The role of excitatory inputs to BNST CRF neurons in alcohol drinking behavior

BNST CRF 神经元兴奋性输入在饮酒行为中的作用

• 批准号: 9461824
• 负责人: Kristen Elizabeth Pleil
• 金额: $ 24.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461824
• 关键词: Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Animal Model; Behavior; Behavioral; Corticotropin-Releasing Hormone; Data; Development; Electrophysiology (science); Glutamates; Goals; Health; Heavy Drinking; Immunohistochemistry; Label; Lead; Literature; Mood Disorders; Mus; Neurons; Neuropeptides; Outcome; Pathway interactions; Peptides; Phase; Population; Regulation; Research; Risk Behaviors; Role; Signal Transduction; Site; Slice; Societies; Stress; Structure; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Training; alcohol abuse therapy; alcohol availability; alcohol behavior; alcohol use disorder; binge drinking; career; chronic alcohol ingestion; drinking behavior; drug relapse; experimental study; in vivo; neural circuit; novel; optogenetics; public health relevance; relating to nervous system; synaptic function; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Binge alcohol drinking, the most common form of excessive alcohol consumption, contributes to a host of long- term negative health consequences, including the development of alcohol dependence. Repeated episodes of binge drinking drive subsequent alcohol consumption, therefore characterizing the neural circuitry underlying this risky behavior is essential to the development of successful pharmacotherapeutic treatments for alcohol use disorders. The bed nucleus of the stria terminalis (BNST) is critically involved in alcohol drinking and stress-induced relapse of drug seeking. The BNST is enriched with neurons that produce and release corticotropin-releasing factor (CRF), a neuropeptide that has also been shown to regulate these behaviors. However, the specific roles of BNST CRF neurons and their synaptic inputs in binge alcohol drinking have not been examined. I hypothesize that the activity of BNST CRF neurons drives binge alcohol drinking, and that repeated episodes of binge drinking dysregulate their function by enhancing the activity of glutamatergic neurons that directly modulate them. The goals of this proposal are 1) to characterize the roles of BNST CRF neurons and their glutamatergic inputs from the paraventricular nucleus of the thalamus (PVT) in alcohol drinking behavior, and 2) to examine how this neural circuit is altered by repeated cycles of binge drinking. During the K99 phase, I will be trained by Dr. Stuber in the use of in vivo optogenetics, and I will employ in vivo optogenetic and chemogenetic approaches to drive or inhibit the activity of CRF neurons in the BNST and evaluate alcohol drinking behaviors. During the R00 phase, I will use techniques that Dr. Kash has given me extensive training in, including neuronal tracing techniques and slice electrophysiology in combination with ex vivo optogenetics, to characterize and assess the strength of the PVT glutamatergic projection to BNST CRF neurons. Then, I will use in vivo optogenetics to evaluate the causal roles of these pathways in binge alcohol drinking. Finally, I will use ex vivo optogenetics, slice electrophysiology, and immunohistochemistry to examine the effects of repeated binge alcohol drinking on the intrinsic excitability of and synaptic function o BNST CRF neurons and glutamatergic neurons in the PVT that modulate them. Together, these studies will integrate my expertise in slice electrophysiology and immunohistochemistry with training in in vivo optogenetics essential to a making a successful transition to an independent research career. Experiments in this proposal will thoroughly characterize how crucial nodes of circuitry that regulate binge alcohol drinking are altered by repeated binge alcohol drinking, which may reveal pharmacotherapeutic targets for the treatment of alcohol use disorders.

描述(申请人提供)：酗酒是最常见的过度饮酒形式，会导致一系列长期的负面健康后果，包括发展对酒精的依赖。反复酗酒会导致随后的酒精消费，因此，确定这种危险行为背后的神经回路对于开发成功的酒精使用障碍药物治疗方法至关重要。终纹床核(BNST)在饮酒和应激诱导的复吸毒品中起重要作用。BNST富含产生和释放促肾上腺皮质激素释放因子(CRF)的神经元，CRF是一种神经肽，也被证明调节这些行为。然而，BNST CRF神经元及其突触输入在酗酒中的具体作用尚未被研究。我假设，BNST CRF神经元的活动推动了酗酒，反复酗酒通过增强直接调节它们的谷氨酸能神经元的活动来失调它们的功能。这项建议的目标是：1)研究BNST CRF神经元及其来自丘脑室旁核(PVT)的谷氨酸能输入在酒精饮酒行为中的作用；2)研究反复酗酒是如何改变这一神经回路的。在K99阶段，我将接受Stuber博士的体内光遗传学使用培训，我将使用体内光遗传学和化学遗传学方法来驱动或抑制BNST中CRF神经元的活动，并评估饮酒行为。在R00阶段，我将使用卡什博士对我进行过广泛培训的技术，包括神经元追踪技术和切片电生理学，结合体外光遗传学，来表征和评估PVT谷氨酸能投射到BNST CRF神经元的强度。然后，我将使用体内光遗传学来评估这些途径在酗酒中的因果作用。最后，我将使用体外光遗传学、切片电生理学和免疫组织化学的方法来检测反复酗酒对BNST CRF神经元和PVT中调节它们的谷氨酸能神经元的内在兴奋性和突触功能的影响。总之，这些研究将把我在切片电生理学和免疫组织化学方面的专业知识与体内光遗传学方面的培训结合起来，这对于成功过渡到独立的研究生涯至关重要。这项提议中的实验将彻底表征调控酗酒的关键电路节点是如何被反复酗酒改变的，这可能揭示治疗酒精使用障碍的药物治疗靶点。