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6 The Nervous System and Behavior The Objective of Modern Neuroscience Is to Understand How the Nerve Cells of the Brain Direct Behavior Many central issues with which neurosciences is concemed, such as how we perceive the world around us, how we learn from experience, how we remember, how we direct our movements, and how we communicate with each other, have commanded the attention of thoughtful men and women for centuries. But it was not until after World War II that neuroscience began to emerge as a separate and increasingly vigorous scientific discipline that has as its ultimate objective pro- viding a satisfactory account of animal (including human) behavior in biological terms. This ambitious goal has as its basis the central realization that all behavior is, in the last analysis, a reflection of the function of the nervous system. It is the organized and coordinated activity of Me nervous system that ultimately mani- fests itself in the behavior of the organism. The challenge to neuroscience then, is to explain, in physical and chemical terms, how the nervous system marshalls its signaling units to direct behavior. The real magnitude of this challenge can perhaps be best judged by consider- ing the structural and functional complexity of the human brain and the bewilder- ing complexity of human behavior. The human brain is thought to be composed of about a hundred billion (10~) nerve cells and about 10 to 50 times that number of supporting elements or glial cells. Some nerve cells have relatively few connections with other neurons or with such effecter organs as muscles or glands, but the great majority receive connections from thousands of other cells and may themselves connect with several hundred other neurons. This means that at a fairly conservative estimate the total number of functional connections (known as synapses) within the human brain is on the order of a hundred trillion (10~4~. But what is most important is that these connections are not random or indiscriminate: 175

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176 OPPORTUNITIES IN BIOLOGY They constitute the essential "wiring" of the nervous system on which the extraor- dinarily precise functioning of the brain depends. We owe to the great neu- roanatomists of the last century, and especially to Ramon y Cajal, the brilliant insight that cells with basically similar properties are able to produce very differ- ent actions because they are connected to each other and to the sensory receptors and effecter organs of the body in different ways. One major objective of modem neuroscience is therefore to unravel the patterns of connections within the nerv- ous system in a word, to map the brain. A second, related objective is to identify the differences that exist between nerve cells. For although nerve cells have a number of properties in common especially their abilities to respond to signals from other cells and to conduct signals along their processes-on morphological grounds alone, thousands of different classes of nerve cells are evident. The morphological differences were the first to be recognized once techniques had been developed that reveal the form of individual neurons. Some cells were found to have only a single process, others just two processes, and still others-including the overwhelming majority of neurons in the brains of vertebrates-have several, often scores, of processes. In most cases we can recognize a single process, the axon, that serves to conduct information-usually in the form of all-or-none signals known as action poten- tials or nerve impulses to other cells. Variable numbers of receptor processes or dendrites receive information from other cells, integrate it, and relay it to the nerve cell body and beyond it to the axon. But it is not only in the morphology of the processes that nerve cells differ. We now know that dozens of different classes of neurons can be recognized on the basis of the chemical messengers or neurotransmitters that they use to communi- cate with other cells. The discovery in the early 1950s that almost all nerve cells communicate with each other through the release of chemical neurotransmitters at specialized sites along the course and at the ends of their axons was one of the major events that marked the beginning of modern neuroscience. Only in the past decade, however, have we come to realize that there may be not just a handful of chemical transmitters as was once thought, but perhaps a hundred or more, and that it is the subtle and distinctive actions of these transmitters that account for much of the functional complexity of the nervous system. We have also come to realize that neurotransmitters can act upon other cells only if the cells have the necessary receptors to selectively bind the neurotransmitter. The interaction of the neurotransmitter with its appropriate receptor is what initiates the response of the target cell. Again, it is only in the past few years that we have come to appreciate that the target cells can respond in several different ways depending on the nature of the transmitter, the types of receptors involved, and the mechanisms that the transmitter-receptor interaction activates. In some cases the response of the target cells is rapid and transitory, with a time course of just a few thousandths of a second; in other cases the cell responds over a fairly long period perhaps many seconds; and in certain situations the behavior of the target cell may be

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THE NERVOUS SYSTEM AND BEIlAVIOR 177 modified for many hours, or even days and weeks. A third major task of neuroscience, therefore, is to understand how nerve cells generate signals, often over long distances, and how these signals change the various target cells with which the neurons are in functional contact. The cellular and molecular mechanisms involved in nerve signaling and synaptic transmission are currently among the most intensively studied and best understood aspects of neuroscience. Less well understood, but no less important, are the longer term changes in nerve cells that must underlie the acquisition and storage of information that we commonly refer to as learning and memory. Although there is a vast body of literature on human learning and memory and on the effects of damage to various parts of the brain on its ability to acquire, store, and retrieve information, it is only relatively recently that the longer term effects of synaptic activity that must be involved in these processes have begun to be studied at the cellular and molecular levels. The first insights that we have gained into these processes suggest that a wide variety of behavioral phenomena may well prove to be explicable on the basis of just a few general mechanisms such as the covalent modification of particular molecules involved in nerve signaling or the activation of specific genes and the synthesis of new proteins. A fourth major objective of neuroscience is to account for the unusual cell biology of neurons. Although nerve cells share many properties with other cells, their special roles in the transduction of sensory information, in the transmission of signals over considerable distances, in being able to respond to signals from other cells, and, in turn, in being able to modify the activity of their target cells imposes on neurons a number of highly specialized functions. These considera- tions raise a number of intriguing questions including (1) how the enormous phenotypic diversity seen among nerve cells is generated, (2) how different parts of each neuron become specialized to either receive or transmit signals, (3) how nerve cells are able to maintain such lengthy processes given that the genetic information is confined to the cell nucleus and most of the synthetic machinery is confined to the relatively small cell body, (4) how communication is maintained between the nerve cell body and its various processes, and (5) what changes occur in the cells in response to "experience" and aging. The fact that most neurons have to survive and continue to function effectively throughout the life of the organism for 70 or more years in the case of neurons in the human brain is one of their most impressive characteristics. Recent developments in molecular and cell biology are beginning to influence the study of these phenomena, and there is every reason to be confident that they will soon be as well understood as the mechanisms involved in impulse conduction and synaptic transmission. Undoubtedly the greatest challenge to contemporary and future neuroscience is to understand what might be referred to as the "information-processing" capac- ity of the brain to determine how the various systems within the brain are organized and function to direct and mediate such behavioral phenomena as sensory perception, language function, motor actions, emotion, cognition, and

