Jewish World Review May 31, 2002 / 20 Sivan, 5762


Memory gene won't let you forget

By Lidia Wasowicz

http://www.NewsAndOpinion.com | (UPI) An international team of neuroscientists has identified a gene that lets people get in touch with their long-term memories.

The discovery opens the door to eventually developing drugs for conditions ranging from the chronic forgetfulness of Alzheimer's patients to the occasional "senior moments" of middle-agers, the investigators speculate.

Those who cannot remember have not "lost" their memories; they are simply unable to retrieve them, the researchers attest. With most of the previous focus on the brain's mechanism for locking away past experiences, the new findings provide a rare glimpse into the neural processes that regulate their release.

"This is a very elegant use of the latest technology and makes a very significant contribution," Roger Nicoll, professor of pharmacology at the University of California at San Francisco, told United Press International in a telephone interview. "Much of the work done in this field has been related to how you lay down memories, but very little's been known about how you might pull them out. Everyone's been focused on the first part because that's hard enough, so the retrieval aspect has been largely neglected."

In a change of pace, the new work put the spotlight on the nerve cells' power to call forth cue-triggered random remembrances, an ability apparently governed by a specific gene in a specific part of the brain that fades with age and with such degenerative diseases as Alzheimer's.

In a little-understood, complex cascade of chemical signals, a simple sensory suggestion can set off vivid recollections resplendent in detail in a process called pattern completion. Thus, a strain of music can conjure up a symphony of images from a long-ago night of dancing under the stars with a sweetheart.

"In day-to-day life, it is everybody's experience that a rich content of memory of a past experience is recalled with a trigger composed of a fraction of information related to the stored information," Nobel laureate Susumu Tonegawa of the Massachusetts Institute of Technology in Cambridge, Mass., who led the U.S. and Japanese team, told UPI.

"The molecular, cellular and neuronal network mechanisms underlying this amazing feature of memory recall have not been understood, although some hypotheses have been suggested."

Using state-of-the-art technology that took three years to develop and enabled them to eliminate a specific gene in a specific brain region, the researchers zeroed in on a key player in long-term memory retrieval. The study of specially designed mice pointed to a chemical receptor called N-methyl-D-aspartate, or NMDA, located in the CA3 region of the hippocampus. This area is known to play a key part in shaping, sorting and storing memories. Previously, researchers had linked the same gene in a different location -- the CA1 region of the hippocampus -- to the retention, but not the retrieval, of long-term memories.

"The findings are important because they provide direct experimental evidence for one of the most fundamental issues in memory research that (has) been debated only on theoretical grounds but without any hard experimental evidence," Tonegawa, Picower Professor of Biology and Neuroscience and director of the Picower Center for Learning and Memory, told UPI. That issue: how memories are recalled.

"Memory recall deficits are close to all of us as aging effects (us) as well as the effects of neurodegenerative diseases," Tonegawa said. "The work does not provide the cure for these problems but provides the molecular target for which drugs can be directed in coming years."

Drugs targeting the gene could enhance memory recall in aging and dementia. Meanwhile, mouse models could serve as tools in studying -- and treating -- neurological impairments associated with growing older or contracting Alzheimer's disease, Tonegawa said.

Much work remains, however, the researchers cautioned.

"There's so little that we know. It's a vast gap between the type of research that's been done and its application to therapeutic avenues," Nicoll told UPI.

Using their cutting-edge technique, the researchers from MIT, Baylor College of Medicine in Houston and Hokkaido University School of Medicine in Sapporo, Japan, found mice with and without the target gene performed equally well in a maze marked with a series of visible cues. This indicated the gene did not play a critical role in acquiring memory.

When the researchers removed some of the clues, however, the rodents with all genes intact continued their well-rehearsed act -- of locating a platform submerged in a pool of water -- but the altered animals forgot the routine. This pointed to the gene's involvement in memory retrieval.

Having implanted electrodes deep within each test rodent's hippocampus, the researchers peered at memories being formed in the mouse brain. They noted as visual cues were removed, the nerve cells in the altered mice weakened in their response.

"This result provides a direct measurement of how failed memory retrieval might appear at the level of individual neurons, and therefore provide the basis for improving memory under these conditions," said study co-author Matthew Wilson, associate professor of brain and cognitive sciences at MIT.

"It appears that the CA3 region of the hippocampus is essential for the phenomenon called 'pattern completion,'" said study co-author Dan Johnston, professor of neuroscience at Baylor. "That is the ability to recall memories from partial representations of the original."

These memories can stay put for up to a year before transferring to other brain regions, specifically the cortex, the investigators said. A person whose hippocampus is injured, for example, cannot form new memories but can access older ones that presumably reside in the cortex.

The mouse model shadows memory processes in humans, scientists said.

Paralleling the blunted agility of remembrance retrieval in an aging person, the mutant mice had trouble accessing -- though not acquiring -- long-term memory of a specific place without the full guidance of visible clues.

"In real life, we always recall memories with limited information," said Tonegawa. "A memory is dormant until it is retrieved from the subconscious to the conscious with cues."

He added, "When people get old, they complain they are losing their memory. In fact, in many cases they are losing their ability to recall memories. It's the tip-of-the-tongue phenomenon -- if they had more triggers, they often can recall the facts."

The same is true in the early phase of Alzheimer's.

"It's not that they lost the memory. It's that they have a retrieval problem," Tonegawa said.

"By understanding how memory retrieval works at the molecular level, this could be the basis for drug development in the future. It's important not only for Alzheimer's patients, but for prolonging the ability of aging people to recall memories and learned facts."

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