Normal memory requires a system of anatomically related medial temporal lobe (MTL) structures, including the hippocampus, and the entorhinal, perirhinal and parahippocampal cortices. Although extensive MTL damage produces robust memory impairment, defining the specific memory processing function of the hippocampus proper has proved challenging. In a series of experiments we are testing the memory effects in adult rhesus monkeys of magnetic resonance imaging (MRI) guided excitotoxin lesions (N-methyl-D- aspartic acid) involving extensive, MRI-confirmed damage restricted to the hippocampus. Initial findings indicated that traditional assessments, developed in the study MTL amnesia in monkeys, fail to capture the key operating characteristics of memory mediated by the primate hippocampus. Ongoing efforts are therefore testing the related view that procedures emphasizing the component processes of episodic memory (e.g., the temporal organization of remembered experience) will provide more sensitive measures of hippocampal integrity. Thus, these experiments are ultimately aimed at establishing assessments with optimal sensitivity for documenting the consequences of the relatively subtle changes in hippocampal integrity associated with normal aging, and for testing the efficacy of interventions intended to reverse age-related memory impairment. Early life events potently influence development and contribute to adult individual differences in cognitive health, reactivity to stress, and disease susceptibility. At the other end of the lifespan, aging is frequently accompanied by declining capacities that compromise the quality of independent living, prominently involving cognitive function. Like early development, there is marked individual variability in neurocognitive aging, and defining the basis of these different outcomes is a critical challenge. In an ongoing collaborative initiative, we have begun to bridge the traditionally distinct fields of early development and aging toward a lifespan perspective on neurocognitive health. The initial goal of the program is to test the hypothesis that differential early rearing in infant monkeys - a manipulation known to substantially influence cognitive, biobehavioral and neurobiological development in childhood and adolescence - influences individual differences in cognitive function at the end of the lifespan. Preliminary indications suggest that while memory mediated by the MTL system is relatively insensitive, early experience may significantly influence the effects of aging on working memory capacities mediated by the prefrontal cortex. Experiments currently in progress are designed to confirm and extend that proposal by testing the same subjects on additional behavioral assessments of prefrontal cortex function. A new, collaborative project direction currently in development aims to identify the critical links between cognitive aging and the effects of early experience with neural network dynamics using MRI to examine resting state activity and functional connectivity in behaviorally characterized subjects. Ultimately, studies of this sort will enable direct comparisons with related human research in other NIH and extramural divisions, providing a valuable translational model for the development of potential interventions for age-related impairment. Complementing these efforts, this project continues to yield uniquely valuable opportunities for the quantitative morphometric analysis of relevant neural circuitry in relation to individual differences in the cognitive outcome of aging. In a recent study, for example, we used stereological methods of quantification to test the possibility that age-related memory decline is coupled with changes in the integrity of inhibitory interneuron populations in the monkey hippocampus - i.e., cells implicated in the excess neuronal firing observed in certain subdivisions of the aged hippocampal formation. The analysis revealed a significant decrease in the number of immunocytochemically labeled inhibitory interneurons selectively among aged subjects with memory impairment, relative to both young adults and aged subjects with intact memory. In rats, pharmacological treatment that rescues inhibitory interneuron staining reverses age-related memory impairment, and our findings in monkeys provide a basis for testing whether this benefit extends to primates. Taken together, these studies have the potential to help guide human studies, with the goal of developing effective strategies for promoting optimally healthy cognitive aging.
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