Prefrontal cortex and adolescent binge drinking: Role of HCN channels

描述(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的医疗费用方面给社会带来的巨大代价。尽管我们做出了越来越多的努力，但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了解仍然不完整。流行病学研究指出，青春期是酒精障碍发展的关键时期。前额叶皮质(PFC)是一个大脑区域，在人类青春期开始时尚未成熟，并在此期间继续发育，在此期间，一些人可能对酒精的影响非常敏感。PFC调节对目标导向行为的控制，而PFC的功能障碍被认为是物质滥用者强制吸毒和复发的基础。酗酒在青少年中非常普遍，大量饮酒与PFC活动和功能下降(“额叶低下”)有关。影像研究表明，额叶下垂在慢性酒精滥用者中持续存在，因此可能是成年后AUDS和行为病理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，发展健壮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可能的分子和治疗干预成为可能，以防止酒精中毒的发展。前额叶功能低下的一个可能机制是抑制“持续活动”，这是一种从啮齿动物前额叶锥体神经元的记录中可以观察到的放电模式。这种类型的活动出现在更多的去极化的膜电位上，并与工作记忆任务中的表现有关，并依赖于Ih电流，Ih电流由一系列超极化激活和环核苷酸调制(HCN)通道介导。我们认为，持续放电的慢性变化可能是长期酒精暴露的结果。到目前为止，很少有关于饮酒后前额叶兴奋性的详细研究，也没有关于青少年啮齿动物的详细研究。在三个独立但综合的目标中，我们计划测试总体假设，即导致PFC PNS中Ih电流的HCN1通道对于酒精饮酒的调节非常重要，具体而言，(A)青春期酗酒通过减少Ih而抑制PFC中持续的放电和兴奋性，(B)PFC第5层中HCN1通道活性的降低可以模拟青春期饮酒的影响，而(C)激活或过度表达HCN1通道可以恢复酗酒青少年动物PFC中的持续活动和正常的兴奋性水平。

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.