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largest sense, these studies revealed that all mental † Howard Hughes Medical Institute processes, no matter how complex, derive from the and Center for Neurobiology and Behavior brain and that the key to understanding any given mental Department of Biochemistry and Molecular Biophysics process resides in understanding how coordinated sig-College of Physicians and Surgeons naling in interconnected brain regions gives rise to beof Columbia University havior. Thus, one consequence of this<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/s0092-8674(00)00251-8">doi:10.1016/s0092-8674(00)00251-8</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/10698132">pmid:10698132</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/rjtvbny2fncm3e4akjgnythii4">fatcat:rjtvbny2fncm3e4akjgnythii4</a> </span>
more »... analy-New York, New York 10032 sis has been initial demystification of aspects of mental ‡ Sackler Institute function: of language perception, action, learning, and Department of Psychiatry memory . Weill Medical College of Cornell University A second consequence of the top-down approach New York, New York 10021 came at the beginning of the twentieth century with the work of the Gestalt psychologists, the forerunners of cognitive psychologists. They made us realize that per-Part I. Introduction cepts, such as those which arise from viewing a visual scene, cannot simply be dissected into a set of indepen-The goal of neural science is to understand the biological dent sensory elements such as size, color, brightness, mechanisms that account for mental activity. Neural scimovement, and shape. Rather, the Gestaltists found that ence seeks to understand how the neural circuits that the whole of perception is more than the sum of its parts are assembled during development permit individuals examined in isolation. How one perceives an aspect of to perceive the world around them, how they recall that an image, its shape or color, for example, is in part perception from memory, and, once recalled, how they determined by the context in which that image is percan act on the memory of that perception. Neural sciceived. Thus, the Gestaltists made us appreciate that ence also seeks to understand the biological underpinto understand perception we needed not only to undernings of our emotional life, how emotions color our thinkstand the physical properties of the elements that are ing and how the regulation of emotion, thought, and perceived, but more importantly, to understand how the action goes awry in diseases such as depression, mania, brain reconstructs the external world in order to create schizophrenia, and Alzheimer's disease. These are enora coherent and consistent internal representation of that mously complex problems, more complex than any we world. have confronted previously in other areas of biology. With the advent of brain imaging, the holistic methods Historically, neural scientists have taken one of two available to the nineteenth century clinical neurologist, approaches to these complex problems: reductionist or based mostly on the detailed study of neurological paholistic. Reductionist, or bottom-up, approaches attients with defined brain lesions, were enhanced dramattempt to analyze the nervous system in terms of its ically by the ability to examine cognitive functions in intact elementary components, by examining one molecule, behaving normal human subjects (Posner and Raichle, one cell, or one circuit at a time. These approaches have 1994). By combining modern cognitive psychology with converged on the signaling properties of nerve cells and high-resolution brain imaging, we are now entering an era used the nerve cell as a vantage point for examining when it may be possible to address directly the higherhow neurons communicate with one another, and for order functions of the brain in normal subjects and to determining how their patterns of interconnections are study in detail the nature of internal representations. assembled during development and how they are modi-The success of the reductionist approach became fied by experience. Holistic, or top-down approaches, fully evident only in the twentieth century with the analyfocus on mental functions in alert behaving human besis of the signaling systems of the brain. Through this ings and in intact experimentally accessible animals and approach, we have learned the molecular mechanisms attempt to relate these behaviors to the higher-order through which individual nerve cells generate their charfeatures of large systems of neurons. Both approaches acteristic long-range signals as all-or-none action pohave limitations but both have had important successes. tentials and how nerve cells communicate through spe-The