PSYCHIATRY, PSYCHOANALYSIS, AND THE NEW BIOLOGY OF MIND - PART 6 pptx

Neurobiology and Molecular Biology 195 chemotransduction from studies of bacteria (Adler; Koshland et al.). Bacte- ria (E. coli, Salmonella) have different chemoreceptors for different attractant and repellent sugars. A few of these receptors are methyl-accepting (chemo- taxis) proteins whose degree of covalent modification is proportional to stimulus intensity. They generate an excitatory signal—the nature of which is still not known—which determines frequency of tumbling: the changes in the direction of rotation of the flagella that move the bacterium. In response to a positive gradient of attractant, the tumbling is suppressed; the flagella rotate counterclockwise for long periods, moving the bacterium in a straight path. For an escape response to a repellent, the flagella rotate clockwise, causing the bacterium to tumble. The response of the bacterium can adapt over time, even though the attractant or repellent is still present. This adap- tation results from a change in the methylation of the methyl-accepting chemotaxis proteins. Thus, as in the adenylate cyclase and transducin systems, chemorecep- tion in bacteria involves more than sensing and recognition of the ligand by the receptor. In each case, the receptors are part of a complex of molecules that initiate a cascade of events both in series and in parallel. In the case of the aspartate receptor (Koshland et al.), the three key functions—recogni- tion, signal transduction, and adaptation—can be separated from each other by the techniques of in situ mutagenesis. Recent studies have indicated that in the multicellular nervous systems of invertebrates and vertebrates there is, imposed upon the network of nerve cells and interconnections that control a behavior, a set of regulatory pro- cesses that can alter the excitable properties of nerve cells and modify the strength of their connections. These regulatory processes are activated by experience, such as learning, and result in the modification of behavior. Learning refers to the modification of behavior by the acquisition of new information about the world; memory refers to the retention of the informa- tion. A given learning process can produce both long- and short-term mem- ory. We are beginning to see in invertebrates how simple neural circuits give rise to elementary forms of behavior and how these behaviors can be modi- fied (Aceves-Piña et al.; Kandel et al.; Schwartz et al.). Insights have come from genetic studies in Drosophila and from cell-biological studies in Aplysia and other opisthobranch mollusks into simple forms of learning and the short-term memory for each. In the three forms that have been studied, ha- bituation, sensitization, and classical conditioning, the learning has been pinpointed to specific neurons and has been shown to involve changes in both cellular properties and synaptic strength. In the instances of short-term memory so far analyzed, the changes in synaptic strength lead to a change in the amount of transmitter released. Altered transmitter release in turn is caused by a modulation of ion channels in the presynaptic terminal. In both 196 Psychiatry, Psychoanalysis, and the New Biology of Mind Drosophila and Aplysia, sensitization and classical conditioning seem to in- volve aspects of the same molecular machinery. Short-term memory has been shown to be independent of new protein synthesis and to involve co- valent modification of preexisting protein by means of cAMP-dependent protein phosphorylation (Aceves-Piña et al.; Camardo et al.; Kandel et al.; Schwartz et al.). In classical conditioning, this cascade is amplified, whereas in sensitization it is not. It is noteworthy that covalent modification of pre- existing proteins also produces behavioral adaptation (this time by methyla- tion) in bacteria (Adler; Koshland et al.). Although we are beginning to understand aspects of the molecular changes underlying short-term memory, we know little about long-term memory. An important clue has been provided by Craig Bailey and Mary Chen (1983), who have found that long-term memory in Aplysia is associ- ated with structural changes in the synapses. It is therefore possible that new protein synthesis is required to produce these changes (Schwartz et al.). With recombinant DNA techniques, one should be able to explore the ques- tion, Does learning produce long-term alterations in behavior by regulating gene expression? Perspectives As this last question and the many earlier questions that I have posed illus- trate, we will be confronting in the nervous system some of the most difficult and profound problems in biology. The early émigrés from molecular biol- ogy were overly optimistic in 1965 in thinking that all but the biology of the brain could be inferred from the principles at hand. But they were correct in thinking