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

摘要： 本论文是对P60-AA011605《分子和回路致病机制》的行政补充 《酒精成瘾对PA-20-227的反应》行政补充研究 膳食补充剂(不允许进行药物补充临床试验)。该副刊将增加一项目标 到项目3，“前额边缘回路、行为灵活性和青少年酗酒史”。这个 Parent项目调查青少年酗酒(人类)或酒精暴露(大鼠) 会损害行为的灵活性，影响会持续到成年。我们使用一种独特的 翻译方法探讨形成能力和灵活运用能力的神经生物学基础 克服自动行为并评估基于理论的双向干预措施 调节行为的灵活性。我们的核心假设是青少年酗酒 促进过度依赖刺激-反应行动选择策略(习惯)和 通过共同基础的共同改变在成年期对奖赏条件反射的高敏感性 神经回路。此外，依赖习惯和对奖励敏感之间的关系 条件反射是由神经回路的变化所介导的，这些变化损害了对 显著的外源性线索。母项目使用静息状态功能磁共振和电生理学来 找出与自动S压倒障碍相关的脑回路功能的差异- R关联性和对奖赏条件作用的敏感性。它还测试了双向 操纵额叶皮质可以促进或减少对行为的自上而下的控制，从而 改善或模仿与青少年酒精暴露相关的损害。这 补充剂增加了一个目的，即确定饮食中补充胆碱是否可以预防或 逆转大鼠行为灵活性及相关神经化学损伤 青少年接触酒精。总体而言，这项工作将确定用于 开发新的治疗方法以促进灵活的、目标导向的行动而不是有害的 自动操作。这种方法可能会大大提高我们应对公众的能力 急性尿毒症的健康挑战是全世界可预防死亡的主要原因。

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.