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Neuroscience and Neuronal Replacement ~ he crowning triumph in human clevelopment is the growth of the brain. By the time of birth, the brain contains several hundred billion nerve cells. An average nerve cell makes connections with thousands of other nerve cells, meaning that there are literally trillions of neural connections in the brain. It is nature's most aston- ishing and daunting creation, an organ that can hope to understand itself. No new neurons are generated in the human brain after birth (although recent research has revealed a remarkable capacity in other species for the generation of new neurons, as described later in this chapter). But a newborn7s brain cells are hardly immutable. They grow and make new connections; existing connections become stronger or weaker; droves of brain cells die, especially cluring the first few years of life, as if a block of marble were being sculpted into a statue. in this way the brain refines its abilities to direct movement, speech, memory, perception emotion, reason all of the vital activities encompassed by the rather nondescript word behavior. The ultimate goal of neuroscience is to explain in biological terms the mechanisms of behavior. It seeks to answer such questions as, How (lo we remember what we have learned? How do we un(lerstancl written or spoken words? How do we perform skilled movements? These ques- tions can be studied at many levels. At the microscopic level, neuro- scientists explore the properties of nerve cells ant! their interactions (see box' pages 56-57~. At the macroscopic level, they examine the functions of specific parts of the brain and how those parts work together to procluce a specific behavior. s3

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Since shortly after Darwin's time, a prominent view of the function and structure of the brain has been based on the theory of evolution. According to this view, the brain evolved by adcling or expanding sections on top of previous sections, culminating in the human brain (Figure 3-~. Each new section added new and more complex behaviors while suppressing the more primitive behaviors generated by lower brain regions. This evolutionary perspective has produced valuable insights, ac- cording to Vernon MountcastIe, professor of neuroscience at the Johns Hopkins University School of Medicine, but in the last few deca(les it has been superseded by a more complex view. Today, the higher func- tions of the brain are seen not as the product of any one level or part of the brain but as the result of simultaneous activity in a number of interconnected regions. Neuroanatomists have shown that the intercon Midt~rain / ~ ' Thalamus Hypothalamus Hindbrain / Pons Cerebellum /~] Meclulla / Spinal Cord FIGURE 3-1 A cross section through the center of the human brain shows its major anatomical divisions. The hindbrain, midbrain (which has few distinctive fea- tures in humans), and forebrain are common to all vertebrates, but the characteristics of these sections vary greatly from species to species. Reprinted, with permission, from F. E. Bloom et al., Brain, Mind, and Behavior. New York: W. H. Freeman and Company, 1985. (I) 1985 by Educational Broadcasting Corporation. 54 SHAPING THE FUTURE

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nections between different parts of the brain are far more numerous than previously realized. The resulting integration of the brain's function argues more for a distributed than a hierarchical view of how the brain works. For instance, MountcastIe points out, motions initiated by the cerebral cortex may be modified and refined by the cerebellum. '~Can you say that the cerebellum, a very ancient part of the brain, is lower than the supplementary motor area, a relatively new area? No. It doesn't make sense to say that." High-Leve! Versus Intermediate-Leve] Functions The greatest single challenge in neuroscience is to understand the higher functions of the human brain thought, memory, emotion. Sci- entists have made great progress over the years in learning about these functions. They have pinpointed parts of the brain involved in such functions, and they have studier! analogous activities in nonhuman species. But most of the important features of the higher functions produced by the human brain remain mysterious. They seem to involve many neurons spreac] throughout the brain interacting in ways that have not yet been described. Nevertheless, neuroscientists are now poised to make rapid progress in answering what Mountcastle calls C`intermediate-leve! questions," such as how the brain perceives its surroundings, how it attends to one sense to the exclusion of others, and how it modifies behavior in the light of past experience. in humans, these functions tend to involve the outermost portion of the brain, known as the cerebral cortex (although, as noted earlier, other brain regions also play roles). The uppermost portion of the cerebral cortex, also called the neocortex because of its relatively late appearance in evolution, consists of a quarter-inch-thick layer of neurons that, if laid out as a flat sheet, would cover a total area of about a foot and a half. This neural mass, deeply wrinkler! and split into two lobes, blankets the top of the brain and gives the human brain its characteristic appearance. It is the greatly increased size of the neocortex that distinguishes primates from other vertebrates and humans from other primates. The activities of the cerebral cortex that are best understood are the ones closest to the input and output functions of the brain. With regard to input, the cerebral cortex receives information from sensory detectors of the body located in the eyes, skin, ears, nose, ant] mouth. These receptors convert environmental stimuli into nerve impulses, which then travel through various way stations to the cerebral cortex and other NEUROSCIENCE AND NEURONAE REPEACEMENT 55

