and Wiesel referred to them as simple cells. For example, a line of a particular orientation (say, a dark 45° line against a white background) might excite a cell if placed in the center of the receptive field but inhibit it if moved away from the center. (See Figure 14a.) Another type of neuron, which the researchers referred to as a complex cell, also responded best to a line of a particular orientation but did not show an inhibitory surround; that is, it continued to respond while the line was moved within the receptive field. In fact, many complex cells increased their rate of firing when the line was moved perpendicular to its angle of orientation—often only in one direction. Thus, these neurons also served as movement detectors. In addition, complex cells responded equally well to white lines against black backgrounds and black lines against white backgrounds. (See Figure 14b.) Finally, hypercomplex cells responded to lines of a particular orientation but had an inhibitory region at the end (or ends) of the lines, which meant that the cells detected the location of ends of lines of a particular orientation. (See Figure 14c.)

Spatial Frequency Although the early studies by Hubel and Wiesel suggested that neurons in the primary visual cortex detected lines and edges, subsequent research found that they actually responded best to sine-wave gratings (De Valois, Albrecht, and Thorell, 1978). Figure 15 compares a sinewave grating with a more familiar square-wave grating. A square-wave grating consists of a simple set of rectangular bars that vary in brightness; the brightness along the length of a line

F I G U R E 13 Orientation Sensitivity. An orientation-sensitive neuron in the striate cortex will become active only when a line of a particular orientation appears within its receptive field. For example, the neuron depicted in this figure responds best to a bar that is vertically oriented. Adapted from Hubel, D. H., and Wiesel, T. N. Journal of Physiology (London), 1959, 148, 574–591.

simple cell An orientation-sensitive neuron in the striate cortex whose receptive field is organized in an opponent fashion. complex cell A neuron in the visual cortex that responds to the presence of a line segment with a particular orientation located within its receptive field, especially when the line moves perpendicularly to its orientation. hypercomplex cell A neuron in the visual cortex that responds to the presence of a line segment with a particular orientation that ends at a particular point within the cell’s receptive field.

Inhibitory region Inhibitory regions

Simple cell is inhibited

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F I G U R E 14 Types of Orientation-Sensitive Neurons. The figure illustrates the response characteristics of three types of orientation-sensitive neurons in the primary visual cortex: (a) simple cell, (b) complex cell, and (c) hypercomplex cell.

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perpendicular to them would vary in a stepwise (square-wave) fashion. (See Figure 15a.) A sine-wave grating looks like a series of fuzzy, unfocused parallel bars. Along any line perpendicular to the long axis of the grating, the brightness varies according to a sine-wave function. (See Figure 15b.) A sine-wave grating is designated by its spatial frequency. We are accustomed to the expression of frequencies (for example, of sound waves or radio waves) in terms of time or distance (such as cycles per second or wavelength in cycles per meter). But because the image of a stimulus on the retina varies in size according to how close it is to the (a) (b) eye, the visual angle is generally used instead of the physical distance between adjacent cycles. Thus, the spatial frequency of a sine-wave gratF I G U R E 15 Parallel Gratings. Two kinds of gratings are compared: (a) square-wave grating and (b) sine-wave grating. ing is its variation in brightness measured in cycles per degree of visual angle. (See Figure 16.) Most neurons in the striate cortex respond best when a sine-wave grating of a particular spatial frequency is placed in the appropriate part of the visual field. But what is the point of having neural circuits that analyze spatial frequency? A complete answer requires some rather complicated mathematics, so I will give a simplified one here. (If you are interested, you can consult a classic book by De Valois and De Valois, 1988.) Consider the types of information provided by high and low spatial frequencies. Small objects, details within a large object, and large objects with sine-wave grating A series of straight parallel bands varying continuously in sharp edges provide a signal rich in high frequencies, whereas large areas of light and dark are brightness according to a sine-wave represented by low frequencies. An image that is deficient in high-frequency information looks function along a line perpendicular to fuzzy and out of focus, like the image seen by a nearsighted person who is not wearing corrective their lengths. lenses. This image still provides much information about forms and objects in the environment; spatial frequency The relative width thus, the most important visual information is that contained in low spatial frequencies. When of the bands in a sine-wave grating, low-frequency information is removed, the shapes of images are very difficult to perceive. (As measured in cycles per degree of visual we will see, the evolutionarily older magnocellular system provides low-frequency information.) angle. retinal disparity The fact that points on objects located at different distances from the observer will fall on slightly different locations on the two retinas; provides the basis for stereopsis. cytochrome oxidase (CO) blob The central region of a module of the primary visual cortex, revealed by a stain for cytochrome oxidase; contains wavelength-sensitive neurons; part of the parvocellular system.

Retinal Disparity We perceive depth by many means, most of which involve cues that can be detected monocularly, by one eye alone. For example, perspective, relative retinal size, loss of detail through the effects of atmospheric haze, and relative apparent movement of retinal images as we move our heads all contribute to depth perception and do not require binocular vision. However, binocular vision provides a vivid perception of depth through the process of stereoscopic vision, or stereopsis. If you have used a stereoscope (such as a View-Master) or have seen a 3-D movie, you know what I mean. Stereopsis is particularly important in the visual guidance of fine movements of the hands and fingers, such as we use when we thread a needle. Most neurons in the striate cortex are binocular—that is, they respond to visual stimulation of either eye. Many of these binocular cells, especially those found in a layer that receives information from the magnocellular system, have response patterns that appear to contribute to the perception of depth (Poggio and Poggio, 1984). In most cases the cells respond most vigorously when each eye sees a stimulus in a slightly different location. That is, the neurons respond to retinal disparity, a stimulus that produces images on slightly different parts of the retina of each eye. This is exactly the information that is needed for stereopsis; each eye sees a three-dimensional scene slightly differently, and the presence of retinal disparity indicates differences in the distance of objects from the observer.

Color F I G U R E 16 Visual Angle and Spatial Frequency. Angles are drawn between the sine waves, with the apex at the viewer’s eye. The visual angle between adjacent sine waves is smaller when the waves are closer together.

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In the striate cortex, information from color-sensitive ganglion cells is transmitted, through the parvocellular and koniocellular layers of the LGN, to special cells grouped together in cytochrome oxidase (CO) blobs. CO blobs were discovered by Wong-Riley (1978), who found that a stain for cytochrome oxidase, an enzyme that is present in mitochondria, showed a

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patchy distribution. (The presence of high levels of cytochrome oxidase Thin stripe Thick stripe Pale stripe in a cell indicates that the cell normally has a high rate of metabolism.) Subsequent research with the stain (Horton and Hubel, 1980; Humphrey and Hendrickson, 1980) revealed the presence of a polka-dot pattern of dark columns extending through layers 2 and 3 and (more faintly) layers 5 and 6. The columns are oval in cross section, approximately 150 x 200 μm in diameter, and spaced at 0.5-mm intervals (Fitzpatrick, Itoh, and V2 Diamond, 1983; Livingstone and Hubel, 1987). Figure 17 shows a photomicrograph of a slice through the striate cortex (also called V1 because it is the first area of visual cortex) and an adjacent area of visual association cortex (area V2) of a macaque monV1 key. The visual cortex has been flattened out and stained for the mitochondrial enzyme. You can clearly see the CO blobs within the striate 5 mm cortex. The distribution of CO-rich neurons in area V2 consists of three F I G U R E 17 Blobs and Stripes in Visual Cortex. kinds of stripes: thick stripes, thin stripes, and pale stripes. The thick and A photomicrograph (actually, a montage of several different tissue thin stripes stain heavily for cytochrome oxidase; the pale stripes do not. sections) shows a slice through the primary visual cortex (area V1) and (See Figure 17.) a region of visual association cortex (V2) of a macaque monkey, stained Researchers previously believed that the parvocellular system trans- for cytochrome oxidase. Area V1 shows spots (“blobs”), and area V2 shows three types of stripes: thick, thin (both dark), and pale. mitted all information pertaining to color to the striate cortex. However, we now know that the parvocellular system receives information only From Sincich, L. C., and Horton, J. C. Annual Review of Neuroscience, 2005, 28, 303–326. By Annual Reviews www.annualreviews.org. from “red” and “green” cones; additional information from “blue” cones is transmitted through the koniocellular system (Hendry and Yoshioka, 1994; Chatterjee and Callaway, 2003). To summarize, neurons in the striate cortex respond to several different features of a visual stimulus, including orientation, movement, spatial frequency, retinal disparity, and color. Now let us turn our attention to the way in which this information is organized within the striate cortex.

Modular Organization of the Striate Cortex

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Most investigators believe that the brain is organized in modules, which probably range in size from a hundred thousand to a few million neurons. Each module receives information from other modules, performs some calculations, and then passes the results to other modules. In recent years investigators have been learning the characteristics of the modules that are found in the visual cortex. The striate cortex is divided into approximately 2500 modules, each approximately 0.5 x 0.7 mm and containing approximately 150,000 neurons. The neurons in each module are devoted to the analysis of various features contained in one very small portion of the visual field. Collectively, these modules receive information from the entire visual field, with the individual modules serving like the tiles in a mosaic mural. The modules actually consist of two segments, each surrounding a CO blob. Neurons located within the blobs have a special function: Most of them are sensitive to color, and all of them are sensitive to low spatial frequencies but relatively insensitive to other visual features. Outside the CO blob, neurons show sensitivity to orientation, movement, spatial frequency, and binocular disparity, but most do not respond to color (Livingstone and Hubel, 1984; Born and Tootell, 1991; Edwards, Purpura, and Kaplan, 1995). Each half of the module receives input from only one eye, but the circuitry within the module combines the information from both eyes, which means that most of the neurons are binocular. If we insert a microelectrode straight down into an interblob region of the striate cortex (that is, in a location in a module outside one of the CO blobs), we will find that all of the orientation-sensitive cells will respond to lines of the same orientation. (See Figure 18.)

Orientation sensitivities

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Input from left eye FIGURE

One Module of the Primary Visual Cortex.

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Optimal spatial frequency (cycles/deg)

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F I G U R E 19 Organization of Responses to Spatial Frequency. Optimal spatial frequency of neurons in striate cortex is shown as a function of the distance of the neuron from the center of the nearest cytochrome oxidase blob.

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How does spatial frequency fit into this organization? Edwards, Purpura, and Kaplan (1995) found that neurons within the CO blobs responded to low spatial frequencies but were sensitive to small differences in brightness. Outside the blobs, sensitivity to spatial frequency varied with the distance from the center of the nearest blob. Higher frequencies were associated with greater distances. (See Figure 19.)

SECTION SUMMARY Analysis of Visual Information: Role of the Striate Cortex The striate cortex (area V1) consists of six layers and several sublayers. Visual information is received from the magnocellular, parvocellular, and koniocellular layers of the LGN. Information from V1 is sent to area V2, the first region of the visual association cortex. The magnocellular system is phylogenetically older, color blind, and sensitive to movement, depth, and small differences in brightness. The parvocellular and koniocellular systems evolved more recently. The parvocellular system receives information from “red” and “green” cones and is able to discriminate finer details. The koniocellular system provides additional information about color, received from “blue” cones. The striate cortex is organized into modules, each surrounding a pair of CO blobs, which are revealed by a stain for cytochrome oxidase,

an enzyme found in mitochondria. Each half of a module receives information from one eye; but because information is shared, most of the neurons respond to information from both eyes. The neurons in the CO blobs are sensitive to color and to low-frequency sine-wave gratings, whereas those between the blobs are sensitive to sine-wave gratings of higher spatial frequencies, orientation, retinal disparity, and movement.

Thought Question Look at the scene in front of you and try to imagine how its features are encoded by neurons in your striate cortex. Try to picture how the objects you see can be specified by an analysis of orientation, spatial frequency, and color.

Analysis of Visual Information: Role of the Visual Association Cortex Although the striate cortex is necessary for visual perception, perception of objects and of the totality of the visual scene does not take place there. Each of the thousands of modules of the striate cortex sees only what is happening in one tiny part of the visual field. Thus, for us to perceive objects and entire visual scenes, the information from these individual modules must be combined. That combination takes place in the visual association cortex.

Two Streams of Visual Analysis extrastriate cortex A region of the visual association cortex; receives fibers from the striate cortex and from the superior colliculi and projects to the inferior temporal cortex.

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Visual information received from the striate cortex is analyzed in the visual association cortex. Neurons in the striate cortex send axons to the extrastriate cortex, the region of the visual association cortex that surrounds the striate cortex. (In this context, extra- means “outside of.”) The primate extrastriate cortex consists of several regions, each of which contains one or more independent maps of the visual field. Each region is specialized, containing neurons that respond

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to a particular feature of visual information, such as orientation, movement, spatial frequency, retinal disparity, or color. So far, investigators have identified over two dozen distinct regions and subregions of the visual cortex of the rhesus monkey. These regions are arranged hierarchically, beginning with the striate cortex (Grill-Spector and Malach, 2004; Wandell, Dumoulin, and Brewer, 2007). Most of the information passes up the hierarchy; each region receives information from regions located beneath it in the hierarchy (closer to the striate cortex), analyzes the information, and passes the results on to “higher” regions for further analysis. The results of a functional-imaging study by Murray, Boyaci, and Kersten (2006) demonstrate a phenomenon that owes its existence to information that follows pathways that travel up the hierarchy, from regions of the visual association cortex back to the striate cortex. First, try the following demonstration. Stare at an object (for example, an illuminated light bulb) that has enough contrast with the background to produce an afterimage. Then look at a nearby surface, such as the back of your hand. Before the afterimage fades away, look at a more distant surface, such as the far wall of the room (assuming you are inside). You will see that the afterimage looks much larger when it is seen against a distant background. The investigators presented subjects with stimuli like those shown in Figure 20: spheres positioned against a background in locations that made them look closer to or farther from the observer. Although the spheres were actually the same size, their location on the background made the one that was apparently farther away look larger than the other one. (See Figure 20.) Murray and his colleagues used fMRI to record activation of the striate cortex while the subjects looked at the spheres. They found that looking at the sphere that appeared to be larger activated a larger area of the striate cortex. We know that perception of apparent distance in a background like that shown in Figure 20 cannot take place in the striate cortex, but requires neural circuitry found in the visual association cortex. This fact means that computations made in higher levels of the visual system can act back on the striate cortex and modify the activity taking place there. Figure 21 shows the location of the striate cortex and several regions in the extrastriate cortex of the human brain. The views of brain in Figures 21a and 21b are nearly normal in appearance. Figures 21c and 21d show “inflated” cortical surfaces, enabling us to see regions that are normally hidden in the depths of sulci and fissures. The hidden regions are shown in dark gray, while regions that are normally visible (the surfaces of gyri) are shown in light gray. Figure 21e shows an unrolling of the cortical surface caudal to the dotted red line and green lines in Figure 21c and 21d. (See Figure 21.) As we saw in the previous subsection, most of the outputs of the striate cortex (area V1) are sent to area V2, a region of the extrastriate cortex just adjacent to V1. At this point, the visual association

F I G U R E 20 Effect of Perceived Distance on Perceived Size. The ball that appears to be farther away looks larger than the closer one, even though the images they cast on the retina are exactly the same size. From Sterzer, P., and Rees, G. Nature Neuroscience, 2006, 9, 302–304. Reprinted with permission.

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F I G U R E 21 Striate Cortex and Regions of Extrastriate Cortex. These views of a human brain show (a) a nearly normal lateral view, (b) a nearly normal midsagittal view, (c) an “inflated” lateral view, (d) an “inflated” midsagittal view, and (e) an unrolling of the cortical surface caudal to the dotted red line and green lines shown in (c) and (d). From Tootell, B. H., and Hadjikhani, N. Cerebral Cortex, 2001, 11, 298–311. Reprinted with permission.

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cortex divides into two pathways. On the basis of their own research and a review of the literature, Ungerleider and Mishkin (1982) conStriate cortex cluded that the visual association cortex contains two streams of analy(primary visual sis: the dorsal stream and the ventral stream. One stream continues cortex) Dorsal lateral forward toward a series of regions that constitute the ventral stream, geniculate nucleus terminating in the inferior temporal cortex. The other stream ascends into regions of the dorsal stream, terminating in the posterior parietal Thalamus cortex. Some axons conveying information received from the magnocellular system bypass area V2: They project from area V1 directly to a region of the extrastriate cortex devoted to the analysis of movement. The ventral stream recognizes what an object is and what color it has, and the dorsal stream recognizes where the object is located and, if it is moving, its speed and direction of movement. (See Figure 22.) The dorsal and ventral streams of the visual association cortex play distinctly different roles in visual processing. The primary behavioral function of the dorsal stream is to provide visual information that guides navigation and skilled movements directed toward objects, and that of the ventral stream is to provide visual informaExtrastriate Inferior temporal tion about the size, shape, color, and texture of objects (including, as cortex cortex: Second Eye Optic level of visual we shall see, other people). association cortex Ventral Stream nerve As we saw, the parvocellular, koniocellular, and magnocellular systems provide different kinds of information. The magnocellular F I G U R E 22 The Human Visual System. The figure shows the human visual system from the eye to the two streams of the visual association system is found in all mammals, whereas the parvocellular and kocortex. niocellular systems are found only in some species of primates. Only the cells in the parvocellular and koniocellular system analyze information concerning color. Cells in the parvocellular system also show high spatial resolution and low temporal resolution; that is, they are able to detect very fine details, but their response is slow and prolonged. The koniocellular system receives information only from “blue” cones and does dorsal stream A system of interconnected not provide information about fine details. Neurons in the magnocellular system are color blind; regions of visual cortex involved in the in addition, they are not able to detect fine details, but can detect smaller contrasts between light perception of spatial location, beginning and dark. They are also especially sensitive to movement. (See Table 2.) The dorsal stream receives with the striate cortex and ending with the mostly magnocellular input, but the ventral stream receives approximately equal input from the posterior parietal cortex. magnocellular and parvocellular/koniocellular systems. ventral stream A system of Second level of visual association cortex in posterior parietal lobe

Dorsal Stream

interconnected regions of visual cortex involved in the perception of form, beginning with the striate cortex and ending with the inferior temporal cortex.

Perception of Color As we saw earlier, neurons within the CO blobs in the striate cortex respond to colors. Like the ganglion cells in the retina (and the parvocellular and koniocellular neurons in the LGN), these neurons respond in opponent fashion. This information is analyzed by the regions of the visual association cortex that constitute the ventral stream.

inferior temporal cortex The highest level of the ventral stream of the visual association cortex; involved in the perception of objects, including people’s bodies and faces.

STUDIES WITH LABORATORY ANIMALS

posterior parietal cortex The highest level of the dorsal stream of the visual association cortex; involved in the perception of movement and spatial location.

TABLE

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Zeki (1980) found that neurons in a region of the extrastriate cortex called V4 respond to a variety of wavelengths, not just those that correspond to red, green, yellow, and blue. This region appears to perform an important role in perception of color. The appearance of the colors of

2 Properties of the Magnocellular, Parvocellular, and Koniocellular Divisions of the Visual System

Property

Magnocellular Division

Parvocellular Division

Koniocellular Division

Color

Yes (from “red” and “green” cones)

Yes (from “blue” cones)

Sensitivity to contrast

High

Low

Spatial resolution (ability to detect fine details)

Low

High

Low

Temporal resolution

Fast (transient response)

Slow (sustained response)

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objects remains much the same whether we observe them under artificial light, under an overcast sky, or at noon on a cloudless day. This phenomenon is known as color constancy. Our visual system does not simply respond according to the wavelength of the light reflected by objects in each part of the visual field; instead, it compensates for the source of the light by comparing the color composition of each point in the visual field with the average color of the entire scene. If the scene contains a particularly high level of long-wavelength light (as it would if an object were illuminated by the light of a setting sun), then some long-wavelength light is “subtracted out” of the perception of each point in the scene. This compensation helps us to see what is actually out there. Electrical recording of the activity of neurons in area V4 of the monkey extrastriate cortex indicates that this region, which receives input from area V2, appears to contain the neural circuits that carry out this analysis (Schein and Desimone, 1990). Walsh et al. (1993) confirmed this prediction; damage to area V4 does disrupt color constancy, but not the ability to discriminate between different colors. Conway, Moeller, and Tsao (2007) performed a detailed analysis of the responsiveness of neurons in a large region of the visual association cortex in monkeys, including area V4. Using fMRI, the investigators identified color “hot spots”—small scattered regions that were strongly activated by changes in the color of visual stimuli. Next, they used microelectrodes to record the response characteristics of neurons inside and outside these spots, which they called globs. (I’m sure the similarity between the terms blobs and globs was intentional.) They found that glob neurons were indeed responsive to colors and had only weak sensitivity to shapes. In contrast, interglob neurons (those located outside globs) did not respond to colors, but were strongly selective to shape. The fact that color-sensitive globs are spread across a wide area of visual association cortex probably explains the fact that only rather large brain lesions cause severe disruptions in perception of color. STUDIES WITH HUMANS Lesions of a region of the human visual association cortex can cause loss of color vision without disrupting visual acuity. The patients describe their vision as resembling a black-and-white film. In addition, they cannot even imagine colors or remember the colors of objects they saw before their brain damage occurred (Damasio et al., 1980; Heywood and Kentridge, 2003). The condition is known as cerebral achromatopsia (“vision without color”). If the brain damage is unilateral, people will lose color vision in only half of the visual field. A functional MRI study by Hadjikhani et al. (1998) found a color-sensitive region in the inferior temporal cortex, which they called area V8. An analysis of ninety-two cases of cerebral achromatopsia by Bouvier and Engel (2006) confirmed that damage to this region (which is adjacent to and partly overlaps the fusiform face area, discussed later in this chapter) disrupts color vision. (Refer to Figure 21.) An interesting functional imaging study by Zeki and Marini (1999) found that although multicolored stimuli activated areas V1, V2, and V4, the color-sensitive region in the inferior temporal cortex that we now call area V8 was activated only when the subjects saw color photographs of real objects. In fact, photographs that showed objects in unnatural colors did not activate area V8. (See Figure 23.) These results suggest that area V8 is involved not only with color perception, but also with the memories of colors of particular objects. Our ability to perceive different colors helps us to perceive different objects in our environment. Thus, for us to perceive and understand what is in front of us, information about color must be combined with other forms of information. Some people with brain damage lose the ability to perceive shapes but can still perceive colors. For example, Zeki et al. (1999) described a patient who could identify colors but was otherwise blind. Patient P. B. had received an electrical shock that caused both cardiac and respiratory arrest. He was revived, but the period of anoxia caused extensive damage to his extrastriate cortex. As a result, he lost all forms of perception. However, even though he could not recognize objects presented on a video monitor, he could still identify their colors.

color constancy The relatively constant appearance of the colors of objects viewed under varying lighting conditions. cerebral achromatopsia (ay krohm a top see a) Inability to discriminate among different hues; caused by damage to area V8 of the visual association cortex.

(a)

(b)

Perception of Form The analysis of visual information that leads to the perception of form begins with neurons in the striate cortex that are sensitive to orientation and spatial frequency. These neurons send information to area V2 that is then relayed to the subregions of the visual association cortex that constitute the ventral stream.

F I G U R E 23 Natural and Unnatural Colors. Neurons in color-sensitive area V8 responded to photographs of objects in their natural colors (a) but not to those of objects in unnatural colors (b). From Zeki, S., and Marini, L. Brain, 1998, 121, 1669–1685.

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STUDIES WITH LABORATORY ANIMALS In primates the recognition of visual patterns and identification of particular objects take place in the inferior temporal cortex, located on the ventral part of the temporal lobe. This region of the visual association cortex is located at the end of the ventral stream. It is here that analyses of form and color are put together and perceptions of three-dimensional objects and backgrounds are achieved. Damage to this region causes severe deficits in visual discrimination (Mishkin, 1966; Gross, 1973; Dean, 1976). In general, neurons in the inferior temporal cortex respond best to specific three-dimensional objects (or photographs of them). They respond poorly to simple stimuli such as spots, lines, or sine-wave gratings. Most of them continue to respond even when complex stimuli are moved to different locations, are changed in size, are placed against a different background, or are partially occluded by other objects (Rolls and Baylis, 1986; Kovács, Vogels, and Orban, 1995). Thus, they appear to participate in the recognition of objects rather than the analysis of specific features. The fact that neurons in the primate inferior temporal cortex respond to very specific complex shapes indicates that the development of the circuits responsible for detecting them must involve learning. STUDIES WITH HUMANS Study of people who have sustained brain damage to the visual association cortex has told us much about the organization of the human visual system. In recent years, our knowledge has been greatly expanded by functional imaging studies. Visual Agnosia Damage to the human visual association cortex can cause a category of deficits known as visual agnosia. Agnosia (“failure to know”) refers to an inability to perceive or identify a stimulus by means of a particular sensory modality, even though its details can be detected by means of that modality and the person retains relatively normal intellectual capacity. Mrs. R., whose case was described in the opening of this chapter, had visual agnosia caused by damage to the ventral stream of her visual association cortex. As we saw, she could not identify common objects by sight, even though she had relatively normal visual acuity. However, she could still read—even small print, which indicates that reading involves different brain regions than object perception does. When she was permitted to hold an object that she could not recognize visually, she could immediately recognize it by touch and say what it is, which proves that she had not lost her memory for the object or simply forgotten how to say its name.

visual agnosia (ag no zha) Deficits in visual form perception in the absence of blindness; caused by brain damage. lateral occipital complex (LOC) A relatively large region of the ventral stream of the visual association cortex that appears to respond to a wide variety of objects and shapes. prosopagnosia (prah soh pag no zha) Failure to recognize particular people by the sight of their faces.

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Analysis of Specific Categories of Visual Stimuli Visual agnosia is caused by damage to those parts of the visual association cortex that contribute to the ventral stream. In fact, damage to specific regions of the ventral stream can impair the ability to recognize specific categories of visual stimuli. Of course, even if specific regions of the visual association cortex are involved in analyzing specific categories of stimuli, the boundaries of brain lesions will seldom coincide with the boundaries of brain regions with particular functions. With the advent of functional imaging, investigators have studied the responses of the normal human brain and have discovered several regions of the ventral stream that are activated by the sight of particular categories of visual stimuli. For example, functional imaging studies have identified regions of the inferior temporal and lateral occipital cortex that are specifically activated by categories such as animals, tools, cars, flowers, letters and letter strings, faces, bodies, and scenes. (See Tootell, Tsao, and Vanduffel, 2003, and Grill-Spector and Malach, 2004 for reviews.) However, not all of these findings have been replicated, and, of course, people can learn to recognize shapes that do not fall into these categories. A relatively large region of the ventral stream of the visual association cortex, the lateral occipital complex (LOC), appears to respond to a wide variety of objects and shapes. A common symptom of visual agnosia is prosopagnosia, an inability to recognize particular faces (prosopon is Greek for “face”). That is, patients with this disorder can recognize that

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The distinction between the behavioral functions of the dorsal and ventral streams is vividly illustrated by a case report by Karnath et al. (2009). Patient J. S. sustained a stroke that damaged the medial occipitotemporal cortex, including the fusiform and lingual gyrus, bilaterally. The ventral stream was seriously damaged, but the dorsal stream was intact. The patient was unable to recognize objects or faces and could no longer read. He could not recognize shapes or orientations of visual stimuli. His ability to reach for and pick up objects was preserved, however, and if he knew in advance what they were, he could handle them appropriately. For example, if he knew where his clothes were, he could pick them up and get dressed. He could shake hands when someone else extended his hand to him. He could walk around his neighborhood, enter a store, and give a written list to the clerk.

they are looking at a face, but they cannot say whose face it is—even if it belongs to a relative or close friend. They see eyes, ears, a nose, and a mouth, but they cannot recognize the particular configuration of these features that identifies an individual face. They still remember who these people are and will usually recognize them when they hear their voice. As one patient said, “I have trouble recognizing people from just faces alone. I look at their hair color, listen to their voices . . . I use clothing, voice, and hair. I try to associate something with a person one way or another . . . what they wear, how their hair is worn” (Buxbaum, Glosser, and Coslett, 1999, p. 43). Studies with brain-damaged people and functional imaging studies suggest that these special face-recognizing circuits are found in the fusiform face area (FFA), located in the fusiform fusiform face area (FFA) A region of the visual association cortex located in gyrus on the base of the temporal lobe. For example, Grill-Spector, Knouf, and Kanwisher the inferior temporal; involved in the (2004) obtained fMRI scans of the brains of people who looked at pictures of faces and several perception of faces. other categories of objects. Figure 24 shows the results, projected on an “inflated” ventral view extrastriate body area (EBA) A region of the cerebral cortex. The black outlines show the regions of the fusiform cortex that were of the visual association cortex located activated by viewing faces, drawn on all images of the brain for comparison with the activation in the lateral occipitotemporal cortex; produced by other categories of objects. As you can see, images of faces activated the regions involved in the perception of the human indicated by these outlines better than other categories of visual stimuli. (See Figure 24.) body and body parts other than faces. Most cases of prosopagnosia occur as a result of damage to the brain of a person who previously had no difficulty recognizing faces. In Right Left contrast, developmental prosopagnosia refers to difficulty recognizing faces that becomes apparent as children develop. Such people often report that their inability to recognize people they have met several times is perceived by the other people as an insult. Our ability to recognize other people’s faces is so automatic that it is difficult for us to understand that someone we have met many times can fail to recognize us, so we conclude that the recognition failure is really a snub. Behrman et al. (2007) found that the anterior fusiform gyrus is smaller in people with developmental prosopagnosia, and a diffusion tensor imaging study by Faces Birds Flowers Thomas et al. (2009) found evidence that people with developmental prosopagnosia show decreased connectivity within the occipitotemporal cortex. Another interesting region of the ventral stream is the extrastriate body area (EBA), which is just posterior to the FFA and partly overlaps it. Downing et al. (2001) found that this region was specifically activated by Fus photographs, silhouettes, or stick drawings of human bodies or body parts and not by control stimuli such as photographs or drawings of tools, scrambled silhouettes, or scrambled stick drawings of human bodies. Figure 25 shows the magnitude of the fMRI response in the non-overlapping regions Houses Guitars Cars of the FFA and EBA to several categories of stimuli (Schwarzlose, Baker, and F I G U R E 24 Responses to Categories of Visual Stimuli. These Kanwisher, 2005). As you can see, the FFA responded to faces more than any functional MRI scans are of people looking at six categories of visual of the other categories, and the EBA showed the greatest response to head- stimuli. Neural activity is shown on “inflated” ventral views of the less bodies and body parts. (See Figure 25.) cerebral cortex. The fusiform face area is shown as a black outline, Urgesi, Berlucchi, and Aglioti (2004) used transcranial magnetic derived from the responses to faces shown in the upper left scan. stimulation to temporarily disrupt the normal neural activity of the From Grill-Spector, K., Knouf, N., and Kanwisher, N. Nature Neuroscience, 2004, 7, EBA. (The TMS procedure applies a strong localized magnetic field 555–561. Reprinted with permission.

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Damage to the patient’s lateral occipital cortex (an important part of the ventral stream) caused a profound visual agnosia for objects. However, she was able to recognize both natural and humanmade scenes (beaches, forests, deserts, cities, markets, and rooms). Functional imaging showed activation of her intact PPA in response to viewing scenes. These results suggest that scene recognition does not depend on recognition of particular objects found within the scene, because D. F. was unable to recognize these objects.

parahippocampal place area (PPA) A region of the medial temporal cortex; involved in the perception of particular places (“scenes”). Assorted objects

Fusiform Face Area (FFA)

Faces

Faces Assorted objects Headless bodies

Extrastriate Body Area (EBA)

Body parts

Faces Assorted objects Headless bodies Body parts 0

to the brain by passing an electrical current through a coil of wire placed on the scalp.) The investigators found that the disruption temporarily impaired people’s ability to recognize photographs of body parts, but not parts of faces or motorcycles. The hippocampus and nearby regions of the medial temporal cortex are involved in spatial perception and memory. Several studies have identified a parahippocampal place area (PPA), located in a region of limbic cortex bordering the ventromedial temporal lobe, that is activated by the sight of scenes and backgrounds. For example, Steeves et al. (2004) reported the case of Patient D. F., a 47-year-old woman who had sustained brain damage caused by accidental carbon monoxide poisoning. By the way, there are three basic ways that we can recognize individual faces: differences in features (for example, the size and shape of the eyes, nose, and mouth), differences in contour (the all-over shape of the face), and differences in configuration of features (for example, the spacing of the eyes, nose, and mouth). Figure 26 illustrates these differences in a series of composite faces (Le Grand et al., 2003). You can see that the face on the left is the same in each of the rows. The faces in the top row contain different features: eyes and mouths from photos of different people. (The noses are all the same.) The faces in the middle row are all of the same person, but the contours of the faces have different shapes. The faces in the bottom row contain different configurations of features from one individual. In these faces, the spacing between the eyes and between the eyes and the mouth have been altered. DifferBody parts Headless bodies ences in configuration are the most difficult to detect. (See Figure 26.) People with autistic disorder fail to develop normal social relations with other people. Indeed, in severe cases they give no signs that they recognize that other people exist. Grelotti, Gauthier, and Schultz (2002) found that people with autistic disorder showed a deficit in the ability to recognize faces and that looking at faces failed to activate the fusiform gyrus. The authors speculate that the lack of interest in other people, caused by the brain abnormalities responsible for autism, resulted in a lack of motivation that normally promotes the acquisition of expertise in recognizing faces as a child grows up. Williams syndrome is a genetic condition caused by a mutation on Chromosome 7. People with this disorder usually show intellectual deficits, but often show an intense interest in music. They are generally very sociable, charming, and kind. They show great interest in other people and spend more time looking closely at their faces. They are generally better at recognizing faces than people without the syndrome. A functional imaging study by Golarai et al. (2010) found (not surprisingly) that the fusiform face area was enlarged in people with Williams syndrome, and that the size of the FFA was positively correlated with a 1.0 0.4 0.6 0.8 person’s ability to recognize faces.

0.2 Mean relative metabolism

F I G U R E 25 Perception of Faces and Bodies. The fusiform face area (FFA) and the extrastriate body area (EBA) were activated by images of faces, headless bodies, body parts, and assorted objects. Based on Schwarzlose, R. F., Baker, C. I., and Kanwisher, N. Journal of Neuroscience, 2005, 23, 11055–11059.

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Perception of Movement We need to know not only what things are, but also where they are, if they are moving, and where they are going. Without the ability to perceive the direction and velocity of movement of objects, we would have

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no way to predict where they will be. We would be unable to catch them (or avoid letting them catch us). This section examines the perception of movement; the final section examines the perception of location. STUDIES WITH LABORATORY ANIMALS One of the regions of a monkey’s extrastriate cortex—area V5, also known as area MT, for medial temporal—contains neurons that respond to movement. Damage to this region severely disrupts a monkey’s ability to perceive moving stimuli (Siegel and Andersen, 1986). Area V5 receives input directly from the striate cortex and from several regions of the extrastriate cortex. It also receives input from the superior colliculus, which is involved in visual reflexes, including reflexive control of eye movements. A region adjacent to area V5 (sometimes called V5a but more often referred to as MST, for medial superior temporal) receives information about movement from V5 and performs a further analysis. MST neurons respond to complex patterns of movement, including radial, circular, and spiral motion (see Vaina, 1998, for a review). One important function of this region— F I G U R E 26 Composite Faces. The faces in the top row contain in particular, the dorsolateral MST, or MSTd—appears to be the analysis of different features: eyes and mouths from photos of different optic flow. people. The middle row of faces are all of the same person, but As we move around in our environment or as objects in our environ- the contours of the faces have different shapes. The faces in the ment move in relation to us, the sizes, shapes, and locations of environbottom row contain different configurations of features from one mental features on our retinas change. Imagine the image seen by a video individual: The spacing between the eyes and between the eyes and the mouth have been altered. camera as you walk along a street, pointing the lens of the camera straight in front of you. Suppose your path will pass just to the right of a mailbox. From Le Grand, R., Mondloch, C. J., Maurer, D., and Brent, H. P. Nature The image of the mailbox will slowly get larger. Finally, as you pass it, it Neuroscience, 2003, 6, 1108–1112. Reprinted with permission. will veer to the left and disappear. Points on the sidewalk will move downward, and branches of trees that you pass under will move upward. Analysis of the relative movement of the visual elements of your environment—the optic flow—will tell you where you are heading, how fast you are approaching different items in front of you, and whether you will pass to the left or right (or under or over) these items. The point toward which we are moving does not move, but all other points in the visual scene move away from it. Therefore, this point is called the center of expansion. If we keep moving in the same direction, we will eventually bump into an object that lies at the center of expansion. We can also use optic flow to determine whether an object approaching us will hit us or pass us by. Britten and van Wezel (1998) found that electrical stimulation of MSTd disrupted monkeys’ ability to perceive the apparent direction in which they were heading; thus, these neurons do indeed seem to play an essential role in heading estimation derived from optic flow. STUDIES WITH HUMANS Perception of Motion Functional imaging studies suggest that a motion-sensitive area (usually called MT/MST) is found within the inferior temporal sulcus of the human brain (Dukelow et al., 2001). However, a more recent study suggests that this region is located in the lateral

optic flow The complex motion of points in the visual field caused by relative movement between the observer and environment; provides information about the relative distance of objects from the observer and of the relative direction of movement.

Patient L. M. had an almost total loss of movement perception. She was unable to cross a street without traffic lights, because she could not judge the speed at which cars were moving. Although she could perceive movements, she found moving objects very unpleasant to look at. For example, while talking with another person, she avoided looking at the person’s mouth because she found its movements very disturbing. When the investigators asked her to try to detect movements of a visual target in the laboratory, she said, “First the target is completely at rest. Then it suddenly jumps upwards and downwards” (Zihl et al., 1991, p. 2244). She was able to see that the target was constantly changing its position, but she was unaware of any sensation of movement.

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occipital cortex, between the lateral and inferior occipital sulci (Annese, Gazzaniga, and Toga, 2005). Annese and his colleagues examined sections of the brains of deceased subjects that had been stained for the presence of myelin. Area V5 received a dense projection of thick, heavily myelinated axons, and the location of this region was revealed by the myelin stain. (See Figure 27.) Bilateral damage to the human brain that includes the motion-sensitive area produces an inability to perceive movement—akinetopsia. For example, Zihl et al. (1991) reported the case of a woman with bilateral lesions that damaged area MT/MST. Walsh et al. (1998) used transcranial magnetic stimulation (TMS) to temporarily inactivate area MT/MST in normal human subjects. The investigators found that during the stimulation, people were unable to detect which of several objects displayed on a computer screen was moving. When the current was off, the subjects had no trouble detecting the motion. The current had no effect on the subjects’ ability to recognize stimuli with different shapes.

