The research program is directed towards an understanding of the electrophysiological, neurochemical and behavioral correlates of the decline in spatial cognition and memory with age. The ultimate goal is the development of preventative or ameliorative treatments for this decline. The investigations focus on aging of the rodent hippocampal system, including its intrinsic connections and information processing characteristics, and those of its major cortical and subcortical connections. Previous research from this laboratory has demonstrated both intrinsic changes in the biophysical properties of pyramidal cells of the hippocampal CA1 subfield and a loss in the specificity of information about spatial relationships transmitted by these neurons in the alert behaving animal. We have also documented a significant reduction in the ability to maintain changes in hippocampal connection strengths induced either by electrical stimulation or by exposure to novel spatial information. There are three main questions addressed in this proposal. The first concerns the degree to which the loss of spatial selectivity in hippocampal unit activity can be accounted for by disruption of cortical afferents, and the consequence of this loss for information processing at subsequent neural levels. This problem will be addressed using a new technique developed in this laboratory (the stereotrode) that enables the simultaneous recording from several single neurons in conscious animals moving freely in a spatially extended environment. Age changes in hippocampal afferent and efferent projection areas will be assessed using a novel multiple regression technique developed in the preceding grant period. The second question concerns the possibility that modulatory influences in the hippocampus from subcortical afferent systems change with age. This question will be addressed using local electrical and chemical excitation or reversible chemical inactivation of discrete subcortical projection nuclei in conscious animals. In addition, the role of behavioral state on these subcortical-hippocampal interactions will be assessed. The third major question is whether information storage throughout the lifespan results in a significant rearrangement in the statistical distribution of connection strengths from a large number of weak connections to a smaller number of strong ones. Such a change might result from competitive mechanisms of information storage and might account for the restriction in the range of behavioral adaptability of older animals. The answer to this question requires the analysis of cellular interactions at the level of single neurons rather than the population techniques employed in previous studies.
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