An Honor For Memory

Last week, Nobel-prize winning scientist Eric Kandel wrote about the five most unforgettable works on memory for The Wall Street Journal. Today we will look more closely at two of these titles, Memory and Brain by Larry R. Squire and Memory From A to Z by Yadin Dudai. Below is an excerpt from the beginning of Memory and Brain. Check back later today to learn more about Memory From A to Z.

Definitions: From Synapses to Behavior

Most organisms can change in response to the events that occur during their lifetimes. Because of this capacity, the experiences that an animal has can modify its nervous system, and it will later behave differently as a result. This adaptive capacity gives organisms the ability to learn and to remember. Neuroscientists and psychologists have generally preferred broad definitions of learning and memory. One can begin with well studied examples of learning, such as the conditioned reflex (Pavlov, 1927), or with familiar examples of rat laboratory behavior, such as bar pressing. Yet it has always been recognized that a complete account of learning and memory must accommodate many different kinds of behavioral change. Memory includes not only the conditioned reflex but also the ability to remember one face out of a thousand that have been seen, the ability to memorize a poem, the ability to demonstrate an improved throwing arm, and the ability to find one’s way around an old neighborhood.

The concepts of learning and memory are closely related. Learning is the process of acquiring new information, while memory refers to the persistence of learning in a state that can be revealed at a later time. Memory is the usual consequence of learning. Hilgard and Marquis (1940), in what is perhaps the best-known review of the psychological principles of conditioning and learning, defined learning as a “change in the strength of an act through training procedures (whether in the laboratory or the natural environment) as distinguished from changes in the strength of the act by factors not attributable to training” (p. 347). McGeoch (1942), in an early, comprehensive review of human learning, wrote, “Learning as we measure it is a change in performance as a function of practice. In most cases, if not in all, this change has a direction which satisfies the current motivating conditions of the individual” (pp. 3, 4).

Neal Miller (1967), wishing to exclude ambiguous cases of learning, wrote that “Learning is a relatively permanent increase in response strength that is based on previous reinforcement and that can be made specific to one out of two or more arbitrarily selected stimulus situations” (p. 644). Miller called this “Grade-A Certified Learning.” But, Miller (and others) recognized that some types of behavioral change do not conform to such a restrictive definition, even though they could provide insight to understanding both the capacity of organisms to change and the neural basis of this capacity. One wants to exclude from consideration the effects of factors like fatigue or injury, which, though resulting from experience, are not at all what is meant by memory. At the same time, other relatively simple forms of behavioral adaptation, such as habituation and sensitization, deserve close attention. They do not depend on association, but they can be long-lasting and might well constitute building blocks for classical conditioning and other forms of learning (Hawkins and Kandel, 1984).

Biologists believe that the capacity for memory provides a special case of a more general phenomenon: neuronal plasticity. Many neurons exhibit plasticity, that is, they can change structurally or functionally, often in a lasting way. Plasticity is evident in such diverse phenomena as drug tolerance, enzyme induction, sprouting of axon terminals after a brain lesion, and strictly synaptic events such as facilitation and depression. The discovery of just how the nervous system performs these and other examples of plasticity would be likely to provide important clues to the problem of how the nervous system accomplishes learning and memory. Kandel and Spencer (1968) made this point in their comprehensive review of the neurophysiological basis of learning. “Since persistence is one of the most distinctive features of learning, we believe that analysis of the plastic properties of neurons is a prerequisite for the neuro-physiological study of learning” (p.65). No matter how learning and memory are defined, at present we understand them so poorly that we cannot afford to discard any phenomenon that might yield clues about their neural basis.