that the nervous system is one of the last frontiers of biology and that insights into its cellular and molecular mechanisms are likely to be par- ticularly penetrating and unifying. For in studying the molecular biology of the brain, we are taking another important step in a philosophical progres- sion to which experimental biology has become almost inexorably commit- ted since Darwin. In Darwin’s time, it was difficult to accept that the human form was not uniquely created but evolved from lower animals. More re- cently, there has been difficulty with the narcissistically even more disturb- ing notion that the mental processes of humans have also evolved from those of animal ancestors and that mentation is not ethereal but can be explained in terms of nerve cells and their interconnections. The next challenge, which this symposium and modern neurobiology have opened up for us, is the pos- sibility—indeed, the likelihood—that many molecules important for the higher nervous functions of humans may be conserved in evolution and found in the brains of much simpler animals, and, moreover, that some of these molecules may not even be unique to the cells of the brain but may be Neurobiology and Molecular Biology 197 used generally by cells throughout the body. The merger of molecular biol- ogy and neurobiology that the two encounters have accomplished is there- fore more than a merger of methods and concepts. Ultimately, molecular neurobiology, the joining of the disciplines, represents the emerging convic- tion that a coherent and biologically unified description of mentation is pos- sible. Acknowledgments I have benefited from the comments on earlier drafts of this summary by James H. Schwartz, Sally Muir, Arthur Karlin, and Richard Axel. References Anderson CR, Stevens CF: Voltage clamp analysis of acetylcholine produced end- plate current fluctuations at frog neuromuscular junction. J Physiol 235:655– 691, 1973 Bailey CH, Chen M: Morphological basis of long-term habituation and sensitization in Aplysia. Science 220:91–93, 1983 Brecha N, Eldred W, Kuljis RO, et al: Identification and localization of biologically active peptides in the vertebrate retina, in Progress in Retinal Research. Edited by Osborne NN, Chader GJ. New York, Plenum, 1983 Fatt P, Katz B: An analysis of the end-plate potential recorded with an intra-cellular electrode. J Physiol 115:320–370, 1951 Gierer A: Molecular models and combinatorial principles in cell differentiation and morphogenesis. Cold Spring Harb Symp Quant Biol 38:951–961, 1974 Hille B: Ionic basis of resting and action potentials, in Handbook of Physiology; the Nervous System, Part 1, Vol 1. Edited by Kandel ER. Bethesda, MD, The Amer- ican Physiological Society, 1977, p 261 Hodgkin AL, Huxley AF: A quantitative description of membrane current and its ap- plication to conduction and excitation in nerve. J Physiol 117:500–544, 1952 Hodgkin AL, Huxley AF, Katz B: Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J Physiol 116:424–448, 1952 Hökfelt T, Johansson O, Ljungdahl Å, et al: Peptidergic neurones. Nature 284:515– 521, 1980 Hughes J, Smith TW, Kosterlitz HW, et al: Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–580, 1975 Katz B, Miledi R: Membrane noise produced by acetylcholine. Nature 226:962–963, 1970 Kidd S, Lockett TJ, Young MW: The notch locus of Drosophila melanogaster. Cell 34:421–433, 1983 Letourneau PC: Cell-to-substratum adhesion and guidance of axonal elongation. Dev Biol 44:92–101, 1975 198 Psychiatry, Psychoanalysis, and the New Biology of Mind Mayeri E, Brownell P, Branton WD: Multiple, prolonged actions of neuroendocrine bag cells on neurons in Aplysia, I. effects on bursting pacemaker neurons. J Neu- rophysiol 42:1165–1184, 1979 Nachmansohn D: Chemical and Molecular Basis of Nerve Activity. New York, Aca- demic Press, 1959 Neher E, Sakmann B: Single-channel currents recorded from membrane of dener- vated frog muscle fibres. Nature 260:799–802, 1976 Rothman BS, Mayeri E, Brown RO, et al: Primary structure and neuronal effects of α- bag cell peptide, a second candidate neurotransmitter encoded by a single gene in bag cell neurons of Aplysia. Proc Natl Acad Sci USA 80:5753–5757, 1983 Rubin LL, Schuetze SM, Weill CL, et al: Regulation of acetylcholinesterase appear- ance at neuromuscular junctions in vitro. Nature 283:264–267, 1980 Takeuchi A, Takeuchi N: On the permeability of the presynaptic terminal of the cray- fish neuromuscular junction during synaptic inhibition and the action of γ- amino-butyric acid. J Physiol 183:433, 1966 199 COMMENTARY “NEURAL SCIENCE” Steven E. Hyman, M.D. The work of Eric Kandel stands as an inspiration to psychiatry because it connects the experiential and biological levels of analysis with each other (Kandel 1998). In so doing, this work suggests a serious forward path for an eventual understanding of the mechanisms by which psychiatric