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brain regions. There, through mechanisms that are still poorly under- stood' these impulses undergo transformations leacling to perception and other higher functions. If these stimuli provoke a physical response, the motor neurons of the neocortex come into play. They generate impulses, drawing upon input from other parts of the brain, and these impulses are in turn modified before reaching the muscles anc! causing movement. Figure 3-2 shows the parts of the neocortex that receive information most directly from the senses (the primary sensory areas) and that initiate The Building Blocks of the Brain "The highest activities of consciousness have their origins in physical occurrences of the brain just as the loveliest melodies are not too sublime to be expressed by notes." W. Somerset Maugham A Writer's Notebook (1896) Neuroscience is based on the assump- tion that human behavior arises from the actions of electrically charged ions shut- tling back and forth through the surfaces of nervous system cells. These cells, known as neurons, occur. in a bewildering variety of shapes and sizes (see figure). But most of them share several common features. Neurons communicate with each other by sending signals through long protru- sions that extend from their cell bodies. One of these protrusions is an axon, which carries signals away from the neuron to- ward other cells. An axon may connect with just one other cell, or it may branch toward its tip and connect with many other cells. The other extensions on a neuron are dendrites. Along with the cell body, den- drites receive messages from the axons that terminate upon them. Thousands of axons may converge upon a single neuron, and it is the dendrites and cell body that inte- grate the incoming messages and deter- mine the cell's response. Neurons maintain an electrical potential across their surfaces by pumping electri- cally charged atoms across their cell mem- branes. When a given neuron receives enough stimulation from other neurons, the electrical potential at the base of its axon abruptly reverses. This sends a wave of reversed electrical potential rushing down the axon. This signal, which is known as an action potential, always has the same magnitude and duration; it is an all-or- nothing proposition. For a neuron to send a stronger message, it therefore has to gen- erate more action potentials in a given time, as if it were being forced to communicate in Morse code using only dots. Electrical charge does not just jump across the junctions between neurons, like a spark of static electricity between a hand and a doorknob. It takes a more indirect but ul- timately much more flexible route. When an action potential reaches the terminals of an axon, it triggers the release of certain chemicals into a gap, known as a synapse, between the sending and receiving cells. These neurotransmitters influence the elec- trical activity of the receiving cell, either encouraging it to fire or inhibiting its firing. (They can also modify the cell in longer- lasting ways, perhaps acting as a basis for some kinds of memory.) Over 50 different neurotransmitters have been discovered, with many more probably remaining to be found. 56 SHAPING THE FUTURE

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movement (the motor area). The interesting thing about Figure 3-2 is the large expanse of the neocortex that is not directly connected to the outside world. Neuroscientists have traditionally referrer] to these re , goons as association areas. Here, they hypothesize, information from the more specialized parts of the brain is compared and integrated. This information may inclucie not only sensory input but emotions, memories, motivational states, ant! other factors. The comparison of sensory input with internally generated information is a key step in perception, the conscious or preconscious awareness of objects and (A) maze (C) :~l (;~-~- (B) Neurons found in vertebrate nervous sys- tems take many different forms, depending partly on the species and partly on the neu- rons' functions. Cell A is from the retina of a lizard. Cell B is from the cerebellum of a mouse. Cell C is from the cerebellum of a hu- man being. Axons are marked with arrows (the full extent of the axon is not shown for C), and the drawings are not to scale. NEUROSCIENCE AND NEURONAL REPLACEMENT 5 7

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actions in the surrounding worIcI' as well as in other higher functions. It has been very difficult to demonstrate the integrative activity of the association areas experimentally. But researchers are now beginning to explore these areas in meaningful ways' and in doing so they are beginning to understand] the mechanisms responsible for many of the brain's remarkable abilities. The Visual World The route from sensory input to perception is better understood for vision than for any other sense. Everything a person sees in the visual field is refracted through the cornea anc! lens to form a small, inverted image on the back of the eye (Figure 3-3~. There, the light-sensitive rods and cones generate electrical impulses corresponding to the light falling on them. These electrical impulses pass through several layers Forebrain Frontal /~ ~ ~ ~ - , Motor Sensory Cortex Cortex Parietal Visual Cortex / -~ Lob: Temporal Lobe FIGURE 3-2 The sensory, visual, and auditory cortexes (the last is tucked inside the temporal lobe) receive impressions directly from the outside world, while the motor cortex controls complex movements. According to theory, the other parts of the neocortex, known as association areas, integrate impressions of the external world with internal information, a key step in such higher functions as the perception of surrounding objects. Reprinted, with permission, from F. E. Bloom et al., Brain, Mind, and Behavior. New York: W. H. Freeman and Company, 1985. @) 1985 by Educational Broadcasting Corporation. 58 SHAPING THE FUTURE

