Normal memory requires a system of anatomically related brain structures in the medial temporal lobe (MTL), including the hippocampus, and the entorhinal, perirhinal and parahippocampal cortices. Although extensive MTL damage produces robust memory impairment, efforts to define the specific memory processing functions of the hippocampus proper and by extension the contribution of hippocampal dysfunction to cognitive aging have proved challenging. In a series of experiments we are testing the memory effects in adult rhesus monkeys of MRI-guided excitotoxin lesions (N-methyl-D- aspartic acid) involving extensive damage restricted to the hippocampus. Our findings indicate that traditional assessments used to study MTL amnesia 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 relational organization of remembered experience) will provide more sensitive measures of hippocampal integrity. These experiments are ultimately aimed at establishing assessments with optimal sensitivity for detecting the consequences of the relatively subtle changes in hippocampal integrity that are associated with 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 decline in capacities necessary to maintain the quality of life and 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 an important challenge. In an ongoing collaborative initiative, we aim to bridge the study 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 - impacts individual differences in cognitive function at the end of the lifespan. Available results suggest that while memory mediated by the MTL system is relatively insensitive, early experience may significantly influence the effects of aging on cognitive capacities mediated by the prefrontal cortex. Experiments currently coming to conclusion are designed to confirm and extend that proposal by testing the same subjects on multiple behavioral assessments of prefrontal cortex function. In alignment with recent NIH policy guidance directing attention to sex as a significant biological factor, these studies include both males and females. Other recent collaborative efforts with the Comparative Medicine Section of the NIA-IRP and investigators at NIDA aim to identify the critical links between cognitive aging and the effects of early experience with neural network dynamics using fMRI to examine resting state functional connectivity in behaviorally characterized subjects. Initial emphasis has been directed at documenting the effects of experimental hippocampal damage on cortical network dynamics in young adults, and available findings from this analysis are scheduled for presentation at the 2015 Society for Neuroscience annual conference. Ultimately, studies of this sort will enable direct comparisons with related human research, providing a valuable translational model for the development of potential interventions for age-related impairment. Complementing these in vivo efforts, this project continues to yield valuable opportunities for the quantitative morphometric analysis of relevant neural circuitry in relation to individual differences in the cognitive outcome of aging. Growing evidence points to changes in excitatory/inhibitory balance associated with cognitive decline as a precursor to neurodegenerative progression in the aged brain, and we are examining this early event by interrogating the integrity of immunocytochemically identified inhibitory interneurons in cortical and subcortical circuitry in behaviorally characterized young and aged monkeys. Results from this extensive analysis are being compiled for publication, and preliminary findings for a related quantification of basal forebrain projection neurons will be outlined in a symposium presentation at the annual Society for Neuroscience meeting later this year. In rats, pharmacological treatment that reverses age-related memory impairment rescues inhibitory interneuron staining, 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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