Figure 15 A John Eccles center with his two protgs Kuffler on the left and Katz in Sydney in 1941 B The same trio at a meeting at Oxford in 1972 Eccles is on the right Courtesy of Marion Hunt

Eccles had long thought that synaptic transmission depended on the direct passage of electrical current from the axonal endings to target cells, although circumstantial evidence already suggested that axon endings released a chemical transmitter agent. This indirect evidence for chemical transmission came largely from the physiological and biochemical studies of John Langley at Cambridge and his student Henry Dale working on the peripheral autonomic nervous system early in the twentieth century, and from Otto Loewi working on the neural control of heart muscle in the 1920s. Despite Eccles's contrary view, Katz and Kuffler provided strong evidence for the chemical nature of neuromuscular transmission during their collaboration in Sydney. In later years, neither Katz nor Kuffler expressed much affection for Eccles, who could be overbearing in the prosecution of his ideas.

When Katz returned to University College London in 1946 as Hill's assistant director, he began a series of studies showing that the arrival of the action at axon terminals causes the release of transmitter molecules stored in small membrane-bound units called synaptic vesicles ( Figure 1.4B). In the presence of sufficient calcium ions, the vesicles fuse with the terminal membrane and release neurotransmitter molecules into the narrow synaptic cleft. Katz and his collaborators eventually showed that calcium ions enter the axon ending through another type of membrane channel specific to axon terminals that the depolarization of nerve terminals opens when the action potential arrives. The transmitter molecules then diffuse across the synaptic cleft and bind to receptor proteins in the membrane of the target cell, an interaction that either opens or closes ion channels associated with the receptors. The net effect of various ions moving through these transmitter-activated channels is to help trigger an action potential in the target cell (synaptic excitation) or to prevent an action potential from occurring (synaptic inhibition).

Katz had chosen to work on the neuromuscular junction instead of synapses in the central nervous system (the choice Eccles had made) because of their simplicity and accessibility. Although synaptic transmission in muscle causes the muscle fibers to contract (in ways that Huxley was then beginning to work out in the 1950s in a lab not far from Katz's at University College), no one really doubted that the same mechanisms operated at synapses in the brain and the rest of the nervous system to pass on information—an idea that has been amply confirmed. Although many details of this process were not filled in until years after our course in 1961, these basic facts that Katz established about chemical synaptic transmission were what we learned listening to Potter and Furshpan's lectures. (Ironically, it turned out that a small but important minority of synapses do operate by the direct passage of electrical current, as Eccles had thought, and this additional mode of synaptic transmission had just been clearly established by Furshpan and Potter during their work as fellows in Katz's lab.)

As prospective physicians—and for me as a prospective psychiatrist—the biochemistry of neurotransmitters and their pharmacology was especially relevant because numerous drug effects depended on mimicking or inhibiting the action of the handful of transmitters that were then known. This instruction fell to Kravitz, the biochemist in Kuffler's group who was working on the chemical identification of the major transmitter in the mammalian brain that inhibits nerve cells from firing action potentials. The transmitter molecule (gamma-amino butyric acid) was obviously important in neural function, and Kravitz was later credited as its codiscoverer. Krayer, the head of the department and Kuffler's sponsor, taught the clinical pharmacology component of the course. With a phalanx of assistants, he set up elaborate demonstrations in anesthetized dogs to show us how various drugs affected the neural control of the cardiovascular system. These demonstrations were satirized mercilessly in the show that the second-year students put on, in which Krayer and his assistants, all in immaculate white coats, were depicted as German geheimrats, with thinly veiled Nazi overtones. None of us knew then that Krayer, who was not a Jew, had in the 1930s refused a German university chair vacated by a Jewish pharmacologist who had been dismissed under the Nazi laws prohibiting Jews from holding academic positions, or that based on his principles he had subsequently emigrated to England with the help of the Rockefeller Foundation.

Hubel and Wiesel rounded out this grounding in neuroscience by telling us how the brain actually used all this cellular and molecular machinery to accomplish things of interest to a physician. Unlike teaching us about the organization of nerve cells and the mechanisms of the action potential and synaptic transmission, conveying some idea of what the brain is actually doing was a difficult a task in 1961, and remains so today. Hubel and Wiesel dealt with this challenge by simply telling us about their work on the organization and function of the visual part of brain, which was just beginning to take off in a major way (see Chapter 7). It was not unusual for professors to cop out by telling us what they had been doing in their labs instead of going to the effort of putting together a broader and more useful introduction to some subject. But in this case, it was obvious that Hubel and Wiesel were trying to do something extraordinary, and none of us complained.

We managed to learn the organizational rudiments of the brain and the rest of the nervous system that we needed to know in complementary laboratory exercises in neuroanatomy (Figures 1.6 and 1.7).