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of neurons before exiting the eye through the optic nerve. Thus, the neural representation of the visual field has already undergone some initial processing before it reaches the brain. After passing through the optic chasm, which (lirects everything from the right side of the visual field to the left part of the brain and vice versa, the optic tract sends most of its nerve fibers to a pair of structures in the thalamus known as the lateral geniculate nuclei. (These structures got their name because they resemble bent, or genuflected, knees.) From this way station in the brain, axons carry the visual signals to the primary visual cortex at the very back of the cerebral cortex. At the same time, some of the fibers of the optic tract go to three subcortical visual centers, which are involved in the control of eye movements, the regulation of light-incluced hormonal changes, and various visual re- flexes. / LEFT EYE <1.~ / / / _ \ \ ~ ~/~ \\\ \~0~ OPTIC TRACT ~ ~JJ~J >~m CHIASM \~ ' OPTIC ~ ~ ' NERVE RIGHT EYE - LATERA: GENICULATE NUCLEUS / / / FIGURE 3-3 Neural impulses generated by the retina travel through the optic nerve to the lateral geniculate nuclei in the thalamus. From the thalamus, visual information travels to processing centers in the primary visual cortex and other brain regions. Reprinted, with permission, from D. H. Hubel and T. N. Wiesel, "Brain Mechanisms of Vision." Pages 85-96 in The Brain. New York: W. H. Freeman and Company, 1979. @) 1979 by Scientific American, Inc. NEUROSCIENCE AND NEURONAL REPLACEMENT 59

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The primary visual cortex is the first of the brain's processing centers for visual information. Neuroscientists have examiner] its function by inserting microelectrodes into the brains of experimental animals, pri- marily cats and monkeys. These microelectrodes record the electrical impulses generate(1 by single neurons. When a specific visual stimuli causes a nerve cell to fire, the microelectrocle can record the electrical impulses generated. In this way, researchers can determine what kincIs of stimuli maximally stimulate a given cell, which in turn indicates the neural processing that the signals generated by the stimuli have un- dergone. The primary visual cortex performs very specific operations on the nerve impulses that reach it from the lateral geniculate nuclei. Some neurons in this region respon(1 only to bars of light oriented in particular directions. Others require that the bars be moving in a given direction at a certain speed. Others fire when presented with a boundary between light and (lark regions. In this way, the primary visual cortex analyzes a complex scene by extracting information about the orientation and movement of the boundaries making up that scene. If this were the only visual processing that occurred in our brains, the florid would be an ocicI-Iooking place. But the primary visual cortex is only the first of many brain regions that analyze the visual world. Neuroscientists have fount} as many as 20 different areas in the cerebral cortex of monkeys that receive projections clirectly or indirectly from the primary visual cortex. Though many of these regions are still poorly understood, each of them seems to extract adclitional information from the nerve impulses coming from the eyes. For instance, one may be involved in the analysis of color, another texture, another form, another movement. Vision in an Association Area MountcastIe and his coworkers have been studying the neurons in one of these visual processing areas the posterior parietal cortex, which is right behind the part of the cerebral cortex responsible for initiating movement (Figure 3-44. The posterior parietal cortex is one of the association areas of the brain, and studies suggest that it does in fact serve an integrative function. It receives information from the eyes, from the muscles and joints, and from the parts of the brain involved in attention. Studies of humans who have suffered an injury to the parietal lobe indicate that one of its major roles is to maintain 60 SHAPING THE FUTURE

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POSTERIOR I' " " it' :' / to i <..'' 'I. ~ ~ . ,. .~ - GENICULATE BODY A\ SUPERIOR it_ POSTERIOR it, ~ CORTEX LATERAL GENICULATE BODY ~ SUPERIOR COLLICULUS FIGURE 3-4 The primary visual cortex of the macaque monkey (top) is relatively much larger than that of humans (bottom). (Though shown here as the same size, the macaque's brain is actually less than half the size of a human's brain.) The posterior parietal cortex is located in comparable areas of the two brains and seems to serve very similar functions. Reprinted, with permission, from R. H. Wurtz et al., Scientific American 246:126, 1982. A) 1982 by Scientific American, Inc. NEUROSCIENCE AND NEURONAL REPLACEMENT 61

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an internal sense of the bocly's relation to the immediate environment (see box, below). Only about 30 percent of the neurons stuclied by MountcastIe in the posterior parietal cortex respond to visual stimuli. Another 15 percent react not to visual stimuli themselves but to objects that are rewarding (such as food)' novel, or aversive. About 10 percent of the neurons in this area are active before, during, or after certain types of eye move- ment. Another 15 percent are active cluring the process of reaching for something. And the function of the rest about 30 percent could not be ascertained by any of the tests that MountcastIe and his colleagues could devise. Mountcastle's experiments were clone using microelectrodes in ma- caque (rhesus) monkeys. in the 1960s it became possible to do such Parietal Lobe Syndrome Many insights into the function of the brain have come from studying the behav- ior of people whose brains have been par- tially damaged through stroke, injury, or disease. One of the strangest of these con- ditions involves damage to one of the par- ietal lobes and is known as parietal lobe syndrome. Patients with the syndrome can still see and move about. But they tend to lose all interest in everything on one side of their bodies. One patient complained that some- one had put a foreign arm in bed with him, even though he could feel normally with his arm. Others may forget to put on one of their shoes, or may shave just one side of their faces, or may eat from only one side of a plate. These patients also have defects of visual and spatial perception (see figure). They cannot perceive their relationship to ob- jects around them. Nor can they reach out to touch objects as easily as they could be- fore. Neurons cannot be regenerated in hu- mans once they are destroyed. But some- times other parts of the brain can take over at least some of the functions of the regions that have been damaged. Thus, the bizarre symptoms of parietal lobe syndrome can fade over time as undamaged parts of the brain learn to process sensory inputs from the neglected side of the body. me, \ 8 A, / A person with parietal lobe syndrome who was asked to draw a clock face put all of the numbers on the right-hand side, reflecting the brain's lack of attention to events occurring on the left-hand side of the body. 62 SHAPING THE FUTURE