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178 OPPORTUNITIES IN BIOLOGY thought. Again, although we know from clinical neurology and pathology that the destruction of certain areas of the brain seriously impairs or effectively abolishes these capacities, how these higher functions are normally carried out remains largely unknown. That it has been possible to produce machines that can dupli- cate some aspects of these higher brain functions has suggested that developments in computer science and especially artificial intelligence may inform our under- standing of how the brain functions in much the same way as molecular and cellular neuroscience have been informed by concurrent developments in molecu- lar and cell biology. But this remains to be seen, and for the present the single greatest challenge to neuroscience is to elucidate how the brain works. It Is Important to Use Both Reductionist and Synthetic Strategies for Studying the Nervous System The strategies that neuroscientists have adopted for studying the nervous system have varied over the years as new techniques and methods have been developed. But from the beginning they have all been based on a few general premises. Among the more important of these have been the following: (1) Animal behavior reflects the activity of the nervous system; (2) no matter how simple or complex the nervous system or the behavior, the essential units-the neurons are alike in most significant respects; and (3) because of the structural and functional similarity in neurons, it is important to select the neuronal system or the neurons that are most advantageous for study, regardless of where they are found. Before the introduction of micropipettes as recording electrodes, the giant axons that control the mantle musculature of the squid were the objects of choice in the study of the physico-chemical mechanism of nerve signaling: They were several centimeters long and up to 0.5 millimeters in diameter, they could be easily dissected out, they remained viable in a recording chamber for many hours, and long, insulated wire electrodes could be inserted for some distance down their length so the potential difference across the axonal membrane (axolemma) at rest and during the conduction of an impulse could be measured. Later when it became important to study the electrical events that occur in both the pre- and postsynaptic elements during synaptic transmission, an unusual "giant" synapse in the squid nervous system proved to be invaluable. Over the years the most useful preparation for studies of synaptic transmission in verte- brates has been the neuromuscular junction, because it is readily identifiable and easy to handle, and because it is relatively easy to record from the postsynaptic cells. Similarly, the modified muscle cells that compose the electric organs of certain fish have provided the richest source of the receptor for the neurotransmit- ter released at nerve-muscle junctions. The availability of the acetylcholine (ACh) receptor in such large amounts made possible, first the isolation and biochemical purification and characterization of the four subunits of which the receptor is composed, and later the cloning of the genes for each subunit.

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THE NERVOUS SYSTEM AND BEHAVIOR 179 The earliest studies of behavior were largely descriptive, but in the hands of the neurophysiologists and ethologists they provided a wealth of information about reflex (including conditioned reflex) and "instinctive" behavior, some of which has since been analyzed electrophysiologically. Because of the difficulty of analyzing behavior in most complex organisms, considerable attention has been paid to the analysis of more simple, rigorously definable behaviors in simple organisms. For example, much of what we know about the way in which motor activity is programmed has come from the analysis of locomotor behavior in crayfish and leeches. More recently, scientists have taken advantage of certain large, readily identifiable neurons in the sea snail Aplysia to analyze the short- and long-term changes that occur in neuronal structural and function in certain well- defined behaviors including an especially useful model for nonassociative and associative learning. The Aplysia nervous system has also proved useful for studying gene expression in specific neurons and for determining the neuropep- tides that mediate even complex behavior such as egg-laying. In an attempt to work out the complete organization of a nervous system in an animal which is readily amenable to genetic manipulation, the nematode Caeno- rhabditis elegans, which has just over 300 neurons, has been studied. The lineage of each of these neurons has been determined (by direct inspection), specific lineage mutants have been identified, and the complete wiring pattern of the nervous system has been reconstructed from serial electron micrographs. Of even greater use for genetic studies is the nervous system of Drosophila. Mutations that affect different parts of the nervous system have been known for many years, but it is only in the past 15 years that a major effort has been made to identify behavioral mutants, to analyze the development of the nervous system (including the eye), and to clone the genes for a number of interesting neuronal proteins such as rhodopsin and one of the potassium (K+) channels. The power of this approach, which has already yielded so much in other systems, holds great promise, especially for understanding the molecular mechanisms involved in neural development. While we cannot emphasize too strongly the importance of this search for simple systems in which to analyze specific aspects of neuronal functions, in the last analysis the greatest interest lies in understanding the functions of the human brain. Until recently the opportunities for doing this were limited. Clinical neurologists led the way by analyzing brain function resulting from localized or more general brain pathologies. Much of what we know about the organization of the human brain has come from studies of this kind, and when patients with specific brain lesions (such as an interruption of the corpus callosum that unites the two cerebral hemispheres, or localized damage to the speech areas or to those concerned with memory processing) have been carefully studied by neuropsy- chologists, they have revealed aspects of brain function that could not have been determined in any other way.

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180 oppo~ruNlTlEs INBlOLOGY In the past decade a number of noninvasive methods have been developed for studying the human brain. These include computerized axial tomography (CAT scanning), positron emission tomography (PET scanning), magnetic resonance imaging (MRI), event-related potential recordings from the scalp with computer- ized averaging techniques, and magnetoencephalography. The full impact of these technologies has yet to be felt, but it is already clear that they will enable us to study many aspects of brain function in the intact human brain that hitherto could be analyzed only in the brains of experimental animals. For the study of those distinctive aspects of human behavior, such as speech, they should prove invaluable. Useful as these noninvasive methods are proving to be, at present they suffer from severe limitations in spatial or temporal resolution (or both). They usually provide information only about the summed activity of larger numbers of neurons rather than about the functions of individual neurons. For studies of this kind, we must still turn to experiments on animals. The need for such experiments will continue, for, despite efforts to find alternatives, the only hope we have in the forseeable future of understanding the organized activity of the brain is by directly studying the brain itself. Simulations and computer modeling of brain functions are no substitute for direct observation. One of the most promising developments in this regard has been the perfect- ing of techniques for recording the activity of individual neurons in conscious, behaving primates. This approach, first introduced about 15 years ago, has become increasingly popular for studies of sensory perception and motor control. It has been possible in several instances to train the experimental animal to carry out a psychophysical task for which comparable human performance can be measured; investigators are now beginning to collect substantial data on the activities of neurons in parts of the brain (including the so-called association areas, which had hitherto defied analysis) that are likely to be directly applicable to human brain function. An extension of this approach that permits simultaneous multiple recordings from many neurons is one of the promising recent develop- ments in neuroscience. Nerve Cells Are the Signaling Units of the Brain As we have seen, almost all nerve cells have at least three or four main parts: (1) a cell body that contains the nucleus and most of the cell's biosynthetic machinery; (2) a number of relatively short processes, called dendrites, which extend from the cell body and provide the largest receptive surface for inputs to the cells; (3) an axon, which usually extends for some distance from the cell body and is used for long-range signaling; and (4) specialized regions, commonly at the end of axons, called synaptic boutons or synaptic endings, where communication with other nerve cells or special effecter tissues (such as gland or muscle cells) is carried out.

