Dietary choline mitigation of adolescent alcohol-induced deficits in adult cognitive flexibility: P60-AA011605 Administrative Supplement

文摘:

Abstract: This is an administrative supplement to P60-AA011605 “Molecular and Circuit Pathogenesis of Alcohol Addiction” in response to PA-20-227 “Administrative Supplements for Research on Dietary Supplements (Admin Supp Clinical Trial Not Allowed).” The supplement will add an aim to Project 3, “Frontolimbic circuitry, behavioral flexibility, and adolescent alcohol history.” The parent project investigates how adolescent binge drinking (humans) or ethanol exposure (rats) impairs behavioral flexibility, with effects persisting into adulthood. We use a unique translational approach to probe the neurobiological bases of the ability to form and to flexibly overcome automatic actions and to evaluate theoretically based interventions to bidirectionally modulate behavioral flexibility. Our core hypothesis is that adolescent binge alcohol exposure promotes both an overreliance on stimulus-response action selection strategy (habit) and hypersensitivity to reward conditioning in adulthood via common alterations in shared underlying neural circuits. Moreover, the relationship between reliance on habit and sensitivity to reward conditioning is mediated by neural circuit changes impairing top-down control of responses to salient exogenous cues. The parent project uses resting-state fMRI and electrophysiology to identify differences in brain circuit function associated with impairment in overriding automatic S- R associations and sensitivity to reward conditioning. It also tests whether bidirectional manipulation of frontal cortex can promote or reduce top-down control over behavior, thereby ameliorating or mimicking the impairment associated with adolescent alcohol exposure. This supplement adds an aim to determine whether dietary choline supplementation can prevent or reverse the impairments in behavioral flexibility and associated neurochemistry induced by adolescent ethanol exposure. Overall, this work will identify objective targets for use in developing novel treatments to promote flexible, goal-directed actions over deleterious automatic actions. This approach may substantially improve our ability to cope with the public health challenges of AUDs, a leading cause worldwide of preventable death.