Nerve cells versus brain systems

The Peripheral Neuropathy Solution

The Peripheral Neuropathy Solution

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It must already be apparent that, to an extraordinary degree, what one does in science is determined more by circumstances and chance than by guiding principles. This was certainly the case for me as I started life as a fully independent neuroscientist in St. Louis. Much of what I pursued depended on the colleagues in my new department and on the people who happened to cross my path. And this, in turn, depended on the organization of the faculty engaged in neuroscience at Washington University in 1973, which was fairly typical of American universities at the time.

Cuy Hunt's Department of Physiology and Biophysics was in the medical school adjacent to Barnes Hospital in the city proper; the rest of the campus was about 2 miles away, across the major city park in the more suburban setting of University City. The separation of medical schools from the rest of the university was common; in Boston, Harvard College in Cambridge had been even further removed physically and intellectually from Harvard Medical School. The reason primarily stemmed from the history of medical education. Medical schools in the United States in the eighteenth and nineteenth centuries had started as trade schools instead of the academic centers they have become. Therefore, they were located adjacent to hospitals, which were often far from the campuses of the universities that eventually came to run them. Washington University School of Medicine arose in this way, having been preceded by two private for-profit schools (St. Louis Medical College and Missouri Medical College) founded in the 1840s to train local physicians. Under the auspices of the university, the medical school incorporated these two proprietary schools in 1891, 20 years before Abraham Flexner's report that established curricular standards for U.S. medical schools nationally. The concept of medical schools as integral parts of research universities was even slower in coming and is still being resolved today with the construction of campuses that facilitate greater unity with undergraduate education. (As an undergraduate at Yale, I never set foot in the medical school, which offered no premed or other undergraduate courses.) The consequence of this geographical separation in St. Louis was that interactions between the faculty in undergraduate departments such as biology, psychology, and philosophy were less frequent than they should have been.

Even within the medical school, varying perspectives and tensions based on the history and traditions of different disciplines were apparent as I settled into my role as a junior faculty member. I had paid little attention to such issues as a postdoc at Harvard or University College London, but these matters were now relevant. In 1973, the integration of neuroscientists from such traditional departments as physiology, anatomy, or biochemistry into a single department of neurobiology was still unique to Kuffler's department at Harvard, which had been established in 1966. This evolutionary change, based on the growing importance of neuroscience, had not yet come to Washington University, so a significant factor in whom you were likely to discuss science with over lunch or in the hall depended very much on the department you were in. Medical students had to be taught the full range of physiology, so the Department of Physiology and Biophysics that Hunt put together included people who worked on the lungs, kidneys, and heart. Nonetheless, Hunt's particular enthusiasms clearly favored neuroscience, and 6 or 7 of the approximately 15 faculty members were neuroscientists. In addition to me (the newest member), the faculty included Carl Rovainen, who had been a graduate student with Ed Kravitz at Harvard and had worked on the nervous system of the lamprey, a simple vertebrate with many of the advantages of invertebrates; Mordy Blaustein, who had been a postdoctoral fellow with Hodgkin at Cambridge and had worked on the role of calcium ions in cell signaling; and Alan Pearlman and Nigel Daw, both of whom had been fellows in Hubel and Wiesel's lab at Harvard and were continuing to work on the visual system. Two others were not quite card-carrying neuroscientists but were close enough, according to the criteria of the day: Roy Costantin had trained with Huxley and worked on muscle contraction, and Paul DeWeer had worked on membrane pumps, the metabolically driven molecules in the membranes of neurons and other cells that generate the ion concentrations on which neuronal signaling depends. This cast of characters represented Hunt's inclination toward the subjects and people he had become familiar with as a fellow with Kuffler, his admiration for what Hodgkin and Huxley had accomplished, and the friendship with Katz that had developed during his sabbatical at UCL. The faculty reflected the remarkable degree to which personal associations influence what goes on in academe.

