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

BNST 至 VTA 神经回路在酗酒中的作用

• 批准号: 9120745
• 负责人: DENNIS R. SPARTA
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120745
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Area; Aversive Stimulus; Behavioral; Brain; Cells; Cessation of life; Complement; Coupled; Data; Development; Disease; Drug Addiction; Electrophysiology (science); Ethanol; Exhibits; Fiber Optics; Glutamates; Goals; Health; Homosynaptic Depression; Implant; Individual; Lead; Learning; Light; Mediating; Morale; Mus; Neural Pathways; Neuronal Plasticity; Neurons; Optics; Pathway interactions; Pattern; Phase; Play; Process; Property; Research; Rewards; Role; Societies; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; System; Techniques; Testing; Therapeutic; United States; Ventral Tegmental Area; abstracting; alcohol behavior; alcohol exposure; alcohol research; alcohol use disorder; alcoholism therapy; binge drinking; career; cell type; in vivo; interest; neural circuit; neuroadaptation; neurobiological mechanism; optogenetics; patch clamp; relating to nervous system; research study; therapeutic target

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.

项目总结/摘要 酗酒是酒精中毒中最有问题的组成部分之一， 在美国可预防的死亡原因（Hingson等人，2005; 2007; Moklad等人，2001年）。定义神经 调节过量饮酒的神经系统对于开发有效的治疗方法来治疗 这种疾病。终纹床核（BNST）至腹侧被盖区（VTA）的神经纤维 通路仍然是一个特别有趣的候选人在关于酗酒消费，因为这个电路 在药物和酒精成瘾中扮演着重要角色。我假设反复的狂欢 酒精暴露导致腹侧被盖投射BNST GABA能神经元的去增强作用， 腹侧被盖区投射的BNST交感神经能神经元进行性增强，这有助于进一步狂欢 喝酒本提案的目标是提供一个彻底的检查BNST-VTA神经回路 经过反复的酒精消费狂欢，以及过渡到一个独立的研究生涯， 酒精研究中心在R 00组成部分。要完成第一个目标，我会在体内学习 电生理学检查反复酗酒后BNST神经元的变化。期间 R 00期，利用膜片钳电生理技术检测VTA投射BNST的兴奋性 GABA能和谷氨酸能神经元，以确定在重复刺激后改变的细胞机制。 酗酒最后，我将在自由行为的小鼠中使用光遗传学来刺激BNST GABA能投射神经元在腹侧被盖区，以减少酒精消费以及刺激 BNST刺激腹侧被盖区的神经元投射，增加酒精的摄入量。总的来说，这 该提案将提供反复酗酒后BNST-VTA神经回路的彻底表征 摄入量，并可能确定治疗酒精中毒的可能药理学靶点。