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 cognitive aging, spanning the full spectrum from impaired to successful outcomes. With respect to underlying molecular contributions, the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein has generated considerable interest, based on evidence that Arc dynamics are specifically linked to neuronal plasticity engaged in forming new memories. 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 synthesized in a narrative review, particularly with reference to the newest discoveries in the basic cell biology of Arc. We recently addressed this gap, consolidating the relevant literature and identifying priorities for future investigation. Despite the complexity of findings across model systems, experimental designs and targets of interest, taken together they 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. The further encouraging suggestion from recent studies is that non-invasive, blood-based measurement of Arc dynamics might 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. Repetitive transcranial magnetic stimulation (rTMS) is increasingly recognized as a promising tool in the treatment of a surprising diversity of neurological conditions, and suggestive early evidence points to potential benefits in the context of Alzheimers disease. The mechanistic basis of therapeutic benefit is unclear, however, and the molecular changes that presumably mediate the clinical response to rTMS have received very little attention. To begin addressing this gap, in a recent exploratory study we examined the genome-wide transcriptional response to electromagnetic stimulation in three complementary rat models using in vitro, ex vivo, and in vivo brain preparations. The overall pattern of microarray results showed that the effects of rTMS are more complex and dynamic than previously appreciated. Stimulation induced hundreds of significant hippocampal and neocortical transcriptional responses, including changes in the expression of genes involved in glutamatergic, GABAergic, and inflammatory pathways, many affecting genes implicated in disorders for which TMS is being tested clinically. The results also indicate that the molecular response to TMS differs depending on brain region, stimulation protocol, subject age and interval after treatment. Together this broad-based preclinical molecular survey provides a starting point for efforts to harness the potential of TMS and related non-invasive brain stimulation approaches for individualized treatment. Social interaction and connectedness are powerful contributors to disease risk and other health outcomes as we age. The mechanisms that mediate these effects have remained elusive, however, owing partly to the limited availability of model systems for basic research on social cognition. A recently launched line of investigation in this project adopts the perspective that this topic can be valuably explored from a socio-neurocognitive perspective examining the structure of social interaction in a rat model of aging. In initial, proof-of-concept studies, young and aged rats previously tested for the status of hippocampal memory function were evaluated on a 3-chamber social interaction procedure, including assessments of both sociability (i.e., preference for social interaction vs. non-social exploration) and social novelty (i.e., preference for social interaction with a novel vs. familiar conspecific). Preliminary results point to substantial individual differences and suggest that a subpopulation of aged rats exhibit a marked age-dependent decrease in preference for social novelty, unrelated to the integrity of recognition memory, and instead coupled with changes in systems implicated in social cognition (e.g., hypothalamic oxytocin neuron number). Overall, this work encourages the view that an ecologically valid animal model can be developed to probe the social neuroscience of cognitive aging.