A few floors away, Max Cowan's Department of Anatomy was the other important department doing neuroscience. Hunt had come from a background in physiology, but Cowan was a neuroanatomist in the tradition of Golgi, Cajal, and the other preeminent anatomists who had followed in the first half of the twentieth century. Cowan had grown up in South Africa and had gone to the University of Witwatersrand, where he began studying medicine. In 1953, he transferred to Oxford at the invitation of British anatomist Wilfred LeGros Clark, where he completed his medical training and obtained a doctoral degree under Le Gros Clark's direction. From the outset, Cowan was interested in methods that could indicate the axonal connections between various brain regions and had carried out experiments with a series of collaborators in England that gained him a well-deserved reputation at an early age. In 1966, he took a faculty job at the University of Wisconsin. After only two years there, Washington University recruited him at the age of 37 to take over the moribund Department of Anatomy. By the time I arrived five years later, Cowan had already proved to be a brilliant choice. He had not only reinvigorated all the usual functions of the department, but had hired a cadre of outstanding young neuroanatomists (along with other good people needed to teach the gross and microscopic anatomy of the rest of the body). The neuroanatomists Cowan had recruited included Tom Woolsey, who worked on the somatic sensory system; Ted Jones, who was studying the connectivity of the thalamus; Harold Burton, who studied the organization of the somatic sensory system; Tom Thach, who studied the cerebellum; and Joel Price, who worked on the anatomy of the olfactory system. He had also recruited a couple cell and molecular biologists who shared his interest in axon biology and methods of tracing axonal connections. A handful of other basic neuroscientists were located in biochemistry and pharmacology, and in the clinical departments of neurology, neurosurgery, psychiatry, or radiology, but these people were less in evidence, and the latter tended to pursue disease-related research that was deemed of relatively little interest to basic research at the time. (In the five years that I had spent as a fellow at Harvard and University College, I don't recall a single seminar on a neurological disease; in sharp distinction to the situation today, the eventual relevance of basic research findings to clinical medicine was simply assumed.)

The two departments Hunt and Cowan ran reflected the distinct traditions of physiology (defined as the study of how cells and organ systems function) and anatomy (defined as the study of their structure). At the same time, both Hunt and Cowan were being driven by the logic of integration in neuroscience that Kuffler's department had been the first to formally realize. Both men saw themselves primarily as neuroscientists and had tilted their faculties strongly in that direction, although with a physiological bent in Hunt's case and an anatomical one in Cowan's. In recognition of the coming change, Cowan had already renamed his burgeoning enterprise the Department of Anatomy and Neurobiology, and considerable overlap between the departments and some competition between the two chairs were evident. Cowan asked me whether I would be interested in joining his department after I had been in St. Louis only a year or so. Although I declined the offer, that sort of poaching did little to improve the sometimes cool relationship between the two men.

The backgrounds, intellectual styles, and overall directions of the faculty in the two departments were characteristic of a dichotomy in neuroscience that persists today and, in some ways, has gotten worse. The difference was not simply whether one was more attracted to physiology or anatomy, but whether one was drawn to study the nervous system at the level of nerve cells and their synaptic connections or at the level of brain systems. The distinction between these different commitments had been apparent even in the nominally integrated Department of Neurobiology at Harvard, where Hubel and Wiesel, working on the visual system, had separated themselves physically—and, to a degree, intellectually—from the majority, working at a more reductionist level on various simple invertebrates or model systems. This divide is even more apparent now, due largely to the advent of molecular biology in neuroscience that began in the late 1960s and accelerated in the following decades. The enormous power of the new understanding of genes and the tools that were soon provided gave a big boost to both reductionists and clinician-scientists interested in neurological diseases, further emphasizing the differences between the neuronal and systems-level camps. Because studying how genes influence nerve cells, their interactions, and their role in various diseases is different than understanding how brain systems work, the gulf between reductionists and those seeking answers to questions about brain systems has widened. The problem has been further exacerbated by the shortsighted view of politicians, funding agencies, and university administrators who believe that research in neuroscience (and biology in general) should focus on human health.

Although my initial interests—philosophy, Freud, and psychiatry, when I graduated from college and started medical school—had been anything but reductionist, everything I had done for the preceding five years in neuroscience had been at a simple model systems level. The issues that Bert Sakmann and I had just been studying did not even involve nerve cells directly. I was ill prepared to launch into a project that focused on the structure and function of the brain, although I worried about whether the reductionist approaches I used could ever say much about the brain functions that had always seemed more interesting than cell and molecular interactions. But I was at least determined to work on nerve cells in a mammal as a step in the right general direction, and on problems that would have more pertinence to brain function and organization than the projects I had cut my teeth on.

