The Role of the BNST to VTA Neural Circuit in Binge Alcohol Consumption

描述（由申请人提供）：酗酒是酒精中毒的一个更有问题的组成部分，是美国可预防死亡的第三大原因（Hingson等人，2005; 2007; Moklad等人，2001年）。确定调节过量饮酒的神经回路对于开发治疗这种疾病的有效疗法至关重要。终纹床核（BNST）到腹侧被盖区（VTA）的神经通路在酗酒方面仍然是一个特别有趣的候选者，因为这个回路在药物和酒精成瘾中起着关键作用。我推测，反复酗酒暴露导致VTA投射BNST GABA能神经元的去增强以及VTA投射BNST GABA能神经元的进行性增强，这有利于进一步酗酒。这项建议的目标是提供一个彻底的检查BNST-VTA神经回路后，反复狂欢乙醇消费，以及过渡到一个独立的研究生涯中的酒精研究中心在R 0组件。为了完成第一个目标，我将学习体内电生理学，以检查反复酗酒后BNST神经元的变化。在R 00阶段，我将利用膜片钳电生理学检查VTA投射BNST GABA能和谷氨酸能神经元的兴奋性，以确定反复酗酒后改变的细胞机制。最后，我将在自由行为的小鼠中使用光遗传学来刺激VTA中的BNST GABA能投射神经元以减少酒精消耗，以及刺激VTA中的BNST GABA能投射神经元以增加酒精摄入量。总之，这一建议将提供一个彻底的表征BNST-VTA神经回路反复酗酒摄入后，并可能确定可能的药理学治疗酒精中毒的目标。

DESCRIPTION (provided by applicant): Binge alcohol consumption is one of the more problematic components of alcoholism and is the third leading cause of preventable death in the USA (Hingson et al., 2005; 2007; Moklad et al., 2001). Defining the neural circuitry that modulates excessive binge alcohol intake is essential for developing effective therapeutics to treat this disease. The bed nucleus of the stria terminalis (BNST) to the ventral tegmental area (VTA) neural pathway remains a particularly interesting candidate in regards to binge alcohol consumption, as this circuit has been implicated in playing a key role in drug and alcohol addiction. I hypothesize that repeated binge alcohol exposure leads to a depotentiation of VTA-projecting BNST GABAergic neurons as well as a progressive enhancement of VTA-projecting BNST glutamatergic neurons, which facilitates further binge drinking. The goals of this proposal are to provide a thorough examination of the BNST-VTA neural circuit after repeated binge ethanol consumption as well as to transition to an independent research career at an alcohol research center during the R0 component. To complete the first goal, I will learn in vivo electrophysiology to examine alterations in BNST neurons after repeated binge ethanol drinking. During the R00 phase, I will utilize patch clamp electrophysiology to examine the excitability of VTA-projecting BNST GABAergic and glutamatergic neurons to determine the cellular mechanisms that are altered after repeated binge alcohol drinking. Finally, I will use optogenetics in freely behaving mice to stimulate the BNST GABAergic projection neurons in the VTA in order to reduce alcohol consumption as well as stimulate the BNST glutamatergic projection neurons in the VTA to increase binge ethanol intake. Taken together, this proposal will provide a thorough characterization of the BNST-VTA neural circuit after repeated binge alcohol intake and may identify possible pharmacological targets for the treatment of alcoholism.