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92 THE LIFE SCIENCES ecdysone and the "juvenile hormone." The former stimulates the processes of metamorphosis in insects. The chromosomes of insects treated with ecdy- sone have been observed to exhibit puffed, swollen areas where the pro- tective coating of protein around DNA has been removed and transcription of RNA is taking place. In contrast, juvenile hormone causes insect larva to remain in the larval stage, preventing them from progressing to the pupate stage and becoming adults. The mechanism of this effect is without explanation. These relations are summarized in Figure 25. Although insect endocrinology may seem a specialty far removed from the cares of man, studies in this area have led to important advances in understanding of the relation between nerve cells and hormones, of the control of cellular growth and death, and of the mechanism of hormone action, while at the same time suggesting, as recounted in Chapter 2, how, one day, we can better control insect pests. Enough has been said above to indicate the main thrust of future research in the field of endocrines, viz., intensive scrutiny of the mechanism of action of these chemical messages. Clues are available in some instances, but in most cases only morphological response or relatively gross chemical changes have been observed to result from endocrine activity. Indeed, it is not clear that any hormone actually enters the cells that it affects. Conceivably, all effects result from binding to cell membranes. Release of cyclic adenylate in some instances, or activation of portions of the genome in others, may be direct or indirect effects of the hormone. Clearly, the effect of insulin in facilitating penetration of glucose into muscle and kidney cells is the consequence of binding of insulin to cell membranes, but other effects of insulin, for example those on amino acid metabolism, must find an alterna- tive explanation. Increasing evidence indicates that many hormones effect a change in the function of some portions of the genome, as we have already noted for cyclic adenylate. Insulin, thyroxin, sex steroids, and the plant kinins have all been shown to elicit a burst of RNA synthesis, presumably of messages previously repressed. Whether they directly affect the genes or operate through altered cellular metabolism remains to be established. When such molecular understanding is at hand, a new era of pharmacology may dawn. THE NERVOUS SYSTEM What strikes one most forcibly in thinking about the human brain is that it is made up of more than a trillion cells and that the interconnections between those cells are many times more numerous still. The nervous

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FRONTIERS OF BIOLOGY 93 Brain Neurosecretory cells \> ~Corpuscardiacum C ~ ....'...'2. "e. ,. \ ~" Hi; ~ ~ ~ ~ /Corpus allatum C:) . . .. I... Brain hormone . . . . . ... Chromosomes .: I:: ,...,, . ~ , ..... ..... .. Protein synthesis .......... Adult structures - ~ Adult ~ eland FIGURE 25 Endocrine relations in insects. JH, juvenile hormone; PGH, ecdysone. (From lI. A. Schneiderman and L. I. Gilbert, "Control of Growth and Development in Insects,', Science, 143:325-333, January 1964. Copyright (A 1964 by the American Association for the Advancement of Science.)

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94 THE LIFE SCIENCES system continually receives, transforms, stores, and updates information concerning the world about us. It is through the interactions of nerve cells that we are aware of the world around us and are capable of learning and remembering, of feeling and acting. The task of studying brain function is, at first thought, staggering. Fortunately, it has been experimentally simplified in a number of ways, and these simplifications have permitted increasing insight into brain function. The most profound simplification has resulted from development of techniques for studying the activity of individual nerve cells, a simplifica- tion that is successful because the building blocks of the different regions of the vertebrate nervous system, and indeed of all nervous systems, are everywhere about the same. What distinguishes one region from another or one brain from the next is the way the building blocks are put together. By this cellular approach some insight has been gained into the complex problems of how sensory stimuli are sorted out at various levels in the brain. It is now apparent that cells in the cerebral cortex are organized into ele- mentary groups arranged in narrow vertical columns, whose function is to perform a particular "transformation" of the neural message. But this explains why the cerebral cortex requires so many cells. It is not that the actions mediated by individual cells are trivial; rather, it is because the cortex receives such an enormous amount and variety of information from the sensory apparatus at the body surface (eyes, ears, nose, skin) that huge numbers of cells are required to handle and to "transform" this information so it can be used for perception and for action. A second simplification has emerged from the study of the brains of relatively simple animals, or even of ganglia, organized bundles of a few thousand nerve cells, since these manifest a variety of interesting charac- teristics that makes them useful as models for study of certain elementary features of behavior in higher animals. Study of neural function has engaged man for many decades. The re- wards of the last 20 years have been rich indeed, but it is apparent that we have merely crossed the threshold of significant understanding. In the years ahead, neural science will be wed to molecular biology, biochemistry, and genetics, on the one hand, and to the concepts and techniques of experi- mental psychology on the other. Only bare beginnings have been made in these directions, but it is already clear that interdisciplinary effort will be essential to bridge the gap between the function of individual cells or groups of cells and psychologically meaningful behavior. The task is vast indeed, and dramatic rapid progress is not likely. New tools must be fashioned, and new approaches must be developed. Nevertheless, those engaged in the study of nervous systems are aware of an unusual excitement and great promise.