How to do this was not obvious, but I had considered possibilities while I was in London. With Jack McMahan, I had worked on small collections of nerve cells in the peripheral nervous system called autonomic ganglia that several of Kuffler's collaborators were working on at the time. Studying the function and organization of these accessible collections of neurons that have connections with both the central nervous system and peripheral targets seemed like a good compromise between plodding onward with some aspect of a model synapse, such as the neuromuscular junction, and taking a more direct attack on some aspect of the brain, which I knew very little about at that point. Figure 4.1 illustrates how the autonomic nervous system in humans and other mammals controls a wide range of involuntary functions mediated by the activity of smooth muscle fibers, cardiac muscle, and glands. The system comprises two major divisions: The sympathetic component of the system mobilizes the body's resources for handling biological challenges. In contrast, the parasympathetic system is active during states of relative quiescence, enabling the restoration of the energy reserves previously expended in meeting some demanding contingency. This ongoing neural regulation of resource expenditure and replenishment to maintain an overall balance of body functions is called homeostasis. Although the major controlling centers for homeostasis are the hypothalamus and the circuitry it controls in the brainstem and the spinal cord, the neurons that directly activate the smooth muscles and glands in various organs are in collections of hundreds or thousands of nerve cells in the autonomic ganglia shown in Figure 4.1.

Autonomic ganglia had been the focus of many key studies of the nervous system since the middle of the nineteenth century. But despite its technical advantages and physiological importance, the autonomic system had always been regarded as a relatively inferior object for research compared to components of the mammalian brain that, understandably, attracted more interest—the visual system, the auditory system, the somatic sensory system, and the voluntary (skeletal) motor system, in particular. Although humans must long ago have observed involuntary motor reactions to stimuli in the environment (such as the pupils narrowing in response to light, superficial blood vessels constricting in response to cold or fear, and heart rate increasing in response to exertion), the neural control of these and other visceral functions was not understood in modern terms until the late nineteenth century. The researchers who first rationalized the workings of the autonomic system were Walter Gaskell and John Langley, two British physiologists at Cambridge. Gaskell, whose work preceded that of Langley, established the overall anatomy of the system and carried out early physiological experiments that demonstrated some of its salient functional characteristics (showing, for example, that the heartbeat of an experimental animal is accelerated by stimulating the outflow to the relevant sympathetic ganglia and slowed by stimulating the outflow to the relevant parasympathetic ganglia; see Figure 4.1). Based on these observations, Gaskell concluded in 1866 that "every tissue is innervated by two sets of nerve fibers of opposite characters" and further surmised that these actions showed "the characteristic signs of opposite chemical processes."

Figure 4.1 The autonomic nervous system, which controls the body's organ systems and glands. These homeostatic functions, much like the information that arises from the muscle sensors described in the last chapter, are critical to survival. Many of the neurons involved are in clusters called autonomic ganglia that lie outside the brain and spinal cord (see Figure 1.6), making it relatively easy to study their organization and function. (From Purves, Augustine, et al., 2008)

Syst Nerveux Autonome

Langley (Figure 4.2) was the real giant in this aspect of neuroscience. He established the function of autonomic ganglia, coined the phrase autonomic nervous system, and carried out studies on the pharmacology of the autonomic system that evenutally established the roles of acetylcholine and the catecholamines, the first of the many neurotransmitter agents that were

Langley (Figure 4.2) was the real giant in this aspect of neuroscience. He established the function of autonomic ganglia, coined the phrase autonomic nervous system, and carried out studies on the pharmacology of the autonomic system that evenutally established the roles of acetylcholine and the catecholamines, the first of the many neurotransmitter agents that were identified in the early decades of the twentieth century. This work set the stage for understanding neurotransmitter action at synapses and, ultimately, for Katz's discoveries of the detailed mechanism of chemical synaptic transmission. Langley's work also led to studies of the autonomic nervous system by Walter Cannon at Harvard Medical School. Among many other accomplishments, Cannon established the effects of denervation during the 1940s, laying the foundation for Miledi's work in the 1960s on the spread of sensitivity when muscle fibers are deprived of their innervation; that, in turn, set up the project that Sakmann and I worked on at University College. For better or for worse, this skein of personal and intellectual associations is characteristic of the way research themes unfold in any branch of science.

Figure 4.2 John Langley, a central figure in late-nineteenth-century neurophysiology and a pioneer in studies of the autonomic nervous system and synaptic transmission by chemical agents

Figure 4.2 John Langley, a central figure in late-nineteenth-century neurophysiology and a pioneer in studies of the autonomic nervous system and synaptic transmission by chemical agents

Whatever the merits of choosing to work on the autonomic system, getting started in St. Louis depended on much more than simply picking a reasonable topic to study. Hunt was a great help, and I soon understood why he had attracted such good people to the three different departments that he had organized, and why their research generally flourished. He was every bit the paternal adviser that I had imagined, and he helped me get going in all kinds of ways, many of them having nothing to do with science. After I had been plugging away for a couple of months with the equipment that he had arranged to have waiting for me in St. Louis (new, and much finer than what I had been used to working with during the preceding two years at University College), he came by the lab one day to ask why I had chosen not to enroll in TIAACREF, the academic pension fund. I told him that I really wasn't worried about retirement at that point, and that Shannon and I couldn't afford to pay the monthly contribution. He patiently explained what an annuity was and extolled the virtues of compound interest, and told me why this would eventually be important. More to the point, he raised my salary that very day so that we could afford to make the contribution.

