Adolescent Alcohol and GABAergic Neurotransmission in the Adult Prefrontal Cortex

描述（由申请人提供）：前额叶皮层（PFC）被认为在受酒精暴露负面影响的认知过程中发挥重要作用。与其他大脑区域相比，PFC的神经元连接在青春期经历了一个重组和完善的关键时期，这与认知控制和决策的改善相吻合。在此期间发生的环境损伤可能对前额叶皮层特别有害，导致神经发育异常沿着对认知功能的长期影响，从而对决策和行为控制产生负面影响。酒精的实验通常在青春期开始，当时它经常在过度的狂欢中被消耗，导致一个非常高水平的醉酒循环，然后是短期的禁欲。该提案将研究青少年酗酒对PFC中GABAA受体介导的神经传递的影响。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中，由突触外δ-GABAA型受体调节的特定强直电流减少，我们假设这将损害PFC的认知功能。这得到了额外的初步数据的支持，这些数据表明，在青春期暴露于酒精的成年大鼠在操作集上表现出行为灵活性的下降-转移任务。该提案将使用生物化学，电生理和行为的方法来研究青少年酒精滥用对GABA能神经传递和认知功能的发展，特别是成年PFC的行为灵活性的影响。该提案的首要假设是，在青春期酗酒导致成年PFC中GABA能神经传递和认知功能的发展中断。拟议的研究和相关的培训计划不仅将进一步促进申请人的职业发展，而且从这些研究中获得的结果将大大促进我们对青少年酗酒对成年人前额叶功能和行为认知控制的长期后果的理解。

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.