treat- ments—especially psychotherapies—might act. That there might be such a connection seems uncontroversial today, but at the time when Kandel began his psychiatric training, links between psyche and brain could only be imag- ined, and were occasionally denied. Indeed, throughout the mid-twentieth century, many important figures in psychiatry treated neuroscience as al- most irrelevant to understanding either illness or treatment. Partly as a re- sult, the typical career path for a person interested both in serious academic psychiatry and in fundamental neuroscience was to give up one or the other. As evidenced by the papers collected here, Kandel never abandoned psychi- atry. Although he devoted his career to the bench, not the ward or consulting room, he reached out to psychiatry at regular intervals to remind its practi- tioners of the important connections that could be established (Kandel 1998). While openly confessing Cartesians (who would declare mind and brain to be completely different substances requiring special mechanisms to inter- act) were rare in late-twentieth century psychiatry, all too many psychiatrists behaved day to day as if Descartes had been right in his dualism. While by 200 Psychiatry, Psychoanalysis, and the New Biology of Mind no means a universal view, many psychiatrists in the middle and even the end of the twentieth century divided disorders into those that were “biolog- ical” and others that resulted from experiences during development. For “bi- ological” disorders, medication would be the treatment, whereas for those based on life experience, the answer would lie in psychotherapy. To some de- gree, this distinction remains enshrined in the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (American Psychiatric Association 2000), in its categorical separation of personality disorders (thought to be experiential in origin) from other psychiatric disorders on its own diagnostic axis. While such a diagnostic structure would not be agreed to today de novo, it exists as a fossil record of the thinking of the 1970s. The group of colleagues who we might describe as “crypto-Cartesians” might have agreed that a brain is required either to administer psychotherapy or to benefit from it, but viewed the brain as a rather general substrate about which detailed understandings might at best serve as a distraction from clinical matters at hand (very much as Kandel describes the training environment at the Mas- sachusetts Mental Health Center in the introduction to this volume). The implication for psychiatry in Kandel’s work and that of others who have worked on brain plasticity is that life experience and indeed all types of learning, including psychotherapy, influence thinking, emotion, and be- havior by modifying synaptic connections in particular brain circuits. More- over, as many scientists have shown, these circuits are shaped over a lifetime by multiple complexly interacting factors including genes, illness, injury, ex- perience, context, and chance. Clearly, we have a long way to go before we can claim understanding of the precise cellular mechanisms and neural circuits involved in psychopa- thology and its treatment, but substantial progress has been made in under- standing the fundamental mechanisms by which memories are inscribed in neural circuits, as the following essay shows. This type of progress in basic neuroscience combined with the rise of cognitive neuroscience, brain imag- ing, progress in genetics (albeit slow), and, above all, open-minded pragma- tism about treatment modalities in a younger generation of psychiatrists, has led to the steady, if not yet complete, emergence of a post-Cartesian psychi- atry. In some sense, psychiatry as a field is now ready to grapple with the work of Kandel and other scientists who have elucidated the mechanisms by which the brain is altered by experience in health and in disease. Besides the undercutting of dualist approaches to mind and brain that is at the core of Kandel’s experimental work, there is an additional take-home message for psychiatry in the following essay, “Neural Science: A Century of Progress and the Mysteries That Remain,” in which the authors take on no less ambitious a task than summarizing the highlights of neuroscience from its very beginnings to the present with some predictions as to its most fruit- Neural Science 201 ful future directions. Beginning with the first page of the essay, the authors distinguish two approaches to neuroscience: a top-down, or holistic, ap- proach to problems versus a bottom-up, or reductionist, approach to prob- lems. The essay makes it compellingly clear not only that both approaches are needed but that they must interact if progress is to be made in under- standing cognition, emotion, the control of behavior, and the underpinnings of psychiatric illness. That should not be a very controversial