In their quest for memory-boosting compounds,neuropsychopharmacologists are ransacking their libraries ofpsychoactive peptides. Their purpose is to tap the growing market oftherapies for Alzheimer's disease and similar senile dementias.

Other scientists, neuropsychologists, are tapping into the memorytraces of rats, to decipher the neuronal code of memory and learningat its deep cerebral levels. In principle, these two disparate researchendeavors should meet in the future.

Meanwhile, said neuroscientist William Skaggs, "in the short-term,there is no clear path to a therapy arising from our inquiry into howthe hippocampus works in memory." Skaggs is first author of a paperin the current Science, dated March 29, 1996, titled: "Replay ofneuronal firing sequences in rat hippocampus during sleep followingspatial experience."

Its senior author, Bruce McNaughton, heads the laboratory of neuralsystems, memory and aging at the University of Arizona, in Tucson.

The hippocampus is a region in the middle of the mammalian brainfor which there is now increasing evidence to confirm the long-heldhunch that it plays a major role in learning and memory.

The roots of this supposition go back to the late 1940s, Skaggs toldBioWorld Today, to "a very influential book, `The Organization ofBehavior.'" Its author, psychologist Donald Hebb of McGillUniversity, "suggested that the way learning occurs is by what hecalled `cell assemblies in the brain,' that is, groups of neurons thattend to fire together."

Hebb's idea, Skaggs explained, was "that whenever you have twobrain cells that fire at the same time, the connection between thosecells _ that is, memory _ gets stronger." He added, "It was Hebb'sidea that that would be the long-sought `engram' _ the fundamentaltrace of memory in the brain."

Ever since, Skaggs continued, "people have been looking for thosekinds of changes, and they found them two decades ago in thehippocampus."

One window into the workings of that cerebral region is sleep. "Weknew that what the rat hippocampus does during sleep shows flashesof reactivation of what it did during earlier waking behavior," Skaggssaid. "But we didn't know whether these were still photographs, orwhether the hippocampus had any information about the order thatthose things happened in."

Sleep Replays Waking Hours _ Fast-Forward

From his and McNaughton's research reported in Science, "we'velearned that there is in fact such information." Their rat experimentsindicate that "when a sequence of events happens while an animal isexperiencing something, it replays about 40 times faster during thevery brief sleep intervals called sharp waves."

That time scale, Skaggs observed, "is at the one-second level, say, thetime difference between throwing a dart and seeing it hit the wall."

Skaggs trained six rats to run around a table-top triangular orrectangular track, milestoned with small rewards of food. Nourishedby the memory of this experience, the animals would curl up and goto sleep on a nearby round platform.

During their slumber, electrodes planted in the rats' hippocampirecorded the reactivated fast-forward replay of those murinememories.

Skaggs cites data suggesting that in rats the reactivation during sleepgoes back a few weeks. In humans, he said, "the evidence is morespeculative: It seems that the hippocampus is involved for a muchlonger time; that it holds information on the order of a year, butprobably not as long as ten years."

This evidence, he recalled, derived from a celebrated operation in the1950s on a patient with epilepsy, identified in the literature only as"H.M." The neurosurgeon removed most of his hippocampus on bothsides of the brain. "And it turned out to everyone's surprise," Skaggssaid, "that he has no conscious recollection of any event thathappened since his operation. H.M. is still alive, perhaps the most-studied patient in medical history."

Relevance To Alzheimer's `In Long Term'

The Arizona post-doctoral fellow expressed the hope that his sleepexperiment in rats "in the long term might possibly have somerelevance to memory loss in Alzheimer's disease. We know that thereare some serious memory problems, and we have good reason tobelieve that they involve the hippocampus."

Three of his rats were young adults, nine months old; another three,elderly _ 27 to 30 months. Normal life expectancy is 36 months.

Differentials in memory performance between these two age groups,Skaggs said, is the subject of further, still unpublished, research byMcNaughton and his co-investigator, aging specialist Carol Barnes.

Other, ongoing work, aims to elucidate the way in which thehippocampus transmits its short-term memory traces to the brain'sneocortex for longer-term processing. In both regions, the principleneurons are pyramidal cells.

"In the hippocampus," Skaggs said, "they comprise 95 percent of theneurons. They project to other parts of the brain, and communicatewith each other over wide distances. Each of these long-distanceoperators makes on the order of 10,000 synapses that connect it toother pyramidal cells."

He concluded: "We have some idea now of how the information isthere in the hippocampus, but we really need to know how it getsfrom there up to the neocortex, where we think the deep forms ofthinking go on. So we're developing experiments to record betweenthe hippocampus and the neocortex at the same time." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.