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THE NERVOUS SYSIEM AND BEHAVIOR 181 The best way to understand how these various components of a neuron work is to consider them in the context of a simple behavior-for example, the reflex withdrawal of a hand that touches a very hot object. Contact with the hot object activates a group of sensory receptors in the skin that respond to heat and causes them to fire a burst of all-or-none signals called action potentials. These action potentials propagate along the length of the sensory neurons, past the cell bodies, and to the axons, which extend into the spinal cord. At the ends of the axons the action potentials cause a chemical transmitter to be released. The chemical transmitter released at the ends of several axons interacts with receptors on the surfaces of the dendrites of certain spinal cord neurons giving rise to an activating signal called an excitatory postsynaptic potential. If the excitatory potentials elicited by impulses in the sensory axons are of sufficient amplitude, they trigger a nerve impulse, or a group of impulses, in the spinal cord cells. These, in turn, through their axons, activate a group of motor or effecter nerve cells. The axons of the motor cells extend out from the spinal cord to the muscles in the forearm and hand, where again a chemical transmitter is released at the nerve-muscle junction. The binding of the transmitter to the appropriate receptor in the muscle causes a brief change in the surface membrane of the muscle cells that leads the muscles to contract and the hand to withdraw. Concurrent with the excitation of neurons in the spinal cord that activates motor neurons, some of the branches of the sensory axons contact yet other spinal neurons that, when activated, inhibit the activity of the motoneurons that normally cause the forearm and hand to extend. The activation of yet other neurons in the spinal cord leads to the propagation of information about the sensory stimulus (its location, nature, and intensity) to higher levels within the nervous system. These lead, among other things, to the conscious perception that the hand has been in touch with a hot object, and if the stimulus is severe enough, a generalized arousal of the individual that focuses attention on the stimulus and its behavioral significance. If the hand is jerked back with sufficient vigor, there may also be a number of reflex adjustments within the spinal cord to maintain the subject's balance and posture. This simple example serves to make several general points about the nervous system and its role in behavior. (1) Most behavior occurs in response to an external sensory stimulus of some kind; (2) sensory signals must be transduced into nerve signals; (3) nerve impulses travel along specific pathways to defined areas of the central nervous system; (4) nerve cells communicate with each other through specialized junctional zones known as synapses; (5) synaptic transmis- sion can be either excitatory or inhibitory depending on the chemical neurotrans- mitter involved; (63 most behavior manifests itself in the form of overt motor actions; and (7) many sensory stimuli are also consciously perceived as a result of the transmission of information to higher brain centers including the central cortex, and this perception may result in conscious arousal and the focusing of attention on the stimulus and its behavioral consequences.

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182 OPPORTUNITIES IN BIOLOGY Considerable progress has been made in recent years in our understanding of all of these steps: sensory transduction, the nature of the nerve impulse, synaptic transmission, the anatomical pathways involved in a variety of sensory and motor mechanisms, and how these pathways are assembled during development. In the sections that follow we shall try to summarize what is known about these issues and to point out the directions in which future work seems to be headed. NERVE CELL COMMUNICATION Nerve Cells Communicate by Electrical awl Chemical Signals To understand how neurons and synapses work, we need to understand how a nerve impulse or action potential in a presynaptic neuron causes the release of a chemical neurotransmitter at the synapses formed by its axon. But fast we must focus on the ionic currents that produce the action potential in the presynaptic neuron and on the way these currents interact with the structures in the terminal parts of the axon to bring about the release of the transmitter. The use of certain naturally occurring neurotoxins that bind specifically to the sodium channel has made possible a preliminary molecular characterization of the sodium channels in muscle and brain. The channel is a large glycoprotein with a molecular weight of 270,000 whose amino acid sequence has been deter- mined from the corresponding complementary DNAs. The amino acid sequence has, in tum, suggested several ideas about the function and evolution of the different segments of the channel protein. For example, the molecule contains four similar sequences (homologous internal repeats), each about 150 amino acid residues long: These repeat sequences suggest that the channel may have evolved from a single ancestral DNA segment that was duplicated within the gene three times. By examining the distribution of specific amino acids within the entire peptide, it is possible to identify candidate domains concerned with various functional properties. In particular, each internal repeat has five long hydropho- bic areas that probably represent the transmembrane domain and a charged segment that is thought to serve in the Bating process (that is, the opening and closing of the channel) and in the selectivity of the channel for sodium. The channel probably responds to changes in membrane potential by undergoing a conformational change and a masking of the positive charges that bound its pore. The techniques of site~irected mutagenesis to modify specific sites in the chan- nel protein should make it possible to test these ideas directly. The analysis of the voltage-gated sodium channel has brought to light two features we shall encounter again when we consider the acetylcholine receptor. First, several stretches of hydrophobic amino acids seem to correspond to trans- membrane alpha helices. Second, the channel is symmetrical, consisting of similar subunits arranged in the plane of the membrane around a central aqueous pore. These early findings encourage us to think that all membrane channels are