point. It must be added, however, that progress comes only when the right approach is taken to the problem at hand. The kind of reductionism to which the essay refers is a scientific approach that is appropriate at a certain stage of problem solving; it is not a philosophical goal or a worldview. In other words, the ex- perimental reductionism of Kandel does not represent the goal of explaining all of human behavior in terms of more and more fundamental components, such as individual cells, genes, molecules, atoms, or quarks. Rather, the point is to break down problems into tractable components, with the ulti- mate goal of understanding how all of the components come together—in full recognition of the fact that identifying and characterizing the individual parts does not explain higher-level phenomena. (Here we have to credit Des- cartes, who recommended this approach to science.) As the following essay illustrates, perhaps most clearly in its extensive discussion of the visual sys- tem, it is not possible to make progress without effective reductionist ap- proaches, but ultimately, purely reductionist explanations will not answer our most fundamental questions. Psychiatry has too often treated holism and reductionism as if they must be opposed to each other instead of being necessarily complementary ap- proaches to be wielded wisely as a particular problem dictates. Taking a re- ductionist approach to understanding a psychiatric illness through genetics or neuropathology is not a denial of the importance of the whole person or the psychosocial context in which he or she functions but an effective route toward understanding. Kandel’s career illustrates the success that comes from a disciplined approach to science. Had he taken a prematurely holistic approach to learning and memory, the results would likely have been super- ficial and ultimately unsatisfying. Knowing Eric as I do, I am quite certain that what he was and is most interested in are the highest integrated aspects of thought and emotion and how memory contributes to them. However, he disciplined himself to ask the most penetrating questions that were still trac- table. Kandel was courageous enough to select as a model organism for the initial stage of his career Aplysia californica, a creature neither well known nor attractive—and presumably not even tasty (others interested in the neu- robiology of behavior chose to work on the lobster). He chose Aplysia for the best of reductionist reasons: the organism was complex enough to exhibit simple forms of learning, but its nervous system was simple enough to be 202 Psychiatry, Psychoanalysis, and the New Biology of Mind thoroughly analyzed. This organism provided a platform from which to gain a mechanistic understanding of memory, especially simple forms such as sensitization. Through years of painstaking investigation, Kandel and his colleagues were able to provide information that proved relevant to higher organisms, and indeed, through their more recent efforts on a mammalian model, the mouse, they have been able to apply what was initially learned from Aplysia. It should be noted that even in disciplines that from the point of view of a psychiatrist might seem inherently fully reductionist, such as cell biology, the dialectic between reductionism and holism is playing itself out today. It turns out that the important protein building blocks of cells do not work in isolation nor can their function within even an individual cell be understood one molecule at a time. What has become clear is that the molecular compo- nents of cells function within complexly interacting networks that exhibit compensation, redundancy, and adaptation. We cannot understand the brain—or individual cells—without knowing the building blocks and their properties, but we cannot understand cells, organs, the brain, or behavior by just knowing their component parts. References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Dis- orders, Fourth Edition. Washington, DC, American Psychiatric Association, 1994 Kandel ER: A new intellectual framework for psychiatry. Am J Psychiatry 155:457– 469, 1998 203 CHAPTER 6 NEURAL SCIENCE A Century of Progress and the Mysteries That Remain Thomas D. Albright, Ph.D. Thomas M. Jessell, Ph.D. Eric R. Kandel, M.D. Michael I. Posner, Ph.D. Introduction The goal of neural science is to understand the biological mechanisms that account for mental activity. Neural science seeks to understand how the neu- ral circuits that are assembled during development permit individuals to perceive the world around them, how they recall that perception from mem- ory, and, once recalled, how they can act on the memory of that perception. Neural science also seeks to understand the biological underpinnings of our emotional life, how emotions color our thinking, and how the regulation of emotion, thought, and action goes awry in diseases such as depression, ma- nia, schizophrenia, and Alzheimer’s disease. These are enormously complex This article was originally published in Cell, Volume 100, and Neuron, Volu me 2 5, 2000, pp. S1–S55. [...]