Adolescent Alcohol and GABAergic Neurotransmission in the Adult Prefrontal Cortex

描述(申请人提供)：前额叶皮质(PFC)被认为在酒精暴露的负面影响的认知过程中发挥着重要作用。与其他脑区相比，PFC的神经元连接在青春期经历了一个关键的重组和精细化时期，这与认知控制和决策的改善不谋而合。在此期间发生的环境侮辱可能会对前额叶皮质造成特别严重的损害，导致神经发育异常，并对认知功能产生长期影响，从而对决策和行为控制产生负面影响。对酒精的实验通常始于青春期，当时人们经常在过度狂欢的情况下饮用酒精，导致一个非常高水平的醉酒循环，然后是短暂的戒酒。这项建议将研究酗酒样青少年酒精暴露对前额叶GABAA受体介导的神经传递发育的影响。提供了强有力的支持性初步数据，表明在青春期暴露于酒精的成年大鼠，由突触外Delta-GABAA型受体调节的特定紧张性电流减少，我们假设这将损害PFC的认知功能。更多的初步数据表明，青春期暴露在酒精中的成年大鼠在可操作的定势转移任务中表现出的行为灵活性降低，这一点得到了支持。这项建议将使用生化、电生理和行为方法来研究青少年酗酒对GABA能神经传递和认知功能发育的影响，特别是对成年PFC行为灵活性的影响。这一建议的首要假设是，青春期过度饮酒会导致成年PFC中GABA能神经传递和认知功能的发育中断。拟议的研究和相关的培训计划不仅将进一步促进申请者的职业发展，而且这些研究的结果将极大地促进我们对青少年酗酒对成人前额叶功能和行为认知控制的长期影响的理解。

DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) is thought to play an important role in the cognitive processes that are negatively impacted by alcohol exposure. Compared to other brain regions, the neuronal connections of the PFC undergo a critical period of reorganization and refinement during adolescence and this coincides with improvement in cognitive control and decision making. Environmental insults that occur during this period may be particularly damaging to prefrontal cortex, resulting in aberrant neurodevelopment along with long-lasting effects on cognitive functioning that negatively impacts decision-making and behavioral control. Experimentation with alcohol typically begins during adolescence when it is often consumed in excessive binge-like episodes resulting in a cycle of very high levels of intoxication followed by a short period of abstinence. This proposal will examine the effects of binge-like adolescent alcohol exposure on development of GABAA receptor-mediated neurotransmission in the PFC. Strong supportive preliminary data is presented that suggests that a specific tonic current regulated by extrasynaptic delta-GABAA-type receptors is reduced in adult rats exposed to alcohol during adolescence, and we hypothesize that this will impair cognitive function of the PFC. This is supported by additional preliminary data showing that adult rats exposed to alcohol during adolescence exhibited decreases in behavioral flexibility on an operant set-shifting task. This proposal will use biochemical, electrophysiological and behavioral approaches to examine the effect of adolescent alcohol abuse on the development of GABAergic neurotransmission and cognitive function and in particular, behavioral flexibility of the adult PFC. The overarching hypothesis of this proposal is that binge-like alcohol exposure during adolescence results in disruption of development of GABAergic neurotransmission in the adult PFC and cognitive function. The proposed studies and related training plan will not only further the career development of the applicant, but the results obtained from these studies will significantly advance our understanding of the long- term consequences of adolescent alcohol abuse on prefrontal function and cognitive control of behavior in the adult.