Fewer Nerve Cells in Aging Brain's Memory Center Due to Slower Cell Division

December 18, 2006 – A new discovery provides a new avenue to pursue in trying to combat the cognitive decline associated with conditions such as Alzheimer's disease and with aging in general, say neurobiologists. They have found why the aging brain produces progressively fewer nerve cells in its learning and short-term memory center – the hippocampus.

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Previous studies had demonstrated that as the brain ages, fewer new nerve cells, or neurons, are born in the hippocampus (two curved ridges of tissue in the brain, located in the floor of the cavity within each of the cerebral hemispheres and concerned with basic drives, emotions, and short-term memory).

In one study by Ashok K. Shetty, Ph.D., professor of neurosurgery at Duke University Medical Center and medical research scientist at Durham VA Medical Center, and colleagues showed that the production of new neurons in rats slows down dramatically by middle age -- the equivalent of 50 years in humans.

But scientists did not know what causes this decline.

The common assumption had been that the brain drain was due to a decreasing supply of neural stem cells in the aging hippocampus, said lead study investigator Bharathi Hattiangady, Ph.D., research associate in neurosurgery.

Neural stem cells are immature cells that have the ability to give rise to all types of nerve cells in the brain.

In the current study, however, the researchers found that the stem cells in aging brains are not reduced in number, but instead they divide less frequently, resulting in dramatic reductions in the addition of new neurons or nerve cells in the hippocampus.

The scientists said the finding, made in rodents, refutes current ideas on how long crucial "progenitor" stem cells persist in the aging brain.

The finding also suggests the possibility of treating various neurodegenerative disorders, including Alzheimer's disease, dementia and depression, by stimulating the brain's ability to produce new nerve cells, said senior study investigator Shetty.

To conduct their census, the researchers attached easy-to-spot fluorescent tags to the neuronal stem cells in the hippocampus in young, middle-aged and old rats.

About the Hippocampus

By Memory Disorders Project at Rutgers University

The hippocampus is a brain structure which lies under the medial temporal lobe, one on each side of the brain. It is sometimes grouped with other nearby structures including the dentate gyrus and called the "hippocampal formation."

The hippocampus is critical for the formation of new autobiographical and fact memories. It may function as a memory "gateway" through which new memories must pass before entering permanent storage in the brain.

Hippocampal damage can result in anterograde amnesia: loss of ability to form new memories, although older memories may be safe. Thus, someone who sustains an injury to the hippocampus may have good memory of his childhood and the years before the injury, but relatively little memory for anything that happened since.

Some memories, such as the memory for new skills or habits, can sometimes be formed even without the hippocampus. A current research area is to determine exactly what kinds of learning and memory can survive hippocampal damage, and how these kinds of learning can be used to guide rehabilitation.

The hippocampus is especially sensitive to global reductions in oxygen level in the body. Thus, periods of oxygen deprivation (hypoxia) which are not fatal may nonetheless result in particular damage to the hippocampus. This could occur during a heart attack, respiratory failure, sleep apnea, carbon monoxide poisoning, near-drowning, etc.

The hippocampus is also a common focus site in epilepsy, and can be damaged through chronic seizures. It is also sometimes damaged in diseases such as herpes encephalitis, and is one of the first brain areas to show damage in Alzheimer's disease.

They found that in young rats, the hippocampus contained 50,000 stem cells -- and, significantly, this number did not diminish with aging. This finding, the researchers said, suggested that the decreased production of new neurons in the aged brain was not due to a lack of starting material.

The researchers then used another fluorescent molecule to tag all stem cells that were undergoing division in the process of staying "fresh" in case they were recruited to become mature nerve cells.

They found that in young rats, approximately 25 percent of the neural stem cells were actively dividing, but only 8 percent of the cells in middle-aged rats and 4 percent in old rats were dividing.

This decreased division of stem cells is what causes the decreased neurogenesis, or birth of nerve cells, seen with aging, the scientists said.

"This discovery provides a new avenue to pursue in trying to combat the cognitive decline associated with conditions such as Alzheimer's disease and with aging in general," Hattiangady said.

The team now is searching for ways to stimulate the brain to replace its own cells in order to improve learning and memory function in the elderly.

One approach being explored is to treat older rats with drugs designed to mimic the action of compounds called neurogenic factors, which encourage stem cells in the brain to divide, Shetty said.

The researchers also are grafting neural stem cells grown in culture dishes into the hippocampus, to stimulate those already present. Additional approaches include using behavioral modification techniques, such as physical exercise and exposure to an enriching environment, that are known to stimulate proliferation of stem cells.

Results of the study appear online in the journal Neurobiology of Aging. The research was funded by the National Institutes of Health and the U.S. Department of Veterans Affairs.

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