After I had been working in St. Louis for about six months, Hunt again wandered into the lab one afternoon and asked me in an offhand way whether I had ever thought of applying for a research grant. When I said, with extraordinary naivete, that I really didn't understand how research grants worked, he explained that science costs money and that the people who do it are expected to raise the funds to pay for it. He did all this in a way that made my extraordinary ignorance seem perfectly okay. With his editorial help, I soon had a research grant. For the following 11 years that I worked in Hunt's department, he never suggested to me—or, as far as I know, to anyone else—what to do or how to do it, although he was always happy to talk about the science and offer his expertise, which was considerable. Promotions happened as if by magic, although I now know that Hunt, who died in 2008 at the age of 89, had to put together dossiers, solicit letters of recommendation, and convince a cantankerous committee of fellow department chairs that a faculty member was worth advancing. He did all this while he successfully pursued his own work on the sensory physiology of muscle spindles, demonstrating by example that being an administrator does not mean relinquishing good science. It no doubt helped that, during all those years,

Hunt—to the best of my memory—convened only a single faculty meeting.

Working on neuronal connections in the mammalian autonomic system turned out to be a good choice. Although I saw this work as a stepping stone toward a more direct attack on problems explicitly related to brain function, the step eventually consumed about a dozen years with results that, in contrast to what I had done up to that point, were regarded as important. During the first few years in St. Louis, I undertook two projects in the peripheral autonomic system of mammals. The first was directly inspired by observations Langley had made 80 years earlier. In the course of brain development in embryonic and early postnatal life, connections between nerve cells must be made appropriately and not just willy-nilly, a process referred to as neural specificity. Experience later in life is important in the ultimate organization and further refinement of connections (see Chapter 3), but the idea that the human brain or any other brain comes into the world as a tabula rasa to be imprinted primarily by knowledge derived from experience—the model suggested by eighteenth-century philosopher John Locke—is silly. Nervous systems at birth are already connected in detailed and highly specific ways based on the experience of the species over evolutionary time. The mechanisms that produce this specificity of connections during development were unclear in 1973 and still aren't fully known today.

Langley examined this issue at the end of the nineteenth century, making use of the fact that neurons at different levels of the spinal cord innervate neurons in sympathetic ganglia in a stereotyped way (Figure 4.3). In the superior cervical ganglion, for example, cells from the highest thoracic level of the spinal cord (T1) innervate ganglion cells that project to smooth muscle targets the muscle that dilates the pupil, whereas neurons from a somewhat lower level of the cord (T4) innervate ganglion cells that cause effects in other targets, such as constricting blood vessels in the ear. Langley had assessed these differences in the innervation of the ganglionic neurons simply by looking at these peripheral effects while electrically stimulating the outflow to the ganglion from different spinal levels in anesthetized cats, dogs, and rabbits. When he stimulated the outflow from the upper segments of the thoracic spinal cord, the animals' pupil dilated on the stimulated side without any effect on the blood vessels of the ear. And when he stimulated the lower thoracic cord segments, the pupils were not affected, but the blood vessels in the ear on that side constricted. When he cut the sympathetic trunk that carried the axons to the ganglion and waited some weeks for them to grow back, he observed the same pattern of peripheral responses. Therefore, Langley surmised that the mechanisms underlying the differential innervation of the ganglion cells must occur at the level of synapse formation on the neurons in the ganglion, and further suggested that selective synapse formation is based on differential affinities of the pre- and postsynaptic elements arising from some sort of biochemical markers on their surfaces.

