Chronic Alcohol Induced Dysregulation of Central Anti-Stress Systems

描述（由申请人提供）：酗酒和滥用酒精是主要的健康问题，也是我们社会巨大的经济负担。越来越多的文献表明，长期饮酒会导致调节情绪行为的关键大脑回路中的中枢压力系统和抗压力系统失衡。这些不平衡会导致病态行为，包括焦虑、压力反应和复发风险增加。尽管这些进展确定了这些系统在酒精相关行为中的作用，但我们对导致这种失调行为的基本生物学、细胞和电路机制的了解仍然存在差距。为了更有效地治疗酒精滥用，有必要确定慢性酒精暴露对神经回路的影响，这对这种行为的调节至关重要。在这里，我们建议描述慢性酒精暴露对抗应激系统的影响，特别是杏仁核和延伸杏仁核中的神经肽Y （NPY）和gaba能神经活性类固醇，这是调节压力和焦虑样行为的关键大脑区域。此外，我们将利用可诱导通道视紫红质病毒与神经化学特异性cre -重组酶驱动系结合来确定慢性酒精暴露对这些脑区域gaba能回路的影响。总的来说，这项工作将开始定义特定的酒精诱导的细胞和电路适应，这些适应可能在与酒精中毒相关的病理行为中起关键作用。

DESCRIPTION (provided by applicant): Alcoholism and alcohol abuse are major health problems and represent a tremendous financial burden on our society. A growing literature indicates that chronic alcohol exposure leads to an imbalance between central stress and anti-stress systems in key brain circuits that regulate emotional behavior. These imbalances can lead to pathological behavior, including increased anxiety, stress-responsivity and enhanced risk of relapse. Despite these advances identifying the role these systems play in alcohol related behaviors, there remains a gap in our knowledge of the fundamental biological, cellular and circuit mechanisms that contribute to this dysregulated behavior. In order to more effectively treat alcohol abuse, it is necessary to define the impact of chronic alcohol exposure on the in the circuitry that is critical for regulation of this behavior. Here, we propose to characterize the impact of chronic alcohol exposure on anti-stress systems, specifically neuropeptide Y (NPY) and GABAergic neuroactive steroids, in the amygdala and extended amygdala, brain regions critical for regulation of stress and anxiety-like behavior. Additionally, we will utilize inducible channel rhodopsin viruses in combination with neurochemically specific Cre-recombinase driver lines to determine the impact of chronic alcohol exposure on GABAergic circuits in these brain regions. In total, the proposed work will begin to define specific alcohol-induced cellular and circuit adaptations that are likely to play key roles in pathological behaviors associated with alcoholism.