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THE NERVOUS SYSTEM AND BEHAVIOR 183 :: ~ : : ::: ~ ::~:::~RE:STINGAND~AGTION~POTE~NTIALS -I ~ ~ : :: ~ : ~ it: ~ ~ ~::~At~::rest, all nerve: cells: ~:have~an ~ el~r~al potential across :their plasma:: :~ :membranes~: of: abobt~50 ~mi:lluro~ks~ (mV)~, th~e~::inside~ Of :~the::~ - ll: being~n~g~tive~: :~1:~ ~: :::~:~:with respect tote outside Refigure 6-1~). An :~adtio~n~potential~:~'s :an: ~all~r-~none~ ::: signal that: not only ~:reduces~b~: actually reverses~th~e mem~b~rane:~potential,~ ::: i: ~1 Moving Ma total:of About 100 m:V~from Isis resting valu:e~of~-5Q: molto +50~ my/. :: The action ~p~ential~ is generated:: by the Movement ~ Fins through Go types ~ of ~ ~'ntr~ns~c membrane prawns ~ G alled~::' voltag~gated~': channels. ~ ~ ~those~for : I:: sodi u m and: those Far ~pot:assiu m. ~ ~ Each Of ~ these ~ channels ~ is Hosed At rent :: and o~pens~'n:::an ::~all~r-nan~e:: fashion as Alar result:: of: a reduction in :fhe mem horn :~tanti;al b~Iow:a~critica:l vie. When open, loach channel permits theta :: : :: it: rapid:~:~:~movement:~ ::~of~::~: ~:io;ns throug~h~::th~:~membran:e,:: givin 9 nse:~::to:: ,ouises~: Ot~:~ :cu~rrent:~ofYariable~d~u~ration~butOo~nsta:ntamplitude.:~::S6dium~,~beTng~:~a:~p~osi-~ ~ tivel~y ~:charged~ mn~ Which, i: ~ rest, finis i: at higher concentratio~r,~outs~ide~:~:;the i: ~ ~neuron: moves: :rapid:ly::into: the ::oell from ~th:e:::::outside: b (ingoing in positive t ~ ~ :c;harge,: this movement causes: ~:the rising :or :depolarizing ph~ase~:~6f::the ~ acting ::: :: : : ~ : :: pat~ential.:::~ln:turn, ~potassi~u:m: ions: carry~posKivQ charge outfox the cell; thirsts ::~ movement~is responsible for the declining or re~lar~zing phase The Ton:: potential. : ~ i:: : ~:~ likely to share certain common structural features. Once these are understood, it may turn out that all membrane channels work in much the same way. But at present, the conceptual gap between the primary structure of the channel proteins and their function is too large to allow us to make this prediction with any degree of confidence. Synaptic Transmission: The Nerve-Muscle Junction as a Prototypical Example The nerve impulse is essentially a form of electrical signaling, with the wave of ionic currents sweeping down the surface of the axon at speeds in the range of 1 to 100 meters per second. Communication between different neurons and be- tween neurons and other cells is chemical in most instances the release from the nerve endings of a small amount of a specialized neurotransmitter that diffuses across the space separating the two cells. The binding of the transmitter to receptor molecules in the membrane of the postsynaptic cell gives rise, in turn, to a new class of signals called synaptic potentials. Thus, whereas the action potential is a purely electrical signal, the synaptic potential is an electrical signal initiated by a chemical one. In the past two decades a large number of such

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184 OPPORTUNITIES IN BIOLOGY On > +50 ._ - .m a) o Q Q -50 a) o FIGURE 6-1 Resting and action potentials. T. Ime chemical transmitters haves been identified: They range from small molecules such as ACh, glutamate, noradrenaline, and serotonin to much larger molecules including a rapidly growing number of peptides. Over the past 30 years, each of the steps involved in synaptic transmission has been characterized in considerable detail, primarily through the use of intra cellular microelectrodes and thin-section electron microscopy. The pace of research on synaptic biology has increased rapidly in recent years since the introduction of rapid freeze-fracture electron microscopy, patch-clamp micro electrode techniques, and the application of modern methods of protein chemis try, recombinant DNA probes, and monoclonal antibodies to the isolation and characterization of the molecular mechanisms involved. Because of its ease of access and because it was the first site at which chemical transmission was identified, the neuromuscular junction between the motor axon terminals and muscle cells-has been the most intensively studied synapse and illustrates the major features of synaptic transmission. When an action potential invades a motor nerve terminal, it releases the transmitter ACh after an irreducible delay of about 0.5 to 1.0 milliseconds. The transmitter then diffuses across the 50-nanometer synaptic cleft between the nerve terminal and the muscle cell in a matter of about 200 msec before binding to ACh receptors in the junctional region of the muscle membrane. The interaction of the transmitter with the receptor leads to a conformational change in the receptor and the opening of its channel. This is followed by an influx of sodium ions that depolarizes the postsynaptic membrane. In contrast to the all-or-none nature of action potentials, the depolarization of the muscle membrane the end-plate potential is a local response proportional to the amount of ACh released. Under

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THE NERVOUS SYSTEM AND BEHAVIOR 185 normal ionic conditions the end-plate potential is usually large enough to trigger an action potential that is then conducted away from the end-plate region along the surface of the muscle cell. The action of the synaptically released ACh is brief: The end-plate current decays within 1.0 to 2.0 msec. The duration of action of the released ACh is limited by its breakdown by an extremely active enzyme, acetylcholinesterase, that is concentrated in the synaptic cleft. The discovery in the early 1960s of a-bungarotoxin, an 8,000-dalton peptide that binds specifically and with high affinity to ACh receptors in skeletal muscle, provided a crucial tool for biochemical studies of ACh receptors. The receptor, first purified from electric organs of the rays Torpedo California and Torpedo marmorata (uniquely rich sources that are embryonically related to muscle cells) is a 275,000-dalton glycoprotein made up of four subunits. Complementary DNA cloning techniques have revealed that each subunit contains four hydrophobic regions that presumably span the lipid bilayer. A fifth, amphipathic domain, located between the third and fourth hydrophobic regions, may also span the membrane. The ACh receptor has led the way because of the relative ease of its purifica- tion from receptor-rich electric organs, but complementary DNAs that code for other receptors or ion channels (ligand-gated and voltage-gated) have now been cloned and sequenced. It has been known since 1914 that ACh activates two broad classes of receptors. Nicotinic ACh receptors of the sort we have so far considered are present at motor end plates, at synapses within autonomic ganglia, and at a few synapses within the central nervous system (CNS). Muscarinic ACh receptors are found in various autonomic effecters including smooth muscle, cardiac muscle, and exocrine glands. Most ACh receptors within the brain are muscarinic. This receptor has now been cloned, as has the p-adrenergic receptor. Relatively Little Is Known About the Molecular Details of Transmitter Release at the Neuromuscular Junction In addition to the two major currents involved in the action potential (the sodium and potassium currents), a third, minor current is particularly important at the presynaptic terminals of the synapse: the calcium current. The calcium current is small, only about 1/100 of the sodium or the potassium current, and therefore it does not usually contribute importantly to the action potential per se. Rather, it serves as a messenger carrying into the cell information that is necessary for release of the chemical transmitter. The function of calcium in this context can best be understood if we shift our attention from the receptors on the postsynaptic cell the muscle to the presyn- aptic terminals of the motor neuron. The chemical transmitter is released from the axon terminals, not as isolated molecules, but in packets containing about 5,000 molecules of ACh. Enclosed in small subcellular organelles called synaptic vesicles, these packets of ACh are released from the expanded terminals of the