Reflection on the physiological basis of memory led most early writers to consider some type of growth or change in the existing structure of the nervous system. William James (1890) wrote, “The only impressions that can be made upon them [brain and spinal cord] are through the blood, on the one hand, and through the sensory nerve-root on the other . . . The currents once in, must find a way out. In getting out they leave their traces in the paths which they take. The only thing they can do, in short, is to deepen old paths or to make new ones” (p. 107). By the late nineteenth century, biologists had learned that most mature nerve cells have lost their capacity to divide. The hypothesis that existing nerve cells can grow therefore appeared to be a reasonable way of accounting for the persistence of memory. Such a concept was first introduced by Ramon y Cajal (1894) and independently by two of his contemporaries (Tanzi, 1893; Lugaro, 1900). During the past century, this basic idea has been restated several times, making explicit the hypothesis that the synapse is the critical site of plastic change (Konorski, 1948; Hebb, 1949 Eccles, 1953; Kandel, 1977). The idea is that memory involves a persistent change in the relationship between neurons, either through structural modification or through biochemical events within neurons that change the way in which neighboring neurons communicate.

Advances in neurobiology have produced two significant and relevant discoveries since synaptic change was first proposed to explain memory. The first of these discoveries is that neurons show many kinds of plasticity. Application of electrical stimulation, neuronal disuse, and more natural treatments such as enriched rearing conditions have all been shown to produce synaptic change: presynaptic changes in the economics of transmitter release (depression, facilitation, and post tetanic potentiation), postsynaptic changes in receptor sensitivity, and morphological alterations in synaptic structure. These results demonstrate that neurons can change in a functionally significant way, and they provide possibilities concerning the actual processes that occur during behavioral learning. The second important discovery is that in favorable invertebrate preparations, alterations in synaptic efficacy can be correlated directly with behavioral learning most clearly in the cases of habituation, sensitization, and classical conditioning. For example, habituation in the sea hare Aplysia depends on a decrease in the tendency of neurons to release neurotransmitter as a function of repeated stimulation (Figure 2).

Prior to the recent technological developments of neuroscience, memory was a problem studied primarily by psychologists. Today, both memory and the broader topic of neural plasticity are major areas of interest within neuroscience itself, and they can be approached in several ways. Although one important and fruitful focus of recent interest has been an understanding of the molecular and cellular facts of synaptic change, the problem of memory raises other types of questions as well. There are many steps between synaptic change and behavioral memory. Do the particular molecules synthesized during learning contain an information code? Does the pattern of synaptic pathways that are changed during learning code for information? What is the code? What happens during forgetting: an irreversible erasure of what occurred during learning, or only a change in accessibility, which is potentially reversible? Where is memory localized in the nervous system? Is it widely distributed, or do restricted loci store specific memories? Are there memory centers?

Many important questions about memory address a more global, psychological level of organization. Is memory one thing or many things? If more than one kind of memory were to exist, then the neural foundations discovered for one kind of memory might not apply to the others, and principles of organization developed for one kind might not generalize to the others. Is it useful or necessary to distinguish between shortlasting and long-lasting memory or between memory for one kind of material (e.g., faces) and memory for other kinds (e.g., words, numbers)? What brain systems participate in information processing, storage, and retrieval? What is the flow diagram of information-processing events, and how can the flow diagram be related to anatomy?

Questions about memory must be addressed at several different levels of analysis, ranging from the molecular events that underlie synaptic change to the broader problems of the organization of memory within the brain and the organization of whole behavior. Answers to these questions have been sought in the analysis of simple preparations, in model systems, and in behavioral studies of experimental animals. Such studies bring to bear all the techniques of modern behavioral neuroscience: lesions, recording of neural activity, biochemical and anatomical measurement, electrical stimulation of brain, and administration of drugs. Clinical procedures or accidents of nature sometimes allow significant studies to be carried out with human subjects. The pages that follow attempt to summarize what is now known about memory. Specific molecular and intracellular events involved in neuronal plasticity will not, for the most part, be discussed. While it is recognized that the molecular biology of synaptic change is of great interest, here the synaptic change itself is considered as the elementary component of memory. The focus is on the links between synaptic change and behavioral memory: neurons, neural systems, and the problem of how memory is organized in the brain.