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FRONTIERS OF BIOLOGY 95 The Neuron Neurons have irregular shapes; each consists of a cell body with numerous processes, axons, and dendrites, with varying prominence from one group of neurons to another. An example of a motor neuron is shown in Figure 26. The dendrite-cell body region most commonly receives the contacts, or synapses, projected to it by other neurons. These contacts vary from relatively few to several thousand. Each contact can influence the excit- ability of the recipient neuron. The essence of this process derives from the fact that the dendrite-cell body region can sum or integrate all the influences that converge upon it via these contacts. Compared with most other cells, the neuronal nucleus is extraordinarily large; although it has the normal species component of DNA, it has an unusually large nucleolus engaged in making ribosomal RNA and possesses a variety of enzymes that in other cell types are restricted to the cytoplasm. Within the cytoplasm, masses of ribosomes (the Nissl bodies) are actively engaged in protein synthesis, the purpose of which is not apparent. Each day a nerve cell manufactures an amount of protein equal to approximately one third of the total protein of the cell. This protein is prepared for export, since it travels down the cell and along the axon and some of it must leave the cell. The function served by this impressive axoplasmic Dow remains unknown. The narrow cylindrical axon varies from a fraction of a milli- meter to more than a meter long and conducts the action potential gen- erated in the cell body to the terminal contacts in a repetitive code of all-or-none impulses. SIGNALING IN NEURONS THE TRANSFER OF INFORMATION The complex organization of the nervous system is based upon a precise, selective interconnection of neurons, many of which are present and opera- tive at birth. Functional connections may not be permanent, and conceiv- ably they can be unmade and others formed, but the mechanism and circumstances of this change, if it occurs, are unknown. Each nerve cell possesses, in miniature, the integrative capacity of an entire nervous system, but the intricacies of the latter should not be understood to be simple addition of large numbers of the former. Each nerve cell evaluates the totality of its inhibitory and excitatory input, and then either fires or does not fire, the only alternatives available to it. Figure 27 summarizes the electrical changes that occur when a nerve fires. As measured with intracellular microelectrodes, at rest, a neuron main- tains across its surface a voltage difference of 60-70 millivolts by maintain- ing an unequal distribution of sodium and potassium ions. This distribution .~

