Neurocognitive Aging: Experience-Dependent Dynamics, Plasticity and Network Contributions

National Institute On Aging

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Abstract

The overarching project goal is to establish a vertically integrated account of impaired and successful cognitive aging, spanning from molecular substrates to their impact on cortical network dynamics. At a molecular level of analysis, the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) has generated particular interest, based on evidence that Arc dynamics are specifically linked to memory-related neuronal plasticity. Although we and others have documented that Arc regulation is significantly disrupted in aging, the available literature on the role of Arc in cognitive aging has not been comprehensively integrated, particularly with reference to the newest discoveries in the basic cell biology of Arc. We recently published an extensive review that addresses this gap, consolidating the relevant findings and identifying priorities for future investigation. Despite differences across model systems, experimental design details, and targets of interest, taken together the findings converge on the view that Arc dynamics are positioned to play a substantive role in cognitive aging, from altered transcriptional regulation to protein function and clearance. Moreover, the encouraging implication from recent progress is that Arc might one day provide a reliable preclinical biomarker of failing synaptic plasticity in the aging brain, opening the door to intervention aimed at bending the arc of cognitive aging toward successful outcomes. The perspective guiding research in this project is that the proximal basis of both age-related cognitive impairment and preservation is altered neural network dynamics arising from the selective vulnerabilities and plasticity of critical circuits. In a recent test of this view we took advantage of an implicit odor recognition task to quantify the distribution of immediate-early gene (c-Fos) positive neurons induced by varied memory demands in a panel of hippocampal and neocortical areas. Conforming to our prediction, cross-correlation network analysis revealed distinct patterns of interregional coherence in memory related activation across aged animals with and without cognitive impairment. Of particular note, despite performing equivalent to young rats, aged animals with intact memory displayed an enhanced network density of increased interregional correlation coefficients, greater intrahippocampal coherence, and elevated parahippocampal coherence with the piriform cortex. Memory-impaired individuals, by comparison, displayed blunted activation and interregional cross-correlation. These observations contribute to a growing body of evidence from rodent models, nonhuman primates and humans, that successful cognitive aging is associated with adaptive neural network reorganization, not simply the preservation of youthful structure and function.