Dopamine Neuronal Microcircuits Controlling Methamphetamine Seeking Behavior

项目摘要/摘要 提交这项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 药物成瘾神经生物学方面的独立研究员，特别是研究多巴胺 控制毒品寻觅行为的微电路。多明格斯-洛佩斯博士在多明格斯-洛佩斯博士的指导下工作。 俄克拉荷马医学研究基金会(OMRF)的迈克尔·贝克斯特德(Michael Beckstead)调查 甲基苯丙胺自身作用下腹侧被盖区的多巴胺神经传递 行政行为。贝克斯特德博士是该领域公认的多巴胺突触传递专家。 上瘾的人。贝克斯特德博士的实验室将药物自我给药的小鼠模型与膜片钳结合起来 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 成为一名有经验的科学家。提交的提案纳入了方法论方面的科学培训 研究Active的线粒体代谢、转录分析、生物信息学和遗传标记 神经元群。申请者将接受教育方法、科学写作、补助金等方面的培训 准备和其他必要的技能，以成为一名独立的脑研究科学家 代表不足的群体。拟议的计划包括与霍莉·范·雷曼博士的指导互动， OMRF成员Willard Freeman博士、Linda Thompson博士和Rajeshwar Awatramani博士 位于芝加哥的西北大学。这项应用的短期目标是增强多明格斯博士的能力- 洛佩兹关于线粒体代谢和单细胞转录的知识在多巴胺能上的应用 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和 研究活动，建立新的合作，并追求他的新的独立研究导致 竞争性拨款提案。多明格斯-洛佩兹博士获得的初步数据表明，延长 小鼠自我给予冰毒后，VTA中的多巴胺神经元减少，多巴胺减少 细胞兴奋性，增加线粒体的耗氧率，降低谷胱甘肽水平。这些 观察到的同时，寻求毒品的行为也在增加。这项研究提案在这些基础上进行了扩展 识别多巴胺回路中提供抵抗力或 对冰毒暴露的脆弱性。中心假设是VTA多巴胺神经元的一个亚群是 负责寻找冰毒的行为，形成抵抗线粒体氧化的微电路 慢性冰毒暴露引起的压力。建议的目标是1)VTA多巴胺的鉴定 编码寻求冰毒行为的微电路，以及2)VTA多巴胺神经元的代谢特征 对冰毒行为进行编码。确定与冰毒成瘾有关的特定脑回路 Property是制定治疗策略帮助吸毒者从冰毒上瘾中康复的第一步。

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.