Figure 4.3 Specificity of synaptic connections in the autonomic nervous system. This diagram shows the superior cervical ganglion and its innervation by neurons located in the thoracic portion of the spinal cord; the ganglion is in the neck (see Figure 4.1). Langley used this part of the mammalian sympathetic system to demonstrate indirectly that neurons in the ganglion can distinguish between axon terminals arising from different levels of the spinal cord as synaptic connections are being made. (After Purves, Augustine, et al., 2008)

Between the 1940s and the early 1960s, Roger Sperry carried out experiments that led to a modern articulation of what is now called the chemoaffinity hypothesis. Sperry was an equally remarkable neuroscientist whose long career unfolded mainly at Cal Tech, where he later worked on the functional specialization of the right and left cerebral hemispheres that won him even greater acclaim. (Most fundamental work on left-right brain differences—and many nonsensical New Age ideas on this subject—can be traced to Sperry's discoveries on patients whose hemispheres had been surgically separated to treat epilepsy.) His conclusions on neural specificity were based on studies similar in principle to Langley's, but carried out in the visual brains of frogs and goldfish instead of in the peripheral nervous system. In humans and other mammals, damage to the optic nerve causes permanent blindness because the axons in the optic nerve fail to regenerate. But in amphibians and fish, optic axon nerves regenerate after they have been cut, and vision is restored (why the optic nerve and other central nervous system axons regenerate quite well in these animals but not in us remains unclear). The terminals of retinal axons normally form a relatively precise map in the visual part of the fish or amphibian brain, a region called the optic tectum. Axons arising from a particular point in the retina innervate a particular point in the tectum, preserving in the brain the neighbor relationships in the retina. When Sperry crushed the optic nerve, he found that the retinal axons reestablished their original pattern of connections in the tectum as they grew back ( Figure 4.4). To emphasize the robustness of the specific chemoaffinities between the growing axons and their target neurons, he turned the eye upside down after cutting the optic nerve and showed that the regenerating axons still grew back to their original tectal destinations. As a result, the frog was left with an erroneous sense of objects locations, misperceptions that persisted even after months of subseuquent experience. Accordingly, Sperry proposed that each cell in the brain carries an identification tag, and that growing axons have complementary tags that enable the axons to seek out and contact specific neurons.

Given these studies by Langley and Sperry, it seemed worthwhile to pursue the issue of neural specificity at the level of electrical recordings from individual neurons in autonomic ganglia. Working with Arild Nja, a postdoctoral fellow from Oslo who was the first to come my way, we pursued the merits of this idea in the autonomic system of guinea pigs by removing the whole upper portion of the sympathetic chain (shown in Figure 4.3), keeping it alive in a chamber, and making intracellular recordings from individual neurons in the superior cervical ganglion while stimulating each of the input levels from the spinal cord. The results showed that the synaptic connections made on ganglion cells by preganglionic neurons of a particular spinal level are indeed preferred, but that contacts from neurons at other levels are not excluded. Furthermore, if the innervation to the superior cervical ganglion was surgically interrupted, recordings made some weeks later indicated that the new connections again established a pattern of segmental preferences. Therefore, spinal cord neurons associate with target neurons in the autonomic ganglia of mammals according to a continuously variable system of preferences during synapse formation that guide the pattern of innervation during development or reinnervation without limiting it in any absolute way.

Figure 4.4 Roger Sperry conducted experiments on the specificity of synaptic connections in the brain more than 60 years after Langley's work, making the same point in the visual system of the frog. When the axons of neurons in the retina grow back to the part of the brain called the optic tectum, they primarily contact the same nerve cells that they did initially. As a result, when the axons regrow after the eye is rotated, the frog's brain provides wrong information about the location of objects in the world. (After Purves, Augustine, et al., 2008)

A RETINA TECTUM

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Although this work with Nja- resulted in several good papers, it was another project I had begun in parallel that eventually occupied most of my attention during the next decade. The ideas on which this work was based came from a different direction and again demonstrate the importance of proximity and happenstance. The theme that Sakmann and I had been working on in London was control of the signaling properites of neurons (although we used muscle cells as a model), and I continued to think—along with many other neuroscientists—that such modulation of signaling and its effects on long-term connectivity were especially important. Hunt and I had discussed his work on the changes of neuronal properties that occur when a neuron's axons are cut, the issue that he had worked on during his 1962 sabbatical in Katz's lab. And I knew that Cowan had used anatomically visible changes in neurons when their axons are severed as a means of tracing axonal pathways in the brain. I was also aware that two neuroantomists at Oxford, Margaret Matthews and Geoff Raisman, had recently published a paper describing changes in the appearance and number of synapses made on superior cervical ganglion cells after cutting the connections of these neurons to their peripheral targets.

