Prefrontal cortex and adolescent binge drinking: Role of HCN channels

前额皮质和青少年酗酒：HCN 通道的作用

• 批准号: 8802218
• 负责人: NEIL L. HARRISON
• 金额: $ 26.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8802218
• 关键词: Abstinence; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; American; Animal Model; Animals; Awareness; Behavior; Behavioral; Brain; Brain region; Chronic; Cyclic Nucleotides; Development; Disease; Drug usage; Epidemiology; Face; Family; Functional disorder; Goals; HCN1 channel; Healthcare; Human; Image; Individual; Knock-out; Knockout Mice; Lead; Life; Measures; Mediating; Medicine; Membrane Potentials; Mental Depression; Molecular; Mus; Pathology; Performance; Personal Satisfaction; Pharmaceutical Preparations; Prefrontal Cortex; Productivity; Protocols documentation; Recovery; Regulation; Relapse; Relative (related person); Research; Resistance; Rest; Risk Factors; Rodent; Role; Short-Term Memory; Societies; Testing; Therapeutic Intervention; Virus; Water; Work; adolescent binge drinking; alcohol abstinence; alcohol abuser; alcohol and other drug; alcohol effect; alcohol exposure; alcohol use disorder; binge drinking; brain cell; cost; critical period; drinking; drinking water; family structure; hippocampal pyramidal neuron; neurobiological mechanism; neuronal excitability; prevent; public health relevance; restoration; substance abuser; underage drinking; voltage clamp

DESCRIPTION (provided by applicant): The consequences of alcohol abuse on the American public are profound, both in terms of individual well-being and impact on the family structure, as well as the enormous cost to society in terms of lost productivity and associated health care expenses. Despite increasing efforts, our understanding of the neurobiological mechanisms that underlie the effects of alcohol and the development of alcohol use disorders (AUD) remains incomplete. Epidemiological research has pointed to adolescence as a critical period in the development of alcohol disorders. The prefrontal cortex (PFC) is a brain region that is not yet mature at the onset of human adolescence and continues to develop during this period, during which some individuals may be highly susceptible to the effects of alcohol. The PFC mediates control over goal-directed behaviors and dysfunction of the PFC is thought to underlie compulsive drug-taking and relapse in substance abusers. Binge drinking is highly prevalent in adolescents, and episodes of high alcohol intake have been associated with decreased PFC activity and function ("hypofrontality"). Imaging studies suggest that hypofrontality persists in chronic alcohol abusers, and may therefore be a contributory factor in the development of AUDs and behavioral pathologies in adulthood. The underlying mechanisms of this PFC hypoactivity are unknown, and the development of robust animal models would therefore be useful in investigating the underlying changes in neuronal excitability. A better understanding of these changes would enable possible molecular and therapeutic interventions in order to prevent the development of alcoholism. One plausible mechanism for hypofrontality involves the depression of "persistent activity", a mode of firing that can be observed in recordings from pyramidal neurons in the PFC of rodents. This type of activity is seen at more depolarized membrane potentials and is associated with performance in working memory tasks, and is dependent on the Ih current, which is mediated by a family of hyperpolarization-activated and cyclic nucleotide modulated (HCN) channels. We propose that chronic changes in persistent firing might result from prolonged alcohol exposure. To date there have been few detailed studies of excitability in the PFC after drinking and none in adolescent rodents. In three separate but integrated aims, we plan to test the overall hypothesis that the HCN1 channel that contributes to the Ih current in PFC PNs is important for the regulation of alcohol drinking, and specifically that (a) binge drinking of alcohol during adolescence inhibits persistent firing and excitability in the PFC via reduction of Ih and (b) reduction in HCN1 channel activity in layer 5 of PFC can mimic the effects of alcohol consumption during adolescence, while (c) activation or over-expression of HCN1 channels can restore persistent activity and normal levels of excitability in PFC of binge drinking adolescent animals.

描述（由申请人提供）：酗酒对美国公众的影响是深远的，无论是在个人福祉和对家庭结构的影响方面，还是在生产力损失和相关医疗保健费用方面给社会造成的巨大成本。尽管付出了越来越多的努力，我们对酒精影响和酒精使用障碍 (AUD) 发展的神经生物学机制的理解仍然不完整。流行病学研究指出青春期是酒精障碍发展的关键时期。前额皮质（PFC）是人类青春期开始时尚未成熟的大脑区域，并在此期间继续发育，在此期间某些人可能非常容易受到酒精的影响。 PFC 介导对目标导向行为的控制，PFC 功能障碍被认为是药物滥用者强迫性吸毒和复发的基础。酗酒在青少年中非常普遍，大量饮酒的发作与 PFC 活性和功能下降（“额叶功能减退”）有关。影像学研究表明，长期酗酒者的额叶功能低下持续存在，因此可能是成年后 AUD 和行为病理学发展的一个促成因素。这种 PFC 活性低下的潜在机制尚不清楚，因此开发稳健的动物模型将有助于研究神经元兴奋性的潜在变化。更好地了解这些变化将使分子和治疗干预成为可能，以防止酗酒的发展。额叶功能减退的一个可能机制涉及“持续活动”的抑制，这是一种可以在啮齿类动物前额皮层锥体神经元的记录中观察到的放电模式。这种类型的活动见于去极化程度较高的膜电位，与工作记忆任务的表现相关，并且依赖于 Ih 电流，该电流由一系列超极化激活和环核苷酸调节 (HCN) 通道介导。我们认为持续放电的慢性变化可能是由于长期接触酒精造成的。迄今为止，关于饮酒后 PFC 兴奋性的详细研究很少，而且没有针对青少年啮齿动物的研究。在三个独立但综​​合的目标中，我们计划测试总体假设，即在 PFC PN 中贡献 Ih 电流的 HCN1 通道对于调节饮酒非常重要，特别是（a）青春期酗酒通过减少 Ih 抑制 PFC 的持续放电和兴奋性，以及（b）PFC 第 5 层 HCN1 通道活性的减少可以模拟酒精的影响 (c) HCN1 通道的激活或过度表达可以恢复狂饮青少年动物 PFC 的持久活性和正常水平的兴奋性。