Dopamine neuronal microcircuits controlling methamphetamine seeking behavior

项目总结/摘要 提交该提案是为了支持多明格斯-洛佩斯博士从接受指导的实习生过渡到 他是一名独立的药物成瘾神经生物学研究者，专门研究多巴胺， 控制寻药行为的微电路。多明格斯-洛佩兹博士在博士的指导下工作。 俄克拉荷马州医学研究基金会（OMRF）的迈克尔·贝克斯特德（Michael Beckstead）调查了 多巴胺神经传递在腹侧被盖区（VTA）在甲基苯丙胺（METH）自我- 行政行为贝克斯特德博士是多巴胺突触传递领域公认的专家 上瘾的人Beckstead博士的实验室将自我给药的小鼠模型与膜片钳技术相结合 电生理学和免疫细胞化学，为多明格斯-洛佩兹博士提供了一个动态的环境， 成为一名经验丰富的科学家。所提交的提案纳入了方法学方面的科学培训， 研究线粒体代谢，转录分析，生物信息学和基因标记的活性 神经元群体。申请人将接受教育方法，科学写作，资助 准备和其他必要的技能，成为一个独立的大脑研究科学家， 代表性不足的群体。拟议的计划包括与冬青货车雷门博士的指导互动， 博士Willard Freeman博士、琳达汤普森博士、OMRF成员和Rajeshwar Awatramani博士 芝加哥的西北大学。这项申请的短期目标是提高多明格斯博士- 洛佩斯的线粒体代谢和单细胞转录组学的知识应用于多巴胺能 电路.从长远来看，这将使多明格斯-洛佩斯博士能够获得受保护的培训时间， 研究活动，建立新的合作，并追求他的新颖的独立研究， 有竞争力的赠款提案。多明格斯-洛佩兹博士获得的初步数据表明， 在小鼠中METH自我给药产生腹侧被盖区中多巴胺神经元的减少， 细胞兴奋性，增加线粒体耗氧率和降低谷胱甘肽水平。这些 观察结果与增加的药物寻求行为同时发生。这项研究计划扩展了这些 研究结果，以确定多巴胺回路中的代谢和分子特征， 暴露于甲基苯丙胺的脆弱性。中心假设是腹侧被盖多巴胺神经元的亚群 负责寻找甲基的行为，形成一个微电路，是抵抗线粒体氧化 长期接触甲基苯丙胺引起的应激反应提出的目标是：1）鉴别VTA多巴胺 微电路编码的甲基苯丙胺寻求行为，和2）腹侧被盖区多巴胺神经元的代谢特征 编码寻找冰毒的行为识别负责METH成瘾的特定脑回路 属性是第一步，以制定治疗策略，以帮助成瘾者从METH成瘾恢复。

Project Summary/Abstract This proposal is being submitted to support the transition of Dr. Dominguez-Lopez from mentored trainee to an independent investigator in the neurobiology of drug addiction, specifically studying the dopamine microcircuits controlling drug-seeking behavior. Dr. Dominguez-Lopez works under the mentorship of Dr. Michael Beckstead at the Oklahoma Medical Research Foundation (OMRF) investigating the role of dopamine neurotransmission in the ventral tegmental area (VTA) in methamphetamine (METH) self- administration behavior. Dr. Beckstead is a recognized expert in dopamine synaptic transmission in the fields of addiction. Dr. Beckstead’s laboratory combines mouse models of drug self-administration with patch-clamp electrophysiology and immunocytochemistry, providing a dynamic environment for Dr. Dominguez-Lopez to become an experienced scientist. The submitted proposal incorporates scientific training in methodologies to study mitochondrial metabolism, transcriptional analysis, bioinformatics and genetic labeling of active neuronal populations. The applicant will be receiving training in educational methods, scientific writing, grant preparation and other skills necessary to become an independent brain research scientist from an underrepresented group. The proposed program includes mentoring interactions with Dr. Holly Van Remmen, Dr. Willard Freeman, Dr. Linda Thompson, members of OMRF, and Dr. Rajeshwar Awatramani from Northwestern University in Chicago. The short-term objective of this application is to enhance Dr. Dominguez- Lopez’s knowledge of mitochondrial metabolism and single cell transcriptomics applied to dopaminergic circuits. In the long-term, this will enable Dr. Dominguez-Lopez to secure protected time for training and research activities, establish new collaborations, and pursue his novel independent research resulting in competitive grant proposals. Preliminary data obtained by Dr. Dominguez-Lopez indicates that prolonged METH self-administration in mice produces a decrease of dopamine neurons in the VTA, decreases dopamine cell excitability, increases mitochondrial oxygen consumption rate and decreases levels of glutathione. These observations are concurrent with increased drug-seeking behavior. This research proposal expands on those findings to identify metabolic and molecular characteristics in dopamine circuits that provide resistance or vulnerability to METH exposure. The central hypothesis is that a subpopulation of VTA dopamine neurons is responsible for METH-seeking behavior, forming a microcircuit that is resistant to mitochondrial oxidative stress induced by chronic METH exposure. The proposed aims are 1) Identification of VTA dopamine microcircuits encoding METH-seeking behavior, and 2) Metabolic characteristics of VTA dopamine neurons encoding METH-seeking behavior. Identification of the specific brain circuits responsible for METH addictive properties is a first step to develop therapeutic strategies to help addicts recover from METH addiction.