Chronic Alcohol and the Neurocircuitry of Aversion

慢性酒精与厌恶的神经回路

基本信息

批准号：
9253343
负责人：
Elizabeth J Glover
金额：
$ 13.39万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-05 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9253343
关键词：
Address Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcohol-Related Disorders Alcohols Anatomy Area Aversive Stimulus Award Behavior Behavioral Model Brain region Cell Nucleus Cells Cessation of life Chronic Cocaine Confocal Microscopy Consumption Data Dendritic Spines Dependence Electrophysiology (science)Environment Ethanol Ethanol dependence Foundations In Vitro Investigation Knowledge Laboratories Learning Measures Mediating Mentors Methods Midbrain structure Molecular Morphology Nature Neurons Opiates Pathway interactions Pattern Pharmaceutical Preparations Phase Play Population Prefrontal Cortex Property Rattus Reporting Research Research Personnel Resistance Rewards Role Signal Transduction Slice Substantia nigra structure Synapses Synaptic plasticity Techniques Testing Time Training Ventral Tegmental Area Viral Withdrawal Work addiction alcohol abuse therapy alcohol exposure alcohol use disorder base behavior test behavioral outcome career development design dopaminergic neuron drinking drug of abuse experimental study improved in vivo innovation insight interest new therapeutic target novel optogenetics patch clamp programs public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Continued alcohol use is facilitated by alcohol's positive (rewarding) properties, whereas its negative (aversive) properties serve to limit consumption. Dependence is associated with greater tolerance to ethanol's aversive properties than its rewarding properties, which is thought to promote continued consumption. The rostromedial tegmental nucleus (RMTg) exerts inhibitory control over mesolimbic dopamine neurons and is critically involved in signaling the aversive properties of drugs of abuse. The prelimbic (PrL) subregion of the prefrontal cortex shares several critical functional similarities with the RMTg including facilitating aversion learning and responding to aversive stimuli. Despite these similarities, the projection from the PrL to the RMTg has been largely ignored and remains an open area of investigation. This K99/R00 proposal comprises a comprehensive training and research plan based upon the candidate's (Dr. Elizabeth Burnett) preliminary data identifying a role for the RMTg in signaling the aversive properties of alcohol. During the mentored K99 phase of the award, Dr. Burnett will receive training in cutting-edge laboratory techniques including slice electrophysiology, optogenetics, analysis of synaptic morphology, and virally-mediated trans-synaptic tracing. These techniques will augment her existing expertise in cellular and molecular approaches and behavioral models of alcohol abuse and dependence. Under the guidance of the candidate's mentoring team, which includes the primary mentor (Dr. Judson Chandler) and co-mentor (Dr. John Woodward), the candidate will expand her current studies by testing a novel hypothesis that alcohol-induced plasticity in the PrL-RMTg pathway plays a role in the functional consequences of chronic ethanol exposure. Aim 1 will investigate the effect of selective activation of the PrL-RMTg pathway during dependence-induced escalated and aversion-resistant ethanol intake using in vivo optogenetics in combination with operant behavioral testing. Aim 2 will use whole-cell patch-clamp slice electrophysiology and in vitro optogenetics to examine the effect of chronic ethanol exposure on synaptic plasticity within the PrL-RMTg. Aim 3 will define the PrL-RMTg's expanded neurocircuitry by identifying neurons that synapse onto PrL neurons projecting to the RMTg using virally-mediated trans- synaptic retrograde tracing. Experiments under this aim will also determine the involvement of these newly identified second-order RMTg inputs in chronic ethanol exposure by measuring cFos induction in these neurons during withdrawal. The results of these studies will provide new insights into the role of the PrL-RMTg pathway in promoting escalated alcohol consumption. Improving our understanding of the neurocircuitry involved in mediating the aversive component(s) of alcohol consumption may help uncover new therapeutic targets for the treatment of alcohol use disorders. The training Dr. Burnett will receive during the mentored K99 phase of the award will facilitate her career development and the results obtained during the R00 phase of the award will form the foundation of Dr. Burnett's independent research program.

描述（由申请人提供）：酒精的积极（有益）特性促进了持续饮酒，而其消极（厌恶）特性则有助于限制消费。人们认为，对乙醇厌恶特性的耐受性比其有益特性更大。促进持续消耗。嘴内侧被盖核（RMTg）对中脑边缘多巴胺神经元发挥抑制性控制，并在发出厌恶信号方面发挥着重要作用。前额皮质的前边缘 (PrL) 亚区域与 RMTg 具有一些重要的功能相似之处，包括促进厌恶学习和对厌恶刺激的反应，尽管有这些相似之处，但从 PrL 到 RMTg 的投射在很大程度上被忽视了。该 K99/R00 提案包含一项基于候选人（Elizabeth Burnett 博士）初步数据的综合培训和研究计划，该数据确定了 RMTg 在发出信号方面的作用，并且仍然是一个开放的调查领域。在该奖项的 K99 指导阶段，伯内特博士将接受尖端实验室技术的培训，包括切片电生理学、光遗传学、突触形态分析和病毒介导的跨突触追踪。她在酒精滥用和依赖的细胞和分子方法以及行为模型方面的现有专业知识在候选人的指导团队（包括主要导师（贾德森·钱德勒博士）和共同导师）的指导下。（约翰·伍德沃德博士），候选人将通过测试一个新的假设来扩展她目前的研究，即酒精诱导的 PrL-RMTg 途径的可塑性在长期乙醇暴露的功能后果中发挥作用，目标 1 将研究选择性的影响。目标 2 将使用全细胞膜片钳切片电生理学和体外技术，利用体内光遗传学与操作行为测试相结合，在依赖性诱导的逐步增加和厌恶的乙醇摄入过程中激活 PrL-RMTg 通路。光遗传学检查长期乙醇暴露对 PrL-RMTg 内突触可塑性的影响，目标 3 将通过使用病毒介导的跨突触逆行追踪识别突触到投射到 RMTg 的 PrL 神经元的神经元来定义 PrL-RMTg 的扩展神经回路。该目标下的实验还将通过测量这些神经元在这些研究的结果将为 PrL-RMTg 通路在促进饮酒量增加中的作用提供新的见解，提高我们对调节饮酒厌恶成分的神经回路的理解，可能有助于发现新的治疗靶点。伯内特博士将在该奖项的 K99 指导阶段接受的培训将促进她的职业发展，而在该奖项的 R00 阶段获得的结果将构成伯内特博士的基础。独立研究计划。