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

膳食胆碱缓解青少年酒精引起的成人认知灵活性缺陷：P60-AA011605 行政补充

• 批准号: 10330051
• 负责人: Thomas L. Kash
• 金额: $ 15.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330051
• 关键词: ARHGEF5 gene; Administrative Supplement; Adolescence; Adolescent; Adult; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Attention; Basic Science; Behavior; Behavior Control; Behavioral; Biological Process; Brain; Choline; Choline O-Acetyltransferase; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Cues; Development; Electrophysiology (science); Ethanol; Functional Magnetic Resonance Imaging; Funding; Goals; Growth Factor; Habits; Human; Human Genetics; Hypersensitivity; Impairment; Intervention; Lead; Learning; Link; Magnetic Resonance Imaging; Measures; Mediating; Membrane; Metabolism; Molecular; Neurobiology; Nutrient; Outcome; Pathogenesis; Pattern; Phenotype; Prefrontal Cortex; Public Health; Rattus; Recording of previous events; Research; Response to stimulus physiology; Rest; Reversal Learning; Rewards; Rodent; Signal Transduction; Substance Use Disorder; System; Testing; Time; Translations; Work; adolescent alcohol exposure; adolescent binge drinking; alcohol exposure; alcohol sensitivity; alcohol use disorder; alcohol-related death; basal forebrain; base; behavioral impairment; binge drinking; choline supplementation; cholinergic; clinical application; conditioning; dietary; dietary supplements; economic cost; epigenetic regulation; experimental study; fetal; flexibility; frontal lobe; improved; insight; neural circuit; neurochemistry; neurotoxic; novel; optogenetics; parent grant; parent project; prevent; preventable death; relating to nervous system; response; tool; translational approach; transmission process; underage drinking

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.

抽象的： 这是P60-AA011605的管理补充 对PA-20-227的回应”饮酒成瘾” 饮食补充剂（不允许临床试验）。”补充剂将增加目标 要项目3，“额叶电路，行为灵活性和青少年酒精历史。” 父母项目调查青少年饮酒（人类）或乙醇暴露（大鼠）如何 损害行为灵活性，效果持续到成年。我们使用独特的 翻译方法来探测形成能力和灵活的能力的神经生物学基础 克服自动动作并评估理论上的双向干预措施 调节行为灵活性。我们的核心假设是青春期的Benge酒精暴露 促进对刺激反应行动选择策略（习惯）和 通过共享基础的共同改变，超敏反应在成年期间奖励条件 神经回路。此外，宗教在习惯上的关系和奖励的敏感性 调节是由神经回路变化介导的，损害了对响应的自上而下控制 显着的外源线索。父项目使用静止状态fMRI和电生理学 确定与压倒自动s-损伤相关的脑电路功能的差异 R联合和对奖励条件的敏感性。它还测试了双向 额叶皮层的操纵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有关的损害。这 补充补充旨在确定补充饮食胆碱是否可以预防或 扭转行为灵活性和相关神经化学的损害 青少年乙醇暴露。总体而言，这项工作将确定用于使用的客观目标 开发新颖的治疗方法，以促进灵活的，目标指导的行动而不是有害 自动操作。这种方法可能会大大提高我们应对公众的能力 AUDS的健康挑战，这是全球可预防死亡的主要原因。