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96 THE LIFE SCIENCES Cell body Nissl 4 ~SUES ance // ID 4,J,,~,~, /' M itochondrion // / <` )~, Synapse \ / / ~ vesicles:, Axo~Nucleol~o,,, ,Oo 0~ it. yellnated hillock / {Plasma \\ / -Node Of R~nvier Hi/ Motor end Voluntary muscle / // membrane \~( D Neuri lemma Sag_ ~ ~ ' - 1 ~ _ ~ i_ .... ~ ~ - - - ' - ' 1 ~ , ~_ Synaptic gutter (cleft) Subsynaptic~l_ i. membrane Presynaptic membrane .,, Am, Synaptic cleft 1 Endoplasmic reticulum Presynaptic vesicles E Neurilemma / SO We ~ ~ . `. ~ ,. Do Secondary , clefts FIGURE 26 The neuron. Diagrams of a motor neuron of the ventral horn of the spinal cord. (A) The neuron includes a cell body and its processes (dendrites and axons). Within the cell body, there is Nissl substance, nucleus, nucleolus, and axon hillock. The axon collateral process branches at a node of Ranvier. (B ) Several axons form synapses on the cell body and base of dendrites; motor neurons are densely covered with such synapses. Some have an excitative, others an inhibitory action. (C) A chemical synapse as reconstructed from electron micrographs, includ- ing synaptic vesicles in bulbous ending, mitochondria, Presynaptic membrane, thick subsynaptic membrane on the postsynaptic side, and the synaptic cleft, which is 200-300 angstrom units wide. (D ) Enlargement of a portion of the motor end plate region of (A). (E) Cross section through (D). (From The Human Nervous System by C. R. Noback Copyright (I) 1967 McGraw-Hill, Inc. Used with permis- sion of McGraw-Hill Book Company. Drawn by R. J. Demarest.)

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Surface polarity Stimulus applied FRONTIERS OF BIOLOGY 97 Action Resting potential potential pi -i At- row Temporal sequence of sodium and potassium fluxes N,a + PROPAGATING NEURON new \ 4. ./1 Recovery of resting potential + + + ~ Na k=G Impulse propagation FIGURE 27 Monophasic nerve action potential. Diagram shows overshoot above zero and temporal sequence of sodium ion influx and potassium ion efflux during propagation of an impulse. (From Tuttle, W. W., and Schottelius, Byron A.: Text- book of physiology, ed. 16, St. Louis, 1969, The C. V. Mosby Co.)

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98 THE LIFE SCIENCES is achieved by the sodium-transporting pump characteristic of most cells. If the resting potential is reduced by 10 or 15 millivolts, the nerve-action potential is initiated because of a sudden reversal of the characteristic sodiu~potassium selectivity of the membrane. Sodium ions enter rapidly, and potassium ions leave the cell somewhat more slowly. As this happens in a given patch of membrane, it results in lowering of the potential in the adjoining patch, where the same events then ensue and the wave is propa- gated in this manner along the axon and dendrites. During the subsequent period, while the original sodium and potassium concentrations are being restored, the nerve cannot fire. INITIATION OF IMPULSE ACTIVITY AT SENSE ORGANS Entering the central nervous system is a vast network of nervous fibers whose peripheral endings constitute the sensory apparatus, distributed in sheets such as those of the retina of the eye, the cochlea of the ear, or the skin. At the periphery, some transduction process is required to convert pressure or temperature on the skin surface, absorption of light by the visual purple of the eye, or vibration of the minute hairs of the ear, into depolari- zation (reduction of the potential) at the nerve terminal, resulting in initiation of an impulse that then travels away from the initiating event. Details of these transducer mechanisms are scanty, but it is evident that the spatial and temporal patterns of such stimuli are transformed into impulses of varying patterns and frequency. The transduction process and the tropic effect of the nerve itself upon the tissue surrounding it constitute a subject of intensive interest. In no case does the signal go directly from the initiating site to the central nervous system as a single impulse. Interposed is a set of relay stations, or interneurons. The junction between two neurons occurs at the synapse, where a dendrite from one neuron is brought into close apposition to the cell body, the axon hillock, or even a dendrite of a second neuron. In most instances, they do not make actual contact. Between them is a cleft, perhaps 250 ~ wide. In the peripheral nervous system, arrival at the dendrite of an impulse from the afferent neuron results in the discharge into the cleft of a "chemical transmitter," either acetylcholine or norepineph- rine, found in minute vesicles just at the tips of the dendrites. Diffusing across this slender space, they result in depolarization of the apposing neuron and in initiation of a new impulse to travel along its axon. The mechanism of such cell-cell interaction in the central nervous system has not been established with certainty. But since the same chemical species are to be found in the brain proper, it seems likely that the peripheral system may offer a fair model of transmission in the central nervous system. For