LOS

IOS F I G U R E 27 Location of Visual Area V5. The location of visual area V5 (also called MT/MST or MT+) in the human brain was identified by a stain that showed the presence of a dense projection of thick, heavily myelinated axons. LOS = lateral occipital sulcus, IOS = inferior occipital sulcus. From Annese, J., Gazzaniga, M. S., and Toga, A. W. Cerebral Cortex, 2005, 15, 1044–1053. Reprinted with permission.

akinetopsia Inability to perceive movement, caused by damage to area V5 (also called MST) of the visual association cortex.

Tracking moving objects by the visual system is an important role in many skill activities. Rudi Von Briel/PhotoEdit Inc.

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Optic Flow As we saw in the previous subsection, neurons in area MSTd of the monkey brain respond to optic flow, an important source of information about the direction in which the animal is heading. A functional imaging study by Peuskens et al. (2001) found that the corresponding area in the human brain became active when people judged their heading while viewing a display showing optic flow. Vaina and her colleagues (Jornales et al., 1997; Vaina, 1998) found that people with damage to this region were able to perceive motion but could not perceive their heading from optic flow.

Form from Motion Perception of movement can even help us to perceive three-dimensional forms—a phenomenon known as form from motion. Johansson (1973) demonstrated just how much information we can derive from movement. He dressed actors in black and attached small lights to several points on their bodies, such as their wrists, elbows, shoulders, hips, knees, and feet. He made movies of the actors in a darkened room while they were performing various behaviors, such as walking, running, jumping, limping, doing push-ups, and dancing with a partner who was also equipped with lights. Even though observers who watched the films could see only a pattern of moving lights against a dark background, they could readily perceive the pattern as belonging to a moving human and could identify the behavior the actor was performing. Subsequent studies (Kozlowski and Cutting, 1977; Barclay, Cutting, and Kozlowski, 1978) showed that people could even tell, with reasonable accuracy, the sex of the actor wearing the lights. The cues appeared to be supplied by the relative amounts of movement of the shoulders and hips as the person walked. A functional imaging study by Grossman et al. (2000) found that when people viewed a video that showed form from motion, a small region on the ventral bank of the posterior end of the superior temporal sulcus became active. More activity was seen in the right hemisphere, whether the images were presented to the left or right visual field. Grossman and Blake (2001) found that this region became active even when people imagined that they were watching points of light representing form from motion. (which illustrates that the perception of form can be produced by coordinated movements of points of light.) Perception of form from motion might not seem like a phenomenon that has any importance outside the laboratory. However, this phenomenon does occur under natural circumstances, and it appears to involve brain mechanisms different from those involved in normal object perception. For example, as we saw in the prologue to this chapter, people with visual agnosia can often still perceive actions (such as someone pretending to stir something in a bowl or deal out some playing cards) even though they cannot recognize objects by sight. They may be able to recognize friends by the way they walk, even though they cannot recognize their faces. As we saw earlier in this chapter, neurons in the extrastriate body area (EBA) are activated by the sight of human body parts. A functional imaging study by Pelphrey et al. (2005) observed activation of a brain region just anterior to the EBA when subjects viewed people’s hand, eye, and mouth movements.

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Lê et al. (2002) reported the case of patient S. B., a 30-year-old man whose ventral stream was damaged extensively bilaterally by encephalitis when he was three years old. As a result, he was unable to recognize objects, faces, textures, or colors. However, he could perceive movement and could even catch a ball that was thrown to him. Furthermore, he could recognize other people’s arm and hand movements that mimed common activities such as cutting something with a knife or brushing one’s teeth, and he could recognize people he knew by their gait.

Perception of Spatial Location

Rostral

The parietal lobe is involved in spatial and somatosensory perception, and it receives visual, auditory, somatosensory, and vestibular information to perFrontal form these tasks. Damage to the parietal lobes disrupts performance on a lobe variety of tasks that require perceiving and remembering the locations of objects and controlling movements of the eyes and the limbs. The dorsal stream of the visual association cortex terminates in the posterior parietal cortex. Temporal The anatomy of the posterior parietal cortex is shown in Figure 28. lobe We see an “inflated” dorsal view of the left hemisphere of a human brain. Five regions indicated within the intraparietal sulcus (IPS) are of particular interest: AIP, LIP, VIP, CIP, and MIP (anterior, lateral, ventral, caudal, and medial IPS). (See Figure 28.) Single-unit studies with monkeys and functional imaging studies with Medial humans indicate that neurons in the IPS are involved in visual attention and control of saccadic eye movements (LIP and VIP), visual control of AIP reaching and pointing (VIP and MIP), visual control of grasping and maLIP VIP nipulating hand movements (AIP), and perception of depth from stereopsis (CIP) (Snyder, Batista, and Andersen, 2000; Culham and Kanwisher, Region of 2001; Astafiev et al., 2003; Tsao et al., 2003; Frey et al., 2005). intraparietal sulcus Goodale and his colleagues (Goodale and Milner, 1992; Goodale et al., MIP CIP 1994; Goodale and Westwood, 2004) suggested that the primary function of MT the dorsal stream of the visual cortex is to guide actions rather than simply to perceive spatial locations. As Ungerleider and Mishkin (1982) originally put V4 it, the ventral and dorsal streams tell us “what” and “where.” Goodale and his colleagues suggested that the better terms are what and how. They cited the case of a woman with bilateral lesions of the posterior parietal cortex who had F I G U R E 28 The Posterior Parietal Cortex. An “inflated” dorsal no difficulty recognizing line drawings (that is, her ventral stream was intact) view of the left hemisphere of a human brain shows the anatomy of but who had trouble picking up objects (Jakobson et al., 1991). The patient the posterior parietal cortex. could easily perceive the difference in size of wooden blocks that were set out from Astafiev, S. V., Shulman, G. L., Stanley, C. M., et al. Journal of before her, but she failed to adjust the distance between her thumb and fore- Adapted Neuroscience, 2003, 23, 4689–4699. finger to the size of the block she was about to pick up. In contrast, a patient with profound visual agnosia caused by damage to the ventral stream could not distinguish between wooden blocks of different sizes but could adjust the distance between her thumb and forefinger when she picked them up. She made this adjustment by means of vision, before she actually touched them (Milner et al., 1991; Goodale et al., 1994). A functional imaging study of this patient (James et al., 2003) showed normal activity in the dorsal stream while she was picking up objects—especially in the anterior intraparietal sulcus (AIP), which is involved in manipulating and grasping. The suggestion by Goodale and his colleagues seems a reasonable one. Certainly, the dorsal stream is involved in perception of the location of an object’s space—but then, if its primary role is to direct movements, it must be involved in the location of these objects, or else how could it direct movements toward them? In addition, it must contain information about the size and shape of objects, or else how could it control the distance between the thumb and forefinger? A fascinating (and delightful) study with young children demonstrates the importance of communication between the dorsal and ventral streams of the visual system (DeLoache, Uttal, intraparietal sulcus (IPS) The end and Rosengren, 2004). The experimenters let children play with large toys: an indoor slide that of the dorsal stream of the visual they could climb and slide down, a chair that they could sit on, and a toy car that they could enassociation cortex; involved in the ter. After the children played in and on the large toys, the children were brought out of the room, perception of location, visual attention, the large toys were replaced with identical miniature versions, and the children were then brought and control of eye and hand movements.

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FFA

PPA

EBA MT/MST LO

Lip

V8 V7

V4v

V4d

V3A V3

V2 V1

F I G U R E 29 Components of the Ventral and Dorsal Streams of the Visual Cortex. The figure shows some major components of the ventral stream and dorsal stream of the visual cortex. The view is similar to that seen in Figure 21e.

back into the room. When the children played with the miniature toys, they acted as if they were the large versions: They tried to climb onto the slide, climb into the car, and sit on the chair. The authors suggest that this behavior reflects incomplete maturation of connections between the dorsal and ventral streams. The ventral stream recognizes the identity of the objects and the dorsal stream recognizes their size, but the information is not adequately shared between these two systems. (which presents a delightful video that indicates the importance of neural connections that integrate the functions of the dorsal and ventral streams of the visual system.) The importance of the visual system is shown by the fact that approximately 25 percent of our cerebral cortex is devoted to this sense modality and by the many discoveries being made by the laboratories that are busy discovering interesting things about vision. Figure 29 shows the location of the regions that make up the ventral stream and some of the dorsal stream. (See Figure29.) (The rest of the dorsal stream lies in the intraparietal sulcus, which is illustrated in Figure 28.) Table 3 lists these regions and summarizes their major functions. (See Table 3.)

Adapted from Tootell, R. B. H., Tsao, D., and Vanduffel, W. Journal of Neuroscience, 2003, 23, 3981–3989.

SECTION SUMMARY Analysis of Visual Information: Role of the Visual Association Cortex The visual cortex consists of area V1 (the striate cortex), area V2, and two streams of visual association cortex. The ventral stream, which ends with the inferior temporal cortex, is involved with perception of objects. The dorsal stream, which ends with the posterior parietal cortex, is involved with perception of movement, location, visual attention, and control of eye and hand movements. There are at least two dozen different subregions of the visual cortex, arranged in a hierarchical fashion. Each region analyzes a particular characteristic of visual information and passes the results of this analysis to other regions in the hierarchy. Damage to area V4 abolishes color constancy (accurate perception of color under different lighting conditions), and damage to area V8 causes cerebral achromatopsia, a loss of color vision but not of form perception. Functional imaging studies indicate that specific regions of the cortex are involved in perception of form, movement, and color, and these studies are enabling us to discover the correspondences between the anatomy of the human visual system and that of laboratory animals. Studies of humans who have sustained damage to the ventral stream of the visual association cortex sustain a perceptual impairment known as visual agnosia. Prosopagnosia—failure to recognize faces—is caused by damage to the fusiform face area (FFA), a region on the medial surface of the extrastriate cortex on the base of the brain. Developmental prosopagnosia appears to be associated with an FFA that is smaller than normal, and people with Williams syndrome have a special interest in people and their faces, recognize faces well, and have a FFA that is larger than normal. The fusiform face region fails to develop in people with autism,

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presumably because of insufficient motivation to become expert in recognizing other people’s faces. Other specialized regions of the visual association cortex are involved in the recognition of body parts and environmental scenes. Damage to area V5 (also called area MT/MST) disrupts an animal’s ability to perceive movement, and damage to the posterior parietal cortex disrupts perception of the spatial location of objects. Damage to the human visual association cortex corresponding to area V5 disrupts perception of movement, producing a disorder known as akinetopsia. In addition, transcranial magnetic stimulation of V5 causes a temporary disruption of perception of motion, and functional imaging studies show that perception of moving stimuli activate this region. In both monkeys and humans, area MSTd, a region of extrastriate cortex adjacent to area V5, appears to be specialized for perceiving optic flow, one of the cues we use to perceive the direction in which we are heading. The ability to perceive form from motion—recognition of complex movements of people indicated by lights attached to parts of their body—is probably related to the ability to recognize people by the way they walk. This ability apparently depends on a region of the cerebral cortex on the ventral bank of the posterior end of the superior temporal sulcus. Most of the visual association cortex at the end of the dorsal stream is located in the intraparietal sulcus: LIP and VIP are involved in visual attention and control of saccadic eye movements, VIP and MIP are involved in visual control of reaching and pointing, AIP is involved in visual control of grasping and manipulating, and CIP is involved in perception of depth from stereopsis.

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Section Summary (continued) Goodale and his colleagues suggest that the primary function of the dorsal stream of the visual association cortex is better characterized as how rather than what; the role of the posterior parietal cortex in control of reaching, grasping, and manipulation requires visually derived information of movement, depth, and location.

Thought Questions 1. Some psychologists are interested in “top-down” processes in visual perception—that is, the effects of context on perceiving ambiguous stimuli. For example, if you are in a dimly lighted kitchen and see a shape that could be either a loaf of bread or a country mailbox, you

TABLE

will be more likely to perceive the object as a loaf of bread. Where in the brain might contextual information affect perception? 2. I recently rented a car and soon discovered that one of the digital displays on the dashboard consisted of bright blue numbers against a black background. I found it difficult to clearly distinguish the numbers even though the blue color was really quite bright. The other digital displays were yellow, and I had no trouble recognizing the numbers they presented. Based on what you have learned in this chapter, can you offer a possible explanation for this phenomenon? (Hint: See the last paragraph in “Two Streams of Visual Analysis.”)

3 Regions of the Human Visual Cortex and Their Functions

Region of Human Visual Cortex

Name of Region (If Different)

Function

Striate cortex

Small modules that analyze orientation, movement, spatial frequency, retinal disparity, and color

Further analysis of information from V1

Ventral Stream V3 and VP

Further analysis of information from V2

V3A

Processing of visual information across the entire visual field of the contralateral eye

V4d/V4v

V4 dorsal/ventral

Analysis of form Processing of color constancy V4v = upper visual field, V4d = lower visual field

Color perception

Lateral occipital complex

Object recognition

FFA

Fusiform face area

Face recognition, object recognition by experts (“flexible fusiform area”)

PPA

Parahippocampal place area

Recognition of particular places and scenes

EBA

Extrastriate body area

Perception of body parts other than face

Dorsal Stream V7

Visual attention Control of eye movements

V5 (also called MT/MST or MT+)

LIP

Medial temporal/medial superior temporal (named for locations in monkey brain) Lateral intraparietal area

Perception of motion Perception of biological motion and optic flow in specific subregions Visual attention Control of saccadic eye movements

VIP

Ventral intraparietal area

Control of visual attention to particular locations Control of eye movements Visual control of pointing

AIP

Anterior intraparietal area

Visual control of hand movements: grasping, manipulation

MIP

Middle intraparietal area

Visual control of reaching

CIP

Caudal intraparietal area

Parietal reach region (monkeys) Perception of depth from stereopsis

Caudal parietal disparity region

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EPILOGUE

| Case Studies

The discussion of Mrs. R. in the prologue raises an issue about research that I would like to address: the issue of making generalizations from the study of an individual patient. Some researchers have argued that because no two people are alike, we cannot make generalizations from a single individual such as Mrs. R. They say that valid inferences can be made only from studies that involve groups of people, so that individual differences can be accounted for statistically. Is this criticism valid? The careful, detailed investigation of the abilities and disabilities of a single person is called a case study. In my opinion, case studies of people with brain damage can provide very useful information. In the first place, even if we were not able to make firm conclusions from the study of one person, a careful analysis of the pattern of deficits shown by an individual patient might give us some useful ideas for further research, and sources of good ideas for research should not be neglected. But under some circumstances we can draw conclusions from a single case. Before describing what kinds of inferences we can and cannot make from case studies, let me review what we hope to accomplish by studying the behavior of people with brain damage. The brain seems to be organized in modules. A given module receives information from other modules, performs some kinds of analysis, and sends the results on to other modules with which it communicates. In some cases, the wiring of the module may change. That is, synaptic connections may be modified so that in the future the module will respond differently to its inputs. (The ability of modules to modify their synaptic connections serves as the basis for the ability to learn and remember.) If we want to understand how the brain works, we have to know what the individual modules do. A particular module is not responsible for a behavior; instead, it performs one of the many functions that are necessary for a set of behaviors. For example, as I sit here typing this epilogue, I am using modules that perform functions

related to posture and balance, to the control of eye movements, to memories related to the topic I am writing about, to memories of English words and their spellings, to control of finger movements . . . well, you get the idea. We would rarely try to analyze such a complex task as sitting and writing an epilogue; but we might try to analyze how we spell a familiar English word. Possibly, we use modules that perform functions normally related to hearing: We use these modules to “hear” the word in our head and then use other modules to convert the sounds into the appropriate patterns of letters. Alternatively, we may picture the word we want to spell, which would use modules that perform functions related to vision. I do not want to go into the details of spelling and writing here, but I do want you to see why it is important to try to understand the functions performed by groups of modules located in particular parts of the brain. In practice, this means studying and analyzing the pattern of deficits shown by people with brain damage. What kinds of conclusions can we make by studying a single individual? We cannot conclude that because two behaviors are impaired, the deficit is caused by damage to a set of common modules needed for both behaviors. Instead, it could be that behavior X is impaired by damage to module A and behavior Y is impaired by damage to module B, and it just happens that modules A and B were both damaged by the brain lesion. However, we can conclude that if a brain lesion causes a loss of behavior X but not of behavior Y, then the functions performed by the damaged modules are not required to perform behavior Y. The study of a single patient permits us to make this conclusion. You can see that although case studies do not permit us to make sweeping conclusions, under the right circumstances we can properly draw firm if modest conclusions that help us to understand the organization of the brain and suggest hypotheses to test with further research.

KEY CONCEPTS THE STIMULUS

1. Light, a form of electromagnetic radiation, can vary in wavelength, intensity, and purity; it can thus give rise to differences in perceptions of hue, brightness, and saturation.

3. Information from the eye is sent to the parvocellular, koniocellular, and magnocellular layers of the dorsal lateral geniculate nucleus and then to the primary visual cortex (striate cortex).

ANATOMY OF THE VISUAL SYSTEM

2. The eyes are complex sensory organs that focus an image of the environment on the retina. The retina consists of three layers: the photoreceptor layer (rods and cones), the bipolar cell layer, and the ganglion cell layer.

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CODING OF VISUAL INFORMATION IN THE RETINA

4. When light strikes a molecule of photopigment in a photoreceptor, the molecule splits and initiates a receptor potential.

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5. Ganglion cells of the retina respond in an opposing center/ surround fashion. 6. Colors are detected by three types of cones, and the code is changed into an opponent-process system by the time it reaches the retinal ganglion cells. ANALYSIS OF VISUAL INFORMATION: ROLE OF THE STRIATE CORTEX

7. Neurons in the striate cortex are organized in modules, each containing two blobs. Neurons within the blobs respond to color; those outside the blobs respond to orientation, movement, spatial frequency, and retinal disparity. 8. Visual information is processed by two parallel systems: the magnocellular system and the parvocellular/koniocellular system. ANALYSIS OF VISUAL INFORMATION: ROLE OF THE VISUAL ASSOCIATION CORTEX

9. Specific regions of the extrastriate cortex receive information about specific features of the visual scene from the striate

cortex, analyze it, and send their information on to higher levels of the visual association cortex. 10. The association cortex of the inferior temporal lobe (ventral stream) recognizes the shape of objects, whereas the parietal cortex (dorsal stream) recognizes their location. 11. Damage to the visual association cortex can disrupt visual perception. The fusiform gyrus on the base of the occipital lobe is involved in the perception of faces. An adjacent region is involved in the perception of bodies and body parts, and the parahippocampal gyrus contains a region involved in the perception of environmental scenes. A region located in the extrastriate cortex (V8) is involved in color vision. 12. The region corresponding to area V5 is involved in the perception of movement, and a nearby region (MSTd) is involved in the perception of optic flow. Five regions within the intraparietal sulcus are involved in visual attention; control of eye movements; visual control of reaching, pointing, grasping, and manipulating; and perception of depth from stereopsis.

EXPLORE the Virtual Brain in VISUAL SYSTEM Explore the components of the visual system, from the cornea to the secondary visual cortex. The function of each component and the pathways for processing visual information are explained in detail. Engaging videos and animations show the contributions of each component of the visual system to overall visual perception.

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Siegel, R. M., and Andersen, R. A. Motion perceptual deficits following ibotenic acid lesions of the middle temporal area (MT) in the behaving monkey. Society for Neuroscience Abstracts, 1986, 12, 1183. Snyder, L. H., Batista, A. P., and Andersen, R. A. Intention-related activity in the posterior parietal cortex: A review. Vision Research, 2000, 40, 1433–1441. Steeves, J. K. E., Humphrey, G. K., Culham, J. C., Menon, R. A., et al. Behavioral and neuroimaging evidence for a contribution of color and texture information to scene classification in a patient with visual form agnosia. Journal ofCognitive Neuroscience, 2004, 16, 955–965. Thomas, O., Avidan, G., Humphreys, K., et al. Reduced structural connectivity in ventral visual cortex in congenital prosopagnosia. Nature Neuroscience, 2009, 12, 29–31. Tootell, R. B. H., Tsao, D., and Vanduffel, W. Neuroimaging weighs in: Humans meet macaques in “primate” visual cortex. Journal of Neuroscience, 2003, 23, 3981–3989. Tsao, D. Y., Vanduffel, W., Sasaki, Y., Fize, D., et al. Stereopsis activates V3A and caudal intraparietal areas in macaques and humans. Neuron, 2003, 39, 555–568. Ungerleider, L. G., and Mishkin, M. Two cortical visual systems. In Analysis of Visual Behavior, edited by D. J. Ingle, M. A. Goodale, and R. J. W. Mansfield. Cambridge, Mass.: MIT Press, 1982. Urgesi, C., Berlucchi, G., and Aglioti, S. M. Magnetic stimulation of extrastriate body area impairs visual processing of nonfacial body parts. Current Biology, 2004, 13, 2130–2134. Vaina, L. M. Complex motion perception and its deficits. Current Opinion in Neurobiology, 1998, 8, 494–502. Walsh, V., Carden, D., Butler, S. R., and Kulikowski, J. J. The effects of V4 lesions on the visual abilities of macaques: Hue discrimination and color constancy. Behavioural Brain Research, 1993, 53, 51–62. Walsh, V., Ellison, A., Battelli, L., and Cowey, A. Task-specific impairments and enhancements induced by magnetic stimulation of human visual area V5. Proceedings in Biological Sciences, 1998, 265, 537–543. Wandell, B. A., Dumoulin, S. O., and Brewer, A. A. Visual field maps in human cortex. Neuron, 2007, 56, 366–383. Wissinger, B., and Sharpe, L. T. New aspects of an old theme: The genetic basis of human color vision. American Journal of Human Genetics, 1998, 63, 1257–1262. Zeki, S. The representation of colours in the cerebral cortex. Nature, 1980, 284, 412–418. Zeki, S., Aglioti, S., McKeefry, D., and Berlucchi, G. The neurological basis of conscious color perception in a blind patient. Proceedings of the National Academy of Sciences, USA, 1999, 96, 13594–13596. Zihl, J., Von Cramon, D., Mai, N., and Schmid, C. Disturbance of movement vision after bilateral posterior brain damage. Further evidence and follow up observations. Brain, 1991, 114, 2235–2252.

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OUTLINE ■

Audition The Stimulus

Audition, the Body Senses, and the Chemical Senses

Anatomy of the Ear Auditory Hair Cells and the Transduction of Auditory Information The Auditory Pathway Perception of Pitch Perception of Timbre Perception of Spatial Location Perception of Complex Sounds ■

Vestibular System Anatomy of the Vestibular Apparatus The Vestibular Pathway

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Somatosenses The Stimuli Anatomy of the Skin and Its Receptive Organs Perception of Cutaneous Stimulation The Somatosensory Pathways Perception of Pain

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Gustation The Stimuli Anatomy of the Taste Buds and Gustatory Cells Perception of Gustatory Information The Gustatory Pathway

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Olfaction The Stimulus Anatomy of the Olfactory Apparatus Transduction of Olfactory Information

LEARNING OBJECTIVES 1. Describe the parts of the ear and the auditory pathway. 2. Describe the detection of pitch, timbre, and the location of the source of a sound. 3. Describe the structures and functions of the vestibular system. 4. Describe the cutaneous senses and their response to touch, temperature, and pain. 5. Describe the somatosensory pathways and the perception of pain.

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Perception of Specific Odors

6. Describe the ﬁve taste qualities, the anatomy of the taste buds and how they detect taste, and the gustatory pathway and neural coding of taste. 7. Describe the major structures of the olfactory system, explain how odors are detected, and describe the patterns of neural activity produced by these stimuli.

PROLOGUE

| All in Her Head?

Melissa, a junior at the state university, volunteered to be a subject in an experiment at the dental school. She was told that she might feel a little pain but that everything was under medical supervision and no harm would come to her. She didn’t particularly like the idea of pain, but she would be well paid; in addition, she saw the experience as an opportunity to live up to her own self-image as being as brave as anyone. She entered the reception room, where she signed consent forms stating that she agreed to participate in the experiment, knew that a physician would be giving her a drug, and her reaction to pain would be measured. The experimenter greeted her, led her to a room, and asked her to be seated in a dental chair. He inserted a needle attached to a plastic tube into a vein in her right arm so that he could inject drugs. “First,” he said, “we want to find out how sensitive you are to pain.” He showed her a device that looked something like an electric toothbrush with a metal probe on the end. “This device will stimulate nerves in the pulp of your tooth. Do you have some fillings?” She nodded. “Have you ever bitten on some aluminum foil?” She winced and nodded again. “Good, then you will know what to expect.” He adjusted a dial on the stimulator, touched the tip of it to a tooth, and pressed the button. No response. He turned the dial and stimulated the tooth again. Still no response. He turned the dial again, and this time, the stimulation made her gasp and wince. He recorded the voltage setting in his notebook. “Okay, now we know how sensitive this tooth is to pain. Now I’m going to give you a drug we are testing. It should decrease the pain quite a bit.” He injected the drug and after a short while said, “Let’s try the tooth again.” The drug apparently worked; he had to increase the voltage considerably before she felt any pain. “Now,” he said, “I want to give you some more of the drug to see if we can make you feel even less pain.” He gave another injection and, after a little wait, tested her again. But the drug had not further

decreased her pain sensitivity; instead, it had increased it; she was now as sensitive as she had been before the first injection. After the experiment was over, the experimenter walked with Melissa into a lounge. “I want to tell you about the experiment you were in, but I’d like to ask you not to talk about it with other people who might also serve as subjects.” She nodded her head in agreement. “Actually, you did not receive a painkiller. The first injection was pure salt water.” “It was? But I thought it made me less sensitive to pain.” “It did. When an innocuous substance such as an injection of salt water or a sugar pill has an effect like that, we call it a placebo effect.” “You mean that it was all in my mind? That I only thought that the shock hurt less?” “No. Well, that is, it was necessary for you to think that you had received a painkiller. But the effect was a physiological one. We know that, because the second injection contained a drug that counteracts the effects of opiates.” “Opiates? You mean like morphine or heroin?” “Yes.” He saw her start to protest, shook his head, and said, “No, I’m sure you don’t take drugs. But your brain makes them. For reasons we still do not understand, your believing that you had received a painkiller caused some cells in your brain to release a chemical that acts the way opiates do. The chemical acts on other neurons in your brain and decreases your sensitivity to pain. When I gave you the second injection—the drug that counteracts opiates—your sensitivity to pain came back.” “But then, did my mind or my brain make the placebo effect happen?” “Well, think about it. Your mind and your brain are not really separate. Experiences can change the way your brain functions, and these changes can alter your experiences. Mind and brain have to be studied together, not separately.”

lthough one could easily fill a chapter explaining the sensory responses involved with vision, the rest of the sensory modalities must share a chapter. This unequal allocation of space reflects the relative importance of vision to our species and the relative amount of research that has been devoted to it. This chapter is divided into five major sections, which discuss audition, the vestibular system, the somatosenses, gustation, and olfaction.

Audition For most people, audition is the second most important sense. The value of verbal communication makes it even more important than vision in some respects; for example, a blind person can join others in conversation more easily than a deaf person can. (Of course, deaf people can

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Compressed

Physical Dimension

Perceptual Dimension

Amplitude (intensity)

Loudness

Frequency

Pitch

Complexity

Timbre

Sound waves

Rarefied (negative pressure)

Eardrum

F I G U R E 1 Sound Waves. Changes in air pressure from sound waves move the eardrum in and out. Air molecules are closer together in regions of higher pressure and farther apart in regions of lower pressure.

loud

low

simple

FIGURE

soft

high

complex

Physical and Perceptual Dimensions of Sound Waves.

use sign language to converse with each other.) Acoustic stimuli also provide information about things that are hidden from view, and our ears work just as well in the dark. This section describes the nature of the stimulus, the sensory receptors, the brain mechanisms devoted to audition, and some of the details of the physiology of auditory perception.

The Stimulus

pitch A perceptual dimension of sound; corresponds to the fundamental frequency. hertz (Hz) Cycles per second. loudness A perceptual dimension of sound; corresponds to intensity. timbre (tim ber or tamm ber) A perceptual dimension of sound; corresponds to complexity. tympanic membrane The eardrum. ossicle (ahss i kul) One of the three bones of the middle ear. malleus The “hammer”; the first of the three ossicles.

We hear sounds, which are produced by objects that vibrate and set molecules of air into motion. When an object vibrates, its movements cause molecules of air surrounding it alternately to condense and rarefy (pull apart), producing waves that travel away from the object at approximately 700 miles per hour. If the vibration ranges between approximately 30 and 20,000 times per second, these waves will stimulate receptor cells in our ears and will be perceived as sounds. (See Figure 1.) Light has three perceptual dimensions—hue, brightness, and saturation—that correspond to three physical dimensions. Similarly, sounds vary in their pitch, loudness, and timbre. The perceived pitch of an auditory stimulus is determined by the frequency of vibration, which is measured in hertz (Hz), or cycles per second. (The term honors Heinrich Hertz, a nineteenth-century German physicist.) Loudness is a function of intensity—the degree to which the condensations and rarefactions of air differ from each other. More vigorous vibrations of an object produce more intense sound waves and hence louder ones. Timbre provides information about the nature of the particular sound—for example, the sound of an oboe or a train whistle. Most natural acoustic stimuli are complex, consisting of several different frequencies of vibration. The particular mixture determines the sound’s timbre. (See Figure 2.) The auditory system does a phenomenal job of analyzing the vibrations that reach our ear. For example, we can understand speech, recognize a person’s emotion from his or her voice, appreciate music, detect the approach of a vehicle or another person, or recognize an animal’s call. Furthermore, we can recognize not only what the source of a sound is but where it is located.

incus The “anvil”; the second of the three ossicles.

Anatomy of the Ear

stapes (stay peez) The “stirrup”; the last of the three ossicles.

Figure 3 shows a section through the ear and auditory canal and illustrates the apparatus of the middle and inner ear. (See Figure 3.) Sound is funneled via the pinna (external ear) through the ear canal to the tympanic membrane (eardrum), which vibrates with the sound. The middle ear consists of a hollow region behind the tympanic membrane, approximately 2 ml in volume. It contains the bones of the middle ear, called the ossicles, which are set into vibration by the tympanic membrane. The malleus (hammer) connects with the tympanic membrane and transmits vibrations via the incus (anvil) and stapes (stirrup) to the cochlea, the structure that contains the receptors. The baseplate of the stapes presses against the membrane behind the oval window, the opening in the bony process surrounding the cochlea. (See Figure 3.)

cochlea (cock lee uh) The snail-shaped structure of the inner ear that contains the auditory transducing mechanisms. oval window An opening in the bone surrounding the cochlea that reveals a membrane, against which the baseplate of the stapes presses, transmitting sound vibrations into the fluid within the cochlea.

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Malleus Ossicles (middle Incus ear bones) Stapes Oval window Bone Auditory nerve

Cochlea

Vestibule

Pinna FIGURE

Ear canal

Tympanic membrane

Round window

Eustachian tube (connects with throat)

The Auditory Apparatus.

The cochlea is part of the inner ear. It is filled with fluid; therefore, sounds transmitted through the air must be transferred into a liquid medium. This process normally is very inefficient— 99.9 percent of the energy of airborne sound would be reflected away if the air impinged directly against the oval window of the cochlea. The chain of ossicles serves as an extremely efficient means of energy transmission. The bones provide a mechanical advantage, with the baseplate of the stapes making smaller but more forceful excursions against the oval window than the tympanic membrane makes against the malleus. The name cochlea comes from the Greek word kokhlos, or “land snail.” It is indeed snailshaped, consisting of two and three-quarters turns of a gradually tapering cylinder, 35 mm (1.37in.) long. The cochlea is divided longitudinally into three sections, the scala vestibuli (“vestibular stairway”), the scala media (“middle stairway”), and the scala tympani (“tympanic stairway”), as shown in Figure 4. The receptive organ, known as the organ of Corti, consists of the basilar membrane, the hair cells, and the tectorial membrane. The auditory receptor cells are called hair cells, and they are anchored, via rodlike Deiters’s cells, to the basilar membrane. The cilia of the hair cells pass through the reticular membrane, and the ends of some of them attach to the fairly rigid tectorial membrane, which projects overhead like a shelf. (See Figure 4.) Sound waves cause the basilar membrane to move relative to the tectorial membrane, which bends the cilia of the hair cells. This bending produces receptor potentials. Figure 5 shows this process in a cochlea that has been partially straightened. If the cochlea were a closed system, no vibration would be transmitted through the oval window, because liquids are essentially incompressible. However, there is a membrane-covered opening, the round window, that allows the fluid inside the cochlea to move back and forth. The baseplate of the stapes vibrates against the membrane behind the oval window and introduces sound waves of high or low frequency into the cochlea. The vibrations cause part of the basilar membrane to flex back and forth. Pressure changes in the fluid underneath the basilar membrane are transmitted to the membrane of the round window, which moves in and out in a manner opposite to the movements of the oval window. That is, when the baseplate of the stapes pushes in, the membrane behind the round window bulges out. As we will see in a later subsection, different frequencies of sound vibrations cause different portions of the basilar membrane to flex. (See Figure 5.) Some people suffer from a middle ear disease that causes the bone to grow over the round window. Because their basilar membrane cannot easily flex back and forth, these people have a severe hearing loss. However, their hearing can be restored by a surgical procedure called fenestration (“window making”), in which a tiny hole is drilled in the bone where the round window should be.

organ of Corti The sensory organ on the basilar membrane that contains the auditory hair cells. hair cell The receptive cell of the auditory apparatus. Deiters’s cell (dye terz) A supporting cell found in the organ of Corti; sustains the auditory hair cells. basilar membrane (bazz i ler) A membrane in the cochlea of the inner ear; contains the organ of Corti. tectorial membrane (tek torr ee ul) A membrane located above the basilar membrane; serves as a shelf against which the cilia of the auditory hair cells move. round window An opening in the bone surrounding the cochlea of the inner ear that permits vibrations to be transmitted, via the oval window, into the fluid in the cochlea.

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Outer hair cells

Tectorial membrane (vibrations exert stretch on cilia of hair cells)

Cilia of hair cell

Inner hair cell

Scala media

Scala vestibuli

Basilar membrane

Axons of auditory nerve Organ of Corti

Auditory nerve Scala tympani

Spiral ganglion Bone Membrane surrounding cochlea

Slice Through Cochlea FIGURE

The Cochlea. A cross section through the cochlea, showing the organ of Corti.

Auditory Hair Cells and the Transduction of Auditory Information

cilium (plural: cilia) A hairlike appendage of a cell involved in movement or in transducing sensory information; found on the receptors in the auditory and vestibular system. tip link An elastic filament that attaches the tip of one cilium to the side of the adjacent cilium. insertional plaque The point of attachment of a tip link to a cilium.

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Two types of auditory receptors, inner and outer auditory hair cells, are located on the basilar membrane. Hair cells contain cilia (“eyelashes”), fine hairlike appendages, arranged in rows according to height. The human cochlea contains approximately 3500 inner hair cells and 12,000 outer hair cells. The hair cells form synapses with dendrites of bipolar neurons whose axons bring auditory information to the brain. (Refer to Figure 4.) Sound waves cause both the basilar membrane and the tectorial membrane to flex up and down. These movements bend the cilia of the hair cells in one direction or the other. The tips of the cilia of outer hair cells are attached directly to the tectorial membrane. The cilia of the inner hair cells do not touch the overlying tectorial membrane, but the relative movement of the two membranes causes the fluid within the cochlea to flow past them, making them bend back and forth too. Cilia contain a core of actin filaments surrounded by myosin filaments, and these proteins make the cilia stiff and rigid (Flock, 1977). Adjacent cilia are linked to each other by elastic filaments known as tip links. Each tip link is attached to the end of one cilium and to the side of an adjacent cilium. The points of attachment, known as insertional plaques, look dark under an electron microscope. As we will see, receptor potentials are triggered at the insertional plaques. (See Figure 6.) Normally, tip links are slightly stretched, which means that they are under a small amount of tension. Thus, movement of the bundle of cilia in the direction of the tallest of them further stretches these linking fibers, whereas movement in the opposite direction relaxes them. Each insertional plaque contains a single ion channel, which opens and closes according to the amount

Audition, the Body Senses, and the Chemical Senses

Incus

Stapes vibrates against membrane behind oval window Oval Basilar membrane window

Malleus

Cochlea uncurled to show basilar membrane Sound waves

Eardrum

Round window

A particular region of the basilar membrane flexes back and forth in response to sound of a particular frequency

F I G U R E 5 Responses to Sound Waves. When the stapes pushes against the membrane behind the oval window, the membrane behind the round window bulges outward. Different high-frequency and medium-frequency sound vibrations cause flexing of different portions of the basilar membrane. In contrast, lowfrequency sound vibrations cause the tip of the basilar membrane to flex in synchrony with the vibrations.

Insertional plaque

of stretch exerted by the tip links. Thus, bending of the bundle of cilia produces receptor potentials (Pickles and Corey, 1992; Hudspeth and Gillespie, 1994; Gillespie, 1995; Jaramillo, 1995).

The Auditory Pathway

Cilium

Insertional plaque

CONNECTIONS WITH THE COCHLEAR NERVE Tip link The organ of Corti sends auditory information to the brain by means of the cochlear nerve, a branch of the auditory nerve (eighth cranial nerve). Approximately 95 percent of these thick and myelinated axons receive information from the inner hair cells. Even though the outer hair cells are much more numerous, they send information through only 5percent of the thin and unmyelinated sensory axons in the cochlear nerve. These (b) (a) facts suggest that inner hair cells are of primary importance in the transmission of auditory information to the central nervous system. F I G U R E 6 Transduction Apparatus in Hair Cells. These electron Physiological and behavioral studies confirm this suggestion: micrographs are of the transduction apparatus in hair cells. (a) A The inner hair cells are necessary for normal hearing. In fact, Deol longitudinal section through three adjacent cilia; tip links, elastic and Gluecksohn-Waelsch (1979) found that a mutant strain of mice filaments attached to insertional plaques, link adjacent cilia. (b) A cross whose cochleas contain only outer hair cells apparently cannot hear section through several cilia, showing an insertional plaque. From Hudspeth, A. J., and Gillespie, P. G. Neuron, 1994, 12, 1–9. at all. Subsequent research indicates that the outer hair cells are effector cells, involved in altering the mechanical characteristics of cochlear nerve The branch of the the basilar membrane and thus influencing the effects of sound vibrations on the inner hair auditory nerve that transmits auditory cells. I will discuss the role of outer hair cells in the section on place coding of pitch. information from the cochlea to the brain.

