The objective of this research program is a quantitative understanding of age-related changes in the neuronal organization of the hippocampal formation, and their contribution to the decline of memory function with age. The study of neurological and cognitive function during normal aging is a prerequisite to the development of therapeutic/preventative measures to deal with the specific problems of the elderly. In addition, the aging process involves definable alterations in neural structure and function which are associated with characteristic changes in behavior. Understanding the aging process may thus clarify neural mechanisms of behavior at all ages. The discovery of how and why memory is altered over the lifespan requires the integration of theoretical, behavioral and neurobiological methods. This proposal includes analysis of spatial navigation, intra- and extracellular recording in the in vitro hippocampal slice preparation, and extracellular recording of synaptic potentials in the behaving rat. A guiding principle is that, wherever possible, results from in vitro preparations must be verified in vivo. Based on our previous results, several key hypotheses about specific components of the hippocampal circuit are addressed. First, for the perforant path - granule cell synapse, an observed linear increase in the ratio of non-NMDA receptor-mediated to NMDA receptor-mediated synaptic responses over the lifespan suggests two interesting hypotheses: A) The threshold for LTP induction in this structure should increase with age; B) The altered receptor-specific response ratio might be a consequence of experience, possibly reflecting information storage, and thus might be modifiable by differential experience. Second, in granule cells of old rats, LTP exhibits a maintenance deficit in vivo which is correlated with faster forgetting. We inquire, in the chronic preparation, whether this is a general or specific phenomenon, by studying LTP decay at CAl synapses, and also investigate possible contributions of altered LTD and LTP reversal mechanisms, using both electrophysiological and behavioral manipulations of neural activity patterns. Finally, we apply recently developed advanced technology for parallel neuronal recording to the hippocampal slice preparation to test the hypothesis that CA3 cells in old rats make fewer synaptic contacts in CA3 and CAl. Overall, the results will contribute to a rapidly changing picture of the aging brain, from one of general decay, to one of exquisite specificity of regional, cellular and molecular changes, not all of which are necessarily maladaptive.
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