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

基本信息

批准号：
8805040
负责人：
Kristen Elizabeth Pleil
金额：
$ 11.42万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805040
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 availability alcohol behavior alcohol use disorder binge drinking career chronic alcohol ingestion drinking behavior drug relapse in vivo neural circuit novel optogenetics public health relevance relating to nervous system research study synaptic function therapeutic target transmission process

项目摘要

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（由申请人提供）：暴饮暴食是过度饮酒的最常见形式，导致了许多长期的负面健康后果，包括饮酒的发展。暴饮暴食的重复发作随后饮酒，因此表征这种危险行为的神经回路对于开发成功的药物治疗障碍的药物治疗至关重要。 Stria末端（BNST）的床核与饮酒和压力引起的寻求药物复发有关。 BNST富含产生和释放皮质激素释放因子（CRF）的神经元，这是一种神经肽，也已被证明可以调节这些行为。但是，尚未检查BNST CRF神经元及其突触输入在暴饮暴食中的特定作用。我假设BNST CRF神经元的活性驱动了暴饮暴食的饮酒，并且通过增强直接调节它们的谷氨酸能神经元的活性来增强暴饮暴食的功能失调。该提案的目标是1）表征BNST CRF神经元的作用及其来自丘脑（PVT）（PVT）在酒精饮用行为中的脑室核中的谷氨酸能输入以及2），以检查该神经回路如何通过狂饮饮酒的反复循环而改变。在K99阶段，我将接受Stuber博士的培训，用于使用体内光遗传学，我将采用体内光遗传学和化学遗传学方法来驱动或抑制BNST中CRF神经元的活性并评估饮酒行为。在R00阶段，我将使用Kash博士为我提供了广泛的培训的技术，包括神经元跟踪技术和SLICE电生理学与外体光遗传学结合使用，以表征和评估PVT Glutamatorgic投影的强度，从而对BNST CRF神经元进行了特征。然后，我将使用体内光遗传学来评估这些途径在暴饮暴食中的因果作用。最后，我将使用离体光遗传学，切片电生理学和免疫组织化学来检查重复的暴饮暴食对PVT中调节它们的内在兴奋和突触功能的内在兴奋性和突触功能的影响。总之，这些研究将使我在SLICE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培训有关，这对于成功过渡到独立研究职业至关重要。该提案中的实验将彻底表征如何通过反复的暴饮暴食来改变调节暴饮暴食的关键节点，这可能揭示了用于治疗酒精使用障碍的药物治疗靶标。