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2010 Grants - De Leonibus
Neurobiology of Working Memory Span in Normal and Pathological Aging
Elvira De Leonibus, Ph.D.
Institute of Genetics and Biophysics
2010 New Investigator Research Grant
Various types of memory decline occur during normal aging and Alzheimer's disease. One such memory type, known as working memory, involves the temporary storage of information for use in cognitive tasks. Research on working memory has been limited, largely because of the relatively few cognitive tasks that can measure working memory declines accurately in animal models.
In earlier studies, Elvira De Leonibus, Ph.D., and colleagues created a behavioral task for mice that involves recognition of various objects. They used this procedure to compare the amount of working memory—or working memory span—in healthy mice and in mice with damage to their hippocampus, a brain region affected early on by Alzheimer's disease. Results showed that the diseased animals had about one third less working memory span that did the normal animals. The team also found that the use of working memory in the diseased mice promoted activity in cellular "docking sites" called AMPA receptors. High AMPA receptor activity increases the activity of a chemical messenger called glutamate—which in turn causes neurons to become overexcited and die. This process, called excitotoxicity, is a key feature of Alzheimer's disease.
For their proposed grant, Dr. De Leonibus and colleagues will conduct a larger study with mice to clarify the associations between working memory loss, aging and AMPA receptor activity. The researchers will assess cognitively normal animals over time to determine the effect that normal aging has on working memory loss. They will also administer some of their mice with drugs designed to block AMPA receptor activity in the brain. The team will then assess whether, as expected, the treated animals will experience less working memory decline over time than will the non-treated aging mice. In addition, Dr. De Leonibus' group will search for possible correlations between levels of beta-amyloid, a protein fragment associated with Alzheimer's disease, and working memory span in the mice.
Results of this study could clarify the biological mechanisms underlying working memory loss. They could also promote the development of drugs to tackle such memory loss.