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

描述（由申请人提供）：酗酒是酗酒的一个更有问题的组成部分，是美国第三大可预防死亡的原因（Hingson等人，2005;2007；Moklad等人，2001）。确定调节过量酒精摄入的神经回路对于开发有效的治疗方法至关重要。终纹（BNST）至腹侧被盖区（VTA）神经通路的床核在酗酒方面仍然是一个特别有趣的候选，因为该回路在药物和酒精成瘾中起着关键作用。我假设反复酗酒会导致vta投射的BNST gaba能神经元减弱，以及vta投射的BNST谷氨酸能神经元的逐渐增强，从而促进进一步的酗酒。本提案的目标是对反复狂饮乙醇后的bst - vta神经回路进行彻底检查，并在R0组件期间过渡到酒精研究中心的独立研究生涯。为了完成第一个目标，我将学习体内电生理学来检查反复狂饮乙醇后BNST神经元的变化。在R00阶段，我将利用膜片钳电生理学检查vta投射的BNST gaba能和谷氨酸能神经元的兴奋性，以确定反复狂饮后改变的细胞机制。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，并刺激VTA中的BNST谷氨酸能投射神经元以增加暴饮乙醇摄入量。综上所述，该建议将提供反复酗酒后bst - vta神经回路的全面特征，并可能确定酒精中毒治疗的可能药理靶点。

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.