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Ackerman S. Discovering the Brain. Washington (DC): National Academies Press (US); 1992.
The brain regulates an array of functions necessary to survival: the action of our five senses, the continuous monitoring of the spatial surround, contraction and relaxation of the digestive muscles, the rhythms of breathing and a regular heartbeat. As the vital functions maintain their steady course without our conscious exertion, we are accustomed to consider the brain as preeminently the organ of thought. The brain houses our mind and our memories, and we rely on its information-processing capacities when we set out to learn something new.
But where in the brain can we locate memory or thought itself? Chapter 7 offered some clues about the ways scientific investigation—from the molecular level to studies of the alert, behaving animal—has begun to define in physical terms an abstract quality such as "attention." Similar techniques and approaches are being applied to other mental functions, too, even those as seemingly intangible as learning, remembering, or thinking about the outside world.
Learning and memory, which for many years were considered central problems in psychology, the social sciences, and philosophy, have recently assumed greater importance in the area of neurobiology, itself a confluence of several lines of investigation.
Most available evidence suggests that the functions of memory are carried out by the hippocampus and other related structures in the temporal lobe. (The hippocampus and the amygdala, nearby, also form part of the limbic system, a pathway in the brain (more...)
Neuroscientific interest in learning and memory has recently increased for two reasons, according to psychiatrist Eric Kandel, a senior scientist in the Howard Hughes Medical Institute at Columbia University. One reason is the proposal of cellular mechanisms that account for a basic kind of learning and long-term memory. The model was first identified in the relatively simple nervous systems of the marine snail and the crayfish, but it appears to hold good in the hippocampus of vertebrates as well, where it also may be associated with the formation of long-term memories.
The second reason for a new interest in learning and memory is the evidence accumulating to suggest that mechanisms involved in the structural change in the nervous system that accompanies learning may strongly resemble certain important steps in the nervous system"s development. In other words, the sorts of adjustments among synapses that account for learning may be the same as the "fine-tuning" that occurs while the maturing system is assuming its unique elaborated form. Thus, the biological changes that accompany learning may be seen—in a very schematic way—as an old process put to a new use, or as a specialized way in which the brain continues to "grow" after maturation.
A Molecular Account Of Long-Term Memory
Eric Kandel is best known for his work on the physical basis of learning and memory in the marine snail Aplysia. This animal, simple as its nervous system is (most of its 20,000 neurons have been identified by number), nevertheless provides an excellent model for the study of learning and memory, through its "gill withdrawal" reflex. When Aplysia perceives something touching its skin, it quickly withdraws both the siphon (a respiratory organ) and the gill, much as a person withdraws a hand from a hot stove without thinking about it. Although this withdrawal is a reflex, it is not completely hard-wired but can be modified by various forms of learning. One such form is sensitization, in which the animal becomes aware of a threatening factor in the environment and to protect itself learns to augment its reflex. The augmented version of the withdrawal reflex can also be maintained in short-term or long-term memory, depending on whether researchers administer the noxious stimulus (the negative reinforcement) only once or twice, or many times within a short period. The two forms of memory can be distinguished not only by their duration—the difference between minutes and days—but also at a molecular level, because it is possible to treat the snail with a chemical compound that interferes with long-term memory but leaves short-term memory unimpaired.
A major set of elements in this reflex are sensory neurons in the siphon skin, which perceive the stimulus; motor neurons in the gill, which contract the muscle and cause the gill to withdraw; and "facilitating neurons," or interneurons, which act on the sensory neurons to enhance their effect. The role of these facilitating neurons has recently become clearer, thanks to observations made from cell cultures, at the simplest level possible: the neurons themselves. A single sensory neuron and a single motor neuron, when implanted in a glass dish with a suitable nourishing culture, form functional interconnections. When a facilitating neuron is added or the cells are exposed to serotonin (the transmitter released by the facilitating neuron), the connection between the sensory and the motor neuron becomes stronger. The connection can last in this enhanced form for more than a day, even up to several weeks, and apparently includes some process of genetic transcription, or expression of part of the nerve cell"s DNA.
This genetic transcription produces two results that set long-term memory apart from short-term memory. One is a sort of extension of a short-term effect, in which the potassium channels in the sensory neuron membrane remain closed for a longer time, while the calcium channels remain open. The net effect is that the sensory neuron is more easily excited and releases more neurotransmitter, which in turn activates the motor neuron more strongly. Actually, this effect can be produced on a short-term basis by increased levels of the second-messenger compound cyclic AMP; but after transcription, it is no longer dependent on such a factor and persists even without it. The effect can be disrupted, however, by inhibitors of protein synthesis and RNA synthesis. This constraint establishes that the recording of long-term memories involves not simply a momentary release of neurotransmitters but actual gene expression, with the synthesis of new proteins in the nerve cells themselves.