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FRONTIERS OF BIOLOGY sensory signals, successive excitation occurs in the direction of the central nervous system; successive motor signals move in the opposite direction. In rare instances, the cleft is missing, and the two dendrites are fused so that the electrical impulse simply continues from neuron to neuron. In the neurons of the brain, each presynaptic cell either excites, i.e., lowers the voltage difference between inside and outside, and leads to initiation of an impulse, or inhibits, i.e., increases the resting potential, thereby preventing or depressing the ability of the receiving cell to dis- charge. On most central interneurons, as is the case for other central neurons, there are both inhibitory and excitatory synapses; the balance of their influences determines whether a neuron will or will not generate an action potential and whether its frequency of discharge will increase or decrease. In both types of chemical synapses, the transmitter substance increases the permeability of the postsynaptic membrane for selected ions only. But at excitatory synapses the transmitter increases the permeability to sodium ions, which reduces the membrane potential and causes current flow, which would initiate an impulse, while at inhibitory synapses permea- bility is increased for potassium ions and chloride ions, which prevent impulse propagation. The basis for this distinction is not understood, but it resides in the structure of the synapse, not in the intrinsic chemistry of the transmitter substance. Whether an interneuron does or does not fire, and how frequently it does discharge, depends entirely upon the balance of inhibition and excitation that it receives at any instant. There is no reason to believe that all transmitter substances are known. In invertebrates, y-amino butyric acid serves as an inhibitory transmitter, and serotonin has been found to act as a chemical transmitter. Since both are present in high concentration in the human brain, as are acetylcholine and norepinephrine, in all likelihood these chemicals serve there as transmitter substances also. Termination of the activity of the transmitter is accomplished by its removal from the field of action; acetylcholine is hydrolyzed, and norepinephrine can be actively transported back into the neuron from which it was released, setting the stage for the next such event. Since norepinephrine also serves as a more conventional hormone when released by the adrenal medulla and may participate in the interaction between the hypothalamus and the pitui- tary, it will be interesting to learn whether the releasing factors of the hypo- thalamus, which governs pituitary secretory activity, also are, in effect, neurotransmitter substances. The Central Nervous System While built of essentially identical subunits, different brains have greatly different capacities for generating behavior. They differ in the number of 99

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100 THE LIFE SCIENCES neurons that compose them and in their interconnections-i.e., not in the nature of their components but in the manner in which these components are organized. As a result of their many types of interconnections, even simple neural systems manifest emergent properties that cannot be intui- tively predicted. To achieve greater understanding, two stratagems have been adopted: (1) the study of small brains and (2) the study of sub- systems of known interconnections in large brains. In each approach, the exercise consists of sequentially examining the responses of a large number of the elements at each level to a given stimulus pattern and making inferences concerning transformations that have occurred from one level to another. SMALL BRAINS The central nervous systems of most invertebrates contain only 104 or 105 cells, and the more primitive contain no more than a few hundred. Even more propitious is the fact that some invertebrate nervous systems contain small organized groups of cells capable of generating rather specific be- havior. For example, a ganglion of only nine interconnected cells is resp~n- sible for the rhythmic beat of the heart of crustaceans. More complex motor reflexes are controlled by segmental ganglia that may contain but 500 cells; an excellent beginning has been made in tracing the connection of the individual nerve cells in such an apparatus. In insects, rather simple types of avoidance learning can be accomplished by a segmented ganglion con- taining only 3,000 cells. Among these, neurons vary in their size and in the efficacy the influence on the receptor neuron of individual connec- tions. One of the major tasks of the next few years is achievement of further understanding of some of these simpler systems by combined anatomical? biochemical, physiological, and psychological approaches. But a beginning has been made. The primary tool in all such studies is the electrical detec- tion of passage of a nervous impulse. To illustrate the nature of such progress, we will consider some findings with respect to the visual systems of several types of brains. Visual phenomena commence with the absorption of light by specially adapted nerve cells in the retina at the back of the eye. Rod cells "see" only in black and white and are effective in dim light; cones "see" in colors but only at relatively high light intensity. The functional material in rods is visual purple or rhodopsin, a dye that is bleached when light of the proper wavelength is absorbed. This material consists of a protein (an opsin) to which is bound the aldehyde form of vitamin A (retinal). In the latter, all bonds are in the trans-configuration. (See diagram at top of page 101.) When a quantum of light is absorbed, the bond at position 11-12 is isomer- ized to the cis-configuration, swinging the bulk of the molecule away from