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experiments in awake animals performing specific tasks, whereas before the animals had to be anesthetized, since then, this technique has become one of the most valuable in neuroscience. Essentially, a portion of the monkey's skull is replaced Luring surgery with a sterile metal plate. Microelectrodes can then be passer! into the monkey's brain through the plate without causing the animal any pain, since the brain does not contain pain receptors. Meanwhile, the monkey can be trained to perform certain tasks. Once the monkey has learned those tasks, researchers can sequentially monitor the activities of hundreds of dif- ferent neurons over periods of weeks or months. in MountcastIets experiments, monkeys were trained to fix their eyes upon a dim red light projected on a screen clirectly in front of them. When the light climmed further, the monkeys pressed a bar ant! were rewarded with a drink of water. To make sure that the monkeys kept looking straight ahead, a computer monitored the position of their eyes and terminates! the experiment if their gaze shifted. Meanwhile, a square block of light was projected elsewhere on the screen. The monkeys did not look at the square of light, but the microelectrodes indicated that information about it was being sent to neurons in the monkey's posterior parietal lobe. One of the first things that MountcastIe's team observed was that the neurons in the posterior parietal lobe that reacted to visual stimuli (known as parietal visual neurons, or PVNs) had very large receptive fields. In the primary visual cortex, neurons respond to light only in a small area of the visual fielcI. This is because of their close connections with the photoreceptors in the eye, which register the light from just a small portion of the image refracted onto the retina. But individual PVNs fired whenever the square of light appeared in large areas of the screen. Many even fired when the stimulus was on either sicle of the monkey's point of fixation, indicating that, unlike neurons in the primary visual cortex, incliviclual PVNs receive input from both eyes. The PVNs also exhibited a characteristic that MountcastIe calls foveal sparing. When the square of light approached the point of fixation, many of the PVNs stopped firing. This is the exact opposite of what happens in the primary visual cortex. There, a disproportionate number of neurons respond to objects directly in front of the eyes. This enables us to see the things that we are looking at more cleariv than things that . . ~ <~7 are In the periphery ot our vision. But the PVNs behave differently; they respond best to objects that are in the periphery of the visual field. Most of the PVNs studied by Mountcastle were also very sensitive to the movement of the square of light. The speed of the movement was relatively unimportant. But some neurons would only fire when the NEUROSCIENCE AND NEURONAL REPLACEMENT 63

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~ - - _~JJl^" I -~, U. ~ ~ _~JUt ~ ~ I'U Jle Up 11~ ~ _ ~\\ / I 7 \ / _ em_ --~ e l l Mu_,, ~ A, .. ... . 6, ~1~11. 611 11111. ~ tI~e I,. i. 'i t U I I b ~ n l ~ ~ / 1 1 1 111~A, ant, a~ [ ~ ~a __ at, ~ I 2 ~ / j\ 5 . 1 ~ , ~ -` i.1~188.~. .~1~31111~1 ~1 . ILIu jet. . ;..., 1L iU~1~ - lllllUII. ~ ~ "Is . ~ 1. . dI.lL``U~161 1111 1 ,_! ~ l'. ~ ..' 111H l=La`~.llJ.el`L..~` I `,u,.. 4 Vital ~ s ~ In \ ~L~lI~l ~ ~ are ~ ~ u ~ I. Ud1111~]U~ 1 ~ 1~^ ~-1 1 111 ~ ~ 11 _ ~ 1 1 see / ~ ~5 ~ _ Am_ \ FIGURE 3-5 The response of a single visual neuron in the posterior parietal lobe can be measured by a microelectrode as a square of light moves in different parts of the visual field. Each vertical stroke in the readings in the top half of the diagram indicates a single discharge of the neuron. The experimental animal kept its gaze fixed on the dot in the center of the visual field. A light then appeared in the periphery of the visual field moving toward the point of fixation in the directions shown by the long arrows. The appearance of the light is indicated in the readings by the dotted 64 SHAPING THE FUTURE

