Aging of the central nervous system leads to alterations both in neurons as well as the intricate circuit connections between brain regions, due to cell loss, decreased reactivity to insults and intraneuronal changes. However, brain regions (such as the hippocampus) successfully maintain function through a complex series of reactive responses to these aging changes, up to a critical point when these responses become inadequate. These reactive responses may include dendritic lengthening, pre- and post- synaptic sprouting, changes in either synaptic efficacy or cellular responsiveness to afferents, alterations in potentiation and changes in growth factors. Both primary aging changes (such as cell loss) and the reactive alterations induced by such changes (such as denervation responses) are highly individual. Thus, individual behavioral evaluation, analysis of cell loss and the degree of lesion-induced plasticity may partly gauge both the adequacy and extent of reactive changes which have occurred and the nature of further compensation. The objectives of this proposal are to analyze neuronal and synaptic responses to aging in the context of these individual age-related measures. The identification of underlying mechanisms responsible for maintenance of hippocampal function in successful aging and also the decline of function in impaired individuals is crucial to understanding CNS aging responses. The initial hypothesis of this study points to reorganization of neuronal elements and circuitry In the hippocampus as key elements of the reactive responses to aging; this reorganization may be parallel to lesion-induced effects. The second hypothesis indicates that there should be critical differences In the quality and degree of reactive alterations between aged Individuals with either preserved or abnormal indices of behavior, cell loss and lesion-induced plasticity. These hypotheses will be tested with a comprehensive set of research techniques, including behavioral testing of aged animals, in vitro tissue slice recordings of the hippocampus using intracellular techniques and neuronal stains, reconstructions of neurons, assessment of cell loss, lesion-induced alterations using a kainic acid hippocampal lesion and immunohistochemical analysis of dendritic structural elements. Several aspects of this study are directed physiologically, to evaluate the participation of surviving, healthy neurons in ongoing reactive processes. Analysis of successful reactive and compensatory strategies in response to the aging process may lead to an Improved understanding of aging and the spectrum of reactive mechanisms which can occur In the brain in response to lesions. In particular, further understanding of these mechanisms may lead to therapies designed to both maintain functional status of the nervous system and facilitate ongoing recovery processes In the aged CNS.
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