Figure 1.6 The major components of the human brain and the rest of the central nervous system, which is defined as the brain and spinal cord (After Purves, Brannon, et al., 2008)

Figure 1.7 Some basic anatomical features of the human brain. The four lobes of the brain are seen in a lateral view of the left hemisphere (A) and a midline view of the right hemisphere after separating the two halves of the brain (B). (C) and (D) show the areas of the brain (each numbered) that German neurologist Korbinian Brodmann distinguished based on the microscopic studies of the cellular composition of the cerebral cortex. The views are the same as in (A) and (B), respectively. (After Purves, Augustine, et al., 2008)

Figure 1.6 The major components of the human brain and the rest of the central nervous system, which is defined as the brain and spinal cord (After Purves, Brannon, et al., 2008)

Cervical nerves-

By 1961, an enormous amount was known about the brain anatomy, thanks to the work of pioneers such as Cajal and Golgi, and of the neurologists and neuroanatomists such as Korbinian Brodmann who, in the early decades of the twentieth century, had devoted their careers to unraveling these details using increasingly sophisticated staining and microscopical methods ( Figures 1.7C and D). The glut of information was made more tolerable by functional correlations that had been made between behavioral problems and deficits observed in patients with brain damage that was documented postmortem. These clinical-pathological correlations, which we heard about in the clinical lectures that were interspersed with the basic science Kuffler's group taught us, had been made routinely since the second half of the nineteenth century. Together with brain recording and stimulation during neurosurgery that had been carried out since the 1930s, clinical-pathological correlations showed in a general way what many regions of the brain were responsible for. Although Sherrington and others had confirmed and extended some aspects of the clinical evidence in experimental animals, prior to the work that Hubel and Wiesel were then beginning, neuroscientists could not say how individual neurons in the brain contributed to neural processing. Nor could they formulate realistic theories about the operation of an organ that, based on both its gross and cellular anatomy, seemed hopelessly complex.

For Hubel and Wiesel, as for many others before and since, the bellwether for understanding the brain was vision, and their goal was to figure out how the visual system works in terms of the neurons and neural circuits that the system comprises. To do this, they needed a method that would permit them to record from visual neurons in the brain of an experimental animal that, while anesthetized, was nonetheless responsive to visual stimuli. Hubel had devised a way to do this in 1957, using sharpened metal electrodes that would penetrate brain tissue and record the action potentials generated by a few nearby nerve cells. This method is different from the recording technique shown in Figures 1.3A and 14, in which the electrode penetrates a particular nerve cell and records the potential across its membrane ( Figure 1.3B). An extracellular electrode simply monitors local electrical changes in brain tissue, and the results depend on how close the electrode is to an active nerve cell. In the hands of Hubel and Wiesel, this technique led to a series of discoveries about the mammalian visual system during the next 25 years that, as described later, came to dominate thinking about brain function in the latter half of the twentieth century.

Hubel, a Canadian who had been medically trained at McGill, had come to Hopkins as a neurology resident in 1954 and began to work with Kuffler two years later. Wiesel, a Swede, was medically trained at the Karolinska Institute in Stockholm and joined Kuffler as a fellow in ophthalmology the same year Hubel did. In joining Kuffler's lab as fellows in 1956, they benefited greatly from what Kuffler had already accomplished since coming to Hopkins in 1947 following his work with Eccles and Katz in Australia. Kuffler, always eclectic in the research he chose to pursue, had been working on the eye, in part because his appointment at Hopkins happened to be in the Department of Ophthalmology. In 1953, Kuffler had published a landmark paper in which he recorded extracellularly from neurons in the eye of anesthetized cats while stimulating the retina with spots of light, thus pioneering the general method that Hubel and Wiesel would soon apply to record from neurons in the rest of the cat visual system. Kuffler's key finding was that the responses of individual nerve cells in the retina defined the area of visual space that a neuron was sensitive to and the kinds of the stimuli that could activate it. (These response characteristics are referred to as a neuron's receptive field properties) Hubel and Wiesel recognized that this same method could be used to study neuronal responses in the rest of the visual system. With Kuffler's encouragement, they began using this approach at Harvard in

1959 to examine the response properties of visual neurons in their own lab as junior faculty members. Based on what Kuffler had established in the retina, they were exploring the properties of visual neurons in progressively higher stations in the visual system of the cat, and this was the work that we students heard about as an introduction to brain function. Although most of it went over our heads, we all got the idea that the function of at least one part of the brain was being examined in a new and revealing way.

Our course on neuroscience ended in spring 1961, and we moved on to contend with the rest of the first-year curriculum. Despite the excellence of these extraordinary teachers, I soon forgot much of what I had learned. In the subsequent years, the information about the brain we were exposed to was more practical: In neuropathology, we learned about the manifestations and causes of neurological diseases. On rotations through the neurology, neurosurgical, and psychiatric services of various Boston hospitals, we learned about their clinical presentation and treatment. However, I understood that the group of neuroscientists Kuffler had brought together represented a remarkable collection of scientists working on problems that were importantly connected to my conception of what I might eventually do. But we all had to cope with the courses or rotations that were coming next, and I was still wedded to the idea of pursuing psychiatry. As it happened, this seemingly sensible plan began to disintegrate within a few months.

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