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square was moving' and others could cletect a moving stimulus in parts of the visual field where a stationary stimulus hac] no effect. Furthermore' almost all of the neurons were sensitive to the direction in which the stimulus moved. Some fired only when the square mover! towarc} the point of fixation; others fired only when it moved away. What's more' most neurons exhibiter! a distinct preference for one direction over others. For instance' one might fire only when the stim- ulus was moving away from the point of fixation toward the upper left at a 45 degree angle to the horizontal. Another might fire only when the block of light approached the fixation point from below. Most of the neurons stucliec! were not this specific. The neuron de- scribec! in Figure 3-5' for example' Erect whenever the block of light was moving towarc! the point of fixation in the upper half of the visual fielcI. But almost every neuron had a '`best'' direction' defined as the direction of movement in which it wouIc! exhibit its maximum response. Extending this analysis, MountcastIe and his colleagues showed how this ~`best'' response could give a very precise indication of the direction in which something is moving in the peripheral visual field. Because most PVNs' such as the one in Figure 3-5, respond to movement in several different directions a single neuron cannot indicate an exact direction of movement. InsteacI7 the brain may rely on the responses of a large number of neurons to extract this information. By taking the '`best'' direction of a PVN and assigning that direction a magnitude baser! on the intensity with which that neuron responds to movement along any given direction a vector analysis can be macle of a population of PVNs (Figure 3-6~. Viewed in this fashion, the total signal from the PVNs reflects the actual movement of the stimulus quite closely. No mechanisms have yet been clescribed in the brain that couic! perform this kind of vector analysis. But it could be a common way in which the brain circumvents the imprecision of individual neurons in . r. . ma sing tine c ~scr~m~nat~ons. line. The time at which it crossed the center point is indicated by the small arrows. The procedure was repeated for the neuron several times for each of the eight directions of movement shown. Before the stimulus appeared, the neuron fired at a resting state. Movement of the stimulus toward the fixation point anywhere in the top half of the visual field greatly increased the discharge rate. A bar graph (bottom) shows the statistical increase in the discharge rate over the resting state. Reprinted, with per- mission, from M. A. Steinmetz et al., The Journal of Neuroscience 7:177-191, 1987. A) 1987 by the Society for Neuroscience. NEUROSCIENCE AND NEURONAE REPLACEMENT 65

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A Sense of Where You Are Although the experimental conditions used by Mountcastle are quite abstract, the functions of the PVNs give a good indication of their roles in everyday activities. "It is the visual flow through the periphery that we use to control posture and locomotion' drive automobiles, ant] lane! airplanes'" MountcastIe says. `'We're able to compute the relative ve- locities of objects moving across the periphery of our visual fields with great accuracy." If we are walking forward and looking straight aheacI. the object we are looking at floes not move. But everything else in our visual field seems to be moving. We do not consciously monitor this movement, T_ ~ 1 , . FIGURE 3-6 A vector analysis for eight directions of inward movement shows how populations of parietal visual neurons can provide a precise measure of the direction of movement. The small line segments for each of the eight directions correspond to the "best" direction of an individual parietal visual neuron. The length of the line segments corresponds to the relative rate of discharge when the stimulus is moving in the direction indicated by the outside arrows. When the line segments are added as vectors, the arrows extending from their common origin result. Note that this population vector differs very little from the actual direction of movement. Reprinted, with permission, from M. A. Steinmetz et al., The Journal of Neuroscience 7:177-191, 1987. @) 1987 by the Society for Neuroscience. 66 SHAPING THE FUTURE

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but the PVNs receive input about it. For instance, if a runner approaches a branch extending into a path, PVNs seem to be involved in calculating the location of that object in space, allowing the runner to avoid it without ever looking directly at it. In fact, the brain seems to have two separate systems for monitoring objects in the environment-one for objects in the center of the visual field, and another for objects in the periphery. The former system is one we might use to put on a ring; the [Latter to turn the page of a book. These two systems have different properties and seem to draw partially on different parts of the brain. For instance, it is very difficult to move your hand accurately while not looking at it when it is illuminated by a strobe light. But if you look directly at your hand, precise movements are possible even under strobe illumination. The ability to detect the spatial arrangement of objects in the pe- ripheral visual field ant! control movements of the body in the periphery have been very useful to humans, MountcastIe observes. When using tools or weapons, for instance, many movements have to be ma(le in the periphery while attention is directed elsewhere. Another interesting feature of PVNs is their dependence on levels of attention. When the macaques in Mountcastle's experiments were actively fixating on the clim red light in front of them, their PVNs fired an average of several times more strongly in response to the square of light than when they were just looking at the center of the screen. In other words, the more attention the monkeys focused on the task at hand, the more active the PVNs were in monitoring the peripheral visual field. This, too, runs counter to common experience. When a person is focusing on a difficult task, less conscious attention is paid to objects in the surroundings. But preconsciously the PVNs have stepped up their activity. If a person senses something out of the corner of an eye, he or she can immediately bring that preconscious perception to full consciousness by looking at whatever moved. The adaptive value of such a system to early humans, who must often have had to concentrate on manual tasks while remaining wary about enemies, is obvious, MountcastIe observes. Representations of the WorI.1 in broach terms, the activities of the PVNs are comparable to the activities of other light-sensitive neurons throughout the brain. Essen- tially, they receive nerve impulses directly or indirectly from the eye NEUROSCIENCE AND NEURONAE REPLACEMENT 67