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TlIE NERVOUS SYSTEM AND BEHAVIOR 213 for selection of sensory information. Clear electrical signs of selection observable even with scalp electrodes can separate the messages that are being attended to from those that are being ignored, within the first 100 msec after presentation. Recording from single cells in alert monkeys has provided a great deal of infor- mation about the anatomy of the system that selects information from visual space. We know that an area of the midbrain (the superior colliculus) is important for selection when the animal attends by making eye movements, whereas tha- lamic (pulvinar) and cortical (parietal lobe) areas are involved when the animal attends covertly to an area of the visual field not currently being fixated. Lesions of these areas produced by strokes or tumors in humans produce deficits similar to those described in the monkey. We are beginning to relate the detailed computa- tions performed when attention is moved from one visual location to another to these anatomical areas. These signs of selective attention depend on the integrity of the prefrontal cortex. In patients with lesions in this area, electrical activity related to early selection is reduced and performance is impaired. Similar deficits in event- related potentials have been found in schizophrenic subjects who are often de- scnbed as lacking higher levels of attentional control. Furthermore, blood-flow studies of schizophrenic subjects who are performing tasks that require shifting of attention among different stimulus dimensions of color, form, and number show a deficit in flow in the prefrontal cortex. The deficits in adult patients with frontal lesions are often characterized by difficulty in maintaining coherent programs designed to reach a goal. These same patients are frequently distracted from their goals by sensory events, as if they were less able than normal subjects to control sensory activation. Animals with lesions in frontal areas have difficulty in responding correctly when a delay is imposed between the stimulus presentation and their response. These animals have trouble whenever they are required to select a novel or less typical response. They seem to have difficulty in resisting the momentarily strongest response in order to pursue a goal. Psychobiology of Development Studies on the Psychobiology of Development Have Transformed Our Understanding of the Capabilities of the Newborn The genetic endowment of human newborns provides a considerable capabil- ity for perception, learning, and even such higher-level concepts as number. Applications of simple conditioning and habituation methods to infants is provid- ing a basis for exploring differences in cognitive ability. There seems to be some stability from measures in early infancy to later achievement as measured by standardized tests. In addition, temperamental differences among infants in reactivity to external events, emotionality, and inhibitory control are providing a new impetus toward understanding the biological development of personality. Important shifts in temperament seem to occur during definable time periods, in which the maturation of neural systems change the capability of the developing

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214 OPPORTUNITIES IN BIOLOGY infants to regulate their own behavior. These critical periods provide important clues to the changes in behavior resulting from maturation of brain regions during development. Studies of the development of monkeys have already enlarged our understanding of the slow maturation of some areas of the brain. The frontal lobes, for example, continue to develop for some years afterbirth. These develop- mental processes can now be studied in human infants by observing changes in metabolic activity within regional brain areas. The results so far reported with these techniques fit the time course of shifts found by behavioral studies. Behavioral changes seem to occur in parallel for monozygotic twins, who become increasingly concordant with age. Thus, at least some of the shifts observed in development seem to have a genetic basis. These new findings set the occasion for reexamining the fundamental issue of how genetic and environ- mental influences work in concert to shape the social and cognitive development of infants and children. The genetic analysis of the development of behavior promises to provide insight into some disorders. For example, genetic analysis of developmental dyslexia has suggested not only the inheritance of one form of the disorder, but also through linkage analysis provides suggestive evidence for an autosomal dominant locus on chromosome 15. Fundamental Understanding of the Neurobiology of Cognition Will Have Important Practical Applications The analysis of reading in terms of elementary cognitive operations has already begun to guide efforts to produce specific remediation techniques in developmental or acquired dyslexia. Of more importance in terms of public health are the efforts to apply these concepts to closed head injures. Although it is still unclear how successful this kind of cognitive remediation is, the potential benefits are great. Neural imaging techniques have revolutionized the practice of clinical neu- rology. In the near future, our understanding of the neural mechanisms underly- ing selective attention and language should assist the neurosurgeon in the delicate task of avoiding the most critical areas when performing needed surgery. Im- proved assays of cognitive function should also allow better tuning of drug therapies and replacement or transplant methods. The combination of great intellectual interest and obvious practical impor- tance makes this area a central one for the future of neurobiology. BEHAVIORAL ECOLOGY Behavioral Ecology and Sociobiology Encompass the Study of the Evolutionary Adaptiveness of Behavior Evolutionary adaptation refers to differences in structure, physiological pro- cesses, behavioral patterns, or complexes of traits that increase the inclusive

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THE NERVOUS SYSTEM AND BElIAVIOR 215 fitness of one organism over that of another organism of the same species. But because the effect of specific traits on the inclusive fitness of organisms is difficult to measure directly, evolutionary adaptations are usually inferred from the organisms' '~goodness of fit" to their environments. One of the tasks of behavioral ecology is to investigate this particular correlation: to understand how selection pressure, exerted by the ecological and social environment, favors one behavior over another. As a consequence of this evolutionary approach, the closely interlocked fields of behavioral ecology and sociobiology have been revitalized during the past 10 to 15 years. The fields have been energized by the merging of ethology, population genetics, and modern evolutionary theory in a manner that has proven effective in generating new hypotheses about the adaptiveness and evolution of behavior. In the past decade or so, numerous mathematical models have structured the theoretical framework of behavioral ecology. Among these models, which are derived from theoretical population genetics, the most prominent are inclusive fitness theory (now better known as kin selection theory), optimization models (derived from microeconomics), and evolutionary stable-strategy models (de- rived from game theory). These theoretical concepts must now be tested by much more extensive and rigorous experimentation. To that end, we need the techniques and methodologi- cal approaches developed in experimental ethology, psychobiology, and neurobi- ology. We need to understand the neurobiological mechanisms underlying be- havioral expressions to appreciate the framework that defines the animal's re- sponse to environmental conditions. A knowledge of the morphological features and physiological mechanisms underlying behavioral patterns is crucial to our understanding of the evolutionary constraints on behavioral~cological adapta- tions. Without an appreciation of the behavioral mechanisms involved in such key phenomena as competition, parent-offspring relationships, communication, and interspecific interaction within ecological communities, an adequate and precise description of ecological organization is not possible. Ecologists need to appreciate more fully the function of behavior as one of the major keys for understanding ecological systems. Conversely, neurobiologists (despite their recent advances at the molecular level) must not forget that these mechanisms are the products of evolution and, in particular, of natural selection acting in specific environmental and social settings. One of the Most Rewarding Trends in the Study of Behavior Is the Convergence of Field and Laboratory Approaches As ecologists increasingly realize the importance of behavior, they have begun to turn to laboratory techniques developed by experimental behavioral biologists. At the same time, psychobiologists have increasingly applied their experimental methods to investigations of naturally occurring behavior. They