This evidence that a neuron's connection to its target was affecting how other nerve cells made synaptic connections with it seemed like a good topic to pursue, and so I did. In what turned out to be the first couple of papers to come out of my lab in St. Louis, I showed by electrophysiological recording that the efficacy of the synapses made by the spinal neurons on the neurons in the superior cervical ganglion declined during the first few days after the axons from the neurons to peripheral targets in the head and neck had been cut, and that this decline occurred in parallel with the loss of a majority of the synapses made on the ganglion cells that could be counted in the electron microscope (Figure 4.5). Because the loss of synapses from the neurons was reversed when the axons grew back to their peripheral targets, the conclusion seemed clear: The synaptic endings made on nerve cells must be actively maintained. And whatever the mechanism, this maintenance depended on the normal connections between nerve cells and the targets that they innervated. The clarity of these results in a relatively simple system of mammalian neurons was news and encouraged me to study these issues further.

This research led to the beginning of a long collaboration with Jeff Lichtman and a deepening friendship with Viktor Hamburger, both of whom turned out to be critical in determining how this work would progress. Jeff (Figure 4.6) appeared in my lab one day in 1974 and asked whether he could chat about his future. He was then a second-year med student and knew me from the lectures on neural signaling that I had given to his class some months before. Jeff was one of the ten or so med students in his cohort in the M.D./Ph.D. program, and he was trying to figure out what to do for his doctoral work. (The students in this ongoing federally subsidized program in the United States typically spend about four years doing basic research in addition to the four years of med school. This education is meant to generate physicians who can better bridge the gap between clinical medicine and basic science.) Jeff seemed nervous and lacked any good reason for wanting to work with me or ideas about what to do. I think he simply saw me as someone who was young and ambitious, and who, based on the lectures he had heard, might be a good mentor. My inclination was not to take him on because my experience at Harvard and University College had been that the best people populated their labs with postdoctoral fellows and not graduate students (neither Kuffler nor Katz had any graduate students when I worked in their departments; Hubel and Wiesel, whom I admired greatly, were likewise fellow oriented). But before reaching a decision, I thought it would be a good idea to ask Hunt for his thoughts on the matter. He pointed out that the M.D./Ph.D. students were a highly select group, that Lichtman would not cost me anything because the program was fully funded by the National Institutes of Health, and that unless I had a very good reason not to, I should certainly take him on as a graduate student. Hunt was indeed right: Lichtman was—and remains—one of the smartest and most imaginative people I have known in neuroscience. A decade after we had this conversation, Hunt hired him as a faculty member and Lichtman went on to become a major figure in neuroscience.

Figure 4.5 Diagram illustrating the dependence of synapses on nerve cells in autonomic ganglia on the connections of these neurons to peripheral targets. When this link to the targets (such as smooth muscle in the eye and ear) is interrupted by cutting the peripheral (postgangionic) axons, most of the synapses on the nerve cells are lost; however, when the cut axons grow back to their targets, the synapses on the ganglionic neurons are restored. (Reprinted by permission of the publisher from Body and Brain: A Trophic Theory of Neural Connections by Dale Purves, p. 103, Cambridge, Mass: Harvard University Press, Copyright © 1988 by the President and Fellows of Harvard College.)

Figure 4.5 Diagram illustrating the dependence of synapses on nerve cells in autonomic ganglia on the connections of these neurons to peripheral targets. When this link to the targets (such as smooth muscle in the eye and ear) is interrupted by cutting the peripheral (postgangionic) axons, most of the synapses on the nerve cells are lost; however, when the cut axons grow back to their targets, the synapses on the ganglionic neurons are restored. (Reprinted by permission of the publisher from Body and Brain: A Trophic Theory of Neural Connections by Dale Purves, p. 103, Cambridge, Mass: Harvard University Press, Copyright © 1988 by the President and Fellows of Harvard College.)

Figure 4.6 Jeff Lichtman circa 2006. (Courtesy of Jeff Lichtman)

Getting to know Hamburger was equally important, but this happened only gradually during the next few years. Despite the considerable scientific accomplishments of Hunt and Cowan, Hamburger was far and away the most notable neuroscientist at Washington University in 1973. Because he was in the Biology Department on the undergraduate campus, I had not met him on my trip to St. Louis as a faculty candidate; to my great embarrassment, I knew little or nothing about him or his work when I arrived in St. Louis. When I first bumped into Hamburger, I mistook him for another neuroscientist named Hamberger, a researcher of no great distinction who had studied the anatomy of the autonomic system. This woeful ignorance illustrated the parochial nature of my training and exposure up to that point. Hamburger was a consummate biologist, and my conversations with him about his work and the broader field of neural development over the next few years made me think much more about what nervous systems do for animals and less about the details of neurons.

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