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and transform those impulses into a more complex representation of the visual world. It is the same process that neurons in the primary visual cortex undertake in analyzing the orientation and movement of bouncI- aries, or that neurons in other brain regions undertake in analyzing color or depth or texture. The question still remains as to what part the PVNs play in the overall process of perception. Brain scientists have often won~lerec! if all the visual representations generated by different parts of the brain eventually travel to a single destination, where they are combined into a unifier] perception. Often they phrase this question in a more evocative way: Is there a single cell somewhere in the brain that fires only at the sight of onets grandmother? MountcastIe believes not. He believes that perception and other higher mental functions are clistributed processes that draw both se- quentially and in parallel on many different parts of the brain. `'[t is a succession of neural transformations," he says' "a flow-through from sensory input to motor output." The actions of the PVNs are therefore one part of this (listribute(1 system. When these neurons are damagecI, as in parietal lobe syndrome, the process of perception is corresponcI- ingly degraded' but it is not destroyed. The ~listribute<1 nature of perception is mirrored in the importance of populations of neurons in the posterior parietal cortex. "let's highly unlikely that we will be able to understand the neurological higher functions if we un(lerstancl everything about the function of single cells," says Mountcastle. "Reductionism is not enough." To this enct, MountcastIe has begun conducting experiments using arrays of microelectrodes that can detect the activity of several neurons simultaneously. With this technique he hopes to explore the dynamic interactions of groups of neurons working together, rather than single neurons working in isolation. "As we approach the study of higher functions," he says, "we have to study population activity." Neural Regeneration in Canaries Finding the exact sources of higher functions in the human brain has been an elusive goal. But in other species it has been possible to track down the brain areas responsible for quite complex behaviors. A prime example comes from studies of canaries carried out by Fernando Nottebohm, professor of zoology at Rockefeller University, and his coworkers. Their research has also overturned! a tong-standing belief 68 SHAPING THE FUTURE

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in neurology: that the generation of new neurons is rare or nonexistent in the brains of grown vertebrates. Baby canaries typically hatch in the spring. After a month or so, the males begin to sines first in a soft' unformed voice known as subsong - ~--- - - ~ 7 ~ ~] _ ~ ~ . and then in a stronger but still immature voice Known as plastic song. '`Tt almost seems as if the animal were playing with his vocal behavior without having a message to convey, just trying out the properties of his vocal tract," says Nottebohm. For 6 to 10 months canaries imitate the songs of other canaries, gradually building up a repertoire of distinctive syllables or phrases. Researchers can record ant] identify these songs on a spectrograph, a (levice that converts sound waves to traces on graph paper. Finally, by late fall or winter, the canaries have progressed to full song, which typically consists of several clozen distinctive syllables. The spring after they are born, male canaries begin to breed with females, using the songs they have (levelopecl to attract mates and mark 1 ~ . .1 ~ . 1 . ~ .] ~ ~ thelr territories. nut their songs Clo not last. Us soon as tne oreecllng season is over, the males' songs become unstable, reverting to the plastic song that hac! characterized their singing a year earlier. During this period, the males learn new syllables, forget some, and mollify others. Then, in the late fall and winter, full song returns, to be used in the next breeding season. Throughout the canary's lifetime of 10 years or so the cycle repeats itself full song during the breeding season fol- lowe(1 by plastic song. Canaries sing with an organ in their throats known as a syrinx. The centers in the canary brain that control the syrinx begin with the hy- perstriatum ventralis, pars caudalis, abbreviated HVc (Figure 3-7~. The HVc, which is situated right beneath one of the fluid-filled ventricles of the canary brain, receives projections from the brain's auditory re- gion, indicating that it is at least partially involved in interpreting songs the canary hears. The HVc, in turn, sencis messages to a clump of nerve cells known as the robust nucleus of the archistriatum (RA). The RA projects to a nucleus in the hindbrain of the canary' which contains the motor neurons that send their axons to the syrinx. The syrinx is an unusual organ in that it is involved only in singing. As a result, points out Nottebohm, the brain centers responsible for the canary's singing can be identified quite clearly. '`Tt is very seldom that you can point to a part of the brain ant} say that this part is involves! in learning to play the piano or speaking and nothing else." The boundaries of the HVc and RA can also be clefinec! quite pre- cisely, because of the distinctive appearance of the neurons they con- tain. By measuring the size of these brain regions, Nottebohm and his NEUROSCIENCE AND NEURONAE REPLACEMENT 69