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216 OPPORTUNITIES IN BIOLOGY now more fully appreciate the biological and specifically ecological boundaries that affect learning patterns and the development of behavior in general. The "Umwelt" concept, first presented in 1921, has gained new meaning. We now ask with new methods and vision, What is the perceptual environment of an animal? How is it affected by the animal's developmental stage, social status, motivation, and other behavioral contexts? How does an animal filter out extra- neous stimuli or select particular cues from an indescribably rich palette of environmental stimuli? And which cues trigger an animal's predisposition to learn and to store the things learned in its memory? These are important questions not only for understanding adaptive learning mechanisms and sensory-neurobiol- ogical processes, but for understanding the significance of the hierarchical organi- zation of cues in such behaviors as orientation, habitat choice, mate selection, kin recognition, and the identification of competition and enemies. A particularly interesting illustration of the principle is kin recognition. Much of sociobiological theory predicts that animals will behave differently toward close genetic relatives and nonrelatives. As predicted, most instances of apparently altruistic cooperation that have been analyzed reveal nepotism at work. Clearly, animals must be able to recognize their close kin. Animals from many different taxa have this capacity. How they accomplish such often fine-tuned discrimination is now an active area of investigation, and most of the major hypotheses suggest roles for learning, memory, and specific sensory cues. Be- cause adequate tests of these hypotheses will require careful experiments, an array of laboratory techniques in experimental behavioral physiology and psychobiol- ogy are being developed and applied. Studies of Kin Assemblages and Kin Recognition Lead to a New Understanding of Population Structures and Mating Strategies Kin recognition not only makes nepotistic behavior possible, but bears the responsibility for the avoidance (or optimization) of inbreeding. In highly evolved social systems, such as the eusocial insect societies, kin recognition functions as a social immune system, which accepts individuals that carry the right family label and rejects those labeled with foreign markers or lacking the familiar markers. The strategy of recognition of "self" and rejection of "alien" in such societies, which have been called superorganisms, resembles the strategy metazoan organ- isms use to protect bodily integrity. Interesting evolutionary parallels can be drawn between kin recognition systems and the immune system. In most organisms studied to date, kin recognition labels seem to be chemi- cal probably complex blends of specific chemical compounds that are ulti- mately genetically determined. These labels apparently have to be learned by kin- mates, but the learning process also seems to contain specific temporal patterns. Also, learning seems to be programmed and constrained by templatelike neural mechanisms. Substantial evidence has been adduced of similar mechanisms in

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THE NERVOUS SYSTEM AND BEHAVIOR 217 invertebrates, lower and high vertebrates, including primates, and even in human infants and children. A second advance in our understanding of social groups centers on conflicts of interest. A counterpoint to the documentation of cooperation between relatives is the discovery of many instances of subtle and not-so-subtle disharmony in apparently cooperative groups. It follows from the neo-Darwinian "selfish gene" view of evolution that cooperation between individuals should reflect a delicate balance between costs and benefits that could easily tip toward conflict. Here, too, recognition systems play a crucial role. Conflict and competition appear to constitute a major force in structuring ecologial communities, but little is known about the behavioral mechanisms underlying competition. Central questions that should be addressed concern the role of learning in competitor recognition and the comparative assessment of "self" versus "opponent" in competitive interactions. As in the study of coopera- tive and competitive interactions within a single species, the role of learning and memory is a central topic for understanding these naturally occurring behaviors. Direct Links Are Being Made Between Behavioral Ecology and Development Psychobiology The only significant result of evolution by natural selection is the determina- tion of what genes are preserved, or what new genetic variants persist, and which disappear after numerous generations. But the phenotype on which selection acts is not merely an adult, but a life cycle, and therefore behavioral ecologists are not concerned solely with the genes that affect adults but also with those that affect the whole of development Such behaviors as foraging, mating, nursing, helping, and fighting are based on short-term decisions. The evolutionary significance of these behaviors will be fully understood only if they can be related to long-term life-history patterns. Life-history theory deals with questions such as how an individual should allocate resources to growth versus reproduction to achieve the greatest fitness. Attempts to integrate typical behavioral-ecological analyses of short-term decisions with long-term approaches of life history theory should increase. All Social InteractionsInvolve Communication The study of communication will continue to be a major topic in behavioral biology and will entail, on the one hand, the investigation of the signal-receptor systems and the neural mechanisms of information processing and, on the other, the comparative study of the evolution and ecological adaptation of communica- tion strategies. The two main themes of evolutionary biology are adaptation and phylogeny. Both are best examined by comparative methods. Methods developed by taxono