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THE CENTRAL AUDITORY SYSTEM The anatomy of the subcortical components of the auditory system is more complicated than that of the visual system. Rather than giving a detailed writLateral fissure ten description of the pathways, I will refer you to a visual representation. (See Figure 7.) Note that axons enter the cochlear nucleus of the medulla and synapse there. Most of the neurons in the cochlear nucleus send axons to the superior olivary complex, also located in the medulla. Axons of neurons in Auditory these nuclei pass through a large fiber bundle called the lateral lemniscus to cortex the inferior colliculus, which is located in the dorsal midbrain. Neurons there send their axons to the medial geniculate nucleus of the thalamus, which sends its axons to the auditory cortex of the temporal lobe. As you can see, Cerebrum Medial geniculate there are many synapses along the way that complicate the story. Each heminucleus sphere receives information from both ears but primarily from the contralateral one. Auditory information is relayed to the cerebellum and reticular Inferior colliculus formation as well. Midbrain If we unrolled the basilar membrane into a flat strip and followed afferent axons serving successive points along its length, we would reach sucDorsal cochlear cessive points in the nuclei of the auditory system and ultimately successive nucleus points along the surface of the primary auditory cortex. The basal end of the basilar membrane (the end toward the oval window, which responds to Lateral the highest frequencies) is represented most medially in the auditory cortex, Ventral lemniscus cochlear and the apical end is represented most laterally there. Because, as we will nucleus see, different parts of the basilar membrane respond best to different frequencies of sound, this relationship between cortex and basilar membrane Trapezoid is referred to as tonotopic representation (tonos means “tone,” and topos body means “place”). Auditory information from the medial geniculate nucleus of the thalaAuditory mus is transmitted to the primary auditory cortex—the core region—which nerve lies hidden on the upper bank of the lateral fissure. The core regions transSuperior Medulla mit auditory information to the first level of the auditory association cortex, olivary the belt region, which surrounds the core region. Information is then transcomplex mitted to the next level of the auditory association cortex, the parabelt reF I G U R E 7 Pathways of the Auditory System. The major gion. The visual association cortex is arranged in two streams—dorsal and pathways are indicated by heavy arrows. ventral—which are involved in the perception of the form and location of cochlear nucleus One of a group visual stimuli, respectively. The auditory association cortex is similarly of nuclei in the medulla that receive arranged in two streams. The anterior stream, which begins in the anterior parabelt region, is auditory information from the cochlea. involved with the analysis of complex sounds. The posterior stream, which begins in the posterior superior olivary complex A group parabelt region, is involved with sound localization (Rauschecker and Tian, 2000; Rauschecker of nuclei in the medulla; involved with and Scott, 2009). (See Figure 8.) auditory functions, including localization of the source of sounds. lateral lemniscus A band of fibers running rostrally through the medulla and pons; carries fibers of the auditory system. tonotopic representation (tonn oh top ik) A topographically organized mapping of different frequencies of sound that are represented in a particular region of the brain. core region The primary auditory cortex, located on a gyrus on the dorsal surface of the temporal lobe. belt region The first level of the auditory association cortex; surrounds the primary auditory cortex. parabelt region The second level of the auditory association cortex; surrounds the belt region.

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Perception of Pitch As we have seen, the perceptual dimension of pitch corresponds to the physical dimension of frequency. The cochlea detects frequency by two means: moderate to high frequencies by place coding and low frequencies by rate coding. These two types of coding are described next. PLACE CODING Because of the mechanical construction of the cochlea and basilar membrane, acoustic stimuli of different frequencies cause different parts of the basilar membrane to flex back and forth. Figure 9 illustrates the amount of deformation along the length of the basilar membrane produced by stimulation with tones of various frequencies. Note that higher frequencies produce more displacement at the basal end of the membrane (the end closest to the stapes). (See Figure 9.) These results suggest that at least some frequencies of sound waves are detected by means of a place code. In this context a code represents a means by which neurons can represent information. Thus, if neurons at one end of the basilar membrane are excited by higher

Audition, the Body Senses, and the Chemical Senses

Distance from the stapes (mm)

Premotor frequencies and those at the other end are excited by lower frequencortex Parietal cies, we can say that the frequency of the sound is coded by the parlobe ticular neurons that are active. In turn, the firing of particular axons in the cochlear nerve tells the brain about the presence of particular frequencies of sound. Good evidence for place coding of pitch in the human cochlea comes from the effectiveness of cochlear implants. Cochlear implants Belt are devices that are used to restore hearing in people with deafness Core caused by damage to the hair cells. The external part of a cochlear implant consists of a microphone and a miniaturized electronic signal processor. The internal part contains a very thin, flexible array of electrodes, which the surgeon carefully inserts into the cochlea in such a way that it Parabelt follows the snaillike curl and ends up resting along the entire length of Inferior the basilar membrane. Each electrode in the array stimulates a different frontal Anterior Posterior cortex stream part of the basilar membrane. Information from the signal processor is stream passed to the electrodes by means of flat coils of wire, implanted under Superior temporal the skin. (See Figure 10.) sulcus The primary purpose of a cochlear implant is to restore a person’s F I G U R E 8 The Auditory Cortex. Auditory information from the ability to understand speech. Because most of the important acoustical medial geniculate nucleus of the thalamus is received by the primary information in speech is contained in frequencies that are too high to auditory cortex (core region). Information analyzed by the core region is transmitted to the belt region, and from there to the anterior and be accurately represented by a rate code, the multichannel electrode posterior parabelt region. The anterior parabelt region serves as the was developed in an attempt to duplicate the place coding of pitch on beginning of the anterior stream, which is involved with the analysis of the basilar membrane (Copeland and Pillsbury, 2004). When different complex sounds. The posterior parabelt region serves as the beginning regions of the basilar membrane are stimulated, the person perceives of the posterior stream, which is involved with the analysis of sound sounds with different pitches. The signal processor in the external delocalization. vice analyzes the sounds detected by the microphone and sends separate signals to the appropriate portions of the basilar membrane. This device can work well; most people with cochlear implants can understand speech well enough to use a telephone (Shannon, 2007). As I mentioned earlier, the brain receives auditory information solely from the axons of inner hair cells. What role, then, do outer hair cells play? 35 These cells contain contractile proteins, just as muscle fibers do. When they are exposed to an electrical current, outer hair cells contract by up to 10 percent of 30 their length (Brownell et al., 1985; Zenner, Zimmermann, and Schmitt, 1985). 25 When the basilar membrane vibrates, movement of the cilia of the outer hair cells opens and closes ion channels, causing changes in the membrane 20 potential. These changes cause movements of the contractile proteins, thus 15 lengthening and shortening the cells. These changes in length amplify the vibrations of the basilar membrane. As a consequence, the signal that is re10 ceived by inner hair cells is enhanced, which greatly increases the sensitivity 5 of the inner ear to sound waves. 20 50 100 200 500 1000 2000 Figure 11 illustrates the importance of outer hair cells to the sensitivity Frequency (Hz) and frequency selectivity of inner hair cells (Fettiplace and Hackney, 2006). The three V-shaped tuning curves indicate the sensitivity of individual inner F I G U R E 9 Anatomical Coding of Pitch. Stimuli of different hair cells, as shown by the response of individual afferent auditory nerve frequencies maximally deform different regions of the basilar axons to pure tones. The low points of the three solid curves indicate that the membrane. hair cells will respond to a faint sound only if it is of a specific frequency—for Based on von Békésy, G. Journal of the Acoustical Society of America, 1949, 21, these cells, either 0.5 kHz (red curve), 2.0 kHz (green curve), or 8.0 kHz (blue 233–245. curve). If the sound is louder, the cells will respond to frequencies above and below their preferred frequencies. The dotted line indicates the response of the “blue” neuron after the outer hair cells have been destroyed. As you can see, this cell loses both sensitivity and place code The system by which selectivity: It will respond only to loud sounds, but to a wide range of frequencies. (See Figure 11.)

RATE CODING We have seen that the frequency of a sound can be detected by place coding. However, the lowest frequencies do not appear to be accounted for in this manner. Lower frequencies are detected by

information about different frequencies is coded by different locations on the basilar membrane.

cochlear implant An electronic device surgically implanted in the inner ear that can enable a deaf person to hear.

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neurons that fire in synchrony to the movements of the apical end of the basilar membrane. Thus, lower frequencies are detected by means of rate coding. The most convincing evidence of rate coding of pitch also comes from studies of people with cochlear implants. Pijl and Schwarz (1995a, 1995b) found that stimulation of a single electrode with pulses of electricity produced sensations of pitch that were proportional to the frequency of the stimulation. In fact, the subjects could even recognize familiar tunes produced by modulating the pulse frequency. (The subjects had become deaf later in life, after they had already learned to recognize the tunes.) As we would expect, the subjects’ perceptions were best when the tip of the basilar membrane was stimulated, and only low frequencies could be distinguished by this method.

Perception of Timbre

F I G U R E 10 A Child with a Cochlear Implant. The microphone and processor are worn over the ear and the headpiece contains a coil that transmits signals to the implant.

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Frequency (kHz) F I G U R E 11 Tuning Curves. The figure shows the responses of single axons in the cochlear nerve that receive information from inner hair cells on different locations of the basilar membrane. The cells are more frequency selective at lower sound intensities. The dotted line shows the loss of sensitivity and selectivity of the high-frequency neuron after destruction of the outer hair cells. Based on Fettiplace, R., and Hackney, C. M. Nature Reviews: Neuroscience, 2006, 7, 19–29.

rate coding The system by which information about different frequencies of sound waves is coded by the rate of firing of neurons in the auditory system. fundamental frequency The lowest, and usually most intense, frequency of a complex sound; most often perceived as the sound’s basic pitch.

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Although laboratory investigations of the auditory system often employ pure sine waves as stimuli, these waves are seldom encountered outside the laboratory. Instead, we hear sounds with a rich mixture of frequencies—sounds of complex timbre. For example, consider the sound of a clarinet playing a particular note. If we hear it, we can easily say that it is a clarinet and not a flute or a violin. The reason we can do so is that these three instruments produce sounds of different timbre, which our auditory system can distinguish. Figure 12 shows the waveform from a clarinet playing a steady note (top). The shape of the waveform repeats itself regularly at the fundamental frequency, which corresponds to the perceived pitch of the note. A Fourier analysis of the waveform shows that it actually consists of a series of sine waves that includes the fundamental frequency and many overtones, multiples of the fundamental frequency. Different instruments produce overtones with different intensities. (See Figure 12.) Electronic synthesizers simulate the sounds of real instruments by producing a series of overtones of the proper intensities, mixing them, and passing them through a loudspeaker. When the basilar membrane is stimulated by the sound of a clarinet, different portions respond to each of the overtones. This response produces a unique anatomically coded pattern of activity in the cochlear nerve, which is subsequently identified by circuits in the auditory association cortex. Actually, the recognition of complex sounds is not quite that simple. Figure12 shows the analysis of a sustained sound of a clarinet. But most sounds (including those produced by a clarinet) are dynamic; that is, their beginning, middle, and end are different from each other. The beginning of a note played on a clarinet (the attack) contains frequencies that appear and disappear in a few milliseconds. And at the end of the note (the decay), some harmonics disappear before others. If we are to recognize different sounds, the auditory cortex must analyze a complex sequence of multiple frequencies that appear, change in amplitude, and disappear. And when you consider the fact that we can listen to an orchestra and identify several instruments that are playing simultaneously, you can appreciate the complexity of the analysis performed by the auditory system. We will revisit this process later in this chapter.

Perception of Spatial Location So far, I have discussed coding of pitch, loudness, and timbre only (the last of which is actually a complex frequency analysis). The auditory system also responds to other qualities of acoustic stimuli. For example, our ears are very good at determining whether the source of a sound is to the right or left of us. Three physiological mechanisms detect the location of sound sources: We use phase differences for low frequencies (less than approximately 3000 Hz) and intensity

Audition, the Body Senses, and the Chemical Senses

Simple waves that make up sound of clarinet

differences for high frequencies. In addition, we use an analysis of timbre to deWaveform termine the height of the source of a sound and recognize whether it is in front of from clarinet us or behind us. If we are blindfolded, we can still determine with rather good accuracy the location of a stimulus that emits a click. We do so because neurons respond selectively to different arrival times of the sound waves at the left and right ears. If the source of the click is to the right or left of the midline, the sound pressure wave will reach one ear sooner and initiate action potentials there first. Only if the stimulus is straight ahead will the ears be stimulated simultaneously. Neurons in the superior Fundamental olivary complex of the medulla detect differences in arrival times of sound waves frequency produced by clicks. 1 Of course, we can hear continuous sounds as well as clicks, and we can also perceive the location of their source. We detect the source of continuous lowpitched sounds by means of phase differences. Phase differences refer to the si2 multaneous arrival, at each ear, of different portions (phases) of the oscillating sound wave. For example, if we assume that sound travels at 700 miles per hour Overtones 3 through the air, adjacent cycles of a 1000-Hz tone are 12.3 inches apart. Thus, if the source of the sound is located to one side of the head, one eardrum is pulled 4 out while the other is pushed in. The movement of the eardrums will reverse, or be 180° out of phase. If the source were located directly in front of the head, the 5 movements would be perfectly in phase (0° out of phase). (See Figure 13.) Because some auditory neurons respond only when the eardrums (and thus the bending of 6 the basilar membrane) are at least somewhat out of phase, neurons in the superior 7 olivary complex in the brain are able to use the information they provide to detect 8 the source of a continuous sound. The auditory system cannot readily detect binaural phase differences of high9 10 frequency stimuli; the differences in phases of such rapid sine waves are just too 11 short to be measured by the neurons. However, high-frequency stimuli that occur 12 13 to the right or left of the midline stimulate the ears unequally. The head absorbs 14 high frequencies, producing a “sonic shadow,” so the ear closest to the source of the 15 16 sound receives the most intense stimulation. Some neurons in the superior olivary 17 complex respond differentially to binaural stimuli of different intensity in each ear, 18 19 which means that they provide information that can be used to detect the source 20 of tones of high frequency. How can we determine the elevation of the source of a sound and perceive F I G U R E 12 Sound Wave from a Clarinet. The figure shows the shape of a sound wave from a clarinet (top) and whether it is in front of us or behind us? One answer is that we can turn and tilt our heads, thus transforming the discrimination into a left–right decision. But the individual frequencies into which it can be analyzed. Based on Stereo Review, copyright © 1977 by Diamandis we have another means by which we can determine elevation and distinguish Communications Inc. front from back: analysis of timbre. This method involves a part of the auditory system that I have not said much about: the external ear (pinna). People’s external ears contain several folds and ridges. Most of the sound waves that we hear bounce off the folds and ridges of the pinna before they enter the ear canal. Depending on the angle at which the sound waves strike these folds and ridges, different frequencies will be enhanced or attenuated. In other words, the pattern of reflections will change with the location of the source of the sound, which will alter the timbre of the sound that is perceived. Because people’s ears differ in shape, each individual must learn to recognize the subtle changes in the timbre of sounds that originate in locations in front of the head, behind it, above it, or below it. The neural circuits that accomplish this task are not genetically programmed—they must be acquired as a result of experience. Figure 14 shows the effects of elevation on the intensity of sounds of various frequencies overtone The frequency of complex received at an ear (Oertel and Young, 2004). The experimenters placed a small microphone tones that occurs at multiples of the in a cat’s ear and recorded the sound produced by an auditory stimulus presented at various fundamental frequency. elevations relative to the cat’s head. They used a computer to plot the ear’s transfer functions— phase difference The difference in a graph that compares the intensity of various frequencies of sound received by the ear to the arrival times of sound waves at each of intensity of these frequencies received by a microphone in open air. What is important in the eardrums.

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Right eardrum pushed in

Left eardrum pulled out

(a)

Both eardrums pushed in

(b)

F I G U R E 13 Sound Localization. This method localizes the source of low-frequency and medium-frequency sounds through phase differences. (a) Source of a 1000-Hz tone to the right. The pressure waves on each eardrum are out of phase; one eardrum is pushed in while the other is pushed out. (b) Source of a sound directly in front. The vibrations of the eardrums are synchronized (in phase).

Elevation

Figure 14 is not the shape of the transfer functions, but the fact that these functions varied with the elevation of the source of the sound. The transfer function for a sound directly in front of the cat (0° of elevation) is shown in green. This curve is shown at the 60°, 30°, and –30° positions as well, so that they can be compared with the curves obtained with the sound source at these locations, too (red, orange, and blue, respectively). That sounds complicated, I know, but if you look at the figure, you will clearly see that the timbre of sounds that reaches the cat’s ear changed along with the elevation of the source of the sound. (See Figure 14.)

60°

30°

0°

Perception of Complex Sounds

–30° Gain (dB)

30 0

–30

Frequency (kHz) F I G U R E 14 Changes in Timbre of Sounds with Changes in Elevation. The graphs are transfer functions, which compare the intensity of various frequencies of sound received by the ear to the intensity of these frequencies received by a microphone in open air. For ease of comparison, the O° transfer function (green) is superimposed on the transfer functions obtained at 60° (red), 30° (orange), and –30° (blue). The differences in the transfer functions at various elevations provide cues that aid in the perception of the location of a sound source. Based on Oertel, D., and Young, E. D. Trends in Neuroscience, 2004, 27, 104–110.

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Hearing has three primary functions: to detect sounds, to determine the location of their sources, and to recognize the identity of these sources—and thus their meaning and relevance to us (Heffner and Heffner, 1990; Yost, 1991). Let us consider the third function: recognizing the identity of a sound source. Unless you are in a completely silent location, pay attention to what you can hear. Right now, I am sitting in an office and can hear the sound of a fan in a computer, the tapping of the keys as I write this, the footsteps of someone passing outside the door, and the voices of some people talking in the hallway. How can I recognize these sources? The axons in my cochlear nerve contain a constantly changing pattern of activity corresponding to the constantly changing mixtures of frequencies that strike my eardrums. Somehow, the auditory system of my brain recognizes particular patterns that belong to particular sources, and I perceive each of them as an independent entity. PERCEPTION OF ENVIRONMENTAL SOUNDS AND THEIR LOCATION The task of the auditory system in identifying sound sources, then, is one of pattern recognition. The auditory system must recognize that particular patterns of constantly changing activity belong to different sound

Audition, the Body Senses, and the Chemical Senses

sources. And few patterns are simple mixtures of fixed frequencies. Left hemisphere Right hemisphere Consider the complexity of sounds that occur in the environment: cars SPL SFG honking, birds chirping, people coughing, doors slamming, and so on. MFG IPL As I mentioned earlier in this chapter, the auditory cortex is organized into two streams: an anterior stream, involved in the perception of complex sounds (the “what” system), and a posterior stream, involved in the perception of location (the “where” system). A review of thirty-eight functional imaging studies with human subjects (Arnott et al., 2004) reported a consistent result: perception of the identity of IFG STG IFG sounds activated the ventral stream of the auditory cortex and percepWhat Where tion of the location of sounds activated the dorsal stream. An fMRI study by Alain, He, and Grady (2008) supports this conclusion. The investigators presented people with sounds of animals, humans, and F I G U R E 15 “Where” Versus “What”. This figure shows regional musical instruments (for example, the bark of a dog, a cough, and brain activity in response to judgments of category (red) and location (blue) of sounds. IFG = inferior frontal gyrus, IPL = inferior parietal lobule, the sound of a flute) in one of three locations: 90° to the left, straight ahead, or 90° to the right. On some blocks of trials the subjects were MFG = middle frontal gyrus, SFG = superior frontal gyrus, SPL = superior parietal lobule. asked to press a button when they heard two sounds of any kind from From Alain, C., He, Y., and Grady, C. Journal of Cognitive Neuroscience, 2008, 20, the same location. On other blocks of trials they were asked to indicate when they heard the same kind of sound twice in a row, regardless of 285–295. Reprinted with permission. its location. As Figure 15 shows, judgments of location (blue) activated dorsal regions (“where”), and judgments of the nature of a sound (red) activated ventral regions (“what”). (See Figure 15.) The superior auditory abilities of blind people has long been recognized: Loss of vision appears to increase the sensitivity of the auditory system. A functional imaging study by Klinge et al. (2010) found that input to the auditory cortex was identical in blind and sighted people, but that neural connections between the auditory cortex and the visual cortex were stronger in blind people. In addition, the visual cortex showed enhanced responsiveness to auditory stimuli. These findings suggest that the analysis of auditory stimuli can be extended to the visual cortex in blind people. PERCEPTION OF MUSIC Perception of music is a special form of auditory perception. Music consists of sounds of various pitches and timbres played in a particular sequence with an underlying rhythm. Particular combinations of musical notes played simultaneously are perceived as consonant or dissonant, pleasant or unpleasant. The intervals between notes of musical scales follow specific rules, which may vary in the music of different cultures. In Western music, melodies played using notes that follow one set of rules (the major mode) usually sound happy, while those played following another set of rules (the minor mode) generally sound sad. In addition, a melody is recognized by the relative intervals between its notes, not by their absolute value. A melody is perceived as unchanging even when it is played in different keys—that is, when the pitches of all the notes are raised or lowered without changing the relative intervals between them. Thus, musical perception requires recognition of sequences of notes, their adherence to rules that govern permissible pitches, harmonic combinations of notes, and rhythmical structure. Because the duration of musical pieces is several seconds to many minutes, musical perception involves a substantial memory capacity. Thus, the neural mechanisms required for musical perception must obviously be complex. Different regions of the brain are involved in different aspects of musical perception (Peretz and Zatorre, 2005). For example, the inferior frontal cortex appears to be involved in recognition of harmony, the right auditory cortex appears to be involved in the perception of the underlying beat in music, and the left auditory cortex appears to be involved in the perception of rhythmic patterns that are superimposed on the rhythmic beat. (Think of a drummer indicating the regular, underlying beat by operating the foot pedal of the bass drum and superimposing a more complex pattern of beats on smaller drums with the drumsticks.) In addition, the cerebellum and basal ganglia are involved in timing of musical rhythms, as they are in the timing of movements.

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Everyone learns a language, but only some people become musicians. Musical training obviously makes changes in the brain—changes in motor systems involved in singing or playing an instrument, and changes in the auditory system involved in recognizing subtle complexities of harmony, rhythm, and other characteristics of musical structure. Here, I will consider aspects of musical expertise related to audition. Some of the effects of musical training can be seen in changes in the structure or activity of portions of the brain’s auditory system. For example, a study by Schneider et al. (2002) found that the volume of the primary auditory cortex of musicians was 130 percent larger than that of nonmusicians, and the neural response in this area to musical tones was 102 percent greater in musicians. Moreover, both of these measures were positively related to a person’s musical aptitude. Evidence suggests that neural circuits used to process music are already present in newborn infants. A functional imaging study by Perani et al. (2010) found that 1- to 3-day-old infants showed changes in brain activity (primarily in the right hemisphere) when music they were hearing changed key. Brain activity also altered when babies heard dissonant music, which adults find unpleasant.

Patient I. R., a right-handed woman in her early forties, sustained bilateral damage during surgical treatment of an abnormal blood vessel in her brain. Ten years after her surgery, Peretz and her colleagues studied the effects of the brain damage on her musical ability (Peretz, Gagnon, and Bouchard, 1998). Although Patient I. R. had normal hearing, could understand speech and converse normally, and could recognize environmental sounds, she showed a nearly complete amusia—loss of the ability to perceive or produce melodic or rhythmic aspects of music. She had been raised in a musical environment—both her grandmother and brother were professional musicians. After her surgery, she lost the ability to recognize melodies that she had been familiar with previously, including simple pieces such as “Happy Birthday.” She was no longer able to sing. Remarkably, despite her inability to recognize melodic and rhythmic aspects of music, she insisted that she still enjoyed listening to music. Peretz and her colleagues discovered that I. R. was still able to recognize emotional aspects of music. Although she could not recognize pieces that the experimenters played for her, she recognized whether the music sounded happy or sad. She could also recognize happiness, sadness, fear, anger, surprise, and disgust in a person’s tone of voice. I. R.’s ability to recognize emotion in music contrasts with her inability to recognize dissonance in music—a quality that normal listeners find intensely unpleasant. Peretz and her colleagues (2001) discovered that I. R. was totally insensitive to changes in music that irritate normal listeners. Even 4-month-old babies prefer consonant music to dissonant music, which shows that recognition of dissonance develops very early in life (Zentner and Kagan, 1998). I find it fascinating that I. R. could not distinguish between the dissonant and consonant versions but could still identify happy and sad music.

Approximately 4 percent of the population exhibits congenital amusia—a severe and persistent deficit in musical ability (but not in the perception of speech or environmental sounds) that becomes apparent early in life. People with amusia cannot recognize or even tell the difference between tunes, and they even try to avoid social situations that involve music. As one woman reported,

amusia (a mew zia) Loss or impairment of musical abilities, produced by hereditary factors or brain damage.

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“When the music finished the sound was always gone—as though it had never happened. And this bewildered me with a sense of failure, of failure to hold on to what I had just heard. Others told me that if I tried to remember I would. But I never did. I have no idea what people mean when they say: “I have a tune going round in my head.” I have never had a tune tell out its music in my head let alone repeat itself!” (Stewart, 2008, p. 128)

Audition, the Body Senses, and the Chemical Senses

SECTION SUMMARY Audition The receptive organ for audition is the organ of Corti, located on the basilar membrane. When sound strikes the tympanic membrane, it sets the ossicles into motion, and the baseplate of the stapes pushes against the membrane behind the oval window. Pressure changes thus applied to the fluid within the cochlea cause a portion of the basilar membrane to flex, causing the basilar membrane to move laterally with respect to the tectorial membrane that overhangs it. These events cause movements in the fluid within the cochlea, which, in turn, cause the cilia of the inner hair cells to wave back and forth. These mechanical forces open cation channels in the tips of the hair cells and thus produce receptor potentials. The inner hair cells send auditory information to the brain via the cochlear branch of the eighth cranial nerve. The central auditory system involves several brain stem nuclei, including the cochlear nuclei, superior olivary complex, and inferior colliculi. The medial geniculate nucleus relays auditory information to the primary auditory cortex on the medial surface of the temporal lobe. The primary auditory cortex is surrounded by two levels of auditory association cortex: the belt region and the parabelt region. The visual association cortex is divided into two streams, one analyzing color and form, and the other analyzing location and movement. Similarly, the auditory association cortex is organized into streams that analyze the nature of sounds (“what”) and the location of their sources (“where”). Pitch is encoded by two means. High-frequency sounds cause the base of the basilar membrane (near the oval window) to flex; lowfrequency sounds cause the apex (opposite end) to flex. Because high and low frequencies thus stimulate different groups of auditory hair cells, frequency is encoded anatomically. Cochlear implants use the principle of place coding to restore hearing in deaf people. The lowest frequencies cause the apex of the basilar membrane to flex back and forth in time with the acoustic vibrations. Movement of the basilar membrane pulls directly on the cilia of the outer hair cells and changes their membrane potential. This change causes contractions or relaxations of contractile proteins within the cell, which amplify movements of the basilar membrane and enhance the responses of the inner hair cells. The auditory system can discriminate between sounds with different timbres by detecting the individual overtones that constitute the sounds and producing unique patterns of neural firing in the auditory system. Left–right localization is performed by analyzing binaural differences in arrival time, in phase relations, and in intensity. The left–right

location of the sources of brief sounds (such as clicks) and sounds of frequencies below approximately 3000 Hz is detected by neurons in the superior olivary complex, which respond most vigorously when one ear receives the click first or when the phase of a sine wave received by one ear leads that received by the other. The left–right location of the sources of high-frequency sounds is detected by another group of neurons in the superior olivary complex, which respond most vigorously when one organ of Corti is stimulated more intensely than the other. Localization of the elevation of the sources of sounds can be accomplished by turning the head or by the perception of subtle differences in the timbre of sounds coming from different directions. The folds and ridges in the external ear (pinna) reflect different frequencies into the ear canal, changing the timbre of the sound according to the location of its source. To recognize the source of sounds, the auditory system must recognize the constantly changing patterns of activity received from the axons in the cochlear nerve. Electrophysiological, behavioral, and functionalimaging studies indicate that the anterior “what” stream is involved in the analysis of the sound, and the posterior “where” stream is involved in the perception of its location. Localized lesions of the auditory association cortex can impair people’s ability to recognize the nature and location of environmental sounds. Perception of music requires recognition of sequences of notes, their adherence to rules governing permissible pitches, harmonic combinations of notes, and rhythmical structure. Perception of pitch activates regions of the superior temporal gyrus rostral and lateral to the primary auditory cortex. Other regions of the brain—especially in the right hemisphere—are involved in the perception of the underlying beat of music and the specific rhythmic patterns of a particular piece. Musical training appears to increase the size and responsiveness of the primary auditory cortex. A case study indicates that recognition of emotion in music involves some brain mechanisms independent of those that recognize dissonance.

Thought Question A naturalist once noted that when a male bird stakes out his territory, he sings with a very sharp, staccato song that says, in effect, “Here I am, and stay away!” In contrast, if a predator appears in the vicinity, many birds will emit alarm calls that consist of steady whistles that start and end slowly. Knowing what you do about the two means of localizing sounds, why do these two types of calls have different characteristics?

Vestibular System The vestibular system has two components: the vestibular sacs and the semicircular canals. They represent the second and third components of the labyrinths of the inner ear. (We just studied the first component, the cochlea.) The vestibular sacs respond to the force of gravity and inform the brain about the head’s orientation. The semicircular canals respond to angular

vestibular sac One of a set of two receptor organs in each inner ear that detect changes in the tilt of the head. semicircular canal One of the three ringlike structures of the vestibular apparatus that detect changes in head rotation.

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acceleration—changes in the rotation of the head—but not to steady rotation. They also respond (but rather weakly) to changes in position or to linear acceleration. The functions of the vestibular system include balance, maintenance of the head in an upright position, and adjustment of eye movement to compensate for head movements. Vestibular stimulation does not produce any readily definable sensation; certain low-frequency stimulation of the vestibular sacs can produce nausea, and stimulation of the semicircular canals can produce dizziness and rhythmic eye movements (nystagmus). However, we are not directly aware of the information received from these organs. This section describes the vestibular system: the vestibular apparatus, the receptor cells, and the vestibular pathway in the brain.

Anatomy of the Vestibular Apparatus

The vestibular system, in cooperation with the visual system, helps us keep track of our body’s movement and orientation.

Figure 16 shows the labyrinths of the inner ear, which include the cochlea, the semicircular canals, and the two vestibular sacs: the utricle (“little pouch”) and the saccule (“little sack”). (See Figure 16.) The semicircular canals approximate the three major planes of the head: sagittal, transverse, and horizontal. Receptors in each canal respond maximally to sudden turning movements of the head in one particular plane. The semicircular canal consists of a membranous canal floating within a bony one; the membranous canal contains a fluid called

Photo by VAST/vastaction.com.

Semicircular canals

Vestibular sacs (utricle and saccule)

Semicircular canals

Vestibular nerve

Cochlea

Section of ampulla

Cupula

Filled with endolymph Hair cells

utricle (you trih kul) One of the vestibular sacs. saccule (sak yule) One of the vestibular sacs.

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Axons of ampullary nerve FIGURE

The Receptive Organ of the Semicircular Canals.

Audition, the Body Senses, and the Chemical Senses

Hair cell Vestibular nerve

Semicircular canals

Efferent axon

Filamentous base Afferent axon Otoconia

Utricle Saccule

Supporting cell Otolithic membrane FIGURE

Cilia

The Receptive Tissue of the Vestibular Sacs: The Utricle and the Saccule.

endolymph. An enlargement called the ampulla contains the organ in which the sensory receptors reside. The sensory receptors are hair cells similar to those found in the cochlea. Their cilia are embedded in a gelatinous mass called the cupula, which blocks part of the ampulla. Rotation of the head causes the fluid in the semicircular canals to rotate in the opposite direction which pushes against the cupula, triggering receptor potentials in the hair cells located there. (See Figure 16.) The vestibular sacs (the utricle and saccule) work very differently. These organs are roughly circular, and each contains a patch of receptive tissue. The receptive tissue is located on the “floor” of the utricle and on the “wall” of the saccule when the head is in an upright position. The receptive tissue, like that of the semicircular canals and cochlea, contains hair cells. The cilia of these receptors are embedded in an overlying gelatinous mass, which contains something rather unusual: otoconia, which are small crystals of calcium carbonate. (See Figure 17.) The weight of the crystals causes the gelatinous mass to shift in position as the orientation of the head changes. Thus, movement produces a shearing force on the cilia of the receptive hair cells.

The Vestibular Pathway The vestibular and cochlear nerves constitute the two branches of the eighth cranial nerve (auditory nerve). The bipolar cell bodies that give rise to the afferent axons of the vestibular nerve (abranch of the eighth cranial nerve) are located in the vestibular ganglion, which appears as a nodule on the vestibular nerve. Most of the axons of the vestibular nerve synapse within the vestibular nuclei in the medulla, but some axons travel directly to the cerebellum. Neurons of the vestibular nuclei send their axons to the cerebellum, spinal cord, medulla, and pons. There also appear to be vestibular projections to the temporal cortex, but the precise pathways have not been determined. Most investigators believe that the cortical projections are responsible for feelings of dizziness; the activity of projections to the lower brain stem can produce the nausea and vomiting that accompany motion sickness. Projections to brain stem nuclei controlling neck muscles are clearly involved in maintaining an upright position of the head and in producing eye movements to compensate for sudden head movements. Without this compensatory mechanism, our vision of the world would become a blur whenever we walked or ran.

ampulla (am pull uh) An enlargement in a semicircular canal; contains the cupula and the crista. cupula (kew pew luh) A gelatinous mass found in the ampulla of the semicircular canals; moves in response to the flow of the fluid in the canals. vestibular ganglion A nodule on the vestibular nerve that contains the cell bodies of the bipolar neurons that convey vestibular information to the brain.

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SECTION SUMMARY Vestibular System The semicircular canals are filled with fluid. When the head begins rotating or comes to rest after rotation, inertia causes the fluid to push the cupula to one side or the other. This movement exerts a shearing force on the cupula, the organ containing the vestibular hair cells. The vestibular sacs contain a patch of receptive tissue that contains hair cells whose cilia are embedded in a gelatinous mass. The weight of the otoconia in the gelatinous mass shifts when the head tilts, causing a shearing force on some of the cilia of the hair cells. Each hair cell contains one long cilium and several shorter ones. These cells form synapses with dendrites of bipolar neurons whose axons travel through the vestibular nerve. The receptors also receive efferent terminal buttons from neurons located in the cerebellum and medulla, but

the function of these connections is not known. Vestibular information is received by the vestibular nuclei in the medulla, which relay it on to the cerebellum, spinal cord, medulla, pons, and temporal cortex. These pathways are responsible for control of posture, head movements, and eye movements and the puzzling phenomenon of motion sickness.

Thought Question Why can slow, repetitive vestibular stimulation cause nausea and vomiting? Obviously, there are connections between the vestibular system and the area postrema, which controls vomiting. Can you think of any useful functions that might be served by these connections?

Somatosenses The somatosenses provide information about what is happening on the surface of our body and inside it. The cutaneous senses (skin senses) include several submodalities commonly referred to as touch. Proprioception and kinesthesia provide information about body position and movement. I will describe the contributions of sensory receptors in the skin to these perceptual systems in this section. The organic senses arise from receptors in and around the internal organs. Because the cutaneous senses are the most studied of the somatosenses, both perceptually and physiologically, I will devote most of my discussion to them.

The Stimuli

After wearing a wristwatch for several minutes, a person wearing a watch can no longer feel it unless it moves on the wrist. Stock4B/Getty Images.

cutaneous sense (kew tane ee us) One of the somatosenses; includes sensitivity to stimuli that involve the skin. proprioception Perception of the body’s position and posture.

The cutaneous senses respond to several different types of stimuli: pressure, vibration, heating, cooling, and events that cause tissue damage (and hence pain). Feelings of pressure are caused by mechanical deformation of the skin. Vibration is produced in the laboratory or clinic by tuning forks or mechanical devices, but it more commonly occurs when we move our fingers across a rough surface. Thus, we use vibration sensitivity to judge an object’s roughness. Obviously, sensations of warmth and coolness are produced by objects that raise or lower skin temperature from normal. Sensations of pain can be caused by many different types of stimuli, but it appears that most cause at least some tissue damage. One source of kinesthesia is the stretch receptors found in skeletal muscles that report changes in muscle length to the central nervous system. Receptors within joints between adjacent bones respond to the magnitude and direction of limb movement. However, the most important source of kinesthetic feedback appears to come from receptors that respond to changes in the stretching of the skin during movements of the joints or of the muscles themselves, such as those in the face (Johansson and Flanagan, 2009). Muscle length detectors, located within the muscles, do not give rise to conscious sensations; instead, their information is used to help control movement.

kinesthesia Perception of the body’s own movements. organic sense A sense modality that arises from receptors located within the inner organs of the body. glabrous skin (glab russ) Skin that does not contain hair; found on the palms of the hands and the soles of the feet.

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Anatomy of the Skin and Its Receptive Organs The skin is a complex and vital organ of the body—one that we tend to take for granted. We cannot survive without it; extensive skin burns are fatal. Our cells, which must be bathed by a warm fluid, are protected from the hostile environment by the skin’s outer layers. The skin participates in thermoregulation by producing sweat, thus cooling the body, or by restricting its

Audition, the Body Senses, and the Chemical Senses

Glabrous Skin

Hairy Skin Hair Ruffini corpuscles

Merkel's disks

Free nerve endings

Epidermis

Sweat gland

Dermis

circulation of blood, thus conserving heat. Its appearance varies widely across the body, from mucous membrane to hairy skin to the smooth, hairless skin of the palms and the soles of the feet, which is known as glabrous skin. (The word derives from the Latin glaber, “smooth, bald.”) Skin consists of subcutaneous tissue, dermis, and epidermis and contains various receptors scattered throughout these layers. Glabrous skin contains a dense, complex mixture of receptors, which reflects the fact that we use the palms of our hands and the inside surfaces of our fingers to actively explore the environment: We use our hands and fingers to hold and touch objects. In contrast, the rest of our body most often contacts the environment passively; that is, other things come into contact with it. Figure 18 shows the appearance of free nerve endings and the four types of encapsulated receptors (Merkel’s disks, Ruffini corpuscles, Meissner’s corpuscles, and Pacinian corpuscles). The locations and functions of these receptors are listed in Table 1. (See Figure 18 and Table 1.)