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team have been able to correlate the volume of these regions with the singing behavior of individual birds. They have founl(l that canaries with large repertoires of song syllables have larger HVc7s and RA's, while birds with relatively small HVc~s and RA's tend to have smaller repertoires. The HVcis also four times larger in adult males than in adult females, and the RA is three times larger. This makes sense, Nottebohm says' since male canaries sing and females clo not. But this sexual difference is not inviolate. if given the hormone testosterone for a few weeks' females also begin to sing, though with a more limited repertoire than males have. At the same time, the volume of their HVcts nearly doubles' and their RA's grow by about 50 percent. The most remarkable discovery made by Nottebohm anc} his col- leagues is that the volume of the HVc and RA in male aclult canaries fluctuates greatly over the course of the year (Figure 3-8~. Right after the breeding season' when full song reverts to plastic song' the size of the HVc drops by nearly half. At the same time' the levels of testosterone generated by the male plummet, indicating a close correlation between hormone levels and the sizes of these brain regions. Anterior /=~: Posterior I' (\M \ ~ \~\V) ~ it-- ~$ \~OnXIIts~ Trachea Syrinx FIGURE 3-7 The hyperstriatum ventralis, pars caudalis (HVc) of the canary brain, which is situated directly beneath the lateral ventricle of the forebrain (V), receives input from the auditory regions of the brain and projects to the robust nucleus of the archistriatum (RA). The RA sends axons to part of the hypoalossal nucleus {~IT~_N _. L:_L ~ .1 1 r .~ ~ I WllI~ll lllllOlV"~ t11O Il1UbUl~b At one syrinx, Ine organ canaries use to sing. Reprinted, with permission, from F. Nottebohm, The Condor 86:227-236, 1984. @) 1984 by the Cooper Ornithological Society. 70 SHAPING THE FUTURE

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New Neurons or 014? There are two possible ways in which the volumes of the HVc and the RA coup] change so dramatically. The first would be if existing cells in these areas grew, say by forming new dendrites and synapses. indeed, this appears to account for at least part of the increased volume, Nottebohm observes. Then females are given testosterone, the den- clrites in the RA's of the females grew by an average of 50 percent, and the number of synapses in the RA increased by 70 percent. The other possibility is that new neurons are being generated ant] Incorporated into the brain, in direct violation of the dogma that no new neurons are generated in the aclult brains of vertebrates. To test this theory, Nottebohm and his coworkers injectec! canaries with thy- midine containing radioactive hydrogen. Thymidine is one of the four bases incorporated into DNA, so when a cell getting ready to divide reproduces its DNA, it will use the radioactive thymidine to form DNA. . on con - llJ ~ 0.5 . O >~ 0 3 01 1 2 3 4 5 6 7 8 AGE (in months) 1 ~1 .T 1 1 PI PLASTIC SONG )t FULL SONGS Em> Offs ) ~ 12 16 17 27 39 FIGURE 3-8 The volume of the hyperstriatum ventralis, pars caudalis (H\c) varies dramatically over the course of a male canary's life. It reaches its greatest extent at the onset of full song in the winter and spring and drops by about half after every breeding season. The vertical bars indicate one standard deviation of the data from groups of canaries. Subsong (SS) is a young canary's unformed sounds, plastic song (PS) is a stronger but still immature song, and full song (FS) is the adult song used during the breeding season. Reprinted, with permission, from F. Nottebohm, The Condor 86:227-236, 1984. (I) 1984 by the Cooper Ornithological Society. NEUROSCIENCE AND NEURONAL REPLACEMENT 71

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In this way, the daughter cells become radioactive, and new cells can be identified by the radiation they give off. When Nottebohm and his colleagues performed this experiment on male and female canaries, the results were hard to believe. They found that new neurons were indeed being generated, not only in the HVc but throughout the birds' forebrains. Furthermore, they found that new neurons were being generated in females as well as males, even when the females were not being given testosterone. Evidently, neuronal generation is a common feature of canaries throughout their adult lives. New neurons were especially common in the HVc. In female canaries, new neurons were being generated at a rate of about I.5 percent of the total number of neurons in the HVc every day. This raised an obvious problem. The loss of neurons could be accepted in males. Inventories showed that males have an average of about 41,000 neurons in their left HVc's in the spring and about 25,000 in the fall, when full song has degenerated into plastic song. But the size of the HVc remains approximately constant in females. If they were generating such a large number of new neurons every day, neuronal death must be common in their brains as well as in the males' brains. Such a loss of neurons was unprecedented in any other animal. The HVc and other parts of the forebrain in canaries are assumed to contain memories of songs and other behaviors needed for canaries to survive. The constant turnover of neurons suggested either that canaries were constantly losing memories as new neurons replaced old ones or that the new neurons were somehow replacing only those neurons not in- volved in memory. Nottebohm speculates that in fact old memories may be lost but with a corresponding benefit: the newly minted neurons may offer fresh ground for new memories. This wok o.orr`?l~.+f~ wall wi.+h .+h" hell.;+= ^{ 1 ~ ~ ITS canaries in the wild. When the breeding season is over, pairs of birds revert to foraging singly or in flocks and no longer associate. During this period, the need to produce or remember full song is not essential. [I old neurons died and previous memories faded during this period, it might free up space for the formation of new memories, as a new breeding season approached. Similarly, for females, the loss of old memories might create new space to learn the songs of males in the spring. This plasticity in the adult brain could offer a significant advantage to canaries and other birds. ``l[f you needed a brain that will give good service over a ten-year period, you might need a much larger brain. ~t 11 )QU ll~V~ [~1~1~ In0~UleS, Inen you can make do with a smaller brain, which is particularly important with an airborne creature . Ale+ ;r arts .~ ~l___~Ll ~1 1 .1 72 SHAPING THE FUTURE

