RESEARCH
Chemical basis of memory gains firm ground Chemical code words, similar to genetic code words, may explain information processing in the brain "It is up to the biochemist to convince the average man that chemicals may be involved in the formation and storage of memories." So noted Dr. James V. McConnell, University of Michigan, in an attempt to convince not only the average man but also his more skeptical colleagues of the role played by chemicals in memory and learning. Dr. McConnell led off an afternoon of reports and discussion at a seminar held late last month at the University of Tennessee's College of Basic Medical Sciences in Memphis. The seminar, featuring biochemists and psychologists actively studying the chemistry of learning and memory, focused on the status of research—as well as the controversy and personalities involved —in one of biochemistry's newest and fastest-moving fields. Presiding over the day-long forum, sponsored by the Institute for Development of Educational Activities, Inc. ( I D E A ) , was Dr. William L. Byrne, of the university's biochemistry department. Participants at the Memphis seminar espoused, as a sample, these diverse and provocative ideas: • Retention of learning is an active process that goes on after a learning experience is completed. • An incubation period occurring after a learning experience may be important in memory transfer. • The active material involved in chemical transfer of memory is probably a small molecule, possibly an octapeptide, not RNA as some scientists have held. • The time may not be far off when
engram—that physical representation of memory that presumably exists with in us all—proceeded unabated despite criticism from skeptics. Scientists eventually repeated his flatworm results—as some 5000 high school science students each year repeat them. "One of the reasons it is difficult for people to accept the notion that the engram may be chemical," says the biochemist, "is that when we learn something, we can't feel chemical molecules doing little things inside us. We can't feel electrical activity in the central nervous system either, but we have analogies," for example, the busy telephone and telegraph systems that tie society together. Incubation. The most recent work of Dr. McConnell was performed with the help of Dr. Arnold Golub at the University of Michigan. Rats are trained during which time they are rewarded with food (acquisition). Then the rats are put through the same learning experience, only this time they receive no food (extinction). They then receive additional acquisition training (repeated acquisition). Untrained rats are injected with brain extracts from rats trained in this manner with two variations in the method. In some of the donor rats, a period of no training (what Dr. McConnell calls incubation or vacation time) is interposed between the first acquisition and extinction periods. In other donors, incubation occurs after initial acquisition and extinction are completed. Dr. McConnell finds that when incuba-
artificial memories may be implanted in human brains. Smart tails. The most esoteric of these ideas are the brainchildren of Dr. James McConnell, who achieved fame in the late 1950's by showing that even planarians (flatworms) can learn. "Thus," says Dr. McConnell, "by using Planaria, one of the simplest animals having true synapses, I deviated from the only two species used in comparative psychology experiments—the white rat and the college sophomore." Dr. McConnell trained planarians, cut them in half, and let the head portions grow new tails and the tail portions new heads. When he tested each regenerated planarian, he found that both halves retained the memory of the original flatworm. This was one of the first experiments in chemical transfer of memory. The planarian's brain is located in its head so "One thing was clear to me," explains Dr. McConnell. "Memories were stored all over this animal's body, not just in the region of the brain. We did this study in which we showed that memories could migrate and the only thing I could think of that could migrate were chemicals." This hypothesis, though not entirely original with Dr. McConnell, spurred much activity in the field of chemical transfer of memory, not only in his Michigan laboratory but around the world. It also generated a fair amount of skepticism from scientists who failed to replicate his results. Dr. McConnell's search for the
Chemical code words explain possible basis of one kind of learning
>Food
>Bell
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Unconditioned dog treated with brain extract (containing code word) from conditioned dog
If brain extracts containing code words from conditioned dog are injected into unconditioned dog, synaptic bypass forms via chemical molecules; bell alone elicits tail wagging NOV. 3, 1969 C&EN 43