Perception of Cutaneous Stimulation The three most important qualities of cutaneous stimulation are touch, temperature, and pain. These qualities are described in the sections that follow.

Artery Vein FIGURE

Pacinian corpuscle

Meissner's corpuscle

Cutaneous Receptors.

TOUCH Sensitivity to pressure and vibration is caused by movement of the skin, which moves the dendrites of mechanoreceptors. Most investigators believe that the encapsulated nerve endings serve only to modify the physical stimulus transduced by the dendrites that reside within them. But what is the mechanism of transduction? How does movement of the dendrites of mechanoreceptors produce changes in membrane potentials? It appears that the movement causes ion channels to open, and the flow of ions into or out of the dendrite causes a change in the membrane potential. Most information about tactile sensation is precisely localized—that is, we can perceive the location on our skin where we are being touched. However, a study by Olausson et al. (2002) discovered a new category of tactile sensation that is transmitted by small-diameter unmyelinated axons.

TABLE

Subcutaneous fat

Merkel’s disk The touch-sensitive end organs found at the base of the epidermis, adjacent to sweat ducts. Ruffini corpuscle A vibration-sensitive organ located in hairy skin. Meissner’s corpuscle The touchsensitive end organs located in the papillae, small elevations of the dermis that project up into the epidermis. Pacinian corpuscle (pa chin ee un) A specialized, encapsulated somatosensory nerve ending that detects mechanical stimuli, especially vibrations.

1 Categories of Cutaneous Receptors

Speed of Adaptation

Size and Nature of Receptive Field

Identity of Receptor

Location of Receptor

Slow (SA I)

Small, sharp borders

Merkel’s disk

Hairy and glabrous skin Detection of form and roughness, especially by fingertips

Slow (SA II)

Large, diffuse borders Ruffini corpuscles

Rapid (RA I)

Small, sharp borders

Rapid (RA II)

Large, diffuse borders Pacinian corpuscles

Function of Receptor

Hairy and glabrous skin Detection of static force against skin, skin stretching, proprioception

Meissner’s corpuscles Glabrous skin

Detection of edge contours, Braille-like stimuli, especially by fingertips

Hairy and glabrous skin Detection of vibration, information from end of elongated object being held, such as tool

Hair follicle ending

Base of hair follicle

Free nerve ending

Hairy and glabrous skin Detection of thermal stimuli (coolness or warmth), noxious stimuli (pain), tickle

Detection of movement of hair

Free nerve ending

Hairy skin

Detection of pleasurable touch from gentle stroking with soft object

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At age 31, patient G. L., a 54-year-old woman, “suffered a permanent and specific loss of large myelinated afferents after episodes of acute polyradiculitis and polyneuropathy that affected her whole body below the nose. A sural nerve biopsy indicated a complete loss of large-diameter myelinated fibers. . . . Before the present study, she denied having any touch sensibility below the nose, and she lost the ability to perceive tickle when she became ill. She states that her perceptions of temperature, pain and itch are intact” (Olausson et al., 2002, pp. 902–903). G. L. could indeed detect the stimuli that are normally attributed to small-diameter unmyelinated axons—temperature, pain, and itch—but she could not detect vibratory or normal tactile stimuli. But when the hairy skin on her forearm or the back of her hand was stroked with a soft brush, she reported a faint, pleasant sensation. However, she could not determine the direction of the stroking or its precise location. An fMRI analysis showed that this stimulation activated the insular cortex, a region that is known to be associated with emotional responses and sensations from internal organs. The somatosensory cortex was not activated. When regions of hairy skin of control subjects were stimulated this way, fMRI showed activation of the primary and secondary somatosensory cortex as well as the insular cortex because the stimulation activated both large and small axons. The glabrous skin on the palm of the hand is served only by large-diameter, myelinated axons. When this region was stroked with a brush, G. L. reported no sensation at all, presumably because of the absence of small, unmyelinated axons.

The investigators concluded that besides conveying information about noxious and thermal stimuli, small-diameter unmyelinated axons constitute a “system for limbic touch that may underlie emotional, hormonal and affiliative responses to caresslike, skin-to-skin contact between individuals” (Olausson et al., 2002, p. 900) And as we saw, patient G. L. could no longer perceive tickle. Tickling sensations, which were previously believed to be transmitted by these small axons, are apparently transmitted by the large, myelinated axons that were destroyed in patient G. L. Olausson and his colleagues (Löken et al., 2009) note that the sensory endings that detect pleasurable stroking are found only in hairy skin, and that stroking of glabrous skin does not provide these sensations. However, I can think of pleasurable tactile stimuli that can be experienced through the glabrous skin of the palms and fingers—for example, those provided by stroking a warm, furry animal or touching a baby or a lover. When our hairy skin contacts the skin of another person, it is more likely that that person is touching us. In contrast, when our glabrous skin contacts the skin of another person, it is more likely that we are touching him or her. Thus, we might expect receptors in hairy skin to provide pleasurable sensations when someone caresses us but expect receptors in glabrous skin to provide pleasurable sensations when we caress someone else. Studies of people who make especially precise use of their fingertips show changes in the regions of somatosensory cortex that receive information from this part of the body. For example, violinists must make very precise movements of the four fingers of their left hand, which are used to play notes by pressing the strings against the fingerboard. Tactile and proprioceptive feedback are very important in accurately moving and positioning these fingers so that sounds of the proper pitch are produced. In contrast, placement of the thumb, which slides along the bottom of the neck of the violin, is less critical. In a study of violin players, Elbert et al. (1995) found that the portions of their right somatosensory cortex that receive information from the four fingers of their left hand were enlarged relative to the corresponding parts of the left somatosensory cortex. The amount of somatosensory cortex that receives information from the thumb was not enlarged. TEMPERATURE There are two categories of thermal receptors: those that respond to warmth and those that respond to coolness. Cold sensors in the skin are located just beneath the epidermis, and warmth sensors are located more deeply in the skin. Information from cold sensors is conveyed to the CNS by thinly myelinated Aδ fibers, and information from warmth sensors is conveyed by unmyelinated C fibers. We can detect thermal stimuli over a very wide range of temperatures, from less than 8° C (noxious cold) to over 52° C (noxious heat). Investigators have long believed that no single receptor could detect such a range of temperatures, and recent research indicates that this belief was correct. At present, we know of six mammalian thermoreceptors—all members of the

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TABLE

2 Categories of Mammalian Thermal Receptors

Name of Receptor

Type of Stimulus

Temperature Range

TRPV2

Noxious heat

Above 52° C

TRPV1, capsaicin

Heat

Above 43° C

TRPV3

Warmth

Above 31° C

TRPV4

Warmth

Above 25° C

TRPM8, menthol

Coolness

Below 28° C

TRPV2

TRPV1 TRPV3

50 Temperature (°C)

TRP family (Bandell, Macpherson, and Patapoutian, 2007; Romanovsky, 2007). (See Figure19 and Table 2.) Some of the thermal receptors respond to particular chemicals as well as to changes in temperature. For example, the M in TRPM8 stands for menthol, a compound found in the leaves of many members of the mint family. As you undoubtedly know, peppermint tastes cool in the mouth, and menthol is added to some cigarettes to make the smoke feel cooler (and perhaps to try to delude smokers into thinking that the smoke is less harsh and damaging to the lungs). Menthol provides a cooling sensation because it binds with and stimulates the TRPM8 receptor and produces neural activity that the brain interprets as coolness. As we will see in the next subsection, chemicals can produce the sensation of heat also.

TRPM2

40 30

TRPM4 + TRPM5

TRPV4

20 TRPMS

TRPA1

0 0

100

PAIN Activity of channel (percent) Pain reception, like thermoreception, is accomplished by the networks F I G U R E 19 Activity of TRP Channels. The activity of coldof free nerve endings in the skin. There appears to be at least three types activated (blue) and heat-activated (orange) temperature-sensitive TRP channels are shown as a function of temperature. of pain receptors (usually referred to as nociceptors, or “detectors of noxious stimuli”). High-threshold mechanoreceptors are free nerve endings Based on Romanovsky, A. A. American Journal of Physiology, 2007, 292, R37–R46. that respond to intense pressure, which might be caused by something striking, stretching, or pinching the skin. A second type of free nerve ending appears to respond to extremes of heat, to acids, and to the presence of capsaicin, the active ingredient in chile peppers. (Note that we say that chile peppers make food taste “hot.”) This type of fiber contains TRPV1 receptors (Kress and Zeilhofer, 1999). The V stands for vanilloid—a group of chemicals of which capsaicin is a member. Caterina et al. (2000) found that mice with a knockout of the gene for the TRPV1 receptor showed less sensitivity to painful high-temperature stimuli and would drink water to which capsaicin had been added. The mice responded normally to noxious mechanical stimuli. Presumably, the TRPV1 receptor is responsible for pain produced by burning of the skin and to changes in the acid/base balance within the skin. These receptors are responsible for the irritating effect of chemicals such as ammonia on the mucous membrane of the nose (Dhaka et al., 2009). TRPV1 also appear to play a role in regulation of body temperature. In addition, Ghilardi et al. (2005) found that a drug that blocks TRPV1 receptors reduced pain in patients with bone cancer, which is apparently caused by the production of acid by the tumors. Another type of nociceptive fiber contains TRPA1 receptors, which are sensitive to pungent irritants found in mustard oil, wintergreen oil, horseradish, and garlic, and to a variety of environmental irritants, including those found in vehicle exhaust and tear gas (Bautista et al., 2006; Nilius et al., 2007). The primary function of this receptor appears to be providing information about the presence of chemicals that produce inflammation. Pain can be extremely unpleasant, but it provides useful information that can help us avoid injury. Cox et al. (2006) studied three families from northern Pakistan whose members included several people with a complete absence of pain and discovered the location of the gene responsible for this disorder. The gene, an autosomal recessive allele located on chromosome 2, encodes for a voltage-dependent sodium channel, Nax1.7. The case that brought the families to their attention was a 10-year-old boy who performed a “street theater” during which he would thrust knives through his (continued )

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arms and walk on burning coals without feeling any pain. He died just before his fourteenth birthday after jumping off of the roof of a house. All six of the affected people in the three families had injuries to their lips or tongues caused by self-inflicted bites. They all suffered from bruises and cuts, and many sustained bone fractures that they did not notice until the injuries impaired their mobility. Despite their total lack of pain from any type of noxious stimulus, they had normal sensations of touch, warmth, coolness, proprioception, tickle, and pressure.

The Somatosensory Pathways

Primary somatosensory cortex

Somatosensory axons from the skin, muscles, or internal organs enter the central nervous system via spinal nerves. Those located in the face and head primarily enter through the trigeminal nerve (fifth cranial nerve). The cell bodies of the unipolar neurons are located in the dorsal root ganglia and cranial nerve ganglia. Axons that convey precisely localized information, such as fine touch, ascend through the dorsal columns in the white matter of the spinal cord to nuclei in the lower medulla. From there axons cross the brain and ascend through the medial lemniscus to the ventral posterior nuclei of the thalamus, the relay nuclei for somatosensation. Axons from the thalamus project to the primary somatosensory cortex, which in turn sends axons to the secondary somatosensory cortex. In contrast, axons that convey poorly localized information, such as pain or temperature, form synapses with other neurons as soon as they enter the spinal cord. The axons of these neurons cross to the other side of the spinal cord and ascend through the spinothalamic tract to the ventral posterior nuclei of the thalamus. (See Figure 20.) Damage to the visual association cortex can cause visual agnosia, and as we saw earlier in this chapter, damage to the auditory association cortex can cause auditory agnosia. Most likely you will not be surprised, then, to learn that damage to the somatosensory association cortex can cause tactile agnosia. Ventral posterior nucleus of thalamus Midbrain

Medial lemniscus Nuclei of the dorsal columns

Reed, Caselli, and Farah (1996) described patient E. C., a woman with left parietal lobe damage who was unable to recognize common objects by touch. For example, the patient identified a pine cone as a brush, a ribbon as a rubber band, and a snail shell as a bottle cap. The deficit was not due to a simple loss of tactile sensitivity; the patient was still sensitive to light touch and to warm and cold objects, and she could easily discriminate objects by their size, weight, and roughness.

Medulla

Dorsal columns (precise touch, kinesthesia) Spinothalamic tract (pain, temperature)

Spinal Cord

Dorsal root ganglion

F I G U R E 20 The Somatosensory Pathways. The figure shows the somatosensory pathways from the spinal cord to the somatosensory cortex. Note that precisely localized information (such as fine touch) and imprecisely localized information (such as pain and temperature) are transmitted by different pathways.

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Recognition of objects by touch requires cooperation between the somatosensory and motor systems. When we attempt to identify objects by touch alone, we explore them with moving fingers.

Valenza et al. (2001) reported the case of a patient with brain damage to the right hemisphere that produced a disorder they called tactile apraxia. (Apraxia refers to a difficulty in carrying out purposeful movements in the absence of paralysis or muscular weakness.) When the experimenters gave the patient objects to identify by touch with her left hand, the patient explored it with her fingers in a disorganized fashion. (Exploration and identification using her right hand were normal.) If the experimenters guided the patient’s fingers and explored the object the way people normally do, she was able to recognize the object’s shape. Thus, her deficit was caused by a movement disorder and not by damage to brain mechanisms involved in tactile perception.

Audition, the Body Senses, and the Chemical Senses

Perception of Pain

Unpleasantness (immediate emotional consequences)

Pain sensations (sensory component)

Pain is a curious phenomenon. It is more than a mere sensation; it can be defined only by some sort of withdrawal reaction or, in humans, by verPrimary bal report. Pain can be modified by opiates, by hypnosis, by the adminsomatosensory Anterior cortex cingulate istration of pharmacologically inert sugar pills, by emotions, and even by cortex Secondary other forms of stimulation, such as acupuncture. Recent research efforts somatosensory have made remarkable progress in discovering the physiological bases Insular cortex of these phenomena. cortex Prefrontal Pain appears to have three different perceptual and behavioral effects cortex (Price, 2000). First is the sensory component—the pure perception of the intensity of a painful stimulus. The second component is the immediate Dorsomedial thalamic nucleus Ventral posterior emotional consequences of pain—the unpleasantness or degree to which Long-term thalamic nucleus the individual is bothered by the painful stimulus. The third component emotional is the long-term emotional implications of chronic pain—the threat that implications such pain represents to one’s future comfort and well-being. Nociceptive These three components of pain appear to involve different brain information mechanisms. The purely sensory component of pain is mediated by a from spinal cord pathway from the spinal cord to the ventral posterolateral thalamus to the primary and secondary somatosensory cortex. The immediate emoF I G U R E 21 The Three Components of Pain. A simplified, tional component of pain appears to be mediated by pathways that reach schematic diagram shows the brain mechanisms involved in the three the anterior cingulate cortex (ACC) and insular cortex. The long-term components of pain: the sensory component, the immediate emotional emotional component appears to be mediated by pathways that reach component, and the long-term emotional component. the prefrontal cortex. (See Figure 21.) Based on Price, D. B. Science, 2000, 288, 1769–1772. Rainville et al. (1997) produced pain sensations in human subjects by having them put their arms in ice water. Under one condition the researchers used hypnosis to diminish the unpleasantness of the pain. The hypnosis worked; the subjects said that the pain was less unpleasant, even though it was still as intense. Meanwhile, theinvestigators used a PET scanner to measure regional activation of the brain. They found that the painful stimulus increased the activity of both the primary somatosensory cortex and the ACC. When the subjects were hypnotized and found the pain less unpleasant, the activity of the ACC decreased—but the activity of the primary somatosensory cortex remained high. Presumably, the primary somatosensory cortex is involved in the perception of pain, and the ACC is involved in its immediate emotional effects—its unpleasantness. (See Figure 22.) Several functional imaging studies have shown that under certain conditions, stimuli associated with pain can activate the ACC even when no actual painful stimulus is applied. In a test of romantically involved couples, Singer et al. (2004) found that when women received a painful electrical shock to the back of their hand, their ACC, anterior insular cortex, thalamus, and somatosensory cortex became active. When they saw their partners receive a painful shock but did not receive one themselves, the same regions (except for the somatosensory cortex) became active. Thus, the emotional component of pain—in this case, a vicarious experience of pain, provoked by empathy with the feelings of someone a person loved—caused responses in the brain similar to the ones caused by actual pain. Just as we saw in the study by Rainville et al. (1997), the somatosensory cortex is activated only by an actual noxious stimulus. The third component of pain—the emotional consequences of chronic pain—appears to involve the prefrontal cortex. Damage to the prefrontal cortex impairs people’s ability to make plans for the future and to recognize the personal significance of situations in which they are involved. Along with the general lack of insight, people with prefrontal damage tend not to be concerned with the implications of chronic conditions—including chronic pain—for their future. A particularly interesting form of pain sensation occurs after a limb has been amputated. After the limb is gone, up to 70 percent of amputees report that they feel as though the missing limb still existed and that it often hurts. This phenomenon is referred to as the phantom limb (Melzak, 1992). People with feelings of phantom limbs report that the limb feels very real, and they often say that if they try to reach out with it, it feels as though it were responding. Sometimes, they perceive it as sticking out, and they may feel compelled to avoid knocking it against the side of a doorframe or sleeping in a position phantom limb Sensations that appear that would make it come between them and the mattress. People have reported all sorts of sensations in to originate in a limb that has been phantom limbs, including pain, pressure, warmth, cold, wetness, itching, sweatiness, and prickliness. amputated.

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F I G U R E 22 Sensory and Emotional Components of Pain. The PET scans show regions of the brain that respond to sensory and emotional components of pain. Top: Dorsal views of the brain. Activation of the primary somatosensory cortex (circled in red) by a painful stimulus was not affected by a hypnotically suggested reduction in unpleasantness of a painful stimulus, indicating that this region responded to the sensory component of pain. Bottom: Midsagittal views of the brain. The anterior cingulate cortex (circled in red) showed much less activation when the unpleasantness of the painful stimulus was reduced by hypnotic suggestion. From Rainville, P., Duncan, G. H., Price, D. D., Carrier, Benoit, and Bushnell, M. C. Science, 1997, 277, 968–971. Copyright © 1997. Reprinted with permission.

SECTION SUMMARY Somatosenses Cutaneous sensory information is provided by specialized receptors in the skin. Glabrous skin is the hairless skin on the palms of the hands and soles of the feet. Cutaneous receptors in this skin are involved with touching and exploring items in the environment and manipulating objects. Merkel’s disks provide information about form and roughness, especially to the fingertips. Ruffini corpuscles provide information about static forces to the skin, and about stretching of the skin, which contributes to kinesthetic feedback. Meissner’s corpuscles provide information about edge contours and to Braille-like stimuli, especially to the fingertips. Pacinian corpuscles provide information about vibration, especially that detected through contact by the ends of elongated objects such as tools with other objects. Painful stimuli and changes in temperature are detected by free nerve endings. When the dendrites of mechanoreceptors bend, ion channels open, and the movement of ions through these channels produces a receptor potential. Although most tactile information is transmitted to the CNS via fast-conducting myelinated axons, gentle stroking produces a

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pleasant sensation mediated by small, unmyelinated axons. This information is received by the insular cortex, a region associated with emotional responses. Unless the skin is moving, tactile sensation provides little information about the nature of objects we touch. Movement and manipulation provide information about the shape, mass, texture, and other physical characteristics of objects we feel. Tactile experience, such as that gained by musicians, increases the portion of the somatosensory cortex devoted to the fingers involved in this experience. Temperature receptors adapt to the ambient temperature; moderate changes in skin temperature are soon perceived as neutral, and deviations above or below this temperature are perceived as warmth or coolness. Transduction of different ranges of temperatures is accomplished by six members of the TRP (transient receptor potential) family of receptors. One of the coolness receptors, TRPM8, also responds to menthol and is involved in responsiveness to environmental cold. There are at least three different types of pain receptors: high-threshold

Audition, the Body Senses, and the Chemical Senses

Section Summary (continued) mechanoreceptors; fibers with capsaicin receptors (TRPV1 receptors), which detect extremes of heat, acids, and the presence of capsaicin; and fibers with TRPA1 receptors, which are sensitive to chemical irritants and inflammation. Itch is an unpleasant sensation conveyed by two different types of unknown receptors. Pain and itch are mutually inhibitory. Precise, well-localized somatosensory information is conveyed by a pathway through the dorsal columns and their nuclei and the medial lemniscus, connecting the dorsal column nuclei with the ventral posterior nuclei of the thalamus. Information about pain and temperature ascends the spinal cord through the spinothalamic system. Damage to the somatosensory association cortex can disrupt the ability to recognize common objects by touch—a condition known as tactile agnosia. Tactile apraxia is a movement disorder that impairs the ability to explore objects with the fingers. A particular voltage-dependent sodium channel, Nax1.7, plays an essential role in pain sensation. Mutations of the gene for this protein produce total insensitivity to pain. Pain perception is not a simple function

of stimulation of pain receptors; it is a complex phenomenon with sensory and emotional components that can be modified by experience and the immediate environment. The sensory component is mediated by the primary and secondary somatosensory cortex, the immediate emotional component appears to be mediated by the anterior cingulate cortex and the insular cortex, and the long-term emotional component appears to be mediated by the prefrontal cortex. The phantom limb phenomenon, which often accompanies limb amputation, is characterized by a variety of sensory events, including pain.

Thought Questions Our fingertips and our lips are the most sensitive parts of our bodies; relatively large amounts of the primary somatosensory cortex are devoted to analyzing information from these parts of the body. It is easy to understand why fingertips are so sensitive: We use them to explore objects by touch. But why are our lips so sensitive? Does it have something to do with eating?

Gustation The stimuli that we have encountered so far produce receptor potentials by imparting physical energy: thermal, photic (involving light), or kinetic. However, the stimuli received by the last two senses to be studied—gustation and olfaction—interact with their receptors chemically. This section discusses the first of them: gustation.

The Stimuli Gustation is clearly related to eating; this sense modality helps us to determine the nature of things we put in our mouths. For a substance to be tasted, molecules of it must dissolve in the saliva and stimulate the taste receptors on the tongue. Tastes of different substances vary, but much less than we generally realize. There are only six qualities of taste: bitterness, sourness, sweetness, saltiness, umami, and fat. You are undoubtedly familiar with the first four qualities, and I will describe the fifth and sixth later. Flavor, as opposed to taste, is a composite of olfaction and gustation. Much of the flavor of food depends on its odor; anosmic people (who lack the sense of smell) or people whose nostrils are stopped up have difficulty distinguishing between different foods by taste alone. Most vertebrates possess gustatory systems that respond to all six taste qualities. (An exception is the cat family; lions, tigers, leopards, and house cats do not detect sweetness—but then, none of the food they normally eat is sweet.) Clearly, sweetness receptors are food detectors. Most sweet-tasting foods, such as fruits and some vegetables, are safe to eat (Ramirez, 1990). Saltiness receptors detect the presence of sodium chloride. In some environments inadequate amounts of this mineral are obtained from the usual source of food, so sodium chloride detectors help the animal to detect its presence. Injuries that cause bleeding deplete an organism of its supply of sodium rapidly, so the ability to find it quickly can be critical. Researchers now recognize the existence of a fifth taste quality: umami. Umami, a Japanese word that means “good taste,” refers to the taste of monosodium glutamate (MSG), a substance that is often used as a flavor enhancer in Asian cuisine (Kurihara, 1987; Scott and Plata-Salaman, 1991). The umami receptor detects the presence of glutamate, an amino acid found in proteins. Presumably, the umami receptor provides the ability to taste proteins, an important nutrient. Most species of animals will readily ingest substances that taste sweet or somewhat salty. Similarly, they are attracted to foods that are rich in amino acids, which explains the use of MSG as a flavor enhancer. However, they will tend to avoid substances that taste sour or bitter. Because of bacterial activity, many foods become acidic when they spoil. In addition, most unripe fruits

In the past, researchers believed that humans possessed four kinds of taste receptors that are sensitive to sweetness, sourness, bitterness, and saltiness. Now we know that the umami receptor, discovered by Japanese neuroscientists, can detect the savory taste of glutamate, which accounts for the flavor-enhancing effect of MSG. © Marianne Lannen/Alamy.

umami (oo mah mee) The taste sensation produced by glutamate; identifies the presence of amino acids in foods.

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are acidic. Acidity tastes sour and causes an avoidance reaction. (Of course, we have learned to make highly preferred mixtures of sweet and sour, such as lemonade.) Bitterness is almost universally avoided and cannot easily be improved by adding some sweetness. Many plants produce poisonous alkaloids, which protect them from being eaten by animals. Alkaloids taste bitter; thus, the bitterness receptor undoubtedly serves to warn animals away from these chemicals. For many years, researchers have known that many species of animals (including our own) show a distinct preference for high-fat foods. Because there is not a distinct taste that is associated with the presence of fat, most investigators concluded that we detected fat by its odor and texture (“mouth feel”). However, Fukuwatari et al. (2003) found that rats whose olfactory sense was destroyed continued to show a preference for a liquid diet containing a long-chain fatty acid, one of the breakdown products of fat. When fats reach the tongue, some of these molecules are broken down into fatty acids by an enzyme called lingual lipase, which is found in the vicinity of taste buds. The activity of lingual lipase ensures that fatty acid detectors are stimulated when food containing fat enters the mouth. Cartoni et al. (2010) identified two G protein-coupled receptors that appear to be responsible for detecting the presence of fatty acids in the mouth. The investigators found that mice with a targeted mutation against the genes responsible for the production of these receptors showed a decreased preference for fatty acids, and that responses of the taste nerves to fatty acids were also diminished.

Anatomy of the Taste Buds and Gustatory Cells The tongue, palate, pharynx, and larynx contain approximately 10,000 taste buds. Most of these receptive organs are arranged around papilTaste lae, small protuberances of the tongue. Taste buds consist of groups buds of twenty to fifty receptor cells, specialized neurons arranged someTaste what like the segments of an orange. Cilia are located at the end of receptors each cell and project through the opening of the taste bud (the pore) Afferent axons into the saliva that coats the tongue. Tight junctions between adjacent taste cells prevent substances in the saliva from diffusing freely into the taste bud itself. Figure 23 shows the appearance of a papilla; a (a) cross section through the trench that surrounds it contains a taste bud. (b) (See Figure 23.) F I G U R E 23 The Tongue. The figure shows (a) papillae on the Taste receptor cells form synapses with dendrites of bipolar neusurface of the tongue, and (b) taste buds. rons whose axons convey gustatory information to the brain through the seventh, ninth, and tenth cranial nerves. The receptor cells have a life span of only ten days. They quickly wear out, being directly exposed to a rather hostile environment. As they degenerate, they are replaced by newly developed cells; the dendrite of the bipolar neuron is passed on to the new cell (Beidler, 1970). Papilla Surface of tongue

Perception of Gustatory Information Transduction of taste is similar to the chemical transmission that takes place at synapses: The tasted molecule binds with the receptor and produces changes in membrane permeability that cause receptor potentials. Different substances bind with different types of receptors, producing different taste sensations. In this section I will describe what we know about the nature of the molecules with particular tastes and the receptors that detect their presence. To taste salty, a substance must ionize. Although the best stimulus for saltiness receptors is sodium chloride (NaCl), a variety of salts containing metallic cations (such as Na+, K+, and Li+) with a small anion (such as Cl–, Br–, SO42–, or NO3–) taste salty. The receptor for saltiness seems to be a simple sodium channel. When present in the saliva, sodium enters the taste cell and depolarizes it, triggering action potentials that cause the cell to release neurotransmitter (Avenet and Lindemann, 1989; Kinnamon and Cummings, 1992). Sourness receptors respond to the hydrogen ions present in acidic solutions. However, because the sourness of a particular acid is not simply a function of the concentration of hydrogen ions, the anions must have an effect as well. Bitter and sweet substances are difficult to characterize. The typical stimulus for bitterness is a plant alkaloid such as quinine; for sweetness it is a sugar such as glucose or fructose. The fact that some molecules elicit both sensations suggested to early researchers that bitterness and sweetness receptors may be similar. For example, the Seville orange rind

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contains a glycoside (complex sugar) that tastes extremely bitter; however, the addition of a hydrogen ion to the molecule makes it taste intensely sweet (Horowitz and Gentili, 1974). Some amino acids taste sweet. Indeed, the commercial sweetener aspartame consists of just two amino acids: aspartate and phenylalanine. Two different receptors are responsible for detection of sweet tastes. Bitterness is detected by members of a family of about thirty different receptors (Matsunami, Montmayeur, and Buck, 2000; Scott, 2004). The existence of so many different bitterness receptors suggests that although different bitter compounds share a common taste quality, they are detected by different means. As we saw, many compounds found in nature that taste bitter to us are poisonous. Rather than entrusting detection of these compounds to a single receptor, the process of evolution has given us the ability to detect a wide variety of compounds with different molecular shapes. I mentioned earlier that cats are insensitive to sweet tastes. Li et al. (2005) discovered the reason for the absence of sweet sensitivity: The DNA of members of the cat family (the investigators tested domestic cats, tigers, and cheetahs) lacks functional genes that produce a class of proteins that form an essential part of sweet receptors. The investigators concluded that this mutation was probably an important event in the evolution of cats’ carnivorous behavior. Margolskee et al. (2007) found that sweet receptors in the gut of mice detect the presence of sugar and artificial sweeteners and are involved in control of glucose absorption. Mice with a targeted mutation against the gene responsible for the production of this receptor were insensitive to the presence of sweet substances in the gut.

Ventral posteromedial nucleus of thalamus

Lateral hypothalamus

Primary gustatory cortex

Amygdala Chorda tympani (branch of VIIth nerve)

Nucleus of the solitary tract IXth nerve Caudal medulla

FIGURE

Xth nerve

Neural Pathways of the Gustatory System.

The Gustatory Pathway Gustatory information is transmitted through the seventh, ninth, and tenth cranial nerves. The first relay station for taste is the nucleus of the solitary tract, located in the medulla. In primates the taste-sensitive neurons of this nucleus send their axons to the ventral posteromedial thalamic nucleus, a nucleus that also receives somatosensory information from the trigeminal nerve (Beckstead, Morse, and Norgren, 1980). Thalamic taste-sensitive neurons send their axons to the primary gustatory cortex, which is located in the base of the frontal cortex and in the insular cortex (Pritchard et al., 1986). Neurons in this region project to the secondary gustatory cortex, located in the caudolateral orbitofrontal cortex (Rolls, Yaxley, and Sienkiewicz, 1990). Unlike most other sense modalities, taste is ipsilaterally represented in the brain—that is, the right side of the tongue projects to the right side of the brain, and the left projects to the left. (See Figure24.) In a functional imaging study, Schoenfeld et al. (2004) had people sip water that was flavored with sweet, sour, bitter, and umami tastes. The investigators found that tasting each flavor activated different regions in the primary gustatory area of the insular cortex. Although the locations of the taste-responsive regions differed from subject to subject, the same pattern was seen when a subject was tested on different occasions. Thus, the representation of tastes in the gustatory cortex is idiosyncratic but stable. (See Figure 25.) Besides receiving information from taste receptors, the gustatory cortex also receives thermal, mechanical, visceral, and nociceptive (painful) stimuli, which undoubtedly play a role in determining the palatability of food (Carlton, Accola, and Simon, 2010).

nucleus of the solitary tract A nucleus of the medulla that receives information from visceral organs and from the gustatory system.

Sour Bitter Salty Sweet

MSG (umami)

F I G U R E 25 Activation in the Primary Gustatory Cortex. Functional MRI images of six subjects show that the responsive regions varied between subjects but were stable for each subject. From Schoenfeld, M. A., Neuer, G., Tempelmann, C., Schüssler, K., Noesselt, T., Hopf, J.-M., and Heinze, H.-J. Neuroscience, 2004, 127, 347–353.

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SECTION SUMMARY Gustation Taste receptors detect only six sensory qualities: bitterness, sourness, sweetness, saltiness, umami, and fat. Bitter foods often contain plant alkaloids, many of which are poisonous. Sour foods have usually undergone bacterial fermentation, which can produce toxins. On the other hand, sweet foods (such as fruits) are usually nutritious and safe to eat, and salty foods contain an essential cation: sodium. The fact that people in affluent cultures today tend to ingest excessive amounts of sweet and salty foods suggests that these taste qualities are naturally reinforcing. Umami, the taste of glutamate, identifies proteins. Saltiness receptors appear to be simple sodium channels. Sourness receptors appear to detect the presence of hydrogen ions, but various anions also affect these receptors. The umami receptor detects the presence of glutamate. Two receptors are responsible for detection of sweet tastes, and thirty receptors detect bitterness. Two receptors detect molecules of fatty acids produced when an enzyme, lingual lipase, breaks down some molecules of fat in the mouth. Gustatory information is transmitted from the tongue through the seventh, ninth, and tenth cranial nerves to the nucleus of the solitary

tract (located in the medulla) and is relayed by the ventral posteromedial thalamus to the primary gustatory cortex in the basal frontal and insular areas. Different tastes activate different regions of the primary gustatory cortex. The caudolateral orbitofrontal cortex contains the secondary gustatory cortex. Gustatory information is also sent to the amygdala, hypothalamus, and basal forebrain.

Thought Questions Bees and birds can taste sweet substances, but cats and alligators cannot. Obviously, the ability to taste particular substances is related to the range of foods a species eats. If, through the process of evolution, a species develops a greater range of foods, what do you think comes first: the food or the receptor? Would a species start eating something new (say, something with a sweet taste) and later develop the appropriate taste receptors, or would the taste receptors evolve first and then lead the animal to a new taste?

Olfaction Olfaction, the second chemical sense, helps us to identify food and avoid food that has spoiled and is unfit to eat. It helps the members of many species to track prey or detect predators and to identify friends, foes, and receptive mates. For humans olfaction is the most enigmatic of all sensory modalities. Odors have a peculiar ability to evoke memories, often vague ones that seem to have occurred in the distant past—a phenomenon that Marcel Proust vividly described in his book Remembrance of Things Past. Although people can discriminate among many thousands of different odors, we lack a good vocabulary to describe them. It is relatively easy to describe sights we have seen or sounds we have heard, but the description of an odor is difficult. At best, we can say that it smells like something else. Thus, the olfactory system appears to be specialized for identifying things, not for analyzing particular qualities. For years I have told my students that one reason for the differF I G U R E 26 Scent-Tracking Behavior. The path followed by a dog ence in sensitivity between our olfactory system and those of other and a human during the scent tracking is shown in red. mammals is that other mammals put their noses where odors are the From Porter, J., Craven, B., Khan, R. M., Chang, S.-J., Kang, I., Judkewitz, B., Volpe, J., strongest—just above the ground. For example, a dog following an Settles, G., and Sobel, N. Nature Neuroscience, 2007, 10, 27–29. odor trail sniffs along the ground, where the odors of a passing animal may have clung. Even a bloodhound’s nose would not be very useful if it were located five or six feet above the ground, as ours is. I was gratified to learn that a scientific study established the fact that when people sniff the ground like dogs do, their olfactory system works much better. Porter et al. (2007) prepared a scent trail—a string moistened with essential oil of chocolate and laid down in a grassy field. The subjects were blindfolded and wore earmuffs, kneepads, and gloves, which prevented them from using anything other than their noses to follow the scent trail. They did quite well, and they adopted the same zigzag strategy used by dogs. (See Figure 26.) As the authors wrote, these findings “. . . suggest that the poor reputation of human olfaction may reflect, in part, behavioral demands rather than ultimate abilities” (Porter et al., 2007, p. 27).

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The Stimulus The stimulus for odor (known formally as odorants) consists of volatile substances that have a molecular weight in the range of approximately 15 to 300. Almost all odorous compounds are lipid soluble and of organic origin. However, many substances that meet these criteria have no odor at all, so we still have much to learn about the nature of odorants.

Anatomy of the Olfactory Apparatus Our six million olfactory receptor cells reside within two patches of mucous membrane (the olfactory epithelium), each having an area of about 1 square inch. The olfactory epithelium is located at the top of the nasal cavity. (See Figure 27.) Less than 10 percent of the air that enters the nostrils reaches the olfactory epithelium; a sniff is needed to sweep air upward into the nasal cavity so that it reaches the olfactory receptors. The inset in Figure 27 illustrates a group of olfactory receptor cells, along with their supporting cells. (See inset, Figure 27.) Olfactory receptor cells are bipolar neurons whose cell bodies lie within the olfactory mucosa that lines the cribriform plate, a bone at the base of the rostral part of the brain. There is a constant production of new olfactory receptor cells, but their life is considerably longer than those of gustatory receptor cells. Supporting cells contain enzymes that destroy odorant molecules and thus help to prevent them from damaging the olfactory receptor cells. Olfactory receptor cells send a process toward the surface of the mucosa, which divides into ten to twenty cilia that penetrate the layer of mucus. Odorous molecules must dissolve in the mucus and stimulate receptor molecules on the olfactory cilia. Approximately thirty-five bundles of axons, ensheathed by glial cells, enter the skull through small holes in the cribriform (“perforated”) plate. The olfactory mucosa also contains free nerve endings of trigeminal nerve axons; these nerve endings presumably mediate sensations of pain that can be produced by sniffing some irritating chemicals, such as ammonia.

olfactory epithelium The epithelial tissue of the nasal sinus that covers the cribriform plate; contains the cilia of the olfactory receptors.

To thalamus orbitofrontal cortex To hypothalamus

To amygdala

Piriform and entorhinal cortex (primary olfactory cortex)

Myelin sheath To olfactory bulb Axons Olfactory receptor cell

Olfactory bulb

Olfactory mucosa Turbinate bones

Tongue

Supporting cell

Cilia of olfactory receptor cells FIGURE

The Olfactory System.

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The olfactory bulbs lie at the base of the brain on the ends of the stalklike olfactory tracts. Each olfactory receptor cell sends a single axon into an olfactory bulb, where it forms synapses with dendrites of mitral cells (named for their resemblance to a bishop’s miter, a form of ceremonial headgear). These synapses take place in the complex axonal and dendritic arborizations called olfactory glomeruli (from glomus, “ball”). There are approximately 10,000 glomeruli, each of which receives input from a bundle of approximately 2000 axons. The axons of the mitral cells travel to the rest of the brain through the olfactory tracts. Some of these axons terminate in other regions of the ipsilateral forebrain; others cross the brain and terminate in the contralateral olfactory bulb. Olfactory tract axons project directly to the amygdala and to two regions of the limbic cortex: the piriform cortex (the primary olfactory cortex) and the entorhinal cortex. (See Figure 27.) The amygdala sends olfactory information to the hypothalamus, the entorhinal cortex sends it to the hippocampus, and the piriform cortex sends it to the hypothalamus and to the orbitofrontal cortex, via the dorsomedial nucleus of the thalamus (Buck, 1996; Shipley and Ennis, 1996). As you may recall, the orbitofrontal cortex also receives gustatory information; thus, it may be involved in the combining of taste and olfaction into flavor. The hypothalamus also receives a considerable amount of olfactory information, which is probably important for the acceptance or rejection of food and for the olfactory control of reproductive processes seen in many species of mammals. Most mammals have another organ that responds to chemicals in the environment: the vomeronasal organ.