... topology of voltage- and ligand-gated ion channels (opposite page) (A) The basic topology of the α subunit of the voltage-gated Na+ channel, and the corresponding segments of the voltage-gated Ca2+ and K+ channels The α subunit of the Na+ and Ca2+ channels consists of a single polypeptide chain with four repetitions of six membrane-spanning α helical regions The S4 region, the fourth membrane-spanning... learned of the remarkable conservation of both the longrange and the synaptic signaling properties of neurons in various parts of the vertebrate brain—indeed, in the nervous systems of all animals What distinguishes one brain region from another and the brain of one species from the next is not so much the signaling molecules of their constituent nerve cells but the number of nerve cells and the way they... from the work of Golgi, Gerlach, and Deiters, who conceived of the brain as a diffuse nerve net in 208 Psychiatry, Psychoanalysis, and the New Biology of Mind FIGURE 6 1 Ramón y Cajal’s illustration of neural circuitry of the hippocampus A drawing by Ramón y Cajal based on sections of the rodent hippocampus, processed with a Golgi and Weigert stain The drawing depicts the flow of information from the. .. shown in the inset, also fits a Gaussian curve (solid line) Source (A) Adapted from Liley 19 56 (B) Adapted from Boyd and Martin 19 56 2 26 Psychiatry, Psychoanalysis, and the New Biology of Mind pool (tethered to the cytoskeleton) to a releasable pool at the active zone; 2) the docking of vesicles to their release sites at the active zone; 3) the fusion of the synaptic vesicle membrane with the plasma... developed by Cole, Hodgkin, and Huxley, a technique that detected the flow of current that followed the opening of thou- 214 Psychiatry, Psychoanalysis, and the New Biology of Mind Neural Science 215 FIGURE 6 3 The conductance of single ion channels and a preliminary view of channel structure (opposite page) (A) Recording of current flow in single ion channels Patch-clamp record of the current flowing through... by the complex shape of neurons and by the seemingly endless extensions and interdigitations of their axons and dendrites (Shepherd 1991) As a result, these anatomists believed that the elements of the nervous system did not conform to the cell theory of Schleiden and Schwann, the theory that the cell was the functional unit of all eukaryotic tissues The confusion that prevailed among nineteenth-century... accomplished for the cell biology of neurons what the structure of DNA did for the rest of biology It unified the cellular study of the nervous system in general, and in fact, the study of ion channels in general One of the strengths of the ionic hypothesis was its generality and predictive power It provided a common framework for all electrically excitable membranes and thereby provided the first link... estimates of the size and shape of the pore of the Na+ and the K+ channels These experiments led to the defining structural characteristic of each channel the selectivity filter the narrowest region of the pore, and outlined a set of physical-chemical mechanisms that could explain how Na+ channels are able to exclude K+ and conversely, how K+ channels exclude Na+ In parallel, Armstrong addressed the issue of. .. and the New Biology of Mind mitter binding site and the ionic channel constitute different domains within a single multimeric protein (for reviews see Changeux et al 1992; Cowan and Kandel 2000; Karlin and Akabas 1995) As with voltage-gated channels, the single channel measurements of Neher and Sakmann (19 76) brought new insights into ligand-gated channels For example, in the presence of ligand, the. .. extension of the ionic hypothesis (Fatt and Katz 1951, 1952) Fatt and Katz found that the synaptic receptor for chemical transmitters was an ion channel But rather than being gated by voltage as were the Na+ and K+ channels, the synaptic receptor was gated chemically, by a ligand, as Langley, Dale, 2 16 Psychiatry, Psychoanalysis, and the New Biology of Mind Neural Science 217 FIGURE 6 4 The membrane . in the presynaptic terminal. In both 1 96 Psychiatry, Psychoanalysis, and the New Biology of Mind Drosophila and Aplysia, sensitization and classical conditioning seem to in- volve aspects of the. that emerged from the work of Golgi, Gerlach, and Deiters, who conceived of the brain as a diffuse nerve net in 208 Psychiatry, Psychoanalysis, and the New Biology of Mind FIGURE 6 1. Ramón y Cajal’s. attributed to the opening of Na + and K + channels. The shape of the action potential and the underlying con- ductance changes can be calculated from the properties of the voltage-gated Na + and K +