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: 9210583
• 负责人: NEIL L. HARRISON
• 金额: $ 41.73万
• 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/9210583
• 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; Face; Family; Functional disorder; Goals; HCN1 channel; HCN1 gene; Healthcare; Human; Individual; Injectable; Knock-out; Knockout Mice; Lead; Life; Measures; Mediating; Medicine; Membrane Potentials; Mental Depression; Molecular; Mus; Pathology; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Productivity; Protocols documentation; Recovery; Regulation; Relapse; 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 consequences; alcohol effect; alcohol exposure; alcohol use disorder; alcohol use initiation; binge drinking; brain cell; cost; critical period; drinking; epidemiology study; family structure; hippocampal pyramidal neuron; imaging study; neurobiological mechanism; neuronal excitability; overexpression; 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）：在个人福祉和对家庭结构的影响方面，酗酒对美国公众的后果都是深远的，以及在生产力损失和相关的医疗保健费用方面，对社会的巨大成本。尽管做出了越来越多的努力，但我们对酒精效果和酒精使用障碍的影响的神经生物学机制（AUD）仍然不完整。流行病学研究指出，青春期是酒精疾病发展的关键时期。前额叶皮层（PFC）是在人类青春期开始时尚未成熟的大脑区域，并在此期间继续发展，在此期间，某些人可能非常容易受到酒精的影响。 PFC介导对目标指导行为的控制和PFC的功能障碍被认为是强迫性吸毒和药物滥用者的复发的基础。暴饮暴食在青少年中非常普遍，高酒精摄入量的发作与PFC活性和功能的降低有关（“低纤维性”）。成像研究表明，慢性酒精滥用者持续性持续性，因此可能是成年后auds和行为病理学发展的一个因素。该PFC低连接性的潜在机制尚不清楚，因此，健壮动物模型的发展对于研究神经元兴奋性的潜在变化将是有用的。更好地了解这些变化将使可能的分子和治疗性干预措施，以防止酒精中毒的发展。一种合理的低漏洞机制涉及“持续活动”的抑郁症，这是一种可以在啮齿动物PFC中的金字塔神经元的记录中观察到的一种射击方式。这种类型的活性在更具去极化的膜电位上观察到，并且与工作记忆任务的性能有关，并且取决于IH电流，IH电流是由一个超极化激活的家族介导的，并且环状核苷酸调制（HCN）通道介导。我们建议，持续开火的慢性变化可能是由于长时间的酒精暴露而导致的。迄今为止，在饮酒后，很少有关于PFC兴奋性的详细研究，而在青春期啮齿动物中则没有。在三个单独但综合的目的中，我们计划测试总体假设，即在PFC PNS中导致IH电流的HCN1通道对于调节饮酒对调节饮酒至关重要，特别是（a）青春期在青春期抑制酒精饮酒的持续性和兴奋性在PFC中通过降低IH和（b）在HCN中的PFC效果而受到持续的持续性，并且在HC中降低了HCN的效果。青春期的消费，而（c）HCN1通道的激活或过表达可以恢复持续的活动和饮酒青春期动物的PFC的正常兴奋性水平。