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.

摘要： 这是对P60-AA 011605“脑出血的分子和电路发病机制”的管理补充。 对PA-20-227“酒精成瘾研究的行政补充”的回应 膳食补充剂（不允许进行管理补充剂临床试验）。增刊将增加一个目标 项目3，“额边缘电路，行为灵活性，和青少年酒精史。”的 家长项目调查青少年酗酒（人类）或乙醇暴露（大鼠） 损害行为灵活性，影响持续到成年。我们使用一种独特的 翻译的方法来探索形成和灵活的能力的神经生物学基础， 克服自动行动，并评估基于理论的干预措施， 调节行为灵活性。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）， 成年期对奖励条件化的超敏反应通过共享的潜在的 神经回路此外，依赖习惯和对奖励的敏感性之间的关系 条件反射是由神经回路的变化介导的， 显著的外生线索母项目使用静息态功能磁共振成像和电生理学， 识别与超驰自动S- R协会和奖励条件反射的敏感性。它还测试了双向 对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， 改善或模仿与青少年酒精暴露相关的损伤。这 补充剂增加了一个目的，以确定是否饮食胆碱补充剂可以预防或 逆转行为灵活性和相关神经化学的损伤， 青少年酒精暴露总的来说，这项工作将确定客观目标， 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 自动行动。这种做法可能会大大提高我们科普公众的能力 AUD是全球可预防死亡的主要原因。