Transduction of Olfactory Information For many years researchers have recognized that olfactory cilia contain receptors that are stimulated by molecules of odorants, but the nature of the receptors was unknown. Buck and Axel (1991), using molecular genetics techniques, discovered a family of genes that code for a family of olfactory receptor proteins (and in 2004 won a Nobel Prize for doing so). So far, olfactory receptor genes have been isolated in more than twelve species of vertebrates, including mammals, birds, and amphibians (Mombaerts, 1999). Humans have 339 different olfactory receptor genes, and mice have 913 (Godfrey, Malnic, and Buck, 2004; Malnic, Godfrey, and Buck, 2004). Molecules of odorant bind with olfactory receptors, and the G proteins coupled to these receptors open sodium channels and produce depolarizing receptor potentials.

Perception of Specific Odors

olfactory bulb The protrusion at the end of the olfactory tract; receives input from the olfactory receptors. mitral cell A neuron located in the olfactory bulb that receives information from olfactory receptors; axons of mitral cells bring information to the rest of the brain. olfactory glomerulus (glow mare you luss) A bundle of dendrites of mitral cells and the associated terminal buttons of the axons of olfactory receptors.

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Recognition of specific odors has been an enigma for many years. Humans can recognize up to ten thousand different odorants, and other animals can probably recognize even more of them (Shepherd, 1994). Even with 339 different olfactory receptors, that leaves many odors unaccounted for. And every year chemists synthesize new chemicals, many with odors unlike those that anyone has previously detected. How can we use a relatively small number of receptors to detect so many different odorants? Before I answer this question, we should look more closely at the relationship between receptors, olfactory neurons, and the glomeruli to which the axons of these neurons project. First, the cilia of each olfactory neuron contain only one type of receptor (Nef et al., 1992; Vassar, Ngai, and Axel, 1993). As we saw, each glomerulus receives information from many individual olfactory receptor cells. Ressler, Sullivan, and Buck (1994) discovered that although a given glomerulus receives information from many olfactory receptor cells, each of these cells contains the same type of receptor molecule. Thus, there are as many types of glomeruli as there are types of receptor molecules. Furthermore, the location of particular types of glomeruli (defined by the type of receptor that sends information to them) appears to be the same in each of the olfactory bulbs in a given animal and may even be the same from one animal to another. (See Figure 28.) Now let’s get back to the question I just posed: How can we use a relatively small number of receptors to detect so many different odorants? The answer is that a particular odorant binds to more than one receptor. Thus, because a given glomerulus receives information from only one type of receptor, different odorants produce different patterns of activity in different glomeruli. Recognizing a particular odor, then, is a matter of recognizing a particular pattern of activity in

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the glomeruli. The task of chemical recognition is transformed into a task Olfactory bulb of spatial recognition. Figure 29 illustrates this process (Malnic et al., 1999). The left side of the figure shows the shapes of eight hypothetical odorants. The right Axons of mitral cells side shows four hypothetical odorant receptor molecules. If a portion of Mitral cell the odorant molecule fits the binding site of the receptor molecule, it will activate it and stimulate the olfactory neuron. As you can see, each odorant Glomerulus molecule fits the binding site of at least one of the receptors and in most cases fits more than one of them. Notice also that the pattern of receptors activated by each of the eight odorants is different, which means that if we know which pattern of receptors is activated, we know which odorant Olfactory Cribriform is present. Of course, even though a particular odorant might bind with receptor plate several different types of receptor molecules, it might not bind equally well with each of them. For example, it might bind very well with one receptor molecule, moderately well with another, weakly with another, and so on. (See Figure 29.) As we just saw, the spatial pattern of “olfactotopic” information is maintained in the olfactory cortex. Presumably, the brain recognizes particular odors by recognizing different patterns of activation there. Cilia Evidence that supports this model was obtained by Johnson, Leon, and their colleagues (Johnson and Leon, 2007), who found that particuF I G U R E 28 Connections of Olfactory Receptor Cells with Glomeruli. Each glomerulus receives information from only one type lar categories of molecules, with particular types of structures, activated of receptor cell. Olfactory receptor cells of different colors contain particular regions of the olfactory bulb. However, this coding scheme different types of receptor molecules. changes at the level of the piriform cortex (the primary olfactory cortex). A functional-imaging study with humans by Howard et al. (2009) found that odorants normally associated with particular objects (in this case, odorants that people perceive as minty, woody, or citrusy) produced particular patterns of activity in the posterior piriform cortex, regardless of the chemical structure of the odorants. The investigators presented the subjects with three different minty odorants, three different woody odorants, and three different citrusy odorants. Each of the three odorants in each of these categories had very different Odorant Receptors chemical structures. Nevertheless, the patterns of molecules activity on the posterior piriform cortex were correlated with the perceived category of the odor, not its molecular structure. Figure 30 shows the molecular structure of the three minty odorants. As you can see, they show little resemblance to each other. (See Figure 30.) Although we can often identify individual components of mixtures of odors, some odors have the ability to mask others. (The existence of the deodorant and air-freshener industries depends on this fact.) Cooks in various cultures have long known that as long as it is not too strong, the unpleasant, rancid off-flavor of spoiled food can be masked by the spices fennel and clove. Takahashi, Nagayama, and Mori (2004) mapped the O

O OH

O OH Methyl salicylate

F I G U R E 29 Coding of Olfactory Information. A hypothetical explanation of coding of olfactory information shows that different odorant molecules attach to different combinations of receptor molecules. (Activated receptor molecules are shown in blue.) Unique patterns of activation represent particular odorants.

F I G U R E 30 Minty Smelling Molecules. The molecular structures of these molecules are different, but they have similar odors and smelling them produces similar patterns of activity on the posterior piriform cortex.

Based on Malnic, B., Hirono, J., Sato, T., and Buck, L. B. Cell, 1999, 96, 713–723.

Based on Howard, J. D., Plailly, J., Grueschow, M., et al. Nature Neuroscience, 2009, 12, 932–938.

H (–)-R-carvone

(–)-menthol

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regions of the olfactory bulb that responded to bad odorants (alkylamines and aliphatic aldehydes) and to the odors of fennel and clove. They found that responses to the bad odors were suppressed by the presence of the spice odors, indicating that the masking took place in the olfactory bulbs. Presumably, the glomeruli that responded to the spice odors inhibited those that responded to the rancid ones.

SECTION SUMMARY Olfaction The olfactory receptors consist of bipolar neurons located in the olfactory epithelium that lines the roof of the nasal sinuses, on the bone that underlies the frontal lobes. The receptors send processes toward the surface of the mucosa, which divide into cilia. The membranes of these cilia contain receptors that detect aromatic molecules dissolved in the air that sweeps past the olfactory mucosa. The axons of the olfactory receptors pass through the perforations of the cribriform plate into the olfactory bulbs, where they form synapses in the glomeruli with the dendrites of the mitral cells. These neurons send axons through the olfactory tracts to the brain, principally to the amygdala, the piriform cortex, and the entorhinal cortex. The hippocampus, hypothalamus, and orbitofrontal cortex receive olfactory information indirectly. Aromatic molecules produce membrane potentials by interacting with a newly discovered family of receptor molecules, which in humans contains 339 members. Each glomerulus receives information from only one type of olfactory receptor, and “olfactotopic” coding is maintained

EPILOGUE

Thought Questions As I mentioned in the preceding section, odors have a peculiar ability to evoke memories, a phenomenon that Marcel Proust vividly described in his book Remembrance of Things Past. Have you ever encountered an odor that you knew was somehow familiar, but you couldn’t say exactly why? Can you think of any explanations? Might this phenomenon have something to do with the fact that the sense of olfaction developed very early in our evolutionary history?

| Natural Analgesia

The brain contains neural circuitry through which certain types of stimuli can produce analgesia, primarily through the release of the endogenous opiates. What functions does this system perform? Most researchers believe that it prevents pain from disrupting behavior in situations in which pain is unavoidable and in which the damaging effects of the painful stimuli are less important than the goals of the behavior. For example, males fighting for access to females during mating season will fail to pass on their genes if pain elicits withdrawal responses that interfere with fighting. Indeed, these conditions (fighting or mating) do diminish pain. Komisaruk and Larsson (1971) found that genital stimulation produced analgesia. They gently probed the cervix of female rats with a glass rod and found that the procedure diminished the animals’ sensitivity to pain. It also increased the activity of neurons in the periaqueductal gray matter and decreased the pain response in the thalamus (Komisaruk and Steinman, 1987). The phenomenon also occurs in humans; Whipple and Komisaruk (1988) found that self-administered vaginal stimulation reduces women’s sensitivity to painful stimuli but not to neutral tactile stimuli. Presumably, copulation also triggers analgesic mechanisms. The adaptive significance of this phenomenon is clear: Painful stimuli

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all the way to the olfactory cortex. This means that the task of detecting different odors is a spatial one; the brain recognizes odors by means of the patterns of activity created in the olfactory cortex. The olfactory bulb encodes information according to the structure of the odorant molecules, and the posterior piriform cortex codes the information it receives from the anterior region according to the odorants’ perceptual categories—for example, minty, woody, and citrusy.

that are encountered during the course of copulation are less likely to cause the behavior to be interrupted; thus, the chances of pregnancy are increased. (As you will recall, passing on one’s genes is the ultimate criterion of the adaptive significance of a trait.) Pain can also be reduced, at least in some people, by administering a pharmacologically inert placebo. When some people take a medication that they believe will reduce pain, it triggers the release of endogenous opioids and actually does reduce pain sensations. This effect is eliminated if the people are given an injection of naloxone, a drug that blocks opiate receptors (Benedetti, Arduino, and Amanzio, 1999). Thus, for some people a placebo is not pharmacologically inert—it has a physiological effect. The experimenter in the chapter prologue used this drug when he blocked the analgesic effect of Melissa’s own endogenous opiates. The placebo effect may be mediated through connections of the frontal cortex with the periaqueductal gray matter—a region of the midbrain that modulates the transmission of pain information to the brain. A functional-imaging study by Zubieta et al. (2005) found that placebo-induced analgesia did indeed cause the release of endogenous opiates. They used a PET scanner to detect the presence of μ-opioid neurotransmission in the brains of people who responded to

Audition, the Body Senses, and the Chemical Senses

the effects of a placebo. As Figure 31 shows, several regions of the brain, including the anterior cingulate cortex and insular cortex, showed evidence of increased endogenous opioid activity. (See Figure 31.) The endogenous opiates were first discovered by scientists who were investigating the perception of pain; thus, many of the studies using these peptides have examined their role in mechanisms

of analgesia. However, their role in other functions may be even more important. The endogenous opiates may even be involved in learning, especially in mechanisms of reinforcement. This connection should not come as a surprise; as you know, many people have found injections of opiates such as morphine or heroin to be extremely pleasurable. μ -opioid activity High

DLPFC Insula

NAC Low ACC

Insula F I G U R E 31 Effects of a Placebo on μ-Opioid Neurotransmission. The figure shows scans of people who responded to a placebo with the release of endogenous opioids and analgesia. ACC = anterior cingulate cortex, DLPFC = dorsolateral prefrontal cortex, NAC = nucleus accumbens. From Zubieta, J.-K., Bueller, J. A., Jackson, L. R., Scott, D. J., et al. Journal of Neuroscience, 2005, 25, 7754–7762. Reprinted with permission.

KEY CONCEPTS AUDITION

1. The bones of the middle ear transmit sound vibrations from the eardrum to the cochlea, which contains auditory receptors in the hair cells. 2. The hair cells send information through the eighth cranial nerve to nuclei in the brain stem; it is then relayed to the medial geniculate nucleus and finally to the primary auditory cortex. 3. The ear is analytical; it detects individual frequencies by means of place coding and rate coding. Left–right localization is also accomplished by two means: arrival time (phase differences) and binaural differences in intensity. VESTIBULAR SYSTEM

4. The vestibular system helps us to maintain our balance and makes compensatory eye movements to help us maintain fixation when our head moves. The semicircular canals detect head rotations and the vestibular sacs detect changes in the tilt of the head.

6. Pain perception helps to protect us from harmful stimuli. The sensory component of pain involves the thalamus and the somatosensory cortex, the immediate emotional component of pain involves the anterior cingulate cortex and insular cortex, and the long-term emotional component involves the prefrontal cortex. GUSTATION

7. Taste receptors on the tongue respond to bitterness, sourness, sweetness, saltiness, and umami (the taste of glutamate, used to identify proteins). Together with olfactory information, gustation provides us with information about complex flavors. OLFACTION

8. The olfactory system detects the presence of aromatic molecules. A family of several hundred different receptors is involved in olfactory discrimination. Patterns of activation of these receptors lead to the perception of different odorants.

SOMATOSENSES

5. Cutaneous receptors in the skin provide information about touch, pressure, vibration, changes in temperature, and stimuli that cause tissue damage.

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EXPLORE the Virtual Brain in PERCEPTION This module includes the anatomical substrates of audition, olfaction, and gustation. Learn about how each of these systems functions, from the external stimulus (sound waves or chemicals) through the brain pathways involved in the perceptual experience.

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Peretz, I., and Zatorre, R. J. Brain organization for music processing. Annual Review of Psychology, 2005, 56, 89–114. Pickles, J. O., and Corey, D. P. Mechanoelectrical transduction by hair cells. Trends in Neuroscience, 1992, 15, 254–259. Pijl, S., and Schwarz, D. W. F. Intonation of musical intervals by musical intervals by deaf subjects stimulated with single bipolar cochlear implant electrodes. Hearing Research, 1995a, 89, 203–211. Porter, J., Craven, B., Khan, R. M., Chang, S.-J., etal. Mechanisms of scent-tracking in humans. Nature Neuroscience, 2007, 10, 27–29. Price, D. B. Psychological and neural mechanisms of the affective dimension of pain. Science, 2000, 288, 1769–1772. Pritchard, T. C., Hamilton, R. B., Morse, J. R., and Norgren, R. Projections of thalamic gustatory and lingual areas in the monkey, Macaca fascicularis. Journal of Comparative Neurology, 1986, 244, 213–228. Rainville, P., Duncan, G. H., Price, D. D., et al. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science, 1997, 277, 968–971. Ramirez, I. Why do sugars taste good? Neuroscience and Biobehavioral Reviews, 1990, 14, 125–134. Rauschecker, J. P., and Scott, S. K. Maps and streams in the auditory cortex: Nonhuman primates illuminate human speech processing. Nature Neuroscience, 2009, 12, 718–724. Rauschecker, J. P., and Tian, B. Mechanisms and streams for processing of “what” and “where” in auditory cortex. Proceedings of the National Academy of Sciences, USA, 2000, 97, 11800–11806. Reed, C. L., Caselli, R. J., and Farah, M. J. Tactile agnosia: Underlying impairment and implications for normal tactile object recognition. Brain, 1996, 119, 875–888. Ressler, K. J., Sullivan, S. L., and Buck, L. A molecular dissection of spatial patterning in the olfactory system. Current Opinion in Neurobiology, 1994, 4, 588–596. Rolls, E. T., Yaxley, S., and Sienkiewicz, Z. J. Gustatory responses of single neurons in the orbitofrontal cortex of the macaque monkey. Journal of Neurophysiology, 1990, 64, 1055–1066. Romanovsky, A. A. Thermoregulation: Some concepts have changed. Functional architecture of the thermoregulatory system. American Journal of Physiology, 2007, 292, R37–R46. Schneider, P., Scherg, M., Dosch, H. G., Specht, H. L., et al. Morphology of Heschl’s gyrus reflects enhanced activation in the auditory cortex of musicians. Nature Neuroscience, 2002, 5, 688–694. Schoenfeld, M. A., Neuer, G., Tempelmann, C., Schüssler, K., et al. Functional magnetic resonance tomography correlates of taste perception in the human primary taste cortex. Neuroscience, 2004, 127, 347–353. Scott, K. The sweet and the bitter of mammalian taste. Current Opinions in Neurobiology, 2004, 14, 423–427. Scott, T. R., and Plata-Salaman, C. R. Coding of taste quality. In Smell and Taste in Health and Disease, edited by T. N. Getchell. New York: Raven Press, 1991. Shannon, R. V. Understanding hearing through deafness. Proceedings of the National Academy of Sciences, USA, 2007, 104, 6883–6884. Shepherd, G. M. Discrimination of molecular signals by the olfactory receptor neuron. Neuron, 1994, 13, 771–790. Shipley, M. T., and Ennis, M. Functional organization of the olfactory system. Journal of Neurobiology, 1996, 30, 123–176. Singer, T., Seymour, B., O’Doherty, J., Kaube, H., etal. Empathy for pain involves the affective but not sensory components of pain. Science, 2004, 303, 1157–1162. Stewart, L. Fractionating the musical mind: Insights from congenital amusia. Current Opinion in Neurobiology, 2008, 18, 127–130. Takahashi, Y. K., Nagayma, S., and Mori, K. Detection and masking of spoiled food smells by odor maps in the olfactory bulb. Journal of Neuroscience, 2004, 24, 8690–8694. Valenza, N., Ptak, R., Zimine, I., Badan, M., et al. Dissociated active and passive tactile shape recognition: A case study of pure tactile apraxia. Brain, 2001, 124, 2287–2298. Vassar, R., Ngai, J., and Axel, R. Spatial segregation of odorant receptor expression in the mammalian olfactory epithelium. Cell, 1993, 74, 309–318. Whipple, B., and Komisaruk, B. R. Analgesia produced in women by genital self-stimulation. Journal of Sex Research, 1988, 24, 130–140. Yost, W. A. Auditory image perception and analysis: The basis for hearing. Hearing Research, 1991, 56, 8–18. Zenner, H.-P., Zimmermann, U., and Schmitt, U. Reversible contraction of isolated mammalian cochlear hair cells. Hearing Research, 1985, 18, 127–133. Zentner, M., and Kagan, J. Infants’ perception of consonance and dissonance in music. Infant Behavior and Development, 1998, 21, 483–492. Zubieta, J.-K., Bueller, J. A., Jackson, L. R., Scott, D.J., et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. Journal of Neuroscience, 2005, 25, 7754–7762.

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OUTLINE

Sleep and Biological Rhythms

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A Physiological and Behavioral Description of Sleep

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Disorders of Sleep Insomnia Narcolepsy REM Sleep Behavior Disorder Problems Associated with Slow-Wave Sleep

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Why Do We Sleep? Functions of Slow-Wave Sleep Functions of REM Sleep Sleep and Learning

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Physiological Mechanisms of Sleep and Waking Chemical Control of Sleep Neural Control of Arousal Neural Control of Slow-Wave Sleep Neural Control of REM Sleep

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Biological Clocks Circadian Rhythms and Zeitgebers The Suprachiasmatic Nucleus

LEARNINg OBJECTIvES

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Changes in Circadian Rhythms: Shift Work and Jet Lag

1. Describe the course of a night’s sleep: its stages and their characteristics.

6. Evaluate evidence that the onset and amount of sleep is chemically controlled, and describe the neural control of arousal.

2. Discuss insomnia, sleeping medications, and sleep apnea.

7. Discuss the neural control of slow-wave sleep, including the sleep/waking flip-flop and the role of orexinergic neurons.

3. Discuss narcolepsy and sleep disorders associated with REM sleep and slow-wave sleep. 4. Review the hypothesis that sleep serves as a period of restoration by discussing the effects of sleep deprivation, exercise, and mental activity.

8. Discuss the neural control of REM sleep, including the REM sleep flip-flop. 9. Describe circadian rhythms and discuss research on the neural and physiological bases of these rhythms.

5. Discuss research on the effects of REM sleep and slow-wave sleep on learning.

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PROLOgUE

| Waking Nightmares

Lately, Michael felt almost afraid of going to bed because of the unpleasant experiences he had been having. His dreams seemed to have become more intense in a rather disturbing way. Several times in the past few months, he felt as if he were paralyzed as he lay in bed, waiting for sleep to come. It was a strange feeling. Was he really paralyzed, or was he just not trying hard enough to move? He always fell asleep before he was able to decide. A couple of times he woke up just before it was time for his alarm to go off and felt unable to move. Then the alarm would ring, and he would quickly shut it off. That meant that he really wasn’t paralyzed, didn’t it? Was he going crazy? Last night brought the worst experience of all. As he was falling asleep, he felt again as if he were paralyzed. Then he saw his old roommate enter his bedroom. But that wasn’t possible! Since the time he graduated from college, he had lived alone, and he always locked the door. He tried to say something, but he couldn’t. His roommate was holding a hammer. He walked up to his bed, stood over Michael, and suddenly raised the hammer, as if to smash in his forehead. When he awoke in the morning, he shuddered with the remembrance. It had seemed so real! It must have been a dream, but he didn’t think he was asleep. He was in bed. Can a person really dream that he is lying in bed, not yet asleep? That day at the office, he had trouble concentrating on his work. He forced himself to review his notes, because he had to present the details of the new project to the board of directors. This was his big chance; if the project were accepted, he would certainly be chosen to lead it, and that would mean a promotion and a substantial raise. Naturally, with so much at stake, he felt nervous when he entered the boardroom. His boss introduced Michael and asked

electromyogram (EMG) (my oh gram) An electrical potential recorded from an electrode placed on or in a muscle. electro-oculogram (EOG) (ah kew loh gram) An electrical potential from the eyes, recorded by means of electrodes placed on the skin around them; detects eye movements. alpha activity Smooth electrical activity of 8–12 Hz recorded from the brain; generally associated with a state of relaxation. beta activity Irregular electrical activity of 13–30 Hz recorded from the brain; generally associated with a state of arousal. theta activity EEg activity of 3.5–7.5 Hz that occurs intermittently during early stages of slow-wave sleep and REM sleep.

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him to begin. Michael glanced at his notes and opened his mouth to talk. Suddenly, he felt his knees buckle. All his strength seemed to slip away. He fell heavily to the floor. He could hear people running over and asking what had happened. He couldn’t move anything except his eyes. His boss got down on his knees, looked into Michael’s face, and asked, “Michael, are you all right?” Michael looked at his boss and tried to answer, but he couldn’t say a thing. A few seconds later, he felt his strength coming back. He opened his mouth and said, “I’m okay.” He struggled to his knees and then sat in a chair, feeling weak and frightened. “You undoubtedly have a condition known as narcolepsy,” said the doctor whom Michael visited. “It’s a problem that concerns the way your brain controls sleep. I’ll have you spend a night in the sleep clinic and get some recordings done to confirm my diagnosis, but I’m sure that I’ll be proved correct. You told me that lately you’ve been taking short naps during the day. What were these naps like? Were you suddenly struck by an urge to sleep?” Michael nodded. “I just had to put my head on the desk, even though I was afraid that my boss might see me. But I don’t think I slept more than five minutes or so.” “Did you still feel sleepy when you woke?” “No,” he replied, “I felt fine again.” The doctor nodded. “All the symptoms you have reported— the sleep attacks, the paralysis you experienced before sleeping and after waking up, the spell you had today—they all fit together. Fortunately, we can usually control narcolepsy with medication. In fact, we have a new one that does an excellent job. I’m sure we’ll have you back to normal, and there is no reason why you can’t continue with your job. If you’d like, I can talk with your boss and reassure him, too.”

hy do we sleep? Why do we spend at least one-third of our lives doing something that provides most of us with only a few fleeting memories? I will attempt to answer this question in several ways. In the first two parts of this chapter I will describe what is known about the phenomenon of sleep and its disorders, including insomnia, narcolepsy, sleepwalking, and other sleep-related disorders. In the third part I will discuss research on the functions performed by sleep. In the fourth part I will describe the search for the chemicals and the neural circuits that control sleep and wakefulness. In the final part of the chapter I will discuss the brain’s biological clock—the mechanism that controls daily rhythms of sleep and wakefulness.

A Physiological and Behavioral Description of Sleep Sleep is a behavior. That statement might seem peculiar, because we usually think of behaviors as activities that involve movements, such as walking or talking. Except for the rapid eye movements that accompany a particular stage, sleep is not distinguished by movement. What characterizes sleep is that the insistent urge of sleepiness forces us to seek out a quiet, warm, comfortable place; lie down; and remain there for several hours. Because we remember very little about what

Sleep and Biological Rhythms

happens while we sleep, we tend to think of sleep more as a state of consciousness than as a behavior. Thechange in consciousness is undeniable, but it should not prevent us from noticing the behavioral changes. The best research on human sleep is conducted in a sleep laboratory. A sleep laboratory, usually located at a university or medical center, consists of one or several small bedrooms adjacent to an observation room, where the experimenter spends the night (trying to stay awake). The experimenter prepares the sleeper for electrophysiological measurements by attaching electrodes to the scalp to monitor the electroencephalogram (EEG) and to the chin to monitor muscle activity, recorded as the electromyogram (EMG). Electrodes attached around the eyes monitor eye movements, recorded as the electro-oculogram (EOG). In addition, other electrodes and transducing devices can be used to monitor autonomic measures such as heart rate, respiration, and changes in the skin’s ability to conduct electricity. (See Figure 1.) During wakefulness the EEG of a normal person shows two basic patterns of activity: alpha activity and beta activity. Alpha activity consists of regular, medium-frequency waves of 8–12 Hz. The brain produces this activity when a person is resting quietly, not particularly aroused or excited and not engaged in strenuous mental activity (such as problem solving). Although alpha waves sometimes occur when a person’s eyes are open, they are much more prevalent F I G U R E 1 A Subject Prepared for a when they are closed. The other type of waking EEG pattern, beta activity, consists of irregular, Night’s Sleep in a Sleep Laboratory. mostly low-amplitude waves of 13–30 Hz. Beta activity shows desynchrony; it reflects the fact that Philippe Platilly/Science Photo Library/Photo many different neural circuits in the brain are actively processing information. Desynchronized Researchers Inc. activity occurs when a person is alert and attentive to events in the environment or is thinking delta activity Regular, synchronous actively. (See Figure 2.) electrical activity of less than 4 Hz Let’s look at a typical night’s sleep of a female college student in a sleep laboratory. (Of recorded from the brain; occurs during course, we would obtain similar results from a male, with one exception, which is noted the deepest stages of slow-wave sleep. later.) The experimenter attaches the electrodes, turns the lights off, and closes the door. Our slow-wave sleep Non-REM sleep, subject becomes drowsy and soon enters stage 1 sleep, marked by the presence of some theta characterized by synchronized EEg activity (3.5–7.5 Hz), which indicates that the firing of neurons in the neocortex is becoming activity during its deeper stages. more synchronized. This stage is actually a transition between sleep and wakefulness; Awake if we watch our volunteer’s eyelids, we will see that from time to time they slowly open and close and that her eyes roll upward and downward. (See Figure 2.) About ten Alpha activity Beta activity minutes later she enters stage 2 sleep. The EEG during this stage is generally irregular Stage 1 sleep but contains periods of theta activity, sleep spindles, and K complexes. Sleep spindles are short bursts of waves of 12–14 Hz that occur between two and five times a minute Theta activity during stages 1–4 of sleep. K complexes appear to play a role in the consolidation of memories, and increased numbers of sleep spindles are correlated with increased Stage 2 sleep scores on tests of intelligence (Fogel and Smith, 2011). (The role of sleep in memory is discussed later in this chapter.) They are sudden, sharp waveforms that, unlike sleep Sleep spindles, are usually found only during stage 2 sleep. They spontaneously occur at the K complex spindle Seconds rate of approximately one per minute but often can be triggered by noises—especially Stage 3 sleep unexpected noises. Cash et al. (2009) recorded the activity of single neurons in the human cerebral cortex during sleep and found that K complexes consisted of isolated periods of neural inhibition. (The recordings were made from the brains of patients Delta activity who were being evaluated for neurosurgery.) K complexes appear to be the forerunner Stage 4 sleep of delta waves, which appear in the deepest levels of sleep. (See Figure 2.) The subject is sleeping soundly now; if awakened, however, she might report that she has not been asleep. This phenomenon often is reported by nurses who awaken loudly snoring hospital patients early in the night (probably to give them a sleeping Delta activity pill) and find that the patients insist that they were lying there awake all the time. About fifteen minutes later the subject enters stage 3 sleep, signaled by the occurrence of REM sleep high-amplitude delta activity (slower than 3.5 Hz). (See Figure2.) The distinction beTheta activity Beta activity tween stage 3 and stage 4 is not clear-cut; stage 3 contains 20–50percent delta activity, and stage 4 contains more than 50 percent. Because slow-wave EEG activity predomiF I G U R E 2 EEG Recording of the Stages nates during sleep stages 3 and 4, they are collectively referred to as slow-wave sleep. of Sleep. (See Figure 2.) Based on Horne, J. A. Why We Sleep: The Functions of In recent years, researchers have begun studying the details of the EEG activity that Sleep in Humans and Other Mammals. Oxford, England: Oxford University Press, 1988. occurs during slow-wave sleep and the brain mechanisms responsible for this activity 0

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(Steriade, 2003, 2006). It turns out that the most important feature of slow-wave activity during sleep is the presence of slow oscillations of less than 1 Hz. Each oscillation consists of a single high-amplitude biphasic (down and up) wave of slightly less than 1 Hz. The first part of the wave indicates a down state—a period of inhibition during which neurons in the neocortex are absolutely silent. Presumably, it is during this down state that neocortical neurons are able to rest. The second part indicates an up state—a period of excitation during which these neurons briefly fire at a high rate. Figure 3 shows the EEG recording and multiunit recordings from six microelectrodes in the cerebral cortex of a sleeping rat. Several slow oscillations are shown at the top of the figure. Each oscillation 1 consists of an inhibitory hyperpolarizing silent phase (down state, indicated in red) followed by an excitatory depolarizing phase during which the neuron fires 2 at a high rate (up state, indicated in green). (See Figure 3.) About ninety minutes after the beginning of sleep (and about forty-five 3 minutes after the onset of stage 4 sleep), we notice an abrupt change in a number of physiological measures recorded from our subject. The EEG sud4 denly becomes mostly desynchronized, with a sprinkling of theta waves, very similar to the record obtained during stage 1 sleep. (See Figure 3.) We also 5 note that her eyes are rapidly darting back and forth beneath her closed eyelids. We can see this activity in the EOG, recorded from electrodes attached 6 to the skin around her eyes, or we can observe the eye movements directly— the cornea produces a bulge in the closed eyelids that can be seen to move F I G U R E 3 EEG and Single-Cell Activity. Recordings of cortical EEg and multiunit cell activity during slow-wave sleep about. We also see that the EMG becomes silent; there is a profound loss of of a rat. The top of the figure shows several slow oscillations. muscle tone. In fact, physiological studies have shown that, aside from ocDuring the descending phase of the slow oscillation (down state, casional twitching, a person actually becomes paralyzed during REM sleep. indicated in red), the neurons are hyperpolarized and do not fire. This peculiar stage of sleep is quite distinct from the quiet sleep we saw earDuring the ascending phase (up state, indicated in green), the lier. It is usually referred to as REM sleep (for the rapid eye movements that neurons fire. characterize it). From vyazovskiy, v. v., Olcese, U., Lazimy, Y. M., et al. Neuron, 2009, 63, By most criteria, stage 4 is the deepest stage of sleep; only loud noises will 865–878. Reprinted with permission. cause a person to awaken; when awakened, the person acts groggy and confused. down state A period of inhibition During REM sleep a person might not react to noises, but he or she is easily aroused by meaningful during a slow oscillation during slowstimuli, such as the sound of his or her name. Also, when awakened from REM sleep, a person apwave sleep; neurons in the neocortex are pears alert and attentive. silent and resting. If we arouse our volunteer during REM sleep and ask her what was going on, she will almost up state A period of excitation during a certainly report that she had been dreaming. The dreams of REM sleep tend to be narrative in slow oscillation during slow-wave sleep; form, with a storylike progression of events. On the other hand, if we wake her during slow-wave neurons in the neocortex briefly fire at a high rate. sleep and ask, “Were you dreaming?” she will most likely say, “No.” However, if we question her more carefully, she might report the presence of a thought, an image, or some emotion. REM sleep A period of desynchronized EEg activity during sleep, at which time During the rest of the night our subject’s sleep alternates between periods of REM and nondreaming, rapid eye movements, and REM sleep. Each cycle is approximately ninety minutes long, containing a twenty- to thirtymuscular paralysis occur; also called minute bout of REM sleep. Thus, an eight-hour sleep will contain four or five periods of REM paradoxical sleep. sleep. Figure 4 shows a graph of a typical night’s sleep. The vertical axis indicates the EEG activity that is being recorded; thus, REM sleep and stage 1 sleep are W Awake REM sleep placed on the same line because similar patterns of EEG activity occur at these times. Note that most slow-wave sleep (stages 3 and 4) occurs during the first 1 half of night. Subsequent bouts of non-REM sleep contain more and more stage 2 sleep, and bouts of REM sleep (indicated by the horizontal bars) become more 2 prolonged. (See Figure 4.) As we saw, during REM sleep we become paralyzed; most of our spinal and 3 cranial motor neurons are strongly inhibited. (Obviously, the ones that control respiration and eye movements are spared.) At the same time the brain is very 4 active. Cerebral blood flow and oxygen consumption are accelerated. In addition, during most periods of REM sleep, a male’s penis and a female’s clitoris 6 7 1 2 3 4 5 8 will become at least partially erect, and a female’s vaginal secretions will increase Hours (Schmidt and Schmidt, 2004). However, Fisher, Gross, and Zuch (1965) found F I G U R E 4 Sleep Stages During a Single Night. In this that in males, genital changes do not signify that the person is experiencing a typical pattern of sleep stages, the dark blue shading indicates REM sleep. dream with sexual content. (Of course, people can have dreams with frank sexual

EEG stage

Multiunit electrodes in cortex

Cortical EEG

Off

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content. In males some dreams culminate in ejaculation—the so-called nocturnal emissions, or “wet dreams.” Females, too, sometimes experience orgasm during sleep.) The fact that penile erections occur during REM sleep, independent of sexual arousal, has been used clinically to assess the causes of impotence (Karacan, Salis, and Williams, 1978; Singer and Weiner, 1996). A subject sleeps in the laboratory with a device attached to his penis that measures its circumference. If penile enlargement occurs during REM sleep, then his failure to obtain an erection during attempts at intercourse is not caused by physiological problems such as nerve damage or a circulatory disorder. (A neurologist told me that there is a less expensive way to gather the same data: The patient obtains a strip of postage stamps and applies them around his penis before going to bed. In the morning he checks to see whether the perforations are broken.) Table 1 lists the important differences between REM and slow-wave sleep. (See Table 1.) TABLE

1 Principal Characteristics of REM and Slow-Wave Sleep

REM Sleep

Slow-Wave Sleep

EEg desynchrony (rapid, irregular waves)

EEg synchrony (slow waves)

Lack of muscle tonus

Moderate muscle tonus

Rapid eye movements

Slow or absent eye movements

Penile erection or vaginal secretion

Lack of genital activity

Dreams

SECTION SUmmaRy a Physiological and Behavioral Description of Sleep Sleep is generally regarded as a state, but it is nevertheless a behavior. The stages of non-REM sleep, stages 1–4, are defined by EEg activity. Slow-wave sleep (stages 3 and 4) includes the two deepest stages. Alertness consists of desynchronized beta activity (13–30 Hz); relaxation and drowsiness consist of alpha activity (8–12 Hz); stage 1 sleep consists of alternating periods of alpha activity, irregular fast activity, and theta activity (3.5–7.5 Hz); the EEg of stage 2 sleep lacks alpha activity but contains sleep spindles (short periods of 12–14 Hz activity) and occasional K complexes; stage 3 sleep consists of 20–50 percent delta activity (less than 3.5 Hz); and stage 4 sleep consists of more than 50 percent delta activity. About ninety minutes after the beginning of sleep, people enter REM sleep. Cycles of REM and slow-wave sleep alternate in periods of approximately ninety minutes. REM sleep consists of rapid eye movements, a desynchronized EEg, sensitivity to external stimulation, muscular paralysis, genital activity, and dreaming. Mental activity can accompany slow-wave sleep too, but most narrative dreams occur during REM sleep.

Thought Questions 1. Have you ever been resting quietly and suddenly heard someone tell you that you had obviously been sleeping because you were snoring? Did you believe them, or were you certain that you were really awake? Do you think it was likely that you had actually entered stage 1 sleep? 2. What is accomplished by dreaming? Some researchers believe that the subject matter of a dream does not matter; it is the REM sleep itself that is important. Others believe that the subject matter does count. Some researchers believe that if we remember a dream, then the dream failed to accomplish all of its functions; others say that remembering dreams is useful because it can give us some insights into our problems. What do you think of these controversies? 3. Some people report that they are “in control” of some of their dreams, that they feel as if they determine what comes next and are not simply swept along passively. Have you ever had this experience? And have you ever had a “lucid dream,” in which you were aware of the fact that you were dreaming?

Disorders of Sleep Because we spend about one-third of our lives sleeping, sleep disorders can have a significant impact on our quality of life. They can also affect the way we feel while we are awake.

