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

National Institute On Aging

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Abstract

The overarching goal is 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 has generated particular interest, based on evidence that Arc dynamics are specifically linked to memory-related plasticity. For example, we previously reported that Arc regulation is disrupted in the aged rat hippocampus in relation to individual differences in memory function, including alterations in basal expression, experience-dependent induction, and degradation. However, the mechanisms responsible for these effects are largely unknown. In an initial study addressing this gap, we conducted a multiplex survey of the Arc epigenetic landscape, testing whether Arc DNA methylation, histone modifications, and nucleosome positioning are altered in the aged rat hippocampus in relation to cognitive aging. Other work in the area is probing whether Arc-containing extracellular vesicles in peripheral blood might provide a noninvasive and early biomarker for disrupted synaptic plasticity in cognitive aging, and whether rectifying Arc dysregulation might offer an effective strategy to bend the arc of growing older toward successful outcomes. Our perspective is that the proximal basis of age-related cognitive impairment reflects critical circuit vulnerabilities that give rise to disrupted neural network dynamics. Within this framework, some factors implicated in neurocognitive aging are positioned to play broad modulatory roles. Retinoic acid (RA) a metabolite of dietary vitamin A has many systemic physiological functions and pleiotropic effects in brain, including roles in synaptic scaling and regulating excitatory-inhibitory (E/I) balance. Prompted by this background, in a recently reported study we conducted an extensive survey in our aged rat model, measuring RA availability and key RA signaling pathway molecules, including the STRA6 cell surface receptor, RA synthesizing and catabolic enzymes, and the retinoic acid receptor-, together with other synaptic proteins modulated by RA (e.g., FMRP, GluR1). The results showed that RA signaling is altered at nearly all levels of regulation examined. The major substrate for RA, retinol binding protein 4, is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor-, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein. Overall, the net effect points in the direction of increased RA signaling in impaired aged animals, which may contribute to disruption in excitation/inhibition balance, a prominent feature of age-related cognitive impairment and suspected early event in the pathogenesis of Alzheimers disease.