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218 OPPORTUNITIES IN BIOLOGY mists are now being applied to the comparative study of behavior. Adaptive strategies can often be deduced from analogous mechanisms found in phylogen- etically diverse groups of species. As behavioral fossils do not exist, the recon- struction of the most likely history or phylogeny of animal communication is based on comparative studies of organizational levels of communication mecha- nisms in closely related species. A current topic of debate is the question of whether signals, or communica- tion displays, were selected during evolution for their efficacy in transferring information or for their effectiveness in persuading or manipulating others. Only detailed behavioral-ecological analyses of communication strategies in animals can provide answers to these questions. In recent years it has become increasingly clear that communication is rarely characterized by a direct all-or-none response. Communication is not always a deterministic releasing process, but sometimes plays a different and more subtle role, modifying the behavioral properties of the receiver and alerting and focusing the receiver's attention on the situation context. This kind of system has been called modulatory communication. In it, signals do not release specific behavior patterns, but rather modulate the probability of reactions to other stimuli by influencing the motivational state of the receiver. We should expect such modu- latory communication to be most frequent in complex animal societies, where many members perform many different tasks at the same time, and where an economically efficent organization of behavior requires that the work force dis- tribute its energy investment among different tasks through an optimum division of labor. It has recently been argued that the social system itself, by communicators processes, can develop the properties of problem solving; it can develop what amounts to a cognitive system that encompasses but also exceeds the cognitive capabilities of the individual components. It has even been suggested that we compare the coordinating mechanism active in such superorganisms with the interactive neuronal processes that endow central nervous systems with their acknowledged cognitive capacities. It is remarkable that in the brain, as in highly social systems, we find mechanisms that set the overall level of arousal. Recent examples in social insect communication illustrate this point impressively. For example, tonic sensory input from a variety of sense organs and spontaneous activity of neural arousal systems perform in the nervous system the functions that unspecific modulating signals serve in social organizations. In both forms of organization we further find more specific regionalized or addressed mechanisms of focusing the atten- tion to a specific subset of stimuli in a given context We find that, within the larger systems, mechanisms exist that modulate in graded fashion the activity probability of small dedicated subpopulations of neurons or individuals that are thus recruited to perform specific tasks. It is probably more than chance that the neurophysiologist arrives at describing these mechanisms as local modulating

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THE NERVOUS SYSTEM AND BElIAVIOR 219 interactions between neurons just as the student of social communication in animals independently finds it appropriate to qualify basic processes of social organization in this way. ABNORMALITIES OF BEHAVIOR Central to the Study of the Nervous System Is the Desire to Understand the Abnormalities of Behavior Produced by Various Neurological and Psychological Disorders The goal of the modern study of the nervous system is to understand human behavior: how we sense objects in the world around us, execute skilled move- ments, feel, think, learn, and communicate with one another. Study of the nervous system has traditionally provided the scientific and therapeutic underpinnings for neurology and psychiatry. We illustrate this point with two examples: (1) the application of modern molecular genetic approaches to diagnose neurological diseases and (2) the application of modern biochemical and imaging techniques to diagnose and treat psychiatric disorders. Molecular Genetics and the Diagnosis of Neurological Disorders A surprising number of serious neurological diseases have a genetic origin. These include neurof~bromatosis, Huntington's disease, a subform of Alzheimer's disease, retinoblastoma, and various congenital diseases of muscle. The devasta- tion these diseases produce is great. For example, John Merrick, the "Elephant Man" who lived in the late 1880s, was relegated to a life as a side-show circus freak. He suffered from severe neurofibromatosis. The more than 100,000 sufferers of neurofibromatosis today receive no better treatment than Merrick, other than frequent surgeries (as many as 100 a year in some cases) to remove the offending neurof~bromas that can disfigure the entire body, occlude the auditory canal, and extend into the brain and spinal cord to pose an immediate life threat. Neurofibromatosis is an autosomal dominant disorder, which means that each child of a parent with neurof~bromatosis has a 50 percent chance of inheriting the disease. Today, more than half of all nursing homes beds in America are occupied by patients with Alzheimer's disease, an illness considered the fourth leading cause of death in this country. At least 10 percent (and by some estimates a much higher percentage) of cases are autosomal dominant a 50 percent risk to offspring. There is no treatment for Alzheimer's disease, only a growing number of elderly people in the United States who are at risk. Huntington's disease is the genetically programmed loss of nerve cells im- portant for mental and motor function, which usually has its onset in midlife. It, too, is an autosomal dominant disorder for which no effective therapy exists. Folk

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220 OPPORTUNITIES IN BIOLOGY singer Woody Guthrie, who wrote 'This Land is Your Land," died of Hunting- ton's disease. He also wrote from Brooklyn State Hospital a poem ending "there is no hope lulown.'' But with the advent of recombinant DNA technology, there is, for the fast time, real hope. Within the next decade, it should be possible to know the chromosomal assignment and exact DNA sequence of the genes that cause these and some other pernicious diseases that affect the nervous system. It should be possible to trace from a genetic lesion to the biochemical or regulatory disturbances it produces, from DNA through anatomical and physiological tracts to the expression of an aberrant gene in disordered thought or action. We should be able to chart the pathway from gene to brain to behavior, learning how the tiniest defects can cause the wildest movements, severe memory loss, suicidal depression, or the capacity to hear or see what does not exist. We should also be able to identify the genes responsible for normal brain functioning, which will provide powerful new in- sights into mental functioning. Molecular Pharmacology, Modern Imaging, and the Diagnosis and Treatment of Psychiatric Disorders Diagnosis in psychiatry is less precise than in neurology or in the rest of medicine because most psychiatric diseases cannot as yet be localized to specific regions of the brain, much less to particular proteins in specific nerve cells. Thus, the diagnosis of psychiatric disorders must rely primarily upon clinical symp- toms. One major way of grouping psychiatric disturbances is into those which are psychotic and those which are not psychotic. The term psychotic can be loosely defined as reflecting a major loss of contact with reality. Nonpsychotic distur- bances include anxiety, neurosis, and character disorder. The major psychotic disturbances are schizophrenic and affective illness, comprising mania and de- pression. In terms of human suffering and public expense, psychotic disorders present a more serious problem for society than nonpsychotic illness because of the much greater disability caused. Since the major psychoses often commence in early adulthood and persist throughout life, their total cost to society greatly exceeds that of cancer and heart disease. For example, at least 1 percent of the population is schizophrenic, an incidence comparable to that of diabetes. It is likely that the incidence is substantially higher, since many individuals who seem to be schizophrenic are not subjected to rigorous diagnosis. Recent pharmacological studies have provided important insights into schizo- phrenia. The effects of drugs have permitted the development of hypotheses about specific neurochemical abnormalities. Many of the drugs that influence schizophrenic symptoms affect the neurotransmitter dopamine. The neuroleptic antipsychotic drugs act by blocking dopamine receptors. Reserpine, which has antischizophrenic effects, depletes the brain of dopamine. Amphetamines, which often exacerbate schizophrenic symptoms, release dopamine. These findings

