Chronic alcohol and the neurocircuitry of aversion

慢性酒精与厌恶的神经回路

• 批准号: 9914829
• 负责人: Elizabeth J Glover
• 金额: $ 28.37万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-20 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914829
• 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; 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; Opioid; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Play; Population; Prefrontal Cortex; Property; Rattus; Reporting; Research; Research Personnel; Resistance; Rewards; Role; Signal Transduction; Slice; Structure; 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; neural circuit; new therapeutic target; novel; optogenetics; patch clamp; preventable death; programs; public health relevance; response

 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.

 说明(申请人提供)：酒精的积极(有益)特性促进了酒精的持续使用，而酒精的负面(厌恶)特性则限制了消费。依赖与对乙醇有害特性的更大耐受性有关，而不是与其有益特性相关，后者被认为可以促进持续消费。被盖旋转内侧核(RMTg)对中脑边缘多巴胺神经元实施抑制性控制，并在药物滥用的厌恶特性信号中起重要作用。前额叶皮质的PRL亚区与RMTG有几个关键的功能相似之处，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的预测在很大程度上被忽视了，仍然是一个开放的调查领域。这份K99/R00提案包括一项全面的培训和研究计划，该计划基于候选人(伊丽莎白·伯内特博士)的初步数据，确定了RMTG在传递酒精厌恶特性方面的作用。在K99奖项的指导阶段，伯内特博士将接受尖端实验室技术方面的培训，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。这些技术将增强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(Judson Chandler博士)和共同导师(John Woodward博士))的指导下，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途径的可塑性在慢性酒精暴露的功能后果中发挥作用。目的1利用体内光遗传学结合操作行为测试，研究依赖诱导的递增和抗厌恶酒精摄入过程中PRL-RMTg通路的选择性激活的作用。目的2将利用全细胞膜片钳切片电生理学和体外光遗传学研究慢性乙醇暴露对PRL-RMTg内突触可塑性的影响。目的3将通过使用病毒介导的跨突触逆行追踪来识别与投射到RMTg的PRL神经元突触的神经元，从而定义PRL-RMTg的扩展神经回路。在这一目标下的实验也将通过测量戒断过程中这些神经元中CFos的诱导来确定这些新发现的二级RMTg输入在慢性酒精暴露中的参与。这些研究的结果将为PRL-RMTg通路在促进酒精消费升级中的作用提供新的见解。提高我们对参与调节酒精消费厌恶成分(S)的神经回路的了解，可能有助于发现治疗酒精使用障碍的新靶点。伯内特博士将在K99指导阶段接受的培训将促进她的职业发展，而在R00阶段获得的成果将构成伯内特博士独立研究计划的基础。