Studies in rats and humans indicate that cognitive decline is not an inevitable consequence of aging. Variability in the cognitive effects of aging provides a useful basis for identifying neurobiological alterations in the aged brain that are associated with senescent functional impairment. Research proposed in this application will provide the first large-scale, comprehensive survey of individual differences in memory function in the aged nonhuman primate. The major objective of these studies is to evaluate the proposal that only a subpopulation of aged monkeys exhibit a pattern of memory impairment that resembles the effects of medial temporal lobe damage. Taking advantage of a unique resource of animals and facilities available at the California Regional Primate Research Center, memory function will be assessed in 55 aged rhesus monkeys ranging in age from 19 to 30+ years old. Twenty young subjects (4-6 years of age) will be tested as controls. Assessment procedures will include 3 tasks that have been widely used to examine the cognitive effects of experimental brain lesions in young monkeys: 1) a delayed response test of spatiotemporal memory, 2) a delayed nonmatching to sample recognition memory task, and 3) a rapidly acquired 2-choice object discrimination procedure. Cognitive function will also be assessed using a series of newly developed spatial learning and memory tasks analogous to procedures that are extremely sensitive to individual variability in rodent models of aging. These investigations will evaluate the possibility that spatial information processing is disproportionately impaired as a consequence of aging, and will determine whether spatial memory dysfunction occurs in only a subpopulation of aged monkeys. Training will be conducted in a transparent plexiglas open field maze, 9 feet in diameter, with 8 reward locations distributed around the perimeter of the apparatus. A computerized spatial tracking system will monitor performance on an trials and provide measures of distance traversed within the maze, time spent in specified regions of the apparatus, average speed of movement during training sessions, and the sequence of visits to individual reward locations. Testing in the open field maze will consist of procedures designed to examine: 1) exploratory activity and habituation, 2) the acquisition and retention of spatial working and reference memory, and 3) nonspatial learning and memory. At the conclusion of behavioral testing, 5 young and 20 aged monkeys will be sacrificed for an ongoing program of studies aimed at identifying neural alterations in the aged brain that are associated with senescent memory impairment. Taken together, the proposed experiments will yield an extensive survey of individual differences in memory function in a nonhuman primate model of normal aging. These studies will ultimately contribute to the development of therapeutic interventions designed to ameliorate age-related cognitive dysfunction.
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