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TlIE NERVOUS SYSTEM AND BEHAVIOR 221 have suggested that an excess of dopamine might be relevant to schizophrenic pathophysiology. Postmortem studies consistently show increased numbers of dopamine receptors in the schizophrenic brain. This result has been reinforced by recent PET studies in patients, which show that schizophrenics have almost twice as many dopamine receptors as control subjects. It has often been suggested that schizophrenia is a family of diseases that may have different etiologies. One recent classification focuses on the presence of positive or negative symptoms. Positive symptoms refer to florid delusions and hallucinations, while negative symptoms reflect autism and general withdrawal, a "wall-flower" type of behavior. Most neurological drugs are more effective in relieving the positive than the negative symptoms of schizophrenics. Chronic "burnt-out" schizophrenics often display primarily negative symptoms. That patients with chronic schizophrenia have enlarged cerebral ventricles relative to those with the acute forms of the disorder, along with differential drug responses, has prompted the definition of two subtypes of the illness, type I and type II schizophrenia. Type I manifests positive symptoms, a good response to neurolep- tic drugs, and no enlargement of the cerebral ventricles, whereas type II schizo- phrenia is characterized by negative symptoms, a poor drug response, and en- larged ventricles. It is likely that the next five years will witness more characteri- zation of these symptomatic subtypes of the disease and linkages to laboratory abnormalities. The advent of CAT scanning has led to a greater clarification of the enlarged cerebral ventricles in schizophrenics first noted by pneumoencephalography. The recent development of MRI should permit far more extensive delineation of the ventricular enlargement. Novel therapeutic approaches to schizophrenia are likely to focus differen- tially on the positive and negative symptoms. Of the neuroleptics in common use, only the diphenylbutylpiperidines show selective efficacy in relieving negative symptoms. The diphenylbutylpiperidines are just as potent calcium antagonists as dopamine antagonists. Conceivably, centrally active, selective calcium an- tagonists may have utility in the specific therapy of negative symptoms. So far, the most direct insight into the genetic contribution to schizophrenia has come from twin and adoption studies. These studies have ruled out the possibility that environmental factors artifactually account for hereditary patterns. For instance, among schizophrenics who had been adopted at birth, the biological parents display a high incidence of schizophrenia, whereas the incidence in the adoptive parents matches that of the general population. Twin studies, however, show that environmental factors must play some role in the expression of the genetic tendency. The concordance rate for schizophrenia in identical twins is about 50 percent and not 100 percent, as would be expected if genetic factors alone accounted for the disease. Several studies examining identical twins discor- dant for schizophrenia reveal environmental trauma more in the schizophrenic than the nonschizophrenic co-twin. For instance, the schizophrenic co-twins

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222 OPPORTUNITIES IN BIOLOGY generally have a lower birth weight and a greater likelihood of neonatal infection. More detailed studies of this type in the next decade should tease out specific factors that might be crucial in the transformation of a genetic predisposition into frank schizophrenia. Perhaps the most exciting possibility is the potential identi- f~cation of the molecular genetic abnormality associated with schizophrenia, as we have discussed in relation to neurological disease. In families with an extremely high incidence of schizophrenia, one might be able to search for specific genetic markers differentiating schizophrenics from the general popula- tion by using strategies that have been successful in conditions such as Hunting- ton's disease. Being depressed is such a common experience that establishing diagnostic criteria for depressive "disease" is difficult. It is thought that as many as 5 percent of the population suffer from major affective disturbance. Both depression and mania are episodic and have been differentiated by the nature of the episodes. Bipolar disorder is characterized by episodes of both depression and mania, and unipolar illness by recurrent depression but no episodes of mania As with schizophrenia, affective disorders have a strong genetic component. Genetic studies support a fundamental distinction between bipolar and unipolar illness, although there is much overlap. Adoptive and twin studies reveal that affective disturbances and schizophrenia share similar genetic predispositions. Also, as with schizophrenia, drugs that influence neurotransmitters have provided strong hints as to a possible pathophysiology. Hypertensive patients treated with reserpine evince roughly a 15 percent incidence of severe depression, clinically indistinguishable from endogenous major depression. Reserpine de- pletes the brain of its biogenic amines-dopamine, norepinephrine, and serotonin. Alpha-methyldopa, also used to treat high blood pressure, selectively depletes the brain of norepinephrine and causes depression in many patients. Beta-adrenocep- tor blockers used to treat hypertension also elicit depression, presumably by antagonizing endogenous catecholamines. The major antidepressant drugs all seem to act through biogenic amines. The monoamine oxidase inhibitors increase brain concentrations of norepinephrine, dopamine, and serotonin. Tricyclic antidepressants inhibit the inactivation by reuptake of these three amines. Since some of the most effective antidepressants do not inhibit dopamine uptake, it is less likely that dopamine is involved in their action, but norepinephrine and serotonin are important candidates. Recently, several antidepressants have been introduced that selectively inhibit serotonin uptake with no influence on norepinephrine or dopamine. Some psychiatrists feel that drugs more selective for norepinephrine relieve depression by enhancing "drive," whereas serotonin-selective drugs act by increasing a sense of well- being. They hypothesize that there may exist two distinct subtypes of depression, one associated with deficits in norepinephrine functioning and the other, with deficits in serotonin functioning.

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THE NERVOUS SYSTEM AND BElIAVIOR 223 Lithium relieves both mania and depression and is prophylactic against recurrence of all affective episodes. Conceivably, knowledge of its action may shed light on fundamental aberrations that occur in both poles of affective illness. The interference of lithium in the phosphoinositide cycle may be a valuable clue. If lithium acts specifically by inhibiting a phosphatase in the phosphoinositide cycle, organic chemicals can be developed to mimic this effect. Such agents would not compete for intracellular sodium to cause the typical toxic effects of lithium. Direct studies of the seratoninergic biochemical system in depression have been particularly promising. Postmortem brains of suicides manifest abnormally low concentrations of serotonin. The spinal fluid of depressed patients consis- tently shows a bimodal distribution of the serotonin metabolite S-hydroxyindo- leacidic acid. One group of patients has concentrations similar to those of normal subjects, whereas another group of patients of approximately equal numbers has a markedly lower concentration. Several researchers have shown that depressives with the lower hydroxyindoleacidic acid levels are more impulsive and prone to attempt suicide. It is now possible to image serotonin receptors by PET scanning, which may permit an overall evaluation of serotoninergic neuronal function. Similar tech- niques will likely be feasible for noradrenergic and dopaminergic neurons. It is honed that molecular Genetic techniques can be aDDlied to the diagnosis and ---rip -A of ~ treatment of affective illness, with the ultimate view of identifying specific molecular aberrations that reflect the cause of the illness.