Prefrontal cortex and adolescent binge drinking: Role of HCN channels

描述（由申请人提供）：酗酒对美国公众的后果是深远的，无论是在个人福祉和对家庭结构的影响，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。尽管不断努力，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。前额叶皮层（PFC）是一个大脑区域，在人类青春期开始时尚未成熟，并在此期间继续发展，在此期间，一些人可能非常容易受到酒精的影响。前额叶皮层介导对目标导向行为的控制，前额叶皮层功能障碍被认为是物质滥用者强迫性吸毒和复吸的基础。酗酒在青少年中非常普遍，大量饮酒与PFC活性和功能下降（"前额叶功能减退"）有关。影像学研究表明，额叶功能减退持续存在于慢性酒精滥用者中，因此可能是成年期AUD和行为病理发展的一个促成因素。这种PFC功能减退的潜在机制是未知的，因此，强大的动物模型的发展将是有用的，在调查神经元兴奋性的潜在变化。更好地了解这些变化将使可能的分子和治疗干预，以防止酗酒的发展。额叶功能减退的一个合理机制涉及“持续活动”的抑制，这是一种可以在啮齿动物PFC锥体神经元记录中观察到的放电模式。这种类型的活动被认为是在更多的去极化膜电位，并与工作记忆任务的性能，是依赖于Ih电流，这是由超极化激活和环核苷酸调节（HCN）通道的家庭介导的。我们认为，持续放电的慢性变化可能是由于长期的酒精暴露。到目前为止，很少有详细的研究，在PFC的兴奋性饮酒后，没有在青少年啮齿动物。在三个独立但综合的目标中，我们计划检验以下总体假设：促成PFC PN中Ih电流的HCN 1通道对饮酒的调节很重要，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，（B）PFC第5层中HCN 1通道活性的降低可以模拟青春期饮酒的影响，而（c）HCN 1通道的激活或过表达可以恢复酗酒青春期动物PFC中的持续活性和正常水平的兴奋性。

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.