holistic approach had its first success in the midcific connections by means of synaptic transmission. dle of the nineteenth century with the analysis of the From these cellular studies, we have learned of the rebehavioral consequences following selective lesions of markable conservation of both the long-range and the the brain. Using this approach, clinical neurologists, led synaptic signaling properties of neurons in various parts by the pioneering efforts of Paul Pierre Broca, discovof the vertebrate brain, indeed in the nervous systems ered that different regions of the cerebral cortex of the of all animals. What distinguishes one brain region from human brain are not functionally equivalent (Schiller, another and the brain of one species from the next, is 1992; Ryalls and Lecours, 1996). Lesions to different not so much the signaling molecules of their constituent nerve cells, but the number of nerve cells and the way brain regions produce defects in distinctively different Cell/Neuron Millennial Review Supplement S2 they are interconnected. We have also learned from As a result, these anatomists believed that the elements studies of single cells how sensory stimuli are sorted of the nervous system did not conform to the cell theory out and transformed at various relays and how these of Schleiden and Schwann, the theory that the cell was relays contribute to perception. Much as predicted by the functional unit of all eukaryotic tissues. the Gestalt psychologists, these cellular studies have The confusion that prevailed amongst nineteenth censhown us that the brain does not simply replicate the tury anatomists took two forms. First, most were unclear reality of the outside world, but begins at the very first as to whether the axon and the many dendrites of a stages of sensory transduction to abstract and restrucneuron were in fact extensions that originated from a ture external reality. single cell. For a long time they failed to appreciate that In this review we outline the accomplishments and the cell body of the neuron, which housed the nucleus, limitations of these two approaches in attempts to delinalmost invariably gave rise to two types of extensions: eate the problems that still confront neural science. We to dendrites that serve as input elements for neurons first consider the major scientific insights that have and that receive information from other cells, and to an helped delineate signaling in nerve cells and that have axon which serves as the output element of the neuron placed that signaling in the broader context of modern and conveys information to other cells, often over long cell and molecular biology. We then go on to consider distances. Appreciation of the full extent of the neuron how nerve cells acquire their identity, how they send and its processes came ultimately with the histological axons to specific targets, and how they form precise studies of Ramó n y Cajal and from the studies of Ross patterns of connectivity. We also examine the extension Harrison, who observed directly the outgrowth of axons of reductionist approaches to the visual system in an and dendrites from neurons grown in isolation in tissue attempt to understand how the neural circuitry of visual culture. processing can account for elementary aspects of visual A second confusion arose because anatomists could perception. Finally, we turn from reductionist to holistic not visualize and resolve the cell membrane and thereapproaches to mental function. In the process, we confore they were uncertain whether neurons were defront some of the enormous problems in the biology of limited by membranes throughout their extent. As a remental functioning that remain elusive, problems in the sult many believed that the cytoplasm of two apposite biology of mental functioning that have remained comcells was continuous at their points of contact and pletely mysterious. How does signaling activity in differformed a syncytium or reticular net. Indeed, the neurofient regions of the visual system permit us to perceive brils of one cell were thought to extend into the cytodiscrete objects in the visual world? How do we recogplasm of the neighboring cell, serving as a path for nize a face? How do we become aware of that percepcurrent flow from one cell to another. This confusion tion? How do we reconstruct that face at will, in our was solved intuitively and indirectly by Ramó n y Cajal imagination, at a later time and in the absence of ongoing in the 1890s and definitively in the 1950s with the applivisual input? What are the biological underpinnings of cation of electron microscopy to the brain by Sanford our acts of will? Palay and George Palade. As the discussions below attempt to make clear, the Ramó n y Cajal was able to address these two quesissue