Start-up activities have continued during the reporting period, including staff replacement and training following the departure of a long-term member of our group. We have also retained valuable computer software support in an effort to enable the more rapid development of computer-automated behavioral assessment routines for examining the effects of selective brain lesions and other manipulations in nonhuman primate models. Establishment of key project infrastructure (e.g., operant chambers for automated testing) is nearing completion. While we continue to explore strategies to implement our planned program of in vivo brain imaging research, logistical constraints of accessing and reimbursing central MRI and PET facilities on the NIH main campus for animals maintained at the Poolesville facility has proved challenging. Nonetheless, we have retained the necessary analytic expertise and extended the analysis of archival imaging data through collaborative arrangements, and we anticipate succeeding in mounting a local imaging program in next reporting period. In a recent analysis of previously acquired imaging data, for example, we tested whether age-related decline in spatiotemporal and recognition memory are coupled with atrophy of memory-related brain regions in rhesus monkeys. Using T1-weighted magnetic resonance images from behaviorally characterized young and aged monkeys, region-of-interest analyses revealed that chronological age inversely correlated with the volume of the striatum, dorsolateral PFC, and anterior cingulated cortex. In contrast to predictions derived from lesion and electrophysiological studies in young subjects, the volume of selected PFC components was coupled with the status of recognition memory, while hippocampal volume predicted acquisition rates for spatiotemporal memory assessed by the classic delayed response task. These results provide novel support for the view that cognitive aging in primates arises from region-specific morphometric alterations distributed across multiple memory-related brain systems, including subdivisions of the PFC. A full-length report of these findings has been accepted for publication pending minor revision at Cerebral Cortex. Continuing a long-standing project theme, another recently completed collaborative investigation examined individual differences in the neurocognitive outcome of aging in rhesus monkeys in relation to naturally occurring ovarian hormone decline. Briefly, brain material from behaviorally characterized young and aged subjects was used to evaluate synaptic density and morphology in the hippocampal dentate gyrus by quantitative electron microscopy. Key findings were that, although synaptic parameters for the molecular layer of the dentate failed to differ across the young and aged groups, the density of perforated synapses in the outer molecular layer was coupled with individual differences in the accuracy of recognition memory. In addition, when the data were evaluated in relation to reproductive senescence, peri/post-menopausal subjects exhibited impaired memory and lower perforated synapse density in the outer molecular layer than pre-menopausal monkeys. The results suggest that naturally occurring reproductive senescence potently influences synaptic connectivity in the primate hippocampus, contributing to individual differences in the course of normal cognitive aging. A full-length article describing these results has been accepted pending minor revision at Neurobiology of Aging. Our current colony of project animals maintained in NIA facilities includes 11 young adult rhesus monkeys, 6 with MRI-guided and confirmed excitotoxic lesions restricted to the hippocampus. The remaining 5 subjects were acquired from the same source and serve as intact controls. During the current reporting period, these animals were trained on a delayed response task, testing the effects of damage restricted to the hippocampus on spatiotemporal memory. Assessment on this procedure is nearing completion, and animals will progress to extended battery of computer-automated assessments, including a yes/no recognition procedures designed to disentangle the contributions of recollection and familiarity. Additional rhesus monkeys (n=26) are available to explore the effects of early rearing on neurocognitive aging. Ten are young adults and the remainder include a range of ages from late teens and older, when signatures of age-related cognitive decline emerge in rhesus monkeys. As infants, approximately half of the animals in both age groups were reared by adult females while the remainder were maintained in troops of other juveniles. This manipulation of early rearing conditions is known to influence subsequent physiological and psychological development, as measured by parameters that have been tracked into young adulthood. The novel question under investigation through ongoing neuropsychological assessment is whether the influence of early rearing persists throughout life, and predicts the cognitive and neurobiological outcome of normal aging.
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