This research program takes advantage of a well-established rat model with the long-term aim of establishing a multi-level mechanistic account of both impaired and successful neurocognitive aging, spanning from molecular substrates to cortical network dynamics. A key feature of this animal model is that it is optimized for documenting reliable individual differences in the cognitive outcome of aging, from aged individuals that exhibit substantial impairment to other, aged-matched subjects that score on par with young adults. Ultimately, studies in this model are aimed at defining the essential neurobiological condition that renders aging the single greatest risk for Alzheimers disease and related neurodegenerative disorders. Advances from research in this model cut across levels of analysis, from studies of gene expression, to behavioral investigations asking how the interactions between multiple memory systems are altered in the aged brain. At the molecular level, we have devoted considerable effort to exploring the role of the master regulator of memory-related synaptic plasticity, Arc (activity-regulated cytoskeleton-associated protein). A recent set of studies, for example, focused on key mechanisms of epigenetic regulation of Arc in our standard rat model of cognitive aging: i) DNA methylation in the hippocampus examined by bisulfite conversion and analyzed using a next-generation sequencing (NGS) MiSeq platform; ii) histone modification analyzed via chromatin immunoprecipitation followed by RT-qPCR; and iii) nucleosome positioning assessed via micrococcal nuclease digestion followed by Ion Torrent NGS. The results revealed multiple bases in the CA3 field of the hippocampus that are differentially methylated in relation to age and age-related cognitive status, together with effects on histone modifications permissive or repressive for transcription. By comparison, measures of nucleosome positioning showed striking stability between groups. These findings have been submitted for presentation at this year's annual Society for Neuroscience (SfN) meeting, supported in part an NIH FARE Award. Other findings in this model have pursued a broader, circuit-level description of neurocognitive aging. In one study, for example, we pharmacologically induced neuronal activity in behaviorally characterized young and aged rats, and subsequently tested in immunocytochemical histological analysis whether cognitive aging is coupled with changes in the activation of inhibitory interneuron populations in the hippocampus. Interim results suggest that the numbers of interneurons activated is elevated in the aged hippocampus, and that this trend is predominantly driven by older animals with confirmed deficits in hippocampal memory. These results (also to be reported at SfN) contribute to mounting evidence that disrupted excitatory/inhibitory balance in the hippocampus and other memory-related brain regions is a significant driver of cognitive aging. Extending this work to a network level of analysis, a recent collaborative study demonstrated using in vivo brain imaging that the CA3 field of the hippocampus plays a pivotal in the disrupted functional connectivity observed in aged rats between the hippocampal formation and multiple neocortical areas, including the medial prefrontal cortex. A broad theme throughout much of this work is that, in studies of gene expression to neural network dynamics and the fundamental organization of cognitive function, successful cognitive aging is supported by a distinct, life course trajectory of neuroadaptive plasticity. A comprehensive, invited review advancing this perspective, and outlining implications for treatment development, is currently under editorial review for publication in the Handbook of Cognitive (Cambridge University Press).
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