Insomnia Insomnia is a problem that is said to affect approximately 25 percent of the population occasionally and 9 percent regularly (Ancoli-Israel and Roth, 1999). Insomnia is characterized as difficulty

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falling asleep after going to bed or after awakening during the night. A significant problem in identifying insomnia is the unreliability of self-reports. Most patients who receive a prescription for a sleeping medication are given one on the basis of their own description of their symptoms. That is, they tell their physician that they sleep very little at night, and the drug is prescribed on the basis of this testimony. Very few patients are observed during a night’s sleep in a sleep laboratory; thus, insomnia is one of the few medical problems that physicians treat without having direct clinical evidence for its existence. But studies on the sleep of people who complain of insomnia show that most of them underestimate the amount of time they actually spend sleeping. For many years the goal of sleeping medication was to help people fall asleep, and when drug companies evaluated potential medications, they concentrated on that property. However, if we think about the ultimate goal of sleeping medication, it is to make the person feel more refreshed the next day. If a medication puts people to sleep right away but produces a hangover of grogginess and difficulty concentrating the next day, it is worse than useless. In fact, many drugs that are traditionally used to treat insomnia had just this effect. Researchers have now recognized that the true evaluation of a sleeping medication must be made during wakefulness the following day, and “hangover-free” drugs are finally being developed (Hajak et al., 1995; Ramakrishnan and Scheid, 2007). Many people spend much of their time in a sleep-deprived state not because they suffer from insomnia, but because the demands of their daily schedules lead them to stay up late or get up early (or both), thus receiving less than the optimal amount of sleep. Chronic sleep deprivation can lead to serious health problems, including increased risk of obesity, diabetes, and cardiovascular disease (Orzel-Gryglewska, 2010). A particular form of insomnia is caused by an inability to sleep and breathe at the same time. Patients with this disorder, called sleep apnea, fall asleep and then cease to breathe. (Apnos is Greek for “without breathing.”) Nearly all people, especially people who snore, have occasional episodes of sleep apnea, but not to the extent that it interferes with sleep. During a period of sleep apnea the level of carbon dioxide in the blood stimulates chemoreceptors (neurons that detect the presence of certain chemicals), and the person wakes up, gasping for air. The oxygen level of the blood returns to normal, the person falls asleep, and the whole cycle begins again. Because sleep is disrupted, people with this disorder typically feel sleepy and groggy during the day. Fortunately, many cases of sleep apnea are caused by an obstruction of the airway that can be corrected surgically or relieved by a device that attaches to the sleeper’s face and provides pressurized air that keeps the airway open (Sher, 1990; Piccirillo, Duntley, and Schotland, 2000).

Narcolepsy

sleep apnea (app nee a) Cessation of breathing while sleeping. narcolepsy (nahr ko lep see) A sleep disorder characterized by periods of irresistible sleep, attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations. sleep attack A symptom of narcolepsy; an irresistible urge to sleep during the day, after which the person awakens feeling refreshed. cataplexy (kat a plex ee) A symptom of narcolepsy; complete paralysis that occurs during waking.

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Narcolepsy (narke means “numbness,” and lepsis means “seizure”) is a neurological disorder characterized by sleep (or some of its components) at inappropriate times. The symptoms can be described in terms of what we know about the phenomena of sleep. The primary symptom of narcolepsy is the sleep attack. The narcoleptic sleep attack is an overwhelming urge to sleep that can happen at any time but occurs most often under monotonous, boring conditions. Sleep (which appears to be entirely normal) generally lasts for 2–5 minutes. The person usually wakes up feeling refreshed. Another symptom of narcolepsy—in fact, the most striking one—is cataplexy (from kata, “down,” and plexis, “stroke”). During a cataplectic attack a person will sustain varying amounts of muscle weakness. In some cases, the person will become completely paralyzed and slump down to the floor. The person will lie there, fully conscious, for a few seconds to several minutes. What apparently happens is that one of the phenomena of REM sleep—muscular paralysis—occurs at an inappropriate time. This loss of tonus is caused by massive inhibition of motor neurons in the spinal cord. When this happens during waking, the victim of a cataplectic attack loses control of his or her muscles. As in REM sleep, the person continues to breathe and is able to control eye movements. (The brain abnormality responsible for narcolepsy is described later in this chapter.) Cataplexy is quite different from a narcoleptic sleep attack; cataplexy is usually precipitated by strong emotional reactions or by sudden physical effort, especially if the patient is caught unawares. Laughter, anger, or an effort to catch a suddenly thrown object can trigger a cataplectic attack. In fact, as Guilleminault, Wilson, and Dement (1974) noted, even people who do not have cataplexy sometimes lose muscle strength after a bout of intense laughter. (Perhaps

Sleep and Biological Rhythms

that is why we say a person can become “weak from laughter.”) Common situations that bring on cataplexy are attempting to discipline one’s children and making love (an awkward time to become paralyzed!). Michael, the man described in the opener to this chapter, had his first cataplectic attack when he was addressing the board of directors of the company he worked for. Wise (2004) notes that patients with narcolepsy often try to avoid thoughts and situations that are likely to evoke strong emotions because they know that these emotions are likely to trigger cataplectic attacks. REM sleep paralysis sometimes intrudes into waking at a time that does not present any physical danger—just before or just after normal sleep, when a person is already lying down. This symptom of narcolepsy is referred to as sleep paralysis, an inability to move just before the onset of sleep or upon waking in the morning. A person can be snapped out of sleep paralysis by being touched or by hearing someone call his or her name. Sometimes, the mental components of REM sleep intrude into sleep paralysis; that is, the person dreams while lying awake, paralyzed. These episodes, called hypnagogic hallucinations, are often alarming or even terrifying. (The term hypnagogic comes from the Greek words hupnos, “sleep,” and agogos, “leading.”) During a hypnagogic hallucination Michael thought that his former roommate was trying to attack him with a hammer. Fortunately, human narcolepsy is relatively rare, with an incidence of approximately one in two thousand people. This hereditary disorder appears to involve a gene found on chromosome 6, but it is strongly influenced by unknown environmental factors (Mignot, 1998; Mahowald and Schenck, 2005; Nishino, 2007). Years ago, researchers began a program to maintain breeds of dogs that are afflicted with narcolepsy, with the hopes that discovery of the causes of canine narcolepsy would further our understanding of the causes of human narcolepsy. (See Figure 5.) Eventually, this research paid off. Lin et al. (1999) discovered that a mutation of a specific gene is responsible for canine narcolepsy. The product of this gene is a receptor for a peptide neurotransmitter called hypocretin by some researchers, and called orexin by others. The name hypocretin comes from the fact that the lateral hypothalamus contains the cell bodies of all of the neurons that secrete this peptide. The name orexin comes from the role this peptide plays in the control of eating and metabolism (Orexis means “appetite” in Greek.) Two laboratories independently discovered the peptide; hence, it has two names. Most researchers appear to have settled on the word orexin, so I will use this term also. There are two orexin receptors. Lin and his colleagues discovered that the mutation responsible for canine narcolepsy involves the orexin B receptor. Chemelli et al. (1999) prepared a targeted mutation in mice against the orexin gene and found that the animals showed symptoms of narcolepsy. Like human patients with narcolepsy, they went directly into REM sleep from waking and showed periods of cataplexy while they were awake. Gerashchenko et al. (2001, 2003) prepared a toxin that attacked only orexinergic neurons, which they then administered to rats. The destruction of the orexin system produced the symptoms of narcolepsy.

(a)

(b)

sleep paralysis A symptom of narcolepsy; paralysis occurring just before a person falls asleep. hypnagogic hallucination (hip na gah jik) A symptom of narcolepsy; vivid dreams that occur just before a person falls asleep; accompanied by sleep paralysis. orexin A peptide, also known as hypocretin, produced by neurons whose cell bodies are located in the hypothalamus; their destruction causes narcolepsy.

(c)

F I G U R E 5 A Dog Undergoing a Cataplectic Attack. The attack was triggered by the dog’s excitement at finding some food on the floor. (a) The dog sniffs the food. (b) Muscles begin to relax. (c) The dog is temporarily paralyzed, as it would be during REM sleep. Based on the research from the Sleep Disorders Foundation, Stanford University.

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In humans, narcolepsy appears to be caused by a hereditary autoimmune disorder. Most patients with narcolepsy are born with orexinergic neurons, but during adolescence the immune system attacks these neurons, and the symptoms of narcolepsy begin (Fontana et al., 2010). The symptoms of narcolepsy can be treated with drugs. Sleep attacks can be diminished by stimulants such as methylphenidate (Ritalin), a catecholamine agonist (Vgontzas and Kales, 1999). The REM sleep phenomena (cataplexy, sleep paralysis, and hypnagogic hallucinations) have traditionally been treated with antidepressant drugs, which facilitate both serotonergic and noradrenergic activity (Mitler, 1994; Hublin, 1996). At the present time, modafinil, a stimulant drug whose precise site of action is still unknown, is widely used to treat narcolepsy (Fry, 1998; Nishino, 2007). (Michael, the man discussed in the prologue, now takes this drug.) The connections of orexinergic neurons with other regions of the brain involved in sleep and wakefulness are discussed later in this chapter.

REm Sleep Behavior Disorder As you now know, REM sleep is accompanied by paralysis. Although neurons in the motor cortex and subcortical motor systems are extremely active during REM sleep (McCarley and Hobson, 1979), people are unable to move at this time. (The occasional twitches that are seen during REM sleep are apparently signs of intense activity of motor neurons that are not completely suppressed.) The fact that people are paralyzed while they dream suggests the possibility that, if not for the paralysis, they would act out their dreams. Indeed, they would. Schenck et al. (1986) reported the existence of an interesting disorder: REM sleep behavior disorder. The behavior of people with this disorder corresponds with the contents of their dreams. Consider the following case:

I was a halfback playing football, and after the quarterback received the ball from the center he lateraled it sideways to me and I’m supposed to go around end and cut back over tackle and—this is very vivid—as I cut back over tackle there is this big 280-pound tackle waiting, so I, according to football rules, was to give him my shoulder and bounce him out of the way . . . when I came to I was standing in front of our dresser and I had [gotten up out of bed and run and] knocked lamps, mirrors and everything off the dresser, hit my head against the wall and my knee against the dresser. (Schenck et al., 1986, p. 294)

Like narcolepsy, REM sleep behavior disorder appears to be a neurodegenerative disorder with at least some genetic component (Schenck et al., 1993). It is often associated with betterknown neurodegenerative disorders such as Parkinson’s disease (Boeve et al., 2007). The symptoms of REM sleep behavior disorder are the opposite of those of cataplexy; that is, rather than exhibiting paralysis outside REM sleep, patients with REM sleep behavior disorder fail to exhibit paralysis during REM sleep. As you might expect, the drugs that are used to treat the symptoms of cataplexy will aggravate the symptoms of REM sleep behavior disorder (Schenck and Mahowald, 1992). REM sleep behavior disorder is usually treated by clonazepam, a benzodiazepine tranquilizer (Aurora et al., 2010; Frenette, 2010).

Problems associated with Slow-Wave Sleep

REM sleep behavior disorder A neurological disorder in which the person does not become paralyzed during REM sleep and thus acts out dreams.

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Some maladaptive behaviors occur during slow-wave sleep, especially during its deepest phase, stage 4. These behaviors include bedwetting (nocturnal enuresis), sleepwalking (somnambulism), and night terrors (pavor nocturnus). All three events occur most frequently in children. Often bedwetting can be cured by training methods, such as having a special electronic circuit ring a bell when the first few drops of urine are detected in the bed sheet (a few drops usually precede the ensuing flood). Night terrors consist of anguished screams, trembling, a rapid pulse, and usually no memory of what caused the terror. Night terrors and somnambulism usually cure themselves as the child gets older. Neither of these phenomena is related to REM sleep; a sleepwalking person is not acting out a dream. Especially when it occurs in adulthood, sleepwalking appears to have a genetic component (Hublin et al., 1997).

Sleep and Biological Rhythms

Sometimes people can engage in complex behaviors while sleepwalking. Consider the following cases:

One evening Ed Weber got up from a nap on the sofa, polished off a half-gallon of chocolate chip ice cream, then dozed off again. He woke up an hour later and went looking for the ice cream, summoning his wife to the kitchen and insisting, to her astonishment, that someone else must have eaten it. [T]elevision talk show host Montel Williams . . . told viewers he had removed raw foods from his refrigerator because “I wake up in the morning and there’s a pack of chicken and there’s a bite missing out of it. . . . I can take a whole pound of ham or bologna . . . and then wake up in the morning and not realize that I had [eaten] it and ask, ‘Who ate my lunch meat?’” (Boodman, 2004, p. HE01)

Schenck et al. (1991) reported nineteen cases of people with histories of eating during the night while they were asleep, which they labeled sleep-related eating disorder. Almost half of the patients had become overweight from night eating. Once patients realize that they are eating in their sleep, they often employ such stratagems as keeping their food under lock and key or setting alarms that will awaken them when they try to open their refrigerator. Sleep-related eating disorder usually responds well to dopaminergic agonists or topiramate, an antiseizure medication, and may be provoked by zolpidem, a benzodiazepine agonist that has been used to treat insomnia (Howell and Schenck, 2009). An increased incidence of nocturnal eating in family members of people with this disorder suggests that heredity may play a role (DeOcampo et al., 2002).

sleep-related eating disorder A disorder in which the person leaves his or her bed and seeks out and eats food while sleepwalking, usually without a memory for the episode the next day.

SECTION SUmmaRy Disorders of Sleep Although many people believe that they have insomnia—that they do not obtain as much sleep as they would like—insomnia is not a disease. Insomnia can be caused by depression, mania, pain, illness, or even excited anticipation of a pleasurable event. Sometimes insomnia is caused by sleep apnea, which can often be corrected surgically or treated by wearing a mask that delivers pressurized air. Narcolepsy is characterized by four symptoms. Sleep attacks consist of overwhelming urges to sleep for a few minutes. Cataplexy is sudden paralysis, during which the person remains conscious. Sleep paralysis is similar to cataplexy, but it occurs just before sleep or on waking. Hypnagogic hallucinations are dreams that occur during periods of sleep paralysis, just before a night’s sleep. Sleep attacks are treated with stimulants such as amphetamine, and the other symptoms are treated with serotonin agonists or, more commonly, with modafinil. Studies with narcoleptic dogs and humans indicate that this disorder is caused by pathologies in

a system of neurons that secrete a neuropeptide known as orexin (also known as hypocretin). REM sleep behavior disorder is caused by a neurodegenerative disease that damages brain mechanisms that produce paralysis during REM sleep. As a result, the patient acts out his or her dreams. During slow-wave sleep, especially during stage 4, some people are afflicted by bedwetting (nocturnal enuresis), sleepwalking (somnambulism), or night terrors (pavor nocturnus). These problems are most common in children, who usually outgrow them. People with sleep-related eating disorder seek and consume food while sleepwalking.

Thought Question Suppose you spent the night at a friend’s house and, hearing a strange noise during the night, got out of bed and found your friend walking around, still asleep. How would you tell whether your friend was sleepwalking or had REM sleep behavior disorder?

Why Do We Sleep? We all know how insistent the urge to sleep can be and how uncomfortable we feel when we have to resist it and stay awake. With the exception of the effects of severe pain and the need to breathe, sleepiness is probably the most insistent drive that we can experience. People can commit suicide by refusing to eat or drink, but even the most stoical person cannot indefinitely defy the urge to sleep. Sleep will come, sooner or later, no matter how hard a person tries to stay awake. Although the issue is not yet settled, most researchers believe that the primary function of slow-wave sleep

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is to permit the brain to rest. In addition, slow-wave sleep and REM sleep promote different types of learning; REM sleep also appears to promote brain development.

Functions of Slow-Wave Sleep Sleep is a universal phenomenon among vertebrates. As far as we know, all mammals and birds sleep (Durie, 1981). Reptiles also sleep, and fish and amphibians enter periods of quiescence that probably can be called sleep. However, only warm-blooded vertebrates (mammals and birds) exhibit unequivocal REM sleep, with muscular paralysis, EEG signs of desynchrony, and rapid eye movements. Sleep appears to be essential to survival. Evidence for this assertion comes from the fact that sleep is found in some species of mammals that would seem to be better off without it. For example, some species of marine mammals have developed an extraordinary pattern of sleep: The cerebral hemispheres take turns sleeping, presumably because that strategy always permits at least one hemisphere to be alert and Two cerebral hemispheres of some species of porpoises keep the animal from sinking and drowning. In addition, the eye contralateral to the take turns sleeping—although probably not when the active hemisphere remains open. Some birds (for example, mallard ducks) can also animals are as active as the one shown here. sleep with only one hemisphere, keeping the opposite eye open to watch for predators Francois gohier/ Photo Researchers, Inc. (Rattenborg, Lima, and Amlaner, 1999). The bottlenose dolphin (Tursiops truncatus) and the porpoise (Phocoena phocoena) both sleep with one hemisphere at a time (Mukhametov, 1984). Figure 6 shows the EEG recordings from the two hemispheres; note that slow-wave sleep occurs independently in the left and right hemispheres. (See Figure 6.) EffECTS Of SLEEP DEPRivATiON When we are forced to miss a night’s sleep, we become very sleepy. The fact that sleepiness is so motivating suggests that sleep is a necessity of life. If so, it should be possible to deprive people of sleep and see what functions are disrupted. We should then be able to infer the role that sleep plays. The results of sleep deprivation studies suggest that the restorative effects of sleep are more important for the brain than for the rest of the body. Sleep deprivation studies with human subjects have provided little evidence that sleep is needed to keep the body functioning normally. Horne (1978) reviewed over fifty experiments in which people had been deprived of sleep. He reported that most of them found that sleep deprivation did not interfere with people’s ability to perform physical exercise. In addition, the studies found no evidence of a physiological stress response to sleep deprivation. Thus, the primary role of sleep does not seem to be rest and recuperation of the body. However, people’s cognitive abilities were affected; some people reported perceptual distortions or even hallucinations and fatal familial insomnia A fatal inherited had trouble concentrating on mental tasks. Perhaps sleep provides the opportunity for the brain disorder characterized by progressive insomnia. to rest. During slow-wave sleep, both cerebral metabolic rate and cerebral blood flow decline, falling to about 75 percent of the waking level during stage 4 sleep (Sakai et al., 1979; Buchsbaum etal., 1989; Maquet, 1995). In particular, the regions that have the highest levels of activity during waking show the highest levels of delta waves—and the lowest levels of Right Hemisphere metabolic activity—during slow-wave sleep. Thus, the presence of slowwave activity in a particular region of the brain appears to indicate that that region is resting. As we know from behavioral observation, people Intermediate Waking Waking Slow-wave are unreactive to all but intense stimuli during slow-wave sleep and, if sleep sleep awakened, act groggy and confused, as if their cerebral cortex has been shut down and has not yet resumed its functioning. In addition, several Left Hemisphere studies have shown that missing a single night’s sleep impairs people’s cognitive abilities; presumably, the brain needs sleep to function at peak efficiency (Harrison and Horne, 1998, 1999). These observations suggest Waking Waking Waking Slow-wave that during slow-wave sleep the brain is indeed resting. sleep An inherited neurological disorder called fatal familial insomnia F I G U R E 6 Sleep in a Dolphin. The two hemispheres sleep independently, presumably so that the animal remains behaviorally alert. results in damage to portions of the thalamus (Sforza et al., 1995; Gallassi et al., 1996; Montagna et al., 2003). The symptoms of this disease, Based on Mukhametov, L. M., in Sleep Mechanisms, edited by A. A. Borbély and J. L. valatx. Munich: Springer-verlag, 1984. which is related to Creutzfeldt-Jakob disease and bovine spongiform

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encephalopathy (“mad cow disease”), include deficits in attention and memory, followed by a dreamlike, confused state; loss of control of the autonomic nervous system and the endocrine system; and insomnia. The first signs of sleep disturbances are reductions in sleep spindles and K complexes. As the disease progresses, slow-wave sleep completely disappears, and only brief episodes of REM sleep (without the accompanying paralysis) remain. As the name indicates, the disease is fatal. Whether the insomnia, caused by the brain damage, contributes to the other symptoms and to the patient’s death is not known.

Schenkein and Montagna (2006a, 2006b) describe the case of a man diagnosed with a form of fatal familial insomnia that usually causes death within twelve months. Because several relatives had died of this disorder, the man knew what to expect, and he enlisted the aid of several physicians to administer drugs and treatments designed to help him sleep. For several months, the treatments did help him sleep, and the man survived about a year longer than would have been expected. Further studies will be needed to determine whether his increased survival time was a direct result of the increased sleep. In any event, his quality of life during most of the period of his illness was much improved.

EffECTS Of ExERCiSE ON SLOW-WAvE SLEEP Sleep deprivation studies with humans suggest that the brain may need slow-wave sleep in order to recover from the day’s activities. Another way to determine whether sleep is needed for restoration of physiological functioning is to look at the effects of daytime activity on nighttime sleep. If the function of sleep is to repair the effects on the body of physical activity during waking hours, then we should expect that sleep and exercise are related. That is, we should sleep more after a day of vigorous exercise than after a day spent quietly at an office desk. However, the relationship between sleep and exercise is not very compelling. For example, Ryback and Lewis (1971) found no changes in slow-wave or REM sleep among healthy subjects who spent six weeks resting in bed. If sleep repairs wear and tear, we would expect these people to sleep less. Adey, Bors, and Porter (1968) studied the sleep of almost completely immobile quadriplegics and paraplegics and found only a small decrease in slow-wave sleep as compared with uninjured people. Thus, although sleep certainly provides the body with rest, its primary function appears to be something else.

Functions of REm Sleep Clearly, REM sleep is a time of intense physiological activity. The eyes dart about rapidly, the heart rate shows sudden accelerations and decelerations, breathing becomes irregular, and the brain becomes more active. It would be unreasonable to expect that REM sleep has the same functions as slow-wave sleep. An early report on the effects of REM sleep deprivation (Dement, 1960) observed that as the deprivation progressed, subjects had to be awakened from REM sleep more frequently; the “pressure” to enter REM sleep built up. Furthermore, after several days of REM sleep deprivation, subjects would show a rebound phenomenon when permitted to sleep normally; they spent a much greater-than-normal percentage of the recovery night in REM sleep. This rebound suggests that there is a need for a certain amount of REM sleep—that REM sleep is controlled by a regulatory mechanism. If selective deprivation causes a deficiency in REM sleep, the deficiency is made up later, when uninterrupted sleep is permitted. Researchers have long been struck by the fact that the highest proportion of REM sleep is seen during the most active phase of brain development. Perhaps, then, REM sleep plays a role in this process (Siegel, 2005). Infants in species born with immature brains, such as ferrets or humans, spend much more time in REM sleep than infants in species born with well-developed brains, such as guinea pigs or cattle (Roffwarg, Muzio, and Dement, 1966; Jouvet-Mounier, Astic, and Lacote, 1970). But if the function of REM sleep is to promote brain development, why do adults have REM sleep? One possibility is that REM sleep facilitates the massive changes in the brain that occur during development but also some of the more modest changes responsible for

rebound phenomenon The increased frequency or intensity of a phenomenon after it has been temporarily suppressed; for example, the increase in REM sleep seen after a period of REM sleep deprivation.

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learning that occur later in life. As we will see in the next subsection, evidence does suggest that REM sleep facilitates learning—but so does slow-wave sleep.

Sleep and Learning

Discrimination improvement

Research with both humans and laboratory animals indicates that sleep does more than allow the brain to rest: It also aids in the consolidation of long-term memories (Marshall and Born, 2007). In fact, slow-wave sleep and REM sleep play different roles in memory consolidation. There are two major categories of long-term memory: declarative memory (also called explicit memory) and nondeclarative memory (also called implicit memory). Declarative memories include those that people can talk about, such as memories of past episodes in their lives. They also include memories of the relationships between stimuli or events, such as the spatial relationships between landmarks that permit us to navigate around our environment. Nondeclarative memories include those gained through experience and practice that do not necessarily involve an attempt to “memorize” information, such as learning to drive a car, throw and catch a ball, or recognize a person’s face. Research has found that slow-wave sleep and REM sleep play different roles in the consolidation of declarative and nondeclarative memories. Before I tell you about the results of this research, let’s review the consciousness of a person engaged in each of these stages of sleep. During REM sleep, people normally have a high level of consciousness. If we awaken people during REM sleep, they will be alert and clear-headed and will usually be able to describe the details of a dream that they were having. However, if we awaken people during slow-wave sleep, they will tend to be groggy and confused, and will usually tell us that very little was happening. So which stages of sleep do you think aid in the consolidation of declarative and nondeclarative memories? I would have thought that REM sleep would be associated with declarative memories and slow-wave sleep with nondeclarative memories. However, just the opposite is true. Let’s look at evidence from two studies that examined the effects of a nap on memory consolidation. Mednick, Nakayama, and Stickgold (2003) had subjects learn a nondeclarative visual discrimination task at 9:00 a.m. The subjects’ ability to perform the task was tested ten hours later, at 7:00 p.m. Some, but not all, of the subjects took a ninety-minute nap during the day between training and testing. The investigators recorded the EEGs of the sleeping subjects to determine which of them engaged in REM sleep and which of them did not. (Obviously, all of them engaged in slow-wave sleep, because this stage of sleep always comes first in healthy people.) The investigators found that the performance of subjects who did not take a nap was worse when they were tested at 7:00 p.m. than it had been at the end of training. The subjects who engaged only in slow-wave sleep did about the same during testing as they had done at the end of training. However, the subjects who engaged in REM sleep performed significantly better. Thus, REM sleep strongly facilitated the 10 consolidation of a nondeclarative memory. (See Figure 7.) In the second study, Tucker et al. (2006) trained subjects on two tasks: a declara5 tive task (learning a list of paired words) and a nondeclarative task (learning to trace a pencil-and-paper design while looking at the paper in a mirror). Afterwards, some of the subjects were permitted to take a nap lasting for about one hour. Their EEGs were 0 SWS + REM recorded, and they were awakened before they could engage in REM sleep. The subjects’ SWS only performance on the two tasks was then tested six hours after the original training. The –5 investigators found that compared with subjects who stayed awake, a nap consisting of just slow-wave sleep increased the subjects’ performance on the declarative task but had no effect on performance of the nondeclarative task. (See Figure 8.) So these two –10 experiments (and many others I have not described) indicate that REM sleep facilitates consolidation of nondeclarative memories, and slow-wave sleep facilitates consolidation –15 of declarative memories. No nap Peigneux et al. (2004) had human subjects learn their way around a computF I G U R E 7 REM Sleep and Learning. The erized virtual-reality town. This task is very similar to what people do when they graph shows the role of REM sleep in learning a learn their way around a real town. They must learn the relative locations of landnondeclarative visual discrimination task. Only after a marks and streets that connect them so that they can find particular locations when ninety-minute nap that included both slow-wave sleep and REM sleep did the subjects’ performance improve. the experimenter “places” them at various starting points. The hippocampus plays an essential role in learning of this kind. Peigneux and his colleagues used funcBased on data from Mednick, S., Nakayama, K., and Stickgold, R. Nature Neuroscience, 2003, 6, 697–698. tional brain imaging to measure regional brain activity and found that the same

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Improvement (sec)

50 Percent improvement

regions of the hippocampus were activated during route learning and during slow-wave sleep the following night. These patterns were not seen during REM sleep. Using a similar virtual reality navigation task, Wamsley et al. (2010) awakened their subjects from slow-wave sleep during an afternoon nap that followed training and asked them to report everything that was going through their mind. They found that subjects whose thoughts were related to the task performed much better during a subsequent session on the navigation task than those who did not report such thoughts. Thus, although people who are awakened during slow-wave sleep seldom report narrative dreams, the sleeping brain rehearses information that was acquired during the previous period of wakefulness. Many studies with laboratory animals have directly recorded the activity of individual neurons in the animals’ brains. These studies, too, indicate that the brain appears to rehearse newly learned information during slow-wave sleep.

40 30 20 10 0

Wake

Nap

Declarative Learning Task

–60 –40 –20 0

Wake

Nap

Nondeclarative Learning Task

F I G U R E 8 Slow-Wave Sleep and Learning. Subjects learned a declarative learning task (list of paired words) and a nondeclarative learning task (mirror tracing). After a nap that included just slow-wave sleep, only subjects who learned the declarative learning task showed improved performance, compared with subjects who stayed awake. Based on data from Tucker, M. A., Hirota, Y., Wamsley, E. J., Lau, H., Chaklader, A., and Fishbein, W. Neurobiology of Learning and Memory, 2006, 86, 241–247.

SECTION SUmmaRy Why Do We Sleep? The fact that all vertebrates sleep, including some that would seem to be better off without it, suggests that sleep performs some important functions. In humans the effects of several days of sleep deprivation include perceptual distortions, (sometimes) mild hallucinations, and difficulty performing tasks that require prolonged concentration. These effects suggest that sleep deprivation impairs cerebral functioning. Deep slowwave sleep appears to be the most important stage, and perhaps its function is to permit the brain to rest and recuperate. Fatal familial insomnia is an inherited disease that results in degeneration of parts of the thalamus, deficits in attention and memory, a dreamlike state, loss of control of the autonomic nervous system and the endocrine system, insomnia, and death. The primary function of sleep does not seem to be to provide an opportunity for the body to repair the wear and tear that occurs during waking hours. Changes in a person’s level of exercise do not significantly alter the amount of sleep the person needs the following night. Instead, the most important function of slow-wave sleep seems to be to lower the brain’s metabolism and permit the brain to rest. In support of this hypothesis, research has shown that slow-wave sleep does indeed reduce the brain’s metabolic rate.

The functions of REM sleep are even less understood than those of slow-wave sleep. REM sleep may promote brain development. Both REM sleep and slow-wave sleep promote learning: REM sleep facilitates nondeclarative learning, and slow-wave sleep facilitates declarative learning.

Thought Questions The evidence presented in this section suggests that the primary function of sleep is to permit the brain to rest. But could sleep also have some other functions? For example, could sleep serve as an adaptive response to keep animals out of harm’s way, as well as provide some cerebral repose? Sleep researcher William Dement pointed out that one of the functions of the lungs is communication. Obviously, the primary function of our lungs is to provide oxygen and rid the body of carbon dioxide, and this function explains the evolution of the respiratory system. But we can also use our lungs to vibrate our vocal cords and provide sounds used to talk, so they play a role in communication, too. Other functions of our lungs are to warm our cold hands (by breathing on them), to kindle fires by blowing on hot coals, and to blow out candles. With this perspective in mind, can you think of some other useful functions of sleep?

Physiological Mechanisms of Sleep and Waking So far, I have discussed the nature of sleep, problems associated with it, and its functions. Now it is time to examine what researchers have discovered about the physiological mechanisms that are responsible for the behavior of sleep and for its counterpart, alert wakefulness.

Chemical Control of Sleep As we have seen, sleep is regulated; that is, if an organism is deprived of slow-wave sleep or REM sleep, the organism will make up at least part of the missed sleep when permitted to do so.

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Inaddition, the amount of slow-wave sleep that a person obtains during a daytime nap is deducted from the amount of slow-wave sleep he or she obtains the next night (Karacan et al., 1970). These facts suggest that some physiological mechanism monitors the amount of sleep that an organism needs—in other words, keeps track of the sleep debt we incur during hours of wakefulness. The simplest explanation is that the body produces a sleep-promoting substance that accumulates during wakefulness and is destroyed during sleep. The longer someone is awake, the longer he or she has to sleep to deactivate this substance. If such a substance exists, it does not appear to be found in the general circulation of the body. As we saw earlier, the cerebral hemispheres of some species of animals can sleep at different times (Mukhametov, 1984). If sleep were controlled by chemicals in the blood, the hemispheres should sleep at the same time. This observation suggests that if sleep is controlled by chemicals, these chemicals are produced within the brain and act there. In support of this suggestion Oleksenko et al. (1992) obtained evidence that indicates that each hemisphere of the brain incurs its own sleep debt. The researchers deprived a bottlenose dolphin of sleep in only one hemisphere by waking the animal whenever that hemisphere entered a sleep state. When they allowed the animal to sleep normally, they saw a rebound of slow-wave sleep only in the deprived hemisphere. Benington, Kodali, and Heller (1995) suggested that adenosine, a nucleoside neuromodulator, might play a primary role in the control of sleep, and subsequent studies have supported this suggestion. Astrocytes maintain a small stock of nutrients in the form of glycogen, an insoluble carbohydrate that is also stocked by the liver and the muscles. In times of increased brain activity, this glycogen is converted into fuel for neurons; thus, prolonged wakefulness causes a decrease in the level of glycogen in the brain (Kong et al., 2002). A fall in the level of glycogen causes an increase in the level of extracellular adenosine, which has an inhibitory effect on neural activity. This accumulation of adenosine serves as a sleep-promoting substance. During slow-wave sleep, neurons in the brain rest, and the astrocytes renew their stock of glycogen (Basheer et al., 2004; Wigren et al., 2007). If wakefulness is prolonged, even more adenosine accumulates, which inhibits neural activity and produces the cognitive and emotional effects that are seen during sleep deprivation. (caffeine for example, blocks adenosine receptors. I don’t need to tell you the effect that caffeine has on sleepiness.) Halassa et al. (2009) prepared a targeted mutation in the brains of mice that interfered with the release of adenosine by astrocytes. As a result, the animals spent less time than normal in slow-wave sleep. As we all know, people differ in their sleep need. Evidence suggests that genetic factors affect the typical duration of a person’s slow-wave sleep. Rétey et al. (2005) discovered one of these factors—variability in the gene that encodes for an enzyme, adenosine deaminase, which is involved in the breakdown of adenosine. The investigators found that people with the G/A allele for this gene, which encodes for a form of the enzyme that breaks down adenosine more slowly, spent approximately thirty minutes more time in slow-wave sleep than did people with the more common G/G allele. Levels of adenosine in people with the G/A allele decreased more slowly during slow-wave sleep, and as a consequence the slow-wave sleep of these people was prolonged. The role of adenosine as a sleep-promoting factor is discussed in more detail later in this chapter, in a section devoted to the neural control of sleep.

Neural Control of arousal

adenosine (a den oh seen) A neuromodulator that is released by neurons engaging in high levels of metabolic activity; may play a primary role in the initiation of sleep.

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As we have seen, sleep is not a unitary condition but consists of several different stages with very different characteristics. The waking state, too, is nonuniform; sometimes we are alert and attentive, and sometimes we fail to notice much about what is happening around us. Of course, sleepiness has an effect on wakefulness; if we are fighting to stay awake, the struggle might impair our ability to concentrate on other things. But everyday observations suggest that even when we are not sleepy, our alertness can vary. For example, when we observe something very interesting (or frightening, or simply surprising), we become more alert and aware of our surroundings. Circuits of neurons that secrete at least five different neurotransmitters play a role in some aspect of an animal’s level of alertness and wakefulness—what is commonly called arousal: acetylcholine, norepinephrine, serotonin, histamine, and orexin (Wada et al., 1991; McCormick, 1992; Marrocco, Witte, and Davidson, 1994; Hungs and Mignot, 2001).

Sleep and Biological Rhythms

ACETyLChOLiNE

400

300 ACh (pyol//10µl)

One of the most important neurotransmitters involved in arousal— 300 especially of the cerebral cortex—is acetylcholine. Two groups of ACh 200 neurons, one in the dorsal pons and one located in the basal forebrain, 200 produce activation and cortical desynchrony when they are stimulated (Jones, 1990; Steriade, 1996). 100 100 Researchers have long known that ACh agonists increase EEG signs of cortical arousal and that ACh antagonists decrease them (Vanderwolf, 0 0 1992). Marrosu et al. (1995) used microdialysis probes to measure the SWS QW AW REM SWS QW AW REM release of acetylcholine in the hippocampus and neocortex—two regions Cortex Hippocampus whose activity is closely related to an animal’s alertness and behavioral F I G U R E 9 Release of Acetylcholine and the Sleep-Waking arousal. They found that the levels of ACh in these regions were high Cycle. The graphs show the release of acetylcholine from the cortex during both waking and REM sleep—periods during which the EEG dis- and hippocampus during the sleep-waking cycle. SWS = slow-wave played desynchronized activity—but low during slow-wave sleep. (See sleep, QW = quiet waking, AW = active waking. Figure 9.) In addition, Rasmusson, Clow, and Szerb (1994) electrically Based on data from Marrosu et al., 1995. stimulated a region of the dorsal pons and found that the stimulation activated the cerebral cortex and increased the release of acetylcholine there by 350 percent (as measured by microdialysis probes). A group of ACh neurons located in the basal forebrain forms an essential part of the pathway that is responsible for this effect. If these neurons were deactivated by infusing a local anesthetic or drugs that blocked synaptic transmission, the activating effects of the pontine stimulation were abolished. In contrast, Cape and Jones (2000) found that drugs that activated these neurons caused wakefulness. Lee et al. (2004) found that most neurons in the basal forebrain showed a high rate of firing during both waking and REM sleep and a low rate of firing during slow-wave sleep.

SEROTONiN A third neurotransmitter, serotonin (5-HT), also appears to play a role in activating behavior. Almost all of the brain’s serotonergic neurons are found in the raphe nuclei, which are located in the medullary and pontine regions of the reticular formation. The axons of these neurons project to many parts of the brain, including the thalamus, hypothalamus, basal ganglia, hippocampus, and neocortex. Stimulation of the raphe nuclei causes locomotion and cortical arousal (as measured by

Mean firing rate (spikes/sec)

NOREPiNEPhRiNE Investigators have long known that catecholamine agonists such as amphetamine produce arousal and sleeplessness. These effects appear to be mediated primarily by the noradrenergic system of locus coeruleus (sa roo lee us) A darkthe locus coeruleus, located in the dorsal pons. Neurons of the locus coeruleus give rise to axons colored group of noradrenergic cell bodies located in the pons near the that branch widely, releasing norepinephrine (from axonal varicosities) throughout the neocorrostral end of the floor of the fourth tex, hippocampus, thalamus, cerebellar cortex, pons, and medulla; thus, they potentially affect ventricle; involved in arousal and widespread and important regions of the brain. vigilance. Aston-Jones and Bloom (1981) recorded data from noradrenergic neurons of the locus coeraphe nuclei (ruh fay) A group of nuclei ruleus (LC) across the sleep-waking cycle in unrestrained rats. As Figure 10 shows, these neurons located in the reticular formation of the exhibited a close relationship to behavioral arousal. Note the decline in firing rate before and durmedulla, pons, and midbrain, situated ing sleep and the abrupt increase when the animal wakes. In addition, the rate of firing of neurons along the midline; contain serotonergic in the locus coeruleus falls almost to zero during REM sleep and increases dramatically when neurons. the animal wakes. (See Figure 10.) In an experiment using optogenetic methods, Carter etal. (2010) found that stimulation of locus coeruleus 50 neurons caused immediate waking, and that inhibition decreased wakefulness and increased slow-wave sleep. Most investigators believe that 40 activity of noradrenergic LC neurons increases an animal’s vigilance—its ability to pay attention to stimuli in the environment. In fact, a study by 30 Aston-Jones et al. (1994) found that the moment-to-moment activity of noradrenergic LC neurons was directly related to the animals’ current 20 Slow-wave REM Waking sleep sleep performance on a task that required vigilance. Waking 10 0

40 0 % Stage

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F I G U R E 10 Norepinephrine and the Sleep-Waking Cycle. This graph shows the activity of noradrenergic neurons in the locus coeruleus of freely moving rats during various stages of sleep and waking. Based on data from Aston-Jones, g., and Bloom, F. E. The Journal of Neuroscience, 1981, 1, 876–886. Copyright 1981, The Society for Neuroscience.

