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: 8510047
• 负责人: DENNIS R. SPARTA
• 金额: $ 15.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510047
• 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; 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; 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; public health relevance; relating to nervous system; research study; therapeutic target

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.

说明(由申请人提供)：酗酒是酒精中毒中问题较多的部分之一，是美国可预防死亡的第三大原因(Hingson等人，2005；2007；Moklad等人，2001)。确定调节过量酗酒的神经电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区域，因为这一回路被认为在药物和酒精成瘾中发挥关键作用。我推测，反复酗酒会导致投射VTA的BNST GABA能神经元的去增强，以及投射VTA的BNST谷氨酸能神经元的进行性增强，从而促进进一步的酗酒。这项建议的目标是对反复酗酒后的BNST-VTA神经回路进行彻底的检查，并在R0成分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，我将在体内学习电生理学，以检测反复酗酒后BNST神经元的变化。在R00期，我将利用膜片钳电生理学来检测VTA投射的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，我将利用自由行为小鼠的光遗传学来刺激VTA内的BNST GABA能投射神经元，以减少饮酒，以及刺激VTA内的BNST谷氨酸能投射神经元增加酒精的暴饮量。综上所述，这项提议将提供反复酗酒后BNST-VTA神经回路的彻底特征，并可能确定治疗酒精中毒的可能药理学靶点。