The effects of aging and age-related pathology in hippocampal/cortical circuitry are likely to contribute to mild cognitive deficits in normal aging and the progressive cognitive decline caused by Alzheimer's disease. This is a multidisciplinary, integrated program to study the effects of normal aging on cognition and hippocampal/cortical systems. There is now substantial evidence that behavioral testing can distinguish subpopulations of laboratory animals that differ in the severity of neurobiological aging. Considerable background work, by our group and others, supports the use of spatial learning to assess individual differences which predict the status of hippocampal/cortical systems in the aged rat brain. This background work will be extended in the proposed projects by the continued use of pathogen-free male Long- Evans rats, with additional work using non-human primates to examine the generality of models developed to account for age-related impairment. Thus, an important feature of this proposal is that the individual projects will use brain material from a common source and will conduct neurobiological studies against a background provided by a standardized assessment of cognitive function (Animal Resource Core). A number of individual projects will focus on two projection systems that provide major input to the hippocampus, the septohippocampal cholinergic system and the entorhinal (perforant path) projection to the dentate gyrus. Methods will be used to quantitate and map age-related changes in these systems and to examine the hypothesis that such changes are systematically related to the severity of cognitive impairment. Functional studies are aimed at determining the effects of age and cognitive status on information processing and plasticity within the hippocampus. The data generated on the project will also provide an empirical base for a computational modeling effort aimed at stimulating the effects of aging on hippocampal/cortical circuitry. This latter approach has important implications for increasing our understanding of the aging process and for assessing the therapeutic potential of specific neurobiological interventions. A number of features give the program unity: 1) each of the individual projects focuses on the effects of aging and its functional consequences on the same neural systems; 2) either common or complementary methodologies are used across many of the projects; 3) established collaborations exist among a number of the participants and a basis for additional collaborations exists in the proposed work; 4) all neurobiological data obtained for aged rats can be related to a standardized assessment of cognitive function; and 5) a Data Management System will provide the opportunity for across-project analyses. The administrative provisions in the Core will ensure that the specific vigor of the program is maintained by a network of communication and regular scientific review.
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