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FRONTIERS OF BIOLOGY 101 C ~ 4 s: CH3 C: H3C CH3 H3C-C_ ~H3 CH3 ~2 ~ 6~/7C`c'C - C/~`C/13`C'l5`o C 8 10 12 14 H3C' ACHE All-trans-Retinal C CH3 C/ ARC-CH3 l 11 /C`C'C`cklCl`2c /\~i -cis-Retinal ~1 C O the protein surface, resulting secondarily in a subtle change in the three- dimensional conformation of the opsin. It is this event that somehow initiates the nervous impulse, which then passes over the surface of the rod cell. Although each rod contains about 10 million molecules of rhodopsin, absorption of only one light quantum suffices to cause the nerve to fire, and if five to seven rods fire, this is perceived by the dark-adapted indi- vidual as a faint light flash! Much the same arrangement serves in the cones, except that there appear to be three categories of cone cells. In each, there is a visual pigment utilizing retinal, as in the rods. But each category of cone has a different opsin protein, so, when the retinal is bound, one appears to be red, one blue, and one yellow, thus permitting color discrimination. Color blindness con- sists of the genetic inability to make one of these three opsins. At all levels of evolutionary development a few general principles appear to be applicable. The afferent input is distributed widely among various regions of the central nervous system, and a great amount of sensory trans ~ . _ formation occurs at the earliest points in the sensory pathways as a result of lateral interaction between adjacent elements. When excitatory, lateral interactions lead to facilitation and sychronization of the activity in adjacent members of a neural population. When inhibitory, lateral interactions lead to spatial contrast. Lateral interaction has been extensively studied in the visual system of the horseshoe crab, Limulus. The eye of Limulus is constructed of a multitude of individual receptor units (ommatidia), which are not independent in their action. Although the activity of a given receptor unit is principally determined by the light shining on its facet, this activity is significantly modified when light is shone upon neighboring

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102 THE LIFE SCIENCES receptor units, causing them to become less active. The receptor units are mutually inhibitory; excitation in one unit produces inhibition in all the surrounding units. The spatial spread of inhibition is such that it is most effective for the nearest units and falls oft sharply with distance. The strength of the inhibitory influence exerted by a particular receptor channel on neighboring receptor channels depends both on the effects of the stimulus on the reference channel and on the inhibitory influences from its neigh- bors. The strength of this influence depends in turn on the neighbors' level of activity, which is partially determined by the inhibition that the reference receptor elements exert on them. This anatomical arrangement provides an example of the major principle In the dynamic organization of neural populations: balanced opposition of excitatory and inhibitory tendencies in molding patterns of neural activity. In the Limulus eye, these inhibitory influences, exerted quite indiscnmi- nately by receptor channels on their neighbors, result in enhancing contrast in the visual image. If each unit in the mosaic of receptor channels inhibits the activity of its neighbors to a greater degree as it is more strongly excited, then brightly lighted elements will exert a stronger suppressing action on dimly lighted neighbors than the dimly lighted neighbors can exert on the sharply lighted elements. Consequently, the disparity in the activi . - ties of the two channels will be exaggerated and briahtness contrast en ~ :1 t 17 . 1 _ _ ~ 1 , , . - . . ~ . al ills 1lllllulcoly 1n~eracuon is sponger IOr near neighbors in the retinal mosaic than for more distant ones, such contrast effects will be greatest in the vicinity of sharp light discontinuities in the retinal image, and the outline of objects imaged on the retina, their resolution, will be sharpened. Thus the pattern of neuronal activity generated by the action of light and by boundaries between light and dark is transformed in a physiologically important way, by the mosaic of receptor channels, at a very early point in the analysis of sensory input. By using small brains, it has been possible to describe in similar fashion the interrelationships and properties of interneuronal populations, of "com- mand interneurons" that operate at a stage beyond initial interneuronal sensory processing, and to sum up all the influences that lead them to make the equivalent of a decision. By either.firing or not firing they then deter- mine whether efferent impulses will then flow along axons that lead to the musculature. LARGER BRAINS Early studies of the visual systems of larger brains made it evident that the retina projects in an orderly fashion upon the visual cortex region of the central nervous system. But changes in the configuration of the receptive