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the EEG), whereas PCPA, a drug that blocks the synthesis of serotonin, reduces cortical arousal (Peck and Vanderwolf, 1991). Figure 11 shows the activity of serotonergic neurons, recorded by Trulson and Jacobs (1979). As you can see, these neurons, like the noradrenergic neurons studied by Aston-Jones and Bloom (1981), were most active during waking. Their firing rate declined during slow-wave sleep and became virtually zero during REM sleep. However, once the period of REM sleep ended, the neurons temporarily became very active again. (See Figure 11.)

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The fourth neurotransmitter implicated in the control of wakefulness and arousal is histamine, a compound synthesized from histidine, an amino F I G U R E 11 Serotonin and the Sleep-Waking Cycle. This graph acid. You are undoubtedly aware that antihistamines, used to treat allershows the activity of serotonergic (5-HT-secreting) neurons in the dorsal gies, can cause drowsiness. They do so by blocking histamine receptors raphe nuclei of freely moving cats during various stages of sleep and in the brain. More modern antihistamines cannot cross the blood–brain waking. barrier, so they do not cause drowsiness. Based on data from Trulson, M. E., and Jacobs, B. L. Brain Research, 1979, 163, The cell bodies of histaminergic neurons are located in the 135–150. tuberomammillary nucleus (TMN) of the hypothalamus, located at the base of the brain just rostral to the mammillary bodies. The axons of these neurons project primarily to the cerebral cortex, thalamus, basal ganglia, basal forebrain, and other regions of the hypothalamus. The projections to the cerebral cortex directly increase cortical activation and arousal, and projections to ACh neurons of the basal forebrain and dorsal pons do so indirectly, by increasing the release of acetylcholine in the cerebral cortex (Khateb et al., 1995; Brown, Stevens, and Haas, 2001). The activity of histaminergic neurons is high during waking tuberomammillary nucleus (TMN) but low during slow-wave sleep and REM sleep (Steininger et al., 1996). In addition, injections A nucleus in the ventral posterior of drugs that prevent the synthesis of histamine or block histamine receptors decrease waking hypothalamus, just rostral to the and increase sleep (Lin, Sakai, and Jouvet, 1998). Also, infusion of histamine into the basal mammillary bodies; contains forebrain region of rats causes an increase in waking and a decrease in non-REM sleep (Ramesh histaminergic neurons involved in et al., 2004). cortical activation and behavioral arousal. Time

Exploration 5 sp/s

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Unit F I G U R E 12 Orexin and the Sleep-Waking Cycle. This graph shows the activity of single hypocretinergic neurons during various stages of sleep and waking. Based on data from Mileykovskiy, B. Y., Kiyashchenko, L. I., and Siegel, J. M. Neuron, 2005, 46, 787–798.

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ORExiN As we saw in the section on sleep disorders, the cause of narcolepsy is degeneration of orexinergic neurons in humans and a hereditary absence of orexin-B receptors in dogs. The cell bodies of neurons that secrete orexin (as we saw, also called hypocretin) are located in the lateral hypothalamus. Although there are only about 7000 orexinergic neurons in the human brain, the axons of these neurons project to almost every part of the brain, including the cerebral cortex and all of the regions involved in arousal and wakefulness, including the locus coeruleus, raphe nuclei, tuberomammillary nucleus, and acetylcholinergic neurons in the dorsal pons and basal forebrain (Sakurai, 2007). Orexin has an excitatory effect in all of these regions. Mileykovskiy, Kiyashchenko, and Siegel (2005) recorded the activity of single orexinergic neurons in unanesthetized rats and found that the neurons fired at a high rate during alert or active waking, and at a low rate during quiet waking, slow-wave sleep, and REM sleep. The highest rate of firing was seen when the rats were engaged in exploratory activity. (See Figure 12.) Adamantidis, Carter, and de Lecea (2010) used optogenetic methods to activate neurons in the lateral hypothalamus of mice, and found that this activation awakened the animals from either REM or non-REM sleep. As we saw earlier, narcolepsy is most often treated with modafinil, a drug that suppresses the drowsiness associated with this disorder. Ishizuka, Murotani, and Yamatodani (2010) found that the modafinil produces its alerting effects by stimulating the release of orexin in the TMN, which activates the histaminergic neurons located there.

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Neural Control of Slow-Wave Sleep Sleep is controlled by three factors: homeostatic, allostatic, and circadian. If we go without sleep for a long time, we will eventually become sleepy, and once we sleep, we will be likely to sleep longer than usual and make up at least some of our sleep debt. This control of sleep is homeostatic in nature, and follows the principles that regulate our eating and drinking. But under some conditions, it is important for us to stay awake—for example, when we are being threatened by a dangerous situation or when we are dehydrated and are looking for some water to drink. This control of sleep is allostatic in nature, and refers to reactions to stressful events in the environment (danger, lack of water, etc.) that serve to override homeostatic control. Finally, circadian factors, or time of day factors, tend to restrict our period of sleep to a particular portion of the day/night cycle. (Circadian control of sleep cycles is described in the last section of this chapter.) As we saw earlier in this chapter, the primary homeostatic factor that controls sleep is the presence or absence of adenosine, a chemical that accumulates in the brain during wakefulness and is destroyed during slow-wave sleep. Allostatic control is mediated primarily by hormonal and neural responses to stressful situations and by neuropeptides (such as orexin) that are involved in hunger and thirst. This subsection describes the neural circuitry that controls slow-wave sleep and the means by which adenosine exerts its homeostatic effect. When we are awake and alert, most of the neurons in our brain—especially those of the forebrain—are active, which enables us to pay attention to sensory information and process this information, to think about what we are perceiving, to retrieve and think about our memories, and to engage in a variety of behaviors that we are called on to perform during the day. The level of brain activity is largely controlled by the five sets of arousal neurons described in the previous section. A high level of activity of these neurons keeps us awake, and a low level puts us to sleep. But what controls the activity of the arousal neurons? What causes this activity to fall, thus putting us to sleep? The preoptic area, a region of the anterior hypothalamus, is the brain region most involved in the initiation of sleep. The preoptic area contains neurons whose axons form inhibitory synaptic connections with the brain’s arousal neurons. When our preoptic neurons (let’s call them sleep neurons) become active, they suppress the activity of our arousal neurons, and we fall asleep (Saper, Scammell, and Lu, 2005). The majority of the sleep neurons are located in the ventrolateral preoptic area (vlPOA). Damage to vlPOA neurons suppresses sleep (Lu et al., 2000), and the activity of these neurons, measured by their levels of Fos protein, increases during sleep. Experiments have shown that the sleep neurons secrete the inhibitory neurotransmitter GABA, and that they send their axons to the five brain regions involved in arousal described in the previous section (Sherin et al., 1998; Gvilia et al., 2006; Suntsova et al., 2007). As we saw, activity of neurons in these five regions causes cortical activation and behavioral arousal. Inhibition of these regions, then, is a necessary condition for sleep. The sleep neurons in the vlPOA receive inhibitory inputs from some of the same regions they inhibit, including the tuberomammillary nucleus, raphe nuclei, and locus coeruleus (Chou et al., 2002). As Saper and his colleagues (2001, 2010) suggest, this mutual inhibition may provide the basis for establishing periods of sleep and waking. They note that reciprocal inhibition also characterizes an electronic circuit known as a flip-flop. A flip-flop can assume one of two states, usually referred to as on or off—or 0 or 1 in computer applications. Thus, either the sleep neurons are active and inhibit the wakefulness neurons or the wakefulness neurons are active and inhibit the sleep neurons. Because these regions are mutually inhibitory, it is impossible for neurons in both sets of regions to be active at the same time. In fact, sleep neurons in the vlPOA are silent until an animal shows a transition from waking to sleep (Takahashi, Lin, and Sakai, 2009). (See Figure 13.) A flip-flop has an important advantage: When it switches from one state to the other, it does so quickly. Clearly, it is most advantageous to be either asleep or awake; a state that has some of the characteristics of both sleep and wakefulness would be maladaptive. However, there is one problem with flip-flops: They can be unstable. In fact, people with narcolepsy and animals with damage to the orexinergic system of neurons exhibit just this characteristic. They

ventrolateral preoptic area (vlPOA) A group of gABAergic neurons in the preoptic area whose activity suppresses alertness and behavioral arousal and promotes sleep.

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Inhibited

Mutual inhibition

Sleep-promoting region in vlPOA

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F I G U R E 13 The Sleep/Waking flip-flop. According to Saper et al. (2001), the major sleep-promoting region (the vlPOA) and the major wakefulness-promoting regions (basal forebrain and pontine regions that contain acetylcholinergic neurons; the locus coeruleus, which contains noradrenergic neurons; the raphe nuclei, which contain serotonergic neurons; and the tuberomammillary nucleus of the hypothalamus, which contains histaminergic neurons) are reciprocally connected by inhibitory gABAergic neurons. (a) When the flip-flop is in the “wake” state, the arousal systems are active, the vlPOA is inhibited, and the animal is awake. (b) When the flip-flop is in the “sleep” state, the vlPOA is active, the arousal systems are inhibited, and the animal is asleep.

have great difficulty remaining awake when nothing interesting is happening, and they have trouble remaining asleep for an extended amount of time. (They also show intrusions of the characteristics of REM sleep at inappropriate times. I will discuss this phenomenon in the next section.) Saper et al. (2001, 2010) suggest that an important function of orexinergic neurons is to help stabilize the sleep/waking flip-flop through their excitatory connections to the wakefulness neurons. Activity of this system of neurons tips the activity of the flip-flop toward the waking state, thus promoting wakefulness and inhibiting sleep. Perhaps your success at staying awake during a boring lecture depends on maintaining a high rate of firing of your orexinergic neurons, which would keep the flip-flop in the waking state. (See Figure 14.) A mathematical model of the sleep/ waking flip-flop constructed by Rempe, Best, and Terman (2010) confirmed the role of orexigenic neurons in stabilizing the circuit. As we saw earlier in this chapter, adenosine is released by astrocytes when neurons are metabolically active, and the accumulation of adenosine produces drowsiness and sleep. Porkka-Heiskanen, Strecker, and McCarley (2000) used microdialysis to measure adenosine levels in several regions of the brain. They found that the level of adenosine increased during wakefulness and slowly decreased during sleep, Mutual especially in the basal forebrain. Scammell et al. (2001) found that infuInhibited Activated inhibition sion of an adenosine agonist into the vlPOA activated neurons there, Brain stem decreased the activity of histaminergic neurons of the tuberomammilSleep-promoting and forebrain region in vlPOA lary nucleus, and increased slow-wave sleep. arousal systems Seeing that orexinergic neurons help hold the sleep/waking flipflop in the waking state, the obvious question to ask is what factors control the activity of orexinergic neurons? During the waking part ACh NE 5-HT Histamine of the day/night cycle, orexinergic neurons receive an excitatory signal from the biological clock that controls daily rhythms of sleep and Alert Waking State waking. These neurons also receive signals from brain mechanisms that monitor the animal’s nutritional state: Hunger-related signals Motivation Orexinergic activate orexinergic neurons, and satiety-related signals inhibit them. to remain neurons in awake Thus, orexinergic neurons maintain arousal during the times that an the lateral hypothalamus animal should search for food. In fact, if normal mice (but not mice with a targeted mutation against orexin receptors) are given less food Activation holds flip-flop “on” than they would normally eat, they stay awake longer each day (Yamanaka et al., 2003; Sakurai, 2007). Finally, orexinergic neurons reF I G U R E 14 Role of Orexinergic Neurons in Sleep. The schematic ceive inhibitory input from the vlPOA, which means that sleep signals diagram shows the effect of activation of the orexinergic system of that arise from the accumulation of adenosine can eventually overneurons of the lateral hypothalamus on the sleep/waking flip-flop. come excitatory input to orexinergic neurons and sleep can occur. Motivation to remain awake or events that disturb sleep activate the (See Figure 15.) orexinergic neurons.

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Neural Control of REm Sleep As we saw earlier in this chapter, REM sleep consists of desynchronized EEG activity, muscular paralysis, rapid eye movements, and increased genital activity. The rate of cerebral metabolism during REM sleep is as high as it is during waking (Maquet et al., 1990), and were it not for the state of paralysis, the level of physical activity would also be high. As we shall see, REM sleep is controlled by a flip-flop similar to the one that controls cycles of sleep and waking. The sleep/waking flip-flop determines when we wake and when we sleep, and once we fall asleep, the REM flip-flop controls our cycles of REM sleep and slow-wave sleep.

Prolonged wakefulness and metabolic activity of neuron in brain

Sleep/Waking Flip-Flop SWS-on region

Accumulation of adenosine

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signals As we saw earlier in this chapter, acetylcholinergic neurons play an important role in cerebral activation during alert wakefulness. Researchers Satiety signals have also found that they are involved in the neocortical activation that accompanies REM sleep. For example, El Mansari, Sakai, and Jouvet (1989) found that ACh neurons in the dorsal pons fire at a high rate F I G U R E 15 Adenosine, Time of Day, and hunger. This figure shows the role of adenosine, time of day, and hunger and satiety signals during both REM sleep and active wakefulness or during REM sleep on the sleep/waking flip-flop. alone. (See Figure 16.) Such findings suggested that the ACh neurons of sublaterodorsal nucleus (SLD) A region the dorsal pons served as the trigger mechanism that initiated a period of the dorsal pons, just ventral to the of REM sleep. However, more recent research suggests that although ACh neurons are involved locus coeruleus, that forms the REM-ON in neocortical activation that accompanies REM sleep, they are not part of the REM flip-flop. portion of the REM sleep flip-flop. Reviews by Fort, Bassetti, and Luppi (2009) and Saper et al. (2010) summarize the evidence ventrolateral periaqueductal gray for the REM flip-flop. A region of the dorsal pons, just ventral to the locus coeruleus, contains matter (vlPAG) A region of the dorsal REM-ON neurons. In rats, this region is known as the sublaterodorsal nucleus (SLD). A remidbrain that forms the REM-OFF portion gion of the dorsal midbrain, the ventrolateral periaqueductal gray matter (vlPAG), contains of the REM sleep flip-flop. REM-OFF neurons. For simplicity, I will simply refer to the REM-ON and REM-OFF regions. The REM-ON and REM-OFF regions are interWaking connected by means of inhibitory GABAergic neurons. Stimulation of the REM-ON region with infusions of glutamate agonists elicits most of Slow-wave the elements of REM sleep, whereas inhibition of this region with GABA sleep agonists disrupts REM sleep. In contrast, stimulation of the REM-OFF REM sleep region suppresses REM sleep, whereas damage to this region or infusion of GABA agonists dramatically increases REM sleep. (See Figure 17.) 10 sec (a) The mutual inhibition of these two regions means that they function like a flip-flop: Only one region can be active at any given time. During 20 waking, the REM-OFF region receives excitatory input from the orexinergic neurons of the lateral hypothalamus, and this activation tips the REM Slow-wave sleep Pre-REM sleep flip-flop into the OFF state. Additional excitatory input to the REM-OFF 10 region is received from two other sets of wakefulness neurons, the noradREM sleep renergic neurons of the locus coeruleus and the serotonergic neurons of the raphe nuclei. 0 When the sleep/waking flip-flop switches into the sleep phase, slow3 0 2 1 1 wave sleep begins. The activity of the excitatory orexinergic, noradrenerTime (min) gic, and serotonergic inputs to the REM-OFF region begins to decrease. As (b) a consequence, the excitatory input to the REM-OFF region is removed. F I G U R E 16 firing Pattern of a REM-ON Cell. The acetylcholinergic The REM flip-flop tips to the ON state, and REM sleep begins. PresumREM-ON cell is located in the dorsal pons. The figure shows (a) action ably, an internal clock—perhaps located in the pons—controls the alterpotentials during sixty-minute intervals during waking, slow-wave nating periods of REM sleep and slow-wave sleep that follow. Figure 18 sleep, and REM sleep, and (b) the rate of firing just before and after the shows the control of the REM-sleep flip-flop by the sleep/waking flip-flop. transition from slow-wave sleep to REM sleep. The increase in activity begins approximately 80 seconds before the onset of REM sleep. (See Figure 18.) Adapted from El Mansari, M., Sakai, K., and Jouvet, M. Experimental Brain Research, 1989, 76, 519–529.

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We can see now why degeneration of orexinergic neurons causes narcolepsy. The daytime sleepiness and the fragmented sleep occur because without REM-OFF REM-ON the influence of orexin, the sleep/waking flip-flop becomes unstable. The secretion of orexin in the SLD vlPAG REM-OFF region normally keeps the REM flip-flop in the OFF state. With the loss of orexinergic neurons, emotional episodes such as laughter or anger, which activate the amygdala, tip the REM flip-flop Brain regions that into the ON state—even during waking—and the control components result is an attack of cataplexy. (See Figure18.) In of REM sleep fact, a functional imaging study by Schwartz etal. (2008) found that when people with cataplexy watched humorous sequences of photographs, the hypothalamus was activated less, and the amygdala was activated more, than the same structures in control subjects. The investigators suggest that the loss of hypocretinergic neurons removed an inhibitory influence of the hypothalamus on the amygdala. The increased amygdala activity could account at least in part for the increased activity of REM-ON neurons that occurs even during waking in people with cataplexy. (See Figure 19.) As we saw earlier, patients with REM sleep behavior disorder fail to become paralyzed during REM sleep and therefore act out their dreams. The same thing happens to cats when a lesion is placed in a particular region of the midbrain. Jouvet (1972) described this phenomenon: REM Sleep Flip-Flop

Biological clock–time of day Hunger signals

LH orexinergic neurons

Satiety signals

FIGURE

The REM Sleep flip-flop.

To a naive observer, the cat, which is standing, looks awake since it may attack unknown enemies, play with an absent mouse, or display flight behavior. There are orienting movements of the head or eyes toward imaginary stimuli, although the animal does not respond to visual or auditory stimuli. These extraordinary episodes . . . are a good argument that “dreaming” occurs during [REM sleep] in the cat. (Jouvet, 1972, pp. 236–237)

Jouvet’s lesions destroyed a set of neurons that are responsible for the muscular paralysis that occurs during REM sleep. These “paralysis neurons” are located just ventral to the area we now know to be part of the REM-ON region (Lai et al., 2010). Some of the axons that leave this region travel to the spinal cord, where they excite inhibitory interneurons whose axons form synapses with motor neurons. This means that when the REM flip-flop tips to the ON state, motor neurons in the spinal cord become inhibited, and cannot respond to the signals arising from the motor cortex in the course of a dream. Damage to the “paralysis neurons” removes

Sleep/Waking Flip-Flop SWS-on region vlPOA

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F I G U R E 18 REM Sleep. This schematic diagram shows the interaction between the sleep/waking flip-flop and the REM sleep flip-flop.

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fMRI effect size F I G U R E 19 humor and Narcolepsy. The graph shows the activation of the hypothalamus and amygdala in normal subjects and patients with narcolepsy watching neutral and humorous sequences of photos. Based on data from Schwartz et al., 2008.

Sleep and Biological Rhythms

this inhibition, and the person (or one of Jouvet’s cats) acts out his or her dreams. (See Figure20.) The fact that our brains contain an elaborate mechanism whose sole function is to keep us paralyzed while we dream—that is, to prevent us from acting out our dreams—suggests that the motor components of dreams are as important as the sensory components. Perhaps the practice our motor system gets during REM sleep helps us to improve our performance of behaviors we have learned that day. The inhibition of the motor neurons in the spinal cord prevents the movements being practiced from actually occurring, with the exception of a few harmless twitches of the hands and feet. Little is known about the function of genital activity that occurs during REM sleep or about the neural mechanisms responsible for them. A study by Schmidt et al. (2000) found that lesions of the lateral preoptic area in rats suppressed penile erections during REM sleep but had no effect on erections during waking. Salas et al. (2007) found that penile erections could be triggered by electrical stimulation of acetylcholinergic neurons in the pons that become active during REM sleep. The investigators note that evidence suggests that these pontine neurons may be directly connected with neurons in the lateral preoptic area and thus may be responsible for the erections. (See Figure 20).

REM Sleep Flip-Flop REM-OFF

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Motor neurons

Tectum Movements REMs F I G U R E 20 Control of REM Sleep. The diagram shows components of REM sleep that are controlled by the REM-ON region.

SECTION SUmmaRy Physiological mechanisms of Sleep and Waking The fact that the amount of sleep is regulated suggests that a sleeppromoting substance is produced during wakefulness and destroyed during sleep. The sleeping pattern of the dolphin brain suggests that such a substance does not accumulate in the blood. Instead, evidence suggests that adenosine, released when neurons are obliged to utilize the supply of glycogen stored in astrocytes, serves as the link between increased brain metabolism and the necessity of sleep. Five systems of neurons appear to be important for alert, active wakefulness: the acetylcholinergic system of the dorsal pons and the basal forebrain, involved in cortical activation; the noradrenergic system of the locus coeruleus, involved in vigilance; the serotonergic system of the raphe nuclei, involved in activation of automatic behaviors such as locomotion; the histaminergic neurons of the tuberomammillary nucleus, involved in maintaining wakefulness; and the orexinergic system of the lateral hypothalamus, also involved in maintaining wakefulness. Slow-wave sleep occurs when neurons in the ventrolateral preoptic area (vlPOA) become active. These neurons inhibit the systems of neurons that promote wakefulness. In turn, the vlPOA is inhibited by these same wakefulness-promoting regions, thus forming a kind of flip-flop that keeps us either awake or asleep. The accumulation of adenosine promotes sleep by activating the sleep-promoting neurons of the vlPOA, which inhibits the wakefulness-promoting regions. Activity of the

orexinergic neurons of the lateral hypothalamus helps keep the flip-flop that controls sleep and waking in the “waking” state. REM sleep is controlled by another flip-flop. The sublaterodorsal nucleus (SLD) serves as the REM-ON region, and the ventrolateral periaqueductal gray region (vlPAg) serves as the REM-OFF region. This flip-flop is controlled by the sleep/waking flip-flop; only when the sleep/waking flip-flop is in the “sleeping” state can the REM flip-flop switch to the “REM” state. The muscular paralysis that prevents us from acting out our dreams is produced by connections between neurons adjacent to the SLD that excite inhibitory interneurons in the spinal cord. Penile erections during REM sleep (but not during waking) are abolished by lesions of the lateral preoptic area. Rapid eye movements are produced by indirect connections between the SLD and the tectum, through the medial pontine reticular formation and acetylcholinergic neurons in the pons.

Thought Questions Have you ever been lying in bed, almost asleep, when you suddenly thought of something important you had forgotten to do? Did you then suddenly become fully awake and alert? If so, neurons in your brain stem arousal systems undoubtedly became active, which aroused your cerebral cortex. What do you think the source of this activation was? What activated your brain stem arousal systems? How would you go about answering this question?

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Biological Clocks Much of our behavior follows regular rhythms. For example, we saw that the stages of sleep are organized around a ninety-minute cycle of REM and slow-wave sleep. And, of course, our daily pattern of sleep and waking follows a twenty-four-hour cycle. In recent years investigators have learned much about the neural mechanisms that are responsible for these rhythms.

Circadian Rhythms and Zeitgebers Daily rhythms in behavior and physiological processes are found throughout the plant and animal world. These cycles are generally called circadian rhythms. (Circa means “about,” and dies means “day”; therefore, a circadian rhythm is one with a cycle of approximately twenty-four hours.) Some of these rhythms are passive responses to changes in illumination. However, other rhythms are controlled by mechanisms within the organism—by “internal clocks.” For example, Figure 21 shows an idealized activity record of a rat during various conditions of illumination. Each horizontal line represents twenty-four hours. Black lines indicate the time the rat spends in wakefulness. Remember, rats are nocturnal animals, active at night. Of course, actual records from a rat would show more variability and some short periods of waking during the day and perhaps some catnaps (ratnaps?) during the night. The upper portion of the figure shows the activity of the rat during a normal day–night cycle, with alternating twelve-hour periods of light circadian rhythm (sur kay dee un or sur and dark. (See Figure 21.) ka dee un) A daily rhythmical change in Next, the dark–light cycle was shifted; the dark cycle now came on four hours earlier. The behavior or physiological process. animal’s activity cycle quickly followed the change. (See the middle portion of Figure 21.) Fizeitgeber (tsite gay ber) A stimulus nally, dim lights were left on continuously. The cyclical pattern in the rat’s activity remained. (usually the light of dawn) that resets the Because there were no cycles of light and dark in the rat’s environment, the source of rhythmicbiological clock that is responsible for circadian rhythms. ity must be located within the animal; that is, the animal must possess an internal, biological clock. You can see that the rat’s clock was not set precisely to twentyfour hours; when the illumination was held constant, the clock ran a Noon 6 PM 6 AM Noon bit slow. The animal began its bout of activity approximately one hour later each day. (See the bottom portion of Figure 21.) The phenomenon illustrated in Figure 21 is typical of the circadian Days rhythms shown by many species. A free-running clock, with a cycle of approximately twenty-five hours, controls some biological functions— in this case, sleep and wakefulness. Regular daily variation in the level of illumination (that is, sunlight and darkness) normally keeps the clock adjusted to twenty-four hours. Light serves as a zeitgeber (German for “time giver”); it synchronizes the endogenous rhythm. Studies with many species of animals have shown that if they are maintained in constant darkness (or constant dim light), a brief period of bright light will reset their internal clock, advancing or retarding it, depending upon when the light flash occurs (Aschoff, 1979). For example, if an animal is exposed to bright light soon after dusk, the biological clock is set back to an earlier time—as if dusk had not yet arrived. On the other hand, if the light occurs late at night, the biological clock is set ahead to a later time—as if dawn had already come. People, too, have circadian rhythms, but without the benefits of modern civilization we would probably go to sleep earlier and get up earlier than we do; we use artificial lights to delay our bedtime and window shades to extend our time for sleep. Under constant illumination our biological clocks will run free, gaining or losing time like F I G U R E 21 Circadian Rhythms of Wheel-Running Activity of a Rat. Top: The animal’s activity occurs at “night” (that is, during the a watch that runs too slow or too fast. Different people have different twelve hours the light is off). Middle: The period of waking follows the cycle lengths, but most people in that situation will begin to live a new dark period when the light cycle is changed. Bottom: When the “day” that is approximately twenty-five hours long. This works out animal is maintained in constant dim illumination, it displays a freequite well, because the morning light, acting as a zeitgeber, simply running activity cycle of approximately twenty-five hours, which means resets the clock. that its period of waking begins about one hour later each day.

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The Suprachiasmatic Nucleus Researchers working independently in two laboratories (Moore and Eichler, 1972; Stephan and Zucker, 1972) discovered that the primary biological clock of the rat is located in the suprachiasmatic nucleus (SCN) of the hypothalamus; they found that lesions disrupted circadian rhythms of wheel running, drinking, and hormonal secretion. The SCN also provides the primary control over the timing of sleep cycles. Rats are nocturnal animals; they sleep during the day and forage and feed at night. Lesions of the SCN abolish this pattern; sleep occurs in bouts randomly dispersed throughout both day and night (Ibuka and Kawamura, 1975; Stephan and Nuñez, 1977). However, rats with SCN lesions still obtain the same amount of sleep that normal animals do. The lesions disrupt the circadian control of sleep but do not affect the homeostatic control of sleep.

F I G U R E 22 The SCN. The figure shows the location and appearance of the suprachiasmatic nuclei in a rat. Cresyl violet stain was used to color the nuclei in this cross section of a rat brain.

ANATOMy AND CONNECTiONS Figure 22 shows the suprachiasmatic nuclei in a cross section through the hypothalamus of a rat; they appear as two clusters of dark-staining neurons at the base of the Courtesy of geert Devries, University of Massachusetts. brain, just above the optic chiasm. (See Figure 22.) The suprachiasmatic nuclei of the rat consist of approximately 8600 small neurons, tightly packed into a volume of 0.036 mm3 (Moore, Speh, and Leak, 2002). Because light is the primary zeitgeber for most mammals’ activity cycles, we would expect that the SCN receives fibers from the visual system. Indeed, anatomical studies have revealed a direct projection of fibers from the retina to the SCN: the retinohypothalamic pathway (Hendrickson, Wagoner, and Cowan, 1972; Aronson et al., 1993). The photoreceptors in the retina that provide photic information to the SCN are neither rods nor cones—the cells that provide us with the information used for visual perception. Indeed, Freedman et al. (1999) found that targeted mutations against genes necessary for production suprachiasmatic nucleus (SCN) (soo pra ky az mat ik) A nucleus situated atop of both rods and cones did not disrupt the synchronizing effects of light. However, when they the optic chiasm. It contains a biological removed the mice’s eyes, these effects were disrupted. These results suggested that there is a speclock that is responsible for organizing cial photoreceptor that provides information about the ambient level of light that synchronizes many of the body’s circadian rhythms. circadian rhythms. Provencio et al. (2000) found the photochemical responsible for this effect, melanopsin (mell a nop sin) A which they named melanopsin. photopigment present in ganglion Unlike the other retinal photopigments, which are found in rods and cones, melanopsin is cells in the retina whose axons transmit present in ganglion cells—the neurons whose axons transmit information from the eyes to the information to the SCN, the thalamus, rest of the brain. Melanopsin-containing ganglion cells are sensitive to light, and their axons terand the olivary pretectal nuclei. minate in the SCN and in a region of the tectum involved in the pupils’ response to light (Berson, Dunn, and Takao, 2002; Hattar et al., 2002). (See Figure 23.) Evidence indicates that SCN controls cycles of sleep and waking by two means: direct neural connections and the secretion of chemicals that affect the activity of neurons in other regions of the brain. Researchers have found multisynaptic pathways from the SCN to the subparaventricular zone (SPZ), located just dorsal to the SCN, to the dorsomedial nucleus of the hypothalamus (DMH) and then to regions involved in the control of sleep and waking, such as the vlPOA and the orexinergic neurons of the lateral hypothalamus. The projections to the vlPOA are inhibitory and thus inhibit sleep, whereas the projections to the orexinergic neurons are excitatory, and thus promote wakefulness (Saper, Scammell, and Lu, 2005). Of course, the activity of these connections varies across the day/night cycle. In diurnal animals (such as ourselves), the activity of these connections are high during the day and low during the night. (See Figure 24.) Although neurons of the SCN project to several parts of the brain, transplan- F I G U R E 23 Melanopsin-Containing Ganglion Cells tation studies suggest that the SCN controls some functions by releasing chemical in the Retina. The axons of the ganglion cells form the retinohypothalamic tract. These neurons detect the light signals into the brain’s extracellular fluid. Lehman et al. (1987) destroyed the SCN of dawn that resets the biological clock in the SCN. and then transplanted in their place a new set of suprachiasmatic nuclei obtained Hattar, S., Liao, H.-W., Takao, M., et al. Science, 2002, 295, from donor animals. The grafts succeeded in reestablishing circadian rhythms, From 1065–1070. Copyright © 2002 The American Association for the even though very few efferent connections were observed between the graft and the Advancement of Science. Reprinted with permission.

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Sleep/Waking Flip-Flop

SCN biological clock– time of the day

SPZ

DMH

SWS-on region

Waking-on region

vlPOA

Arousal system

Opposite effects of DMH activity

ACh NE 5-HT Histamine LH orexinergic neurons

F I G U R E 24 Control of Circadian Rhythms. The SCN controls circadian rhythms in sleep and waking. During the day cycle, the DMH inhibits the vlPOA and excites the brain stem and forebrain arousal systems, thus stimulating wakefulness.

recipient’s brain. Even more convincing evidence comes from a transplantation study by Silver et al. (1996). Silver and her colleagues first destroyed the SCN in a group of hamsters, abolishing their circadian rhythms. Then, a few weeks later, they removed SCN tissue from donor animals and placed it in very small semipermeable capsules, which they then implanted in the animals’ third ventricles. Nutrients and other chemicals could pass through the walls of the capsules, keeping the SCN tissue alive, but the neurons inside the capsules were not able to establish synaptic connections with the surrounding tissue. Nevertheless, the transplants reestablished circadian rhythms in the recipient animals. Presumably, the chemicals secreted by cells in the SCN affect rhythms of sleep and waking by diffusing into the SPZ and binding with receptors on neurons located there.

F I G U R E 25 Circadian Activity Rhythms in the SCN. The autoradiographs show cross sections through the brains of rats that had been injected with carbon 14-labeled 2-deoxyglucose during the day (top) and the night (bottom). The dark region at the base of the brain (arrows) indicates increased metabolic activity of the suprachiasmatic nuclei. From Schwartz, W. J., and gainer, H. Science, 1977, 197, 1089–1091. Copyright © 1977 The American Association for the Advancement of Science. Reprinted with permission.

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ThE NATURE Of ThE CLOCk All clocks must have a time base. Mechanical clocks use flywheels or pendulums; electronic clocks use quartz crystals. The SCN, too, must contain a physiological mechanism that parses time into units. After years of research, investigators are finally beginning to discover the nature of the biological clock in the SCN. Several studies have demonstrated daily activity rhythms in the SCN, which indicates that the circadian clock is located there. A study by Schwartz and Gainer (1977) nicely demonstrated day–night fluctuations in the activity of the SCN. These investigators injected some rats with radioactive 2-DG during the day and injected others at night. The animals were then killed, and autoradiographs of cross sections through the brain were prepared. Figure 25 shows photographs of two of these cross sections. Note the evidence of radioactivity (and hence a high metabolic rate) in the SCN of the brain that was injected during the day (top). (See Figure 25.) What causes SCN neurons to “tick”? For many years investigators have believed that circadian rhythms were produced by the production of a protein that, when it reached a certain level in the cell, inhibited its own production. As a result, the levels of the protein would begintodecline, which would remove the inhibition, starting the production cycle again. (See Figure 26.) Just such a mechanism was discovered in Drosophila melanogaster, the common fruit fly. Subsequent research with mammals discovered a similar system. (See Golombeck and Rosenstein, 2010, for a review.) The system involves at least seven genes and their proteins and two interlocking feedback loops. When one of the proteins produced by the first loop reaches a sufficient level, it starts the second loop, which eventually inhibits the production of proteins in the first loop, and the cycle begins again. Thus, the intracellular ticking is regulated by the time it takes to produce and degrade a set of proteins. It appears that the circadian clock in the human brain works the same way. Toh et al. (2001) found that a mutation on chromosome 2 of a gene for one of the proteins involved in these

Sleep and Biological Rhythms

Protein The protein enters the nucleus, suppressing the gene responsible for its production. No more messenger RNA is made.

The level of the protein falls, so the gene becomes active again.

mRNA Gene

Protein Nucleus

Cytoplasm

The gene is active; messenger RNA leaves the nucleus and causes the production of the protein. F I G U R E 26 Control of Circadian Rhythms in the SCN. This schematic is a simplified explanation of the molecular control of the “ticking” of neurons of the SCN.

feedback loops (per2) is responsible for the advanced sleep phase syndrome. This syndrome causes a four-hour advance in rhythms of sleep and temperature cycles. People with this syndrome fall asleep around 7:30 p.m. and awaken around 4:30 a.m. The mutation appears to change the relationship between the zeitgeber of morning light and the phase of the circadian clock that operates in the cells of the SCN. Ebisawa et al. (2001) found evidence that the opposite disorder, the delayed sleep phase syndrome, may be caused by mutations of the per3 gene, found on chromosome 1. This syndrome consists of a four-hour delay in sleep/waking rhythms. People with this disorder are typically unable to fall asleep before 2:00 a.m. and have great difficulty waking before midmorning. Allebrandt et al. (2010) found yet another set of gene variants (in the clock gene) that affect people’s sleep duration.

Changes in Circadian Rhythms: Shift Work and Jet Lag

advanced sleep phase syndrome A four-hour advance in rhythms of sleep and temperature cycles, apparently caused by a mutation of a gene (per2) involved in the rhythmicity of neurons of the SCN. delayed sleep phase syndrome A four-hour delay in rhythms of sleep and

When people abruptly change their daily rhythms of activity, their internal circadian rhythms, temperature cycles, possibly caused by a controlled by the SCN, become desynchronized with those in the external environment. For mutation of a gene (per3) involved in the example, if a person who normally works on a day shift begins working on a night shift or if rhythmicity of neurons of the SCN. someone travels east or west across several time zones, his or her SCN will signal the rest of the brain that it is time to sleep during the work shift (or the middle of the day, in the case of jet travel). This disparity between internal rhythms and the external environment results in sleep disturbances and mood changes and interferes with people’s ability to function during waking hours. Problems such as ulcers, depression, and accidents related to sleepiness are more common in people who have work schedules that regularly shift (Drake et al., 2004). Jet lag is a temporary phenomenon; after several days people who have crossed several time zones find it easier to fall asleep at the appropriate time, and their daytime alertness improves. Shift work can present a more enduring problem when people are required to change shifts frequently. Obviously, the solution to jet lag and to the problems caused by shift work is to get the internal clock synchronized with the external environment as quickly as possible. The most obvious way to start is to try to provide strong zeitgebers at the appropriate time. If a person is exposed to bright light before the low point in the daily rhythm of body temperature (which occurs an hour or two before the person usually awakens), the person’s circadian rhythm is delayed. If the exposure to bright light occurs after the low point, the Researchers are beginning to understand the role of the circadian rhythm is advanced (Dijk et al., 1995). In fact, several studies have suprachiasmatic nucleus and the pineal gland in phenomena shown that exposure to bright lights at the appropriate time helps to ease the such as jet lag. transition (Boulos et al., 1995). Similarly, people adapt to shift work more © Denkou Images / Alamy

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pineal gland (py nee ul) A gland attached to the dorsal tectum; produces melatonin and plays a role in circadian and seasonal rhythms. melatonin (mell a tone in) A hormone secreted during the night by the pineal body; plays a role in circadian and seasonal rhythms.

rapidly if artificial light is kept at a brighter level and if their bedroom is kept as dark as possible (Eastman et al., 1995). The control of biological rhythms also involves another part of the brain: the pineal gland (Bartness et al., 1993). This structure sits on top of the midbrain, just in front of the cerebellum. The pineal gland secretes a hormone called melatonin, so named because it has the ability in certain animals (primarily fish, reptiles, and amphibians) to turn the skin temporarily dark. (The dark color is produced by a chemical known as melanin.) Neurons in the SCN make synaptic connections with neurons in the paraventricular nucleus of the hypothalamus (the PVN). The axons of these neurons travel all the way to the spinal cord, where they form synapses with preganglionic neurons of the sympathetic nervous system. The postganglionic neurons innervate the pineal gland and control the secretion of melatonin. In response to input from the SCN, the pineal gland secretes melatonin during the night. This melatonin acts back on various structures in the brain (including the SCN, whose cells contain melatonin receptors) and controls various hormones, physiological processes, and behaviors. Studies have found that melatonin, acting on receptors in the SCN, can affect the sensitivity of SCN neurons to zeitgebers and can itself alter circadian rhythms (Gillette and McArthur, 1995; Starkey et al., 1995). Researchers do not yet understand exactly what role melatonin plays in the control of circadian rhythms, but they have already discovered practical applications. Melatonin secretion normally reaches its highest levels early in the night, at around bedtime. Investigators have found that the administration of melatonin at the appropriate time (in most cases, just before going to bed) significantly reduces the adverse effects of both jet lag and shifts in work schedules (Arendt et al., 1995; Deacon and Arendt, 1996). Blind people who have lost their eyes or sustained retinal damage that includes their melanopsin-containing ganglion cells as well as their rods and cones will show unsynchronized, free-running circadian rhythms. In such cases, bedtime melatonin has been used to synchronize their circadian rhythms and has improved their cycles of sleep (Skene, Lockley, and Arendt, 1999).

