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

项目摘要/摘要 酗酒是酒精中毒的一个更有问题的组成部分，是第三大 美国可预防死亡的原因(Hingson等人，2005年；2007年；Moklad等人，2001年)。定义神经 调节过量酒精摄入的回路对于开发有效的治疗方法是必不可少的 这种病。终纹床核(BNST)至腹侧被盖区(VTA)神经 在酗酒方面，通路仍然是一个特别有趣的候选方案，因为这个回路 在毒品和酒精成瘾中扮演了关键角色。我假设反复的狂欢 酒精暴露导致VTA投射的BNST GABA能神经元去增强，以及 VTA投射的BNST谷氨酸能神经元的渐进性增强，从而促进进一步的狂欢 喝酒。本提案的目的是提供对BNST-VTA神经回路的彻底检查 在反复酗酒之后，以及过渡到独立的研究生涯在一个 酒精研究中心在R00期间的成分。为了完成第一个目标，我将在体内学习 电生理学检查反复狂饮酒精后BNST神经元的变化。在.期间 R00时相，我将利用膜片钳电生理来检测VTA投射的BNST的兴奋性 GABA能和谷氨酸能神经元以确定重复后改变的细胞机制 酗酒。最后，我将利用光遗传学在行为自由的小鼠身上刺激BNST 在VTA内的GABA能投射神经元，以减少饮酒以及刺激 BNST谷氨酸能投射神经元在VTA增加酒精暴饮量。总而言之，这是 提案将提供反复酗酒后BNST-VTA神经回路的彻底特征 摄入量，并可能确定治疗酒精中毒的可能药理靶点。

Project Summary/Abstract 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 R00 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.