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FRONTIERS OF BIOLOGY field occur at various levels between the retina and its final representation, as can be observed with microelectrodes implanted at various levels along the optic tracts. The first neural elements in the mammalian visual system whose receptive fields have been successfully studied are the ganglion cells of the retina, each of which is receiving information from a considerable ~ r ~ number ot rod or cone cells in the retina proper, as shown in Figure 28. The fields of these cells the collection of rods or cones to which they are connected are circular, with an "on" center and an annular antagonistic surround region, or the converse. The most effective excitatory stimulus for cells with an "on" center receptive field is a circular light spot covering the entire central "on" region of the field. If the stimulus is enlarged to include any of the annular surround region, the effectiveness of the stimulus is reduced because of the mutual antagonism between the center and sur- round regions. Accordingly, a retinal ganglion cell does not primarily signal the intensity of light impinging on a given part of the retina, but signals the contrast between the intensity of illumination in the center of its receptive field and that of its surround region. At the next synapse (in the lateral gesticulate region of the brain, Figure 29), the effective excitatory receptive field resembles that of the retinal ganglion cells. However, at the first cortical synapse beyond, the receptive field changes dramatically. Small spots of light, which are effective in stimulating retinal ganglion and gesticulate cells, are practically ineffective. To drive cortical cells, the stimulus impinging on the retina must have linear properties (bars, lines, rectangles). Within this cortical area there are two general classes of receptive fields. The simpler receptive fields resemble gesticulate cells in that they can be described in terms of discrete excitatory and inhibitory zones, although the receptive field must be rectangular and not ~7 circular, and the elective stimulus Is nor a spot of light but a bar with a specific inclination, e.g., a vertical, horizontal, or oblique axis of orienta- tion. For example, the most effective excitatory stimulus for cortical cells with a simple receptive field may be a bar with a receptive-field orientation from 12 to 6 o'clock projected upon some retinal position. This rectangular excitatory zone is framed by a rectangular inhibitory zone, and it must be built up bv receiving inout from a set of gesticulate cells having appro- priate properties ("on" centers) and similar retinal positions. Thus, for a stimulus to be effective on a cortical cell, it must have the proper axis or orientation. Since all areas of the retina must be presented in all orientations and for several stimulus types, one can understand why the cortex needs so many cells for the normal functioning of the visual apparatus. Importantly, although gesticulate cells respond to stimulation of only one eye, cortical cells tend to respond to both eyes; so it is at the level of the first cortical synapse that one finds the first evidence for the binocular-fusion character ~,< _, in, ~ 103

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104 THE LIFE SCIENCES _ .' 1 i4~,~,m,,-,1~ _ ~ a .... b 3} 3 4' b .. C _ I . i, .t C 8 1~71 _d<~ W \/ _,,, it., W1 1~2 FIGURE 28 Primate retina. Diagram representing the structures of the primate retina, based on numerous Golgi-stained preparations of man, chimpanzee, and macaque. In the upper part, the slender structures are the rod cells (a), the thicker ones, the cone cells (b); c, horizontal cell; d, e, I, A, and i, centripetal bipolar cells; l, inner horizontal or association cell; m, n, o, p, and s, ganglion cells; u, parts of the radial fibers of Muller, with their nuclei in 6 and their lower or inner ends forming the inner limiting membrane (10). Note the various synaptic relations between different neurons, reciprocal overlapping of expansion or its absence, the probable direc- tion of the nervous impulses indicated by arrows, and other details. (After Polyak. From W. Bloom and D. W. Fawcett, A Textbook of Histology, 9th ea., 1968. Copyright (I) 1968 W. B. Saunders Company.)

