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

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Our long-term aim is to develop a multi-level account, spanning molecular substrates to cortical network dynamics responsible for impaired and successful cognitive aging. The common feature throughout is the use of an outbred rat model of naturally occurring aging that is optimized for documenting individual differences in memory among old animals matched for chronological age, from those that exhibit substantial impairment to others that perform comparable to young adults. Studies at the cell biological level include a long-standing focus on the master regulator of memory-related synaptic plasticity, Arc (activity-regulated cytoskeleton-associated protein). In a recently published analysis, neuronal activity was induced by systemic injection with a low dose of the muscarinic receptor agonist pilocarpine in young and aged behaviorally characterized rats, followed by quantitatively mapping Arc and c-Fos induction as a proxy for cortical network activation. The principal finding was that, whereas basal constitutive levels of immediate-early gene expression were entirely unrelated to spatial learning capacity, pilocarpine-induced activity was tightly coupled to individual differences in memory function in all regions of the prefrontal cortex and hippocampus examined. In addition, the specific nature of coupling between induced activity and memory was qualitatively distinct across brain regions. Together, the findings support the view that alterations in the dynamic range of activity in critical circuitry contribute to the spectrum of cognitive aging phenotypes. Other areas of ongoing progress cover a wide range of inter-related topics. Priority projects include those examining the effects of aging on sleep architecture, and whether the influence of disrupted sleep on memory is mediated by Arc-dependent dysregulation of consolidation processes. We are also nearing completion of studies exploring whether retinoic acid signaling in brain contributes to individual differences in cognitive aging. Initial results from this work are encouraging and set the stage for integrative, organismal level investigation to test whether retinoic acid supplementation alters neuronal physiology in association with effects on memory function in aged rats. Aging is the single greatest risk for neurodegenerative disease, and preclinical research in animal models can also shed light on the features of brain aging that mediate this risk. Collaborative studies led by investigators at the University of Florida, for example, are exploring how aging in rats modulates the response to driving human tau expression in AD vulnerable brain regions (e.g., the transentorhinal cortex), and our group is assisting in this effort by acquiring 3-dimensional, large volume light sheet microscopy datasets of cleared brains immuno-processed to visualize tau. A comprehensive review, advancing our perspective that successful cognitive aging arises from programs of neuroadaptive plasticity, alongside potential compensation mechanisms and differences in the overall rate of aging, is currently in press.