is no longer whether further progress can be made tions using two methodological strategies. First, he in understanding cognition in the twenty-first century. turned to studying the brain in newborn animals, where We clearly will be able to do so. Rather, the issue is the density of neurons is low and the expansion of the whether we can succeed in developing new strategies dendritic tree is still modest. In addition, he used a spefor combining reductionist and holistic approaches in cialized silver staining method developed by Camillo order to provide a meaningful bridge between molecular Golgi that labels only an occasional neuron, but labels mechanism and mental processes: a true molecular biolthese neurons in their entirety, thus permitting the visualogy of cognition. If this approach is successful in the ization of their cell body, their entire dendritic tree, and twenty-first century, we may have a new, unified, and their axon. With these methodological improvements, intellectually satisfying view of mental processes. Ramó n y Cajal observed that neurons, in fact, are discrete cells, bounded by membranes, and inferred that Part II. The Signaling Capabilities of Neurons nerve cells communicate with one another only at specialized points of appositions, contacts that Charles The Neuron Doctrine Sherrington was later to call synapses (Sherrington, Modern neural science, as we now know it, began at 1897). the turn of the century when Santiago Ramó n y Cajal As Ramó n y Cajal continued to examine neurons in provided the critical evidence for the neuron doctrine, different parts of the brain, he showed an uncanny ability the idea that neurons serve as the functional signaling to infer from static images remarkable functional inunits of the nervous system and that neurons connect sights into the dynamic properties of neurons. One of to one another in precise ways (Ramó n y Cajal, 1894, his most profound insights, gained in this way, was the 1906, 1911). Ramó n y Cajal's neuron doctrine repreprinciple of dynamic polarization. According to this prinsented a major shift in emphasis to a cellular view of ciple, electrical signaling within neurons is unidirecthe brain. Most nineteenth century anatomists-Joseph tional: the signals propagate from the receiving pole of von Gerlach, Otto Deiters, and Camillo Golgi, among the neuron-the dendrites and the cell body-to the them-were perplexed by the complex shape of neurons axon, and then, along the axon to the output pole of the and by the seemingly endless extensions and interdigitations of their axons and dendrites (Shepherd, 1991) . neuron-the presynaptic axon terminal. Neural Science: Past Progress and Remaining Mysteries S5 Despite its profound importance, however, the analy-neurons of the mammalian brain and to study as well a sis of Hodgkin, Huxley, and Katz left something unspecilarge variety of nonneuronal cells. With these advances fied. In particular, it left unspecified the molecular nature came the realization that virtually all cells harbor in their of the pore through the lipid membrane bilayer and the surface membrane (and even in their internal memmechanisms of ionic selectivity and gating. These asbranes) Ca 2ϩ and K ϩ channels similar to those found in pects were first addressed by Bertil Hille and Clay Armnerve cells. Second, the introduction of patch clamping strong. In the late 1960s, Hille devised procedures for also set the stage for the analysis of channels at the measuring Na ϩ and K ϩ currents in isolation (for review molecular level, and not only voltage-gated channels of see Hille et al., 1999). Using pharmacological agents the sort we have so far considered but also of ligandthat selectively block one but not the other ionic conducgated channels, to which we now turn. tance pathway, Hille was able to infer that the Na ϩ and Short-Range Signaling between Neurons: K ϩ conductance pathways of Hodgkin and Huxley corre-Synaptic Transmission sponded to independent ion channel proteins. In the The first interesting evidence for the generality of the 1970s Hille used different organic and inorganic ions of ionic hypothesis of Hodgkin, Huxley, and Katz was the specified size to provide the first estimates of the size realization in 1951 by Katz and Paul Fatt that, in its and shape of the pore of the Na ϩ and the K ϩ channels. simplest form, chemical synaptic transmission repre-These experiments led to the defining structural characsents an extension of the ionic hypothesis (Fatt and teristic of each channel-the selectivity filter-the nar- Katz 1951 . Fatt and Katz found that the synaptic rowest region of the pore, and outlined a set of physicalreceptor for chemical transmitters was an ion channel. chemical mechanisms that could explain how Na ϩ But, rather than being