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FRONTIERS OF BIOLOGY istic of the vision of higher animals. These simpler cortical cells are found in vertical columns within the visual cortex, running from the surface of the brain to the white matter (Figure 29B). Within these columns are also found complex cells for which the effective stimulus is again linear and must have the correct orientation, but its exact position in the receptive field is unimportant. Clearly, these complex cells are receiving their input from a variety of the simpler cells, and the column becomes the elementary unit of neural organization, bringing together cells that are appropriately interconnected to generate a cell with a higher order of receptive field. In the adjoining area of the brain the visual message undergoes still further processing. Here some cells have "hypercomplex receptive-field properties" and respond only to a highly specific stimulus such as an angle or corner. In this region, complex cells feed into hypercomplex cells, which serve to detect curvature or changes in the direction of a line. The totality of these levels of activity permits estimation of such a change in light in- tensity as contrast between light and dark, as well as changes in contour. Elsewhere in the system are cells that recognize only change or movement. From this analysis it is not yet possible to grasp how a total visual image a room and its contents-is built and perceived almost instan- taneously, but the elements are now available. One can now say that the task of understanding the neural basis of perception is no longer impossible or incomprehensible. It is only immense. Indeed, what has been learned about neural mechanisms of perception indicates that the details are not only elegant, they are beautifully simple. Equivalent analyses are available for somaesthetic perception and for the control of motor activity. These differ significantly in detail, but the principle of the experimental approach is equivalent and has yielded, to date, about the same degree of under- standing. INTERCALATED SYSTEMS: HOMEOSTATIC REGULATION Between the major sensory and motor systems there exists the great mass of the central nervous system, composed of subsystems organized for the regulation of intrinsic brain functions and for the control of the function of other organs. These are particularly voluminous and diverse in the forebrain, where they are represented by the large association areas of the cerebral cortex, the limbic system, a heterogeneous array of large neural structures in the medial and basal walls of the cerebral hemispheres and the corpus striatum. Although this portion of the brain has been undergoing analysis for many years, understanding is not comparable to that provided by studies of sensory perception or the governance of motor function, 105

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106 THE LIFE SCIENCES FIELD OF VISION '' I \ , . _,= MACULAR VISION "an, EXTRAMACULAR VISION /~,> MONOCULAR VIS I ON . a/ B ', C) '' 1 ~ E .~' ,~ F , . <~ ~ JO ~_(( ~iL \ ~ _ ~OPTIC CHIASMA PROJECTION ON LEFT OCCIPITAL LOBE mu. A INfERIOR HORN OF LATERAL I VENTRICLE LATERAL GENtCULATE BODY OPTIC RADIATIONS PROJECTION ON RIGHT OCCIPITAL LOBE