tion occurs after extinction, extinction is transferred. In fact, the recipients perform worse than the control group in this case. When incubation occurs between initial acquisition and extinction, memory transfer occurs and animals perform significantly better than controls. "Incubation is only one of the things we must look at in chemical transfer of memory," Dr. McConnell observes. Other questions which must be answered include what chemicals are involved in the memory transfer?; which sites in the brain are involved in learning?; what are the mechanisms by which learning occurs? The payoff of memory transfer studies will come when the chemicals responsible for memory are sufficiently characterized to be artificially synthesized, according to Dr. McConnell. He foresees implanting artificial memories into people to speed up learning processes. These memories could aid slow learners and mental retardates and "might be especially useful in underdeveloped nations," suggests Dr. McConnell. There a person's learning is often handicapped by environmental conditions. Science fiction? Although this suggestion is anathema to many of the scientists who were present in Memphis, the time may not be far off when such an idea becomes reality, according to Dr. Georges Ungar of Baylor University medical school. Dr. Ungar, one of the most respected scientists working in the field of memory transfer, has isolated materials that produce specific behavior in animals. He believes that the active materials may correspond to chemical code words by which information processing occurs in the brain, much as genetic code words control heredity. In the course of his experiments to prove out the idea, Dr. Ungar has found four different memory transfer factors corresponding to four different behavioral patterns. The active material in each case is not deactivated by pancreatic ribonuclease, indicating that RNA is not the major memory transfer factor. The activity of the material is, however, destroyed by the enzymes trypsin and, in some cases, chymotrypsin. Other experiments suggest that the active materials are specific molecules or a family of molecules which may form complexes with RNA as artifacts during extraction from the brain. The active materials are probably peptides containing eight to 12 amino acid residues, Dr. Ungar says. "They are definitely not carbohydrates and we know that a peptide linkage is required for activity." Cade words. Dr. Ungar offers an intriguing hypothesis to explain in44 C&EN NOV. 3f 1969
TRANSFER. Dr. Georges Ungar can transfer specific behavior to untrained rats by injecting them with memory transfer factors (peptides) from trained rats
formation processing on the molecular level, although he notes that this idea has been around for some time. When we are born, he says, we have fully organized neuropathways that have associated chemical code words. These pathways are capable of stereotype responses. As new information comes to the brain, the system is reprogramed through the existing pathways and chemical code words set up connections between the physical pathways to accommodate the new stimuli (see diagram on page 4 3 ) . What Dr. Ungar hopes he has found are some of these chemical code words. If these substances are simple peptides, they can be synthesized and Dr. McConneirs synthetic memory proposals no longer seem quite so incredible. However, Dr. Ungar emphasizes that the real significance of these memory transfer experiments is often obscured by the sensational aspects of imparting knowledge in chemical form by a simple injection. "The outstanding feature of the [memory transfer] experiments is that they enable us to detect the chemical correlates of learned information in the brain of the donor—what happens in the brain of the recipient is merely a heuristic means of finding out more about the brain processes in general." Drugs. For those seminar participants who preferred to take another approach to the chemistry of memory and learning than Dr. McConnell and
Dr. Ungar, Dr. Murray Jarvik explained the three R's of the memory process—"registration, retention, and retrieval." Dr. Jarvik's goal is finding the active changes—which he, too, believes are chemical—taking place during memory retention and consolidation. Dr. Jarvik, of Albert Einstein College of Medicine, Bronx, N.Y., finds that trained mice forget what they had learned (retrograde amnesia) if they are given acetoxycycloheximide (a protein synthesis inhibitor) after training. He believes that the drug works on consolidation and that retention is an active process that goes on after learning. Facilitation. Meanwhile, Dr. James McGaugh, former student of Dr. Jarvik and dean of University of California's school of biological sciences, Irvine, uses drugs to facilitate learning rather than to produce amnesia. For example, in recent work Di\ McGaugh finds that rats injected with D-amphetamine 15 minutes before or after training remember better. Although he has worked in this field for 12 years, the California scientist declines to speculate about possible applications of his findings to the education of slow learners and retardates. He stresses that the field is too new and complex to make predictions adding that "the whole story of memory when it is finished will make carbohydrate metabolism look pathetically simple."