The new protein products that are synthesized—for example, under the stimulus of a repeated threatening signal—do more than merely reduce the dependence of the sensory neurons on serotonin or cyclic AMP for their activation. As a second transcription event, they induce new growth in certain parts of the sensory neurons themselves. These neurons develop many more presynaptic terminals, the structures through which they release neurotransmitter to the motor neurons; in addition, the number and the surface area of active zones in each presynaptic terminal increase, as does the total number of vesicles, the storage containers for the neurotransmitter. Thus, gene expression appears to build long-term memory out of several effective components, which come together in a formidable array: increased excitability of the sensory neurons, with the protein kinase continuing to work on its own to keep calcium channels open, allowing calcium ions in and more neurotransmitter out; more synapses for conveying signals between sensory and motor neurons; greater numbers of active zones in the synapses; and greater quantities of neurotransmitter contained in the active zones, ready for release. No wonder that memories built of such stuff tend to last awhile.
For closer study, the Kandel laboratory has replicated in cell culture the same conditions that in the living animal lead to protein synthesis and neuronal growth: a motor neuron, a sensory neuron (injected with a fluorescent dye to make imaging possible afterward), and exposure to serotonin repeated four or five times. The results are clear: within several hours, the main axon of the sensory neuron shows an increase in the number of synapses. Exposing the neurons to the second messenger cyclic AMP produces a similar result. But regardless of whether the facilitating compound is the neurotransmitter or the second messenger, neuronal growth occurs only if a target—a motor neuron—is also present.
The necessary presence of a target was the first similarity that Kandel and his collaborators noticed between the processes of structural change that accompany long-term memory, or learning, and those of development. The observation fit in well, too, with an earlier finding: the fine axonal branches of a sensory neuron in isolation adhere together in fat bundles, but on first contact with a motor neuron the branches tend to separate, each potentially to form its own synapse with the motor neuron. Here, at a mechanical level, is the explanation for a disassembly process that is required prior to the marked increase in synapses that takes place in the presence of serotonin. But in long-term memory, as in development, the presence of the target is necessary—a feature that makes for plasticity, or the all-important ability to change in response to the environment.
To study this learning-related plasticity at the molecular level, Kandel"s research group is looking at the proteins that change in level when exposed to serotonin or cyclic AMP (or, in the living animal, to a noxious stimulus). Of the 15 proteins that change, 10 show an increase and 5 show a decrease. The reactions are transient: the levels go up, or down, and back again quite quickly.
Most interesting, in the investigators" view, are the proteins whose response is to decrease in level. Is there a way in which producing less of something can figure in a growth process? At a molecular level, the answer can be yes, if the something is an inhibitory factor of some kind. Such an answer may apply in this case, because four of these proteins that have been identified by genetic sequencing turn out to be none other than cell-adhesion molecules of the immunoglobulin type, first discovered by the research team of Gerald Edelman at Rockefeller University.
During development, the proteins apparently play a fundamental role; at least one of them is present at the very first stages, when the fertilized egg begins to divide. In the adult, however, these four proteins appear only in the nervous system, in both sensory and motor neurons. An interesting effect of these cell-adhesion proteins can be demonstrated on an isolated sensory neuron: if an antibody is added that blocks the cell-adhesion effect, the axonal filaments of the neuron start to come apart from their thick bundle and to separate out. The effect is similar to what happens when a sensory neuron is exposed to serotonin in the presence of a target, a motor neuron. This suggests that cell-adhesion molecules can indeed act as an inhibiting factor in particular circumstances. What they inhibit, apparently, is the growth and proliferation of signal-transmitting elements on the axons of sensory neurons.
By this reasoning, the effect of the cell-adhesion molecules would have to be held in abeyance at some point, to allow the sensory neurons to strengthen and increase their synaptic connections with the motor neurons. Perhaps there is even an innate tendency for some neurons, when they are near other target neurons, always to have their axons branching and proliferating, always to be seeking to form more synapses. (Indeed, during development, as discussed in Chapter 6, the brain actually forms a great many more synapses than can ever be functional during the animal"s lifetime.) The inhibitory action of the cell-adhesion molecules may thus be a crucial factor that keeps neuronal growth somewhat under control, and the temporary inhibition of cell-adhesion molecules in favor of long-term memory may be a single, notable exception to this form of containment. Of course, these results come from painstakingly close study of very simple nervous systems. The degree to which such findings can be extrapolated to the brains of primates, for example, which are many times more complex and which follow different patterns of development, is a matter of lively discussion among researchers in various specialized areas of neuroscience.
One striking aspect of such a system is the ingeniously high level of what, in a person, might be called thriftiness—the degree to which the same materials or biological processes are used and reused, but in novel contexts and to different ends. The protein kinase described earlier, which is dependent on cyclic AMP, appears in many other systems of the body and has various effects; but only in the nervous system, in relation to learning, does it play a role in long-term activation. Likewise, cell-adhesion molecules—better known to researchers for their general role in development—play a rather specialized part in the adult nervous system.
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Just as intriguing, from a different perspective, is the evidence for significant common ground between biological mechanisms of learning and the early development of the organism: not only the common use of cell-adhesion proteins (although in different ways) but also the fact that growth in both contexts requires a target. Even the finding that a neurotransmitter such as serotonin is not restricted to moment-by-moment signaling but can actually be a factor that initiates neuronal growth in the case of long-term memory adds to an impression of the two contexts conjoining, with neurotransmitters sometimes acting as growth factors.