gated by voltage as were the channels are able to exclude K ϩ and conversely, how Na ϩ and K ϩ channels, the synaptic receptor was gated K ϩ channels exclude Na ϩ . chemically, by a ligand, as Langley, Dale, Feldberg, and In parallel, Armstrong addressed the issue of gating Loewi had earlier argued. Fatt and Katz and Takeuchi in response to a change in membrane voltage. How and Takeuchi showed that the binding of acetylcholine, does an Na ϩ channel open rapidly in response to voltage the transmitter released by the motor nerve terminal, to change? How, once opened, is it closed? Following iniits receptors leads to the opening of a new type of ion tial experiments of Knox Chandler on excitation contracchannel, one that is permeable to both Na ϩ and K ϩ tion coupling in muscle, Armstrong measured minute (Figure 3) (Takeuchi and Takeuchi, 1960). At inhibitory "gating" currents that accompanied the movement, synapses, transmitters, typically ␥-aminobutyric acid within the transmembrane field, of the voltage sensor (GABA) or glycine, open channels permeable to Cl Ϫ or postulated to exist by Hodgkin and Huxley. This achieve-K ϩ (Boistel and Fatt, 1958; Eccles, 1964). ment led to structural predictions about the number of In the period 1930 to 1950, there was intense conelementary charges associated with the voltage sensor. troversy within the neural science community about In addition, Armstrong discovered that mild intracellular whether transmission between neurons in the central proteolysis selectively suppresses Na ϩ channel inactinervous system occurred by electrical or chemical vation without affecting voltage-dependent activation, means. In the early 1950s Eccles, one of the key propothereby establishing that activation and inactivation innents of electrical transmission, used intracellular revolve separate (albeit, as later shown, kinetically linked) cordings from motor neurons and discovered that synmolecular processes. Inactivation reflects the blocking aptic excitation and inhibition in the spinal cord was action of a globular protein domain, a "ball," tethered mediated by chemical synaptic transmission. He further by a flexible peptide chain to the intracellular side of found that the principles of chemical transmission dethe channel. Its entry into the mouth of the channel rived by Fatt and Katz from studies of peripheral syndepends on the prior activation (opening) of the channel. apses could be readily extended to synapses in the This disarmingly simple "mechanical" model was dranervous system (Brock et al., 1952; Eccles, 1953 Eccles, , 1964. matically confirmed by Richard Aldrich in the early Thus, during the 1960s and 1970s the nature of the 1990s. Aldrich showed that a cytoplasmic amino termipostsynaptic response at a number of readily accessible nal peptide "ball" tethered by a flexible chain does inchemical synapses was analyzed, including those medideed form part of the K ϩ channel and underlies its inactiated by acetylcholine, glutamate, GABA, and glycine vation, much as Armstrong predicted. (see for example Watkins and Evans, 1981). In each Until the 1970s, measurement of current flow was case, the transmitter was found to bind to a receptor carried out with the voltage-clamp technique developed protein that directly regulated the opening of an ion by Cole, Hodgkin, and Huxley, a technique that detected channel. Even prior to the advent in the 1980s of molecuthe flow of current that followed the opening of thoular cloning, which we shall consider below, it had besands of channels. The development of patch-clamp come clear, from the biochemical studies of Jean-Pierre methods by Erwin Neher and Bert Sakmann revolution-Changeux and of Arthur Karlin that in ligand-gated chanized neurobiology by permitting the characterization of nels the transmitter binding site and the ionic channel the elemental currents that flow when a single ion chanconstitute different domains within a single multimeric nel-a single membrane protein-undergoes a transiprotein (for reviews see Changeux et al., 1992; Karlin tion from a closed to an open conformation (Neher and and Akabas, 1995; Cowan and Kandel, 2000). Sakmann, 1976) (Figure 4A). This technical advance had As with voltage-gated channels, the single channel two additional major consequences. First, patch clampmeasurements of Neher and Sakmann brought new ining could be applied to cells as small as 2-5 m in sights into ligand-gated channels (Neher and Sakmann, diameter whereas voltage clamping could only be car-1976). For example, in the presence of ligand, the acetylried out routinely on cells 50 m or larger. Now, it became possible to study biophysical properties of the choline (ACh) channel at the vertebrate neuromuscular
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