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that has to lug a brain arounc! wherever it goes," Nottebohm observes. ``This is strictly hypothetical, and as with most hypotheses in science cannot be expected to survive for more than a few years. But at this time it seems like a hypothesis with some merits to it, in that it focuses on the nucleus of the cell itself for long-term memory, which is a direction others are also going in." The Birthplace of New Neurons The next logical question is where the new neurons in the canaries' brains are coming from. Nottebohm and his team quickly ruler! out the possibility that existing neurons were clividing. ``That part of the dogma remains intact," he says. Instead, neuronal replacement in the brain of aclult canaries seems to draw upon a mechanism normally active only cluring development. The brains of vertebrates take shape in a particular way. New cells are created in zones surrounding the open ventricles of the embryonic brain. Some of these cells are neurons; others are various kinds of glial cells, which will provide nutrients and other support to the neurons throughout life. Among these glial cells are a particular type known as radial glial cells. These cells extent] long arms, or processes, from the ventricular zone to the outer surface of the brain. Like someone shim- mying up a rope, neurons then migrate along these radial glial cells to their final destinations in the developing brain. Normally, the raclial glial cells disappear before birth, converted into other kinds of glia. But Nottebohm has found that radial glial cells persist throughout life in canary brains. His team has found a mono- clonal antibody, an immune system molecule that can be made in virtually unlimited quantities in the laboratory, that selectively binds to racial glial cells. it reveals a network of radial glial processes ex- tending outward from the ventricles of adult canaries, just as in de- velopment. Using radioactive thymidine, Nottebohm's team has been able to demonstrate the generation and migration of neurons along these radial glial cells. If a canary is injected] with radioactive thymidine and killed a (lay later' a rich layer of labeled cells can be seen surrounding the ventricle. If the bird is killed six clays later, some of the labeled cells have started migrating away from the v~ntrio.~3lar zone. As time noes ~fat ~1 1 1 1 1 1 . on, there are tewer labeled cells on the walls of the ventricle anc! more labeled migrating cells. By the fortieth day, there are very few labeler! cells left in the ventricular zone. NEUROSCIENCE AND NEURONAL REPLACEMENT 73

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1 .1 . 1 ~ ~ This still does not answer the question of exactly where the new neurons come from. Are there neuronal stem cells surrounding the ventricle that can clivide and produce neurons? Or do the new neurons have some other birthplace? Nottebohm's experiments have pointed toward an unexpected source. `'We believe that the most likely candidate for neurogenesis in the adult brains are the radial glial cells themselves," Nottebohm says. "Not only do they provide a path for the migration of newly born neurons, but they also provide the parent." "We're still trying to document this further," he acIcis. "We're not a hundred percent sure that all neurons are generated from radial glial cells. But this seems to be the most conservative interpretation at this time. " Implications for Other Species Neuronal replacement has not been observed in the brains of adult humans or other primates. If a part of the brain is injured, it does not seem able to repair itself internally. In some cases, other parts of the brain may be able to take over for the damaged part, as in parietal lobe syndrome. It may also be possible to transplant tissue from an external source into the brain ant! have that tissue take over lost functions. One kind of tissue that may prove especially effective is neural tissue from fetuses that have not come to term because of spontaneous or elective abortions. This fetal tissue is especially adaptable because of its early stage in development~anc] readily adjusts to its new environment. How- ever' consideration of such transplants has been beset by ethical dif- ficulties' because some people believe that using fetal tissue for transplants couIc] make abortion morally more acceptable. The absence of neuronal replacement in humans does not mean that it is impossible, according to Nottebohm. "Neurons are generated in the ventricular zone in all species during development," he says, "and quite likely the genetic control in all species is quite similar. So if you could find the genes that control this behavior and learn how to turn them on and off, it would produce a new kind of brain repair. The brain could be induced to do the work itself rather than bringing foreign cells from outside to do the job, which of course will also solve some of the ethical problems that have been worrying people." 74 SHAPING THE FUTURE