SECTION SUmmaRy Biological Clocks Our daily lives are characterized by cycles in physical activity, sleep, body temperature, secretion of hormones, and many other physiological changes. Circadian rhythms—those with a period of approximately one day—are controlled by biological clocks in the brain. The principal biological clock appears to be located in the suprachiasmatic nuclei of the hypothalamus; lesions of these nuclei disrupt most circadian rhythms, and the activity of neurons located there correlates with the day–night cycle. Light, detected by special cells in the retina that are not involved in visual perception, serves as a zeitgeber for most circadian rhythms. The human biological clocks tend to run a bit slow, with a period of approximately twenty-five hours. The presence of sunlight in the morning is detected by melanopsin-containing photoreceptors in the retina, conveyed to the SCN, and the daily cycle is resynchronized. “Ticking” of the neurons that constitute the biological clock in the SCN is accomplished by cycles of production and destruction of proteins. At least seven genes and their proteins and two interlocking feedback loops are involved in this process. Two human genetic disorders, advanced sleep phase syndrome and delayed sleep phase syndrome, are caused by a mutation of two of the genes responsible for circadian

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rhythms. Information from the SCN is conveyed via the subparaventricular zone and the dorsomedial nucleus of the hypothalamus to regions of the brain involved in sleep and waking. During the night the SCN signals the pineal gland to secrete melatonin, which appears to be involved in synchronizing circadian rhythms: The hormone can help people to adjust to the effects of shift work or jet lag and even synchronize the daily rhythms of blind people for whom light cannot serve as a zeitgeber.

Thought Question Until recently (in terms of the evolution of our species), our ancestors tended to go to sleep when the sun set and wake up when it rose. Once our ancestors learned how to control fire, they undoubtedly stayed up somewhat later, sitting in front of a fire. But it was only with the development of cheap, effective lighting that many members of our species adopted the habit of staying up late and waking several hours after sunrise. Considering that our biological clock and the neural mechanisms it controls evolved long ago, do you think the changes in our daily rhythms impair any of our physical and intellectual abilities?

EPILOgUE

| Functions of Dreams

Even though we are still not sure why REM sleep occurs, the elaborate neural circuitry involved with its control indicates that it must be important. Nature would probably not invent this circuitry if it did not do something useful. Michael’s attacks of sleep paralysis, hypnagogic hallucinations, and cataplexy, described in the chapter prologue, occurred when two of the aspects of REM sleep (paralysis and dreaming) occurred at inappropriate times. Normally, the brain mechanisms responsible for these phenomena are inhibited during waking; in Michael’s case, degeneration of orexinergic neurons caused instability in his sleep/waking flip-flop and permitted some of the phenomena of REM sleep to occur at inappropriate times. As we saw, REM sleep appears to play a role in learning and brain development. But what about the subjective aspect of REM sleep dreaming? Is there some special purpose served by those vivid, storylike hallucinations we have while we sleep, or are dreams just irrelevant side effects of more important things going on in the brain? Since ancient times, people have regarded dreams as important, using them to prophesy the future, decide whether to go to war, or determine the guilt or innocence of a person accused of a crime. In the twentieth century Sigmund Freud proposed a very influential theory about dreaming. He said that dreams arise out of inner conflicts between unconscious desires (primarily sexual ones) and prohibitions against acting out these desires, which we learn from society. According to Freud, although all dreams represent unfulfilled wishes, their contents are disguised. The latent content of the dream (from the Latin word for “hidden”) is transformed into the manifest content (the actual story line or plot). Taken at face value, the manifest content is innocuous, but a knowledgeable psychoanalyst can recognize unconscious desires disguised as symbols in the dream. For example, climbing a set of stairs might represent sexual intercourse. The problem with Freud’s theory is that it is not disprovable; even if it is wrong, a psychoanalyst can always provide

a plausible interpretation of a dream that reveals hidden conflicts, disguised in obscure symbols. Many sleep researchers—especially those who are interested in the biological aspects of dreaming—disagree with Freud and suggest alternative explanations. For example, Hobson (1988) suggests that the brain activation that occurs during REM sleep leads to hallucinations that we try to make sense of by creating a more or less plausible story. As you learned in this chapter, REM sleep is accompanied by rapid eye movements and cortical arousal. The visual system is especially active. So is the motor system—in fact, we have a mechanism that paralyzes and prevents the activity of the motor system from causing us to get out of bed and doing something that might harm us. (As we saw, people who suffer from REM without atonia actually do act out their dreams and sometimes injure themselves. On occasion they have even attacked their spouses while dreaming that they were fighting with someone.) Research indicates that the two systems of the brain that are most active, the visual system and the motor system, account for most of the sensations that occur during dreams. Many dreams are silent, but almost all are full of visual images. In addition, many dreams contain sensations of movements, which are probably caused by feedback from the activity of the motor system. very few dreamers report tactile sensations, smells, or tastes. Hobson, a wine lover, reported that although he has drunk wine in his dreams, he has never experienced any taste or smell. (He reported this fact rather wistfully; I suspect that he would have appreciated the opportunity to taste a fine wine without having to open one of his own bottles.) Why are these sensations absent? Is it because our “hidden desires” involve only sight and movement, or is it because the neural activation that occurs during REM sleep simply does not involve other systems to a very great extent? Hobson suggests the latter, and I agree with him.

KEY CoNCEPTS A PhySiOLOGiCAL AND BEhAviORAL DESCRiPTiON Of SLEEP

1. Sleep consists of slow-wave sleep, divided into four stages, and REM sleep. Dreaming occurs during REM sleep.

at inappropriate times. Narcolepsy is caused by a hereditary disorder that causes the degeneration of orexin-secreting neurons during adolescence.

DiSORDERS Of SLEEP

2. People sometimes suffer from such sleep disorders as insomnia, sleep apnea, narcolepsy, REM without atonia, bedwetting, sleepwalking, or night terrors. Three symptoms of narcolepsy (cataplexy, sleep paralysis, and hypnagogic hallucinations) can be understood as components of REM sleep occurring

Why DO WE SLEEP?

3. Slow-wave sleep appears to permit the cerebral cortex to rest. REM sleep may be important in brain development, and it plays a role in the formation of nondeclarative memories. Slow-wave sleep is involved in formation of declarative memories.

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PhySiOLOGiCAL MEChANiSMS Of SLEEP AND WAkiNG

4. Adenosine, a neuromodulator that is produced as a by-product of cerebral metabolism, appears to play a role in initiating sleep. 5. The brain stem contains an arousal mechanism with five major components: the acetylcholinergic system of the dorsolateral pons and basal forebrain; the noradrenergic system of the locus coeruleus; the serotonergic system of the raphe nuclei; the histaminergic system of the tuberomammillary nucleus of the hypothalamus; and the orexinergic system of the lateral hypothalamus. The ventrolateral preoptic area (vlPOA) appears to be necessary for sleep; its neurons inhibit the brain regions responsible for arousal. 6. Orexinergic neurons help stabilize the sleep/waking flipflop, which consists of the vlPOA and the regions involved in arousal.

7. REM sleep is controlled by the REM sleep flip-flop, which consists of the SLD (the REM-ON region) and the vlPAG (the REM-OFF region) and their reciprocal, inhibitory, connections. BiOLOGiCAL CLOCkS

8. Circadian rhythms are largely under the control of a mechanism located in the suprachiasmatic nucleus. They are synchronized by the day–night light cycle, which is detected by a special category of photoreceptors in the retina. The ticking of the internal clock responsible for these rhythms appears to involve the production and degradation of proteins.

ExPLoRE the virtual Brain in SLEEP AND WAkiNG Explore cortical and subcortical structures involved in the regulation of sleep and waking behaviors. EEg, neurotransmitter, and behavioral components of the different sleep and wake states are explained. Learn about sleep disorders and their effect on the sleep cycle.

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OUTLINE ■

Sexual Development Production of Gametes and Fertilization

Reproductive Behavior

Development of the Sex Organs Sexual Maturation ■

Hormonal Control of Sexual Behavior Hormonal Control of Female Reproductive Cycles Hormonal Control of Sexual Behavior of Laboratory Animals Organizational Effects of Androgens on Behavior: Masculinization and Defeminization Effects of Pheromones Human Sexual Behavior Sexual Orientation

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Neural Control of Sexual Behavior Males Females Formation of Pair Bonds

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Parental Behavior Maternal Behavior of Rodents Hormonal Control of Maternal Behavior Neural Control of Maternal Behavior

LEARNING OBJECTIVES 1. Describe mammalian sexual development and explain the factors that control it. 2. Describe the hormonal control of the female reproductive cycle and of male and female sexual behavior. 3. Describe the role of pheromones in reproductive physiology and sexual behavior. 4. Discuss the activational eﬀects of gonadal hormones on the sexual behavior of women and men.

Neural Control of Paternal Behavior

5. Discuss sexual orientation and the eﬀects of prenatal androgenization of genetic females and the failure of androgenization of genetic males. 6. Discuss the neural control of male sexual behavior. 7. Discuss the neural control of female sexual behavior. 8. Describe the maternal behavior of rodents and discuss the hormonal and neural mechanisms that control maternal behavior and paternal behavior.

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PROLOGUE

| From Boy to Girl

The aftermath of a tragic surgical accident suggested that people’s sexual identity and sexual orientation were not under the strong control of biological factors and that these characteristics could be shaped by the way a child was raised (Money and Ehrhardt, 1972). Identical twin boys were raised normally until seven months of age, at which time the penis of one of the boys was accidentally destroyed during circumcision. The cautery (a device that cuts tissue by means of electric current) was adjusted too high, and instead of removing just the foreskin, the current burned off the entire penis. After a period of agonized indecision, the parents decided, on the advice of an expert in human sexuality, to raise the child as a girl. Bruce became Brenda.

Bruce’s parents started dressing her in girls’ clothing and treating her like a little girl. Surgeons removed the child’s testes. Reports of this case stated that Brenda was a normal, happy girl, and many experts concluded that children’s sexual identities were determined by the way that they were raised, not by their chromosomes or sex hormones. After all, Brenda’s identical twin brother provided the perfect control. Many writers saw this case as a triumph of socialization over biology. As you will see in the chapter epilogue, this conclusion was premature.

eproductive behaviors constitute the most important category of social behaviors, because without them, most species would not survive. These behaviors—which include courting, mating, parental behavior, and most forms of aggressive behaviors—are the most striking categories of sexually dimorphic behaviors, that is, behaviors that differ in males and females (di + morphous, “two forms”). As you will see, hormones that are present both before and after birth play a very special role in the development and control of sexually dimorphic behaviors. This chapter describes male and female sexual development and then discusses the neural and hormonal control of two sexually dimorphic behaviors that are most important to reproduction: sexual behavior and parental behavior.

Sexual Development A person’s chromosomal sex is determined at the time of fertilization. However, this event is merely the first in a series of steps that culminate in the development of a male or female. This section considers the major features of sexual development.

Production of Gametes and Fertilization

sexually dimorphic behavior A behavior that has different forms or that occurs with different probabilities or under different circumstances in males and females. gamete (gamm eet) A mature reproductive cell; a sperm or ovum. sex chromosome The X and Y chromosomes, which determine an organism’s gender. Normally, XX individuals are female, and XY individuals are male.

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All cells of the human body (other than sperms or ova) contain twenty-three pairs of chromosomes. The genetic information that programs the development of a human is contained in the DNA that constitutes these chromosomes. We pride ourselves on our ability to miniaturize computer circuits on silicon chips, but that accomplishment looks primitive when we consider that the blueprint for a human being is too small to be seen by the naked eye. The production of gametes (ova and sperms; gamein means “to marry”) entails a special form of cell division. This process produces cells that contain one member of each of the twentythree pairs of chromosomes. The development of a human begins at the time of fertilization, when a single sperm and ovum join, sharing their twenty-three single chromosomes to reconstitute the twenty-three pairs. A person’s genetic sex is determined at the time of fertilization of the ovum by the father’s sperm. Twenty-two of the twenty-three pairs of chromosomes determine the organism’s physical development independent of its sex. The last pair consists of two sex chromosomes, which contain genes that determine whether the offspring will be a boy or a girl. There are two types of sex chromosomes: X chromosomes and Y chromosomes. Females have two X chromosomes (XX); thus, all the ova that a woman produces will contain an X chromosome. Males have an X and a Y chromosome (XY). When a man’s sex chromosomes divide, half the sperms contain an X chromosome and the other half contain a Y chromosome. A Y-bearing sperm produces an XY-fertilized ovum and therefore a male. An X-bearing sperm produces an XX-fertilized ovum and therefore a female. (See Figure 1.)

Reproductive Behavior

Development of the Sex Organs Men and women differ in many ways: Their bodies are different, parts of their brains are different, and their reproductive behaviors are different. Are all these differences encoded on the tiny Y chromosome, the sole piece of genetic material that distinguishes males from females? The answer is no. The X chromosome and the twenty-two nonsex chromosomes found in the cells of both males and females contain all the information needed to develop the bodies of either sex. Exposure to sex hormones, both before and after birth, is responsible for our sexual dimorphism. What the Y chromosome does control is the development of the glands that produce the male sex hormones. X X

X Y

GONADS There are three general categories of sex organs: the gonads, the internal sex organs, and Sperms Ova X X X Y the external genitalia. The gonads—testes or ovaries—are the first to develop. Gonads (from the Greek gonos, “procreation”) have a dual function: They produce ova or sperms, and they secrete hormones. Through the sixth week of prenatal development, male and female fetuses are identical. Both sexes have a pair of identical undifferentiated gonads, which have the potential of developing into either testes or ovaries. The factor that controls their development appears to be a single gene on the Y chromosome called Sry X X X X X Y X Y (sex-determining region Y). This gene produces a protein that binds to the DNA of cells Females Males in the undifferentiated gonads and causes them to become testes. (Testes are also known 1 Determination of Gender. The F I G U R E as testicles, Latin for “little testes.”) Believe it or not, the words testis and testify have the gender of the offspring depends on whether the same root, meaning “witness.” Legend has it that ancient Romans placed their right hand sperm cell that fertilizes the ovum carries an X or a over their genitals while swearing that they would tell the truth in court. (Only men were Y chromosome. permitted to testify.) If the Sry gene is not present, the undifferentiated gonads become ovaries. In fact, a few cases of XX males have been reported. This anomaly can occur when the gonad (rhymes with moan ad) An ovary Sry gene becomes translocated from the Y chromosome to the X chromosome during production or testis. of the father’s sperms. Sry The gene on the Y chromosome Once the gonads have developed, a series of events is set into action that determines the whose product instructs the individual’s gender. These events are directed by hormones, which affect sexual development undifferentiated fetal gonads to develop in two ways. During prenatal development these hormones have organizational effects, which into testes. influence the development of a person’s sex organs and brain. These effects are permanent; once organizational effect (of hormone) a particular path is followed in the course of development, there is no going back. The second role The effect of a hormone on tissue of sex hormones is their activational effect. These effects occur later in life, after the sex organs differentiation and development. have developed. For example, hormones activate the production of sperms, make erection and activational effect (of hormone) The ejaculation possible, and induce ovulation. Because the bodies of adult males and females have effect of a hormone that occurs in the been organized differently, sex hormones will have different activational effects in the two sexes. fully developed organism; may depend INTERNAL SEX ORGANS Early in embryonic development, the internal sex organs are bisexual; that is, all embryos contain the precursors for both female and male sex organs. However, during the third month of gestation, only one of these precursors develops; the other withers away. The precursor of the internal female sex organs, which develops into the fimbriae and Fallopian tubes, the uterus, and the inner two-thirds of the vagina, is called the Müllerian system. The precursor of the internal male sex organs, which develops into the epididymis, vas deferens, and seminal vesicles, is called the Wolffian system. (These systems were named after their discoverers, Müller and Wolff. See Figure 2.) The gender of the internal sex organs of a fetus is determined by the presence or absence of hormones secreted by the testes. If these hormones are present, the Wolffian system develops. If they are not, the Müllerian system develops. The Müllerian (female) system needs no hormonal stimulus from the gonads to develop; it just normally does so. (Turner’s syndrome, a disorder of sexual development that I will discuss later, provides the evidence for this assertion.) In contrast, the cells of the Wolffian (male) system do not develop unless they are stimulated to do so by a hormone. Thus, testes secrete two types of hormones. The first, a peptide hormone called anti-Müllerian hormone, does exactly what its name says: It prevents the Müllerian (female) system from developing. It therefore has a defeminizing effect. The second, a set of steroid hormones called androgens, stimulates the development of the Wolffian system. (This class of

on the organism’s prior exposure to the organizational effects of hormones. Müllerian system The embryonic precursors of the female internal sex organs. Wolffian system The embryonic precursors of the male internal sex organs. anti-Müllerian hormone A peptide secreted by the fetal testes that inhibits the development of the Müllerian system, which would otherwise become the female internal sex organs. defeminizing effect An effect of a hormone present early in development that reduces or prevents the later development of anatomical or behavioral characteristics typical of females. androgen (an dro jen) A male sex steroid hormone. Testosterone is the principal mammalian androgen.

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Fallopian tube

Fimbria Ovary

Uterus Precursor of female internal sex organs (Mullerian system)

Vagina Opening of urethra

Immature gonad

Labia

Precursor of male internal sex organs (Wolffian system) Adult Female Seminal vesicle Prostate Vas deferens Urethra Epididymis Early in Fetal Development

Testis Penis Scrotum

Adult Male FIGURE

masculinizing effect An effect of a hormone present early in development that promotes the later development of anatomical or behavioral characteristics typical of males. testosterone (tess tahss ter own) The principal androgen found in males. dihydrotestosterone (dy hy dro tess tahss ter own) An androgen produced from testosterone through the action of an enzyme. androgen insensitivity syndrome A condition caused by a congenital lack of functioning androgen receptors; in a person with XY sex chromosomes, it causes the development of a female with testes but no internal sex organs.

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Development of the Internal Sex Organs.

hormone is also aptly named: Andros means “man,” and gennan means “to produce.”) Androgens have a masculinizing effect. Two different androgens are responsible for masculinization. The first, testosterone, is secreted by the testes and gets its name from these glands. An enzyme converts some of the testosterone into another androgen, known as dihydrotestosterone. Hormonesexert their effects on target cells by stimulating the appropriate hormone receptor. Thus, the precursor of the male internal sex organs—the Wolffian system—contains androgen receptors that are coupled to cellular mechanisms that promote growth and division. When molecules of androgens bind with these receptors, the epididymis, vas deferens, and seminal vesicles develop and grow. In contrast, the cells of the Müllerian system contain receptors for anti-Müllerian hormone that prevent growth and division. Thus, the presence of anti-Müllerian hormone prevents the development of the female internal sex organs. The fact that the internal sex organs of the human embryo are bisexual and could potentially develop as either male or female is dramatically illustrated by two genetic disorders: androgen insensitivity syndrome and persistent Müllerian duct syndrome. Some people are insensitive to androgens; they have androgen insensitivity syndrome, one of the more aptly named disorders (Money and Ehrhardt, 1972; MacLean, Warne, and Zajac, 1995). The cause of androgen insensitivity syndrome is a genetic mutation that prevents the formation of functioning androgen receptors. (The gene for the androgen receptor is located on the X chromosome.) The primitive gonads of a genetic male fetus with androgen insensitivity syndrome become testes and secrete both anti-Müllerian hormone and androgens. The lack of androgen receptors prevents the androgens from having a masculinizing effect; thus, the epididymis, vas deferens, seminal vesicles, and prostate fail to develop. However, the anti-Müllerian hormone still has its defeminizing effect, preventing the female internal sex organs from developing. The uterus, fimbriae, and Fallopian

Reproductive Behavior

tubes fail to develop, and the vagina is shallow. The external genitalia are female, and at puberty the person develops a woman’s body. Of course, lacking a uterus and ovaries, the person cannot have children. The second genetic disorder, persistent Müllerian duct syndrome, has two causes: either a failure to produce anti-Müllerian hormone or the absence of receptors for this hormone (Warne and Zajac, 1998). When this syndrome occurs in genetic males, androgens have their masculinizing effect but defeminization does not occur. Thus, the person is born with both sets of internal sex organs, male and female. The presence of the additional female sex organs usually interferes with normal functioning of the male sex organs. So far, I have been discussing only male sex hormones. What about prenatal sexual development in females? A chromosomal anomaly indicates that the hormones produced by female sex organs are not needed for development of the Müllerian system. This fact has led to the dictum “Nature’s impulse is to create a female.” People with Turner’s syndrome have only one sex chromosome: an X chromosome. (Thus, instead of having XX cells, they have X0 cells—0 (zero) indicating a missing sex chromosome.) In most cases the existing X chromosome comes from the mother, which means that the cause of the disorder lies with a defective sperm (Knebelmann et al., 1991). Because a Y chromosome is not present, testes do not develop. In addition, because two X chromosomes are needed to produce ovaries, these glands are not produced either. But even though people with Turner’s syndrome have no gonads at all, they develop into females, with normal female internal sex organs and external genitalia—which proves that fetuses do not need ovaries or the hormones they produce to develop as females. Of course, they must be given estrogen pills to induce puberty and sexual maturation. And they cannot bear children, because without ovaries they cannot produce ova. EXTERNAL GENITALIA The external genitalia are the visible sex organs, including the penis and scrotum in males and the labia, clitoris, and outer part of the vagina in females. (See Figure 3.) As we just saw, the external genitalia do not need to be stimulated by female sex hormones to become female; they just naturally develop that way. In the presence of dihydrotestosterone the external genitalia will become male. Thus, the gender of a person’s external genitalia is determined by the presence or absence of an androgen, which explains why people with Turner’s syndrome have female external genitalia even though they lack ovaries. People with androgen insensitivity syndrome have female external genitalia too, because without androgen receptors their cells cannot respond to the androgens produced by their testes. Figure 4 summarizes the factors that control the development of the gonads, internal sex organs, and genitalia. (See Figure 4.)

persistent Müllerian duct syndrome A condition caused by a congenital lack of anti-Müllerian hormone or receptors for this hormone; in a male, it causes development of both male and female internal sex organs. Turner’s syndrome The presence of only one sex chromosome (an X chromosome); characterized by lack of ovaries but otherwise normal female sex organs and genitalia. gonadotropin-releasing hormone (go nad oh trow pin) A hypothalamic hormone that stimulates the anterior pituitary gland to secrete gonadotropic hormone. gonadotropic hormone A hormone of the anterior pituitary gland that has a stimulating effect on cells of the gonads.

Phallus

Urethral fold

Genital swelling

Urethral slit Tail (cut off) Indifferent Stage Glans Urethral fold Urogenital slit Labioscrotal swelling Perineal raphe Anus Seventh to Eighth Week Clitoris

Sexual Maturation The primary sex characteristics include the gonads, internal sex organs, and external genitalia. These organs are present at birth. The secondary sex characteristics, such as enlarged breasts and widened hips or a beard and deep voice, do not appear until puberty. Without seeing genitals, we must guess the sex of a prepubescent child from his or her haircut and clothing; the bodies of young boys and girls are rather similar. However, at puberty the gonads are stimulated to produce their hormones, and these hormones cause the person to mature sexually. The onset of puberty occurs when cells in the hypothalamus secrete gonadotropinreleasing hormones (GnRH), which stimulate the production and release of two gonadotropic hormones by the anterior pituitary gland. The gonadotropic (“gonad-turning”) hormones stimulate the gonads to produce their hormones, which are ultimately responsible for sexual maturation. (See Figure 5.)

Labia majora

Urethral meatus Glans penis

Urethral meatus Prepuce Vaginal orifice

Shaft of penis

Labia minora

Scrotum

Raphe Anus

Twelfth Week FIGURE

Development of the External Genitalia.

Adapted from Spaulding, M. H., in Contributions to Embryology, Vol. 13. Washington, DC: Carnegie Institute of Washington, 1921.

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Anti-Mullerian hormone Testis-determining factor Male

Defeminization

Primordial gonads develop into testes

Androgens

Mullerian system develops into fimbriae, fallopian tubes, uterus, inner vagina

Mullerian system withers away

Wolffian system develops into vas deferens, seminal vesicles, prostate

Female XX

Primordial gonads develop into ovaries

No hormones

Wolffian system, without androgens, withers away

Masculinization

Androgens

FIGURE

Primordial external genitalia develop into penis and scrotum

Primordial external genitalia develop into clitoris, labia, outer vagina

Hormonal Control of Development of the Internal Sex Organs.

follicle-stimulating hormone (FSH) The hormone of the anterior pituitary gland that causes development of an ovarian follicle and the maturation of an ovum.

The two gonadotropic hormones are follicle-stimulating hormone (FSH) and luteinizing hormone (LH), named for the effects they produce in the female (production of a follicle and its subsequent luteinization, to be described in the next section of this chapter). However, the same luteinizing hormone (LH) (lew tee a nize hormones are produced in the male, where they stimulate the testes to produce sperms and to ing) A hormone of the anterior pituitary secrete testosterone. gland that causes ovulation and development of the ovarian follicle into a corpus The secretion of GnRH, which directs the production of the gonadotropic hormones, which luteum. in turn stimulate puberty and production of the sex hormones secreted by the gonads, is under kisspeptin A peptide essential for the control of another peptide: kisspeptin. (The unusual name of this peptide does not refer the initiation of puberty and the mainteto a behavior that sometimes serves as the beginning of a sexual encounter. Instead, it refers to nance of male and female reproductive Hershey, Pennsylvania, the location of the laboratory where the gene that encodes for the pepability; controls the secretion of GnRH, tide was discovered. This city is also the home of the company that makes Hershey’s Kisses, a which directs the production and release chocolate candy.) Kisspeptin, produced by neurons in the arcuate nucleus of the hypothalamus, of the gonadotropic hormones. is essential for the initiation of puberty and the maintenance of male and female reproductive estradiol (ess tra dye ahl) The principal ability (Millar et al., 2010). estrogen of many mammals, including humans. In response to the gonadotropic hormones (usually called gonadotropins), the gonads secrete steroid sex hormones. The ovaries produce estradiol, one of a class of hormones known estrogen (ess trow jen) A class of sex hormones that causes maturation of the as estrogens. As we saw, the testes produce testosterone, an androgen. Both types of glands also female genitalia, growth of breast tissue, produce a small amount of the hormones of the other sex. The gonadal steroids affect many parts and development of other physical of the body. Both estradiol and androgens initiate closure of the growing portions of the bones features characteristic of females. and thus halt skeletal growth. In females, estradiol also causes breast deMale Female velopment, growth of the lining of the uterus, changes in the deposition of body fat, and maturation of the female genitalia. In males, androgens stimulate growth of facial, axillary (underarm), and pubic hair; lower the voice; alter the hairline on the head (often causing baldness later in life); stimulate muscular development; and cause genital growth. This description leaves out two of the female secondary characteristics: axilGnRH GnRH lary hair and pubic hair. These characteristics are produced not by estradiol but rather by androgens secreted by the cortex of the adrenal glands. Even a male who is castrated before puberty (whose testes are removed) will grow axillary and pubic hair, stimulated by his own adrenal androGonadotropic hormones gens. A list of the principal sex hormones and examples of their effects is presented in Table 1. Note that some of these effects are discussed later in this chapter. (See Table 1.) The bipotentiality of some of the secondary sex characteristics Ovary Testis remains throughout life. If a man is treated with an estrogen (for example, to control an androgen-dependent tumor), he will grow breasts, and his facial hair will become finer and softer. However, his voice will remain low, because the enlargement of the larynx is permanent. Conversely, a Testosterone Estradiol woman who receives high levels of an androgen (usually from a tumor F I G U R E 5 Sexual Maturation. Puberty is initiated when the hypothalthat secretes androgens) will grow a beard, and her voice will become amus secretes gonadotropin-releasing hormones (GnRH), which stimulate the release of gonadotropic hormones by the anterior pituitary gland. lower.

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TABLE 1

Classification of Sex Steroid Hormones

Class

Principal Hormone in Humans (Where Produced)

Androgens

Testosterone (testes)

Development of Wolffian system; production of sperms; growth of facial, pubic, and axillary hair; muscular development; enlargement of larynx; inhibition of bone growth; sex drive in men (and women?)

Dihydrotestosterone (produced from testosterone by action of an enzyme)

Maturation of male external genitalia

Androstenedione (adrenal glands)

In women, growth of pubic and axillary hair; less important than testosterone and dihydrotestosterone in men

Estrogens

Estradiol (ovaries)

Maturation of female genitalia; growth of breasts; alterations in fat deposits; growth of uterine lining; inhibition of bone growth; sex drive in women (?)

Gestagens

Progesterone (ovaries)

Maintenance of uterine lining

Hypothalamic hormones

Gonadotropin-releasing hormone (hypothalamus)

Secretion of gonadotropins

Gonadotropins

Follicle-stimulating hormone (anterior pituitary)

Development of ovarian follicle

Luteinizing hormone (anterior pituitary)

Ovulation; development of corpus luteum

Prolactin (anterior pituitary)

Milk production; male refractory period (?)

Oxytocin (posterior pituitary)

Milk ejection; orgasm; pair bonding (especially females); bonding with infants

Vasopressin (posterior pituitary)

Pair bonding (especially males)

Other hormones

Examples of Effects

SECTION SUMMARY Sexual Development Gender is determined by the sex chromosomes: XX produces a female, and XY produces a male. Males are produced by the action of the Sry gene on the Y chromosome, which contains the code for the production of a protein that in turn causes the primitive gonads to become testes. The testes secrete two kinds of hormones that cause a male to develop. Testosterone and dihydrotestosterone (androgens) stimulate the development of the Wolffian system (masculinization), and antiMüllerian hormone suppresses the development of the Müllerian system (defeminization). Androgen insensitivity syndrome results from a hereditary defect in androgen receptors, and persistent Müllerian duct syndrome results from a hereditary defect in production of anti-Müllerian hormone or its receptors. By default the body is female (“Nature’s impulse is to create a female”); only by the actions of testicular hormones does it become male. Masculinization and defeminization are referred to as organizational effects of hormones; activational effects occur after development is complete. A person with Turner’s syndrome (X0) fails to develop gonads but nevertheless develops female internal sex organs and external genitalia. The external genitalia develop from common precursors. In the absence of gonadal hormones the precursors develop the female form; in the presence of androgens (primarily dihydrotestosterone, which derives

from testosterone through the action of an enzyme) they develop the male form (masculinization). Sexual maturity occurs when neurons in the arcuate nucleus of the hypothalamus begin secreting kisspeptin, which stimulates the secretion of gonadotropin-releasing hormone (GnRH), which stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary gland. These hormones stimulate the gonads to secrete their hormones, thus causing the genitals to mature and the body to develop the secondary sex characteristics (activational effects).

Thought Questions 1. Suppose that people could easily determine the sex of their child, say, by having one of the would-be parents take a drug before conceiving the baby. What would be the consequences? 2. With appropriate hormonal treatment, the uterus of a postmenopausal woman can be made ready for the implantation of another woman’s ovum, fertilized in vitro, and she can become a mother. In fact, several women in their fifties and sixties have done so. What do you think about this procedure? Should decisions about using it be left to couples and their physicians, or does the rest of society (represented by their legislators) have an interest?

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Hormonal Control of Sexual Behavior We have seen that hormones are responsible for sexual dimorphism in the structure of the body and its organs. Hormones have organizational and activational effects on the internal sex organs, genitals, and secondary sex characteristics. Naturally, all of these effects influence a person’s behavior. Simply having the physique and genitals of a man or a woman exerts a powerful effect. But hormones do more than give us masculine or feminine bodies; they also affect behavior by interacting directly with the nervous system. Androgens that are present during prenatal development affect the development of the nervous system. In addition, both male and female sex hormones have activational effects on the adult nervous system that influence both physiological processes and behavior. This section considers some of these hormonal effects.

menstrual cycle (men strew al) The female reproductive cycle of most primates, including humans; characterized by growth of the lining of the uterus, ovulation, development of a corpus luteum, and (if pregnancy does not occur) menstruation. estrous cycle The female reproductive cycle of mammals other than primates. ovarian follicle A cluster of epithelial cells surrounding an oocyte, which develops into an ovum. corpus luteum (lew tee um) A cluster of cells that develops from the ovarian follicle after ovulation; secretes estradiol and progesterone. progesterone (pro jess ter own) A steroid hormone produced by the ovary that maintains the endometrial lining of the uterus during the later part of the menstrual cycle and during pregnancy; along with estradiol, it promotes receptivity in female mammals with estrous cycles.

Anterior pituitary gland FSH

Estradiol

Ovary

Hormonal Control of Female Reproductive Cycles The reproductive cycle of female primates is called a menstrual cycle (from mensis, meaning “month”). Females of other species of mammals also have reproductive cycles, called estrous cycles. Estrus means “gadfly”; when a female rat is in estrus, her hormonal condition goads her to act differently than she does at other times. (For that matter, it goads male rats to act differently too.) The primary feature that distinguishes menstrual cycles from estrous cycles is the monthly growth and loss of the lining of the uterus. The other features are approximately the same—except that the estrous cycle of rats takes four days. Also, the sexual behavior of female mammals with estrous cycles is linked with ovulation, whereas most female primates can mate at any time during their menstrual cycle. Menstrual cycles and estrous cycles consist of a sequence of events that are controlled by hormonal secretions of the pituitary gland and ovaries. These glands interact, the secretions of one affecting those of the other. A cycle begins with the secretion of gonadotropins by the anterior pituitary gland. These hormones (especially FSH) stimulate the growth of ovarian follicles, small spheres of epithelial cells surrounding each ovum. Women normally produce one ovarian follicle each month; if two are produced and fertilized, dizygotic (fraternal) twins will develop. As ovarian follicles mature, they secrete estradiol, which causes the lining of the uterus to grow in preparation for implantation of the ovum, should it be fertilized by a sperm. Feedback from the increasing level of estradiol eventually triggers the release of a surge of LH by the anterior pituitary gland. (See Figure 6) The LH surge causes ovulation: The ovarian follicle ruptures, releasing the ovum. Under the continued influence of LH, the ruptured ovarian follicle becomes a corpus luteum (“yellow body”), which produces estradiol and progesterone. (See Figure 6.) The latter hormone promotes pregnancy (gestation). It maintains the lining of the uterus, and it inhibits the ovaries from producing another follicle. Meanwhile, the ovum enters one of the Fallopian tubes and begins its progress toward Hypothalamus the uterus. If it meets sperm cells during its travel down the Fallopian tube and becomes fertilized, it begins to divide, and several days later it Progesterone attaches itself to the uterine wall. If the ovum is not fertilized or if it is fertilized too late to develop Estradiol LH sufficiently by the time it gets to the uterus, the corpus luteum will stop Corpus producing estradiol and progesterone, and then the lining of the walls luteum of the uterus will slough off. At this point, menstruation will commence.

Luteinization Ovum Growth of Follicle Ovulation FIGURE

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Neuroendocrine Control of the Menstrual Cycle.

Hormonal Control of Sexual Behavior of Laboratory Animals The interactions between sex hormones and the human brain are difficult to study. We must turn to two sources of information: experiments with animals and various developmental disorders in humans, which serve as nature’s own “experiments.” Let us first consider the evidence gathered from research with laboratory animals.

Reproductive Behavior

MALES Male sexual behavior is quite varied, although the essential features of intromission (entry of the penis into the female’s vagina), pelvic thrusting (rhythmic movement of the hindquarters, causing genital friction), and ejaculation (discharge of semen) are characteristic of all male mammals. Humans, of course, have invented all kinds of copulatory and noncopulatory sexual behavior. For example, the pelvic movements leading to ejaculation may be performed by the woman, and sex play can lead to orgasm without intromission. The sexual behavior of rats has been studied more than that of any other laboratory animal (Hull and Dominguez, 2007). When a male rat encounters a receptive female, he will spend some time nuzzling her and sniffing and licking her genitals, mount her, and engage in pelvic thrusting. He will mount her several times, achieving intromission on most of the mountings. After eight to fifteen intromissions approximately one minute apart (each lasting only about one-quarter of a second), the male will ejaculate. After ejaculating, the male refrains from sexual activity for a period of time (minutes, in the rat). Most mammals will return to copulate several times, finally showing a longer pause, called a refractory period. (The term comes from the Latin refringere, “to break off.”) An interesting phenomenon occurs in some mammals. If a male, after finally becoming “exhausted” by repeated copulation with the same female, is presented with a new female, he begins to respond quickly—often as fast as he did in his initial contact with the first female. Successive introductions of new females can keep up his performance for prolonged periods of time. This phenomenon is undoubtedly important in species in which a single male inseminates all the females in his harem. Species with approximately equal numbers of reproductively active males and females are less likely to act this way.

In one of the most unusual studies I have read about, Beamer, Bermant, and Clegg (1969) tested the ability of a ram (male sheep) to recognize ewes with which he had mated. A ram that is given a new ewe each time will quickly begin copulating and will ejaculate within two minutes. (In one study, a ram kept up this performance with twelve ewes. The experimenters finally got tired of shuffling sheep around; the ram was still ready to go.) Beamer and his colleagues tried to fool rams by putting trench coats and Halloween face masks on females with which the rams had mated. (No, I’m not making this up.) The males were not fooled by the disguise; they apparently

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