SYNAPTIC SUBSTRATES OF AGE-DEPENDENT MEMORY DEFICITS

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DESCRIPTION (Adapted from applicant's abstract): Loss of memory, especially for newly acquired information, is one of the hallmarks of normal aging. Yet, it has long been noted that some individuals retain remarkably intact memory even at advanced chronological age. An important and still unresolved problem in the neurobiology of aging is how to explain why memory is preserved in some aged individuals and lost or impaired in others. The proposed project is designed to investigate this problem by testing the hypothesis that memory deficits typical of the majority of aged individuals are due to a loss of synapses in pertinent brain regions. Young adult, middle-aged and old rats will be examined. A battery of behavioral tasks will be used to separate old rats into memory-impaired and memory-intact subgroups based on the presence or absence of memory deficits as compared with young adult and middle aged rats. The behavioral tasks to be employed include the Morris water maze, trace eyeblink conditioning and trace fear conditioning. The structural integrity of the hippocampus is a prerequisite for successful performance of animals on these tasks. Synapses will be analyzed in two hippocampal subregions, in the CA1 subfield and the dentate gyrus. Electrophysiologically, the efficacy of impulse transmission will be evaluated at Schaffer collateral-pyramidal cell synapses in the CA1 subregion and at medial perforant path-granule cell synapses in the dentate gyrus, using field potential recordings in vivo. At the electron microscopic level, unbiased techniques of moderm stereology will be employed to obtain estimates of the total number of synapses in the total volume of the CA1 stratum radiatum and the dentate middle molecular layer. Additionally, such techniques will also be used at the light microscopic level to make unbiased estimates of the total number of principal neurons in various hippocampal subregions. The results to be obtained will definitively demonstrate whether old animals with marked impairments of hippocampus-dependent memory function are the ones that exhibit a loss of hippocampal synapses and a decline in synaptic efficacy when compared with memory-intact old, middle-aged or young animals. These results will also show if a loss of hippocampal neurons occurs in memory-impaired old animals but not in memory-intact animals of different ages. Such data are important for a better understanding of the cellular mechanisms that underlie deficits in learning and memory typical of normal aging, as well as of memory disorders such as Alzheimer's disease. Moreover, the data may be useful for designing preventive measures to make aging "successful."