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FRONTIERS OF BIOLOGY 107 largely because of the experimental difficulties in establishing the nature of effective input stimuli to the cells of these structures. Most current understanding has come from clinical and behavioral studies of the deficits . . .. ~ .. . ~ ~ , .- ~ _1 ~ At ~ by_ __ _~ ~ ~:= ~ that result from pathological destruction or surgical anon or spacing regions within this vast part of the brain. These have permitted somewhat detailed mapping of the responsibilities of specific regions of this portion of the brain, and it is clear that the association areas are involved in the elaboration of specific sensory information into percepts of varying com- plexity. Further, reference has been made earlier to the role of the hypo- thalamus (part of the limbic system) in the regulation of the pituitary gland. This small region is sensitive to diverse other stimuli and responds by driving appropriate motor neurons controlling autonomic functions such as respiration, heart rate, and blood pressure. One more aspect of the study of the central nervous system may be cited merely to indicate the patterns of current research. No problem is older than man's concern with himself- with the relation between the physical entity of the brain and "mind" or "self-awareness." Little progress can be recorded, but one aspect of self-awareness, the phenomenon of sleep, is subject to experimental approach. Even now it is unclear what the under- lying physiological function of sleep may be. One can only ask how it occurs and in what phenomena arousal consists. The extensive changes in cerebral action associated with sleep-wakefulness transitions are not limited to the level of consciousness. There are also changes in muscle tone and reflex thresholds, for example, which are signs of central nervous system excitability. Yet there is no general diminution in the overall activity of the sleeping brain no change in cerebral blood flow or oxygen consump- tion, no apparent overall decrease in the activity of cortical neurons. Two important discoveries underlie modern concepts of the mechanisms involved. The first is that slow (eight per second) rhythmic electrical FIGURE 29 Primate vision. (A ) Diagram of the central visual pathways showing the course of impulses from the retinal quadrants to the visual cortex. Small inserts beside eyeball show projection of image within the visual field on the retina. Images on the right side of the subject are projected on the left side of the retina; those above, on the lower half of the retina, and so on; i.e., the visual field is inverted on the retina. There is normally a region of maximum acuity in the central field, with a decline in the resolving power periph- erally. The visual field of one eye overlaps that of the other, providing the basis for stereoscopic sight (notion of depth). The notion of depth can be given in monocular vision but is far more perfect in binocular vision. (B) Projection of optic radiations to the occipital visual cortex. Corresponding visual quadrants, 1, 2, 3, 4, 5, 6, and A, B. C, D, E, F of the visual field. (From S. Grollman, The Human Body, Its Structure and Physiology, 2nd ea., The Macmillan Co., New York, 1969, (if) copyright Sigmund Grollman 1969.)

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108 THE LIFE SCIENCES stimulation of the general thalamocortical portion of the brain, entrains the electroencephalogram (EEG) in rhythmic oscillation and provokes all the behavioral signs of sleep, whereas more rapid electrical stimulation of the same region, or of the ascending reticular system of the brain that impinges upon it, wakes a sleeping animal. The second observation is that deafferentation of the forebrain by a midbrain transection leaves it with electrical and behavioral signs of continued sleep, while transection of the brain below the medulla leaves the sleep-wakefulness cycle intact. These observations and the studies that have followed from them have led to the proposition that sleep is due both to a withdrawal of driving electrical input and to an active process, originating in the brain stem, which tends to drive the forebrain electrical activity in slow rhythmic oscillation that produces sleep. According to this concept, sleep is neither exclusively active nor a passive process, but a combination of both. Much current research is aimed at clarifying the nature and mode of operation of these reciprocal mech- anisms. An alternative approach, which appears to warrant aggressive continued study, rests on the observation that spinal fluid taken from a goat that has been kept awake for several days contains a material of low molecular weight that induces deep natural sleep in other animals. If confirmed, this observation offers enormous potential, not only for understanding of the mechanisms involved in sleep, but also for the development of the ideal sedative or anesthetic. A quite independent set of problems originates in the fact of the existence of the two major cerebral hemispheres. These are connected through the corpus callosum, a bundle of perhaps 100 million nerve fibers. If this structure is severed, the functioning of each hemisphere remains intact, but quite independent. Learning in each hemisphere becomes dependent upon its own sensory input, with no crossover unless the hemispheres receive identical input. For example, an animal with a severed corpus callosum can be taught, with one eye, that a given signal represents the availability of food, and subsequently, with the other eye, taught that quite a different signal indicates such availability. Thereafter, it will continue to respond to these signals entirely in accord with whichever eye is left uncovered. In a dramatic instance, prefrontal lobotomy was performed on only the right hemisphere of a "split-brain" monkey. When introduced into a cage containing a snake, this subject cowered with fear when one eye was cov- ered and the snake was perceived with the left hemisphere, but completely ignored the snake when it was perceived only with the right hemisphere. These studies have had practical utility. Surgical separation of the hemi- spheres has been accomplished in individuals with certain forms of epilepsy who were thereby returned to a semblance of normal life. These patients