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，专门研究多巴胺 控制毒品寻觅行为的微电路。多明格斯-洛佩兹博士将在多明格斯-洛佩兹博士的指导下工作。 马里兰大学医学院(UMSOM)的Mary Kay Lobo，研究多巴胺的作用 甲基苯丙胺(冰毒)自身给药时腹侧被盖区(VTA)的神经传递 行为。Lobo博士是一位公认的动机行为和多巴胺神经传递方面的专家 药物滥用的背景。洛博博士的实验室将药物自我给药的小鼠模型与 线粒体代谢、分子生物学、遗传学和免疫细胞化学，提供了一个动态的 多明格斯-洛佩兹博士成为一名经验丰富的科学家的环境。提交的建议书 结合了研究线粒体新陈代谢、转录分析、 生物信息学和活跃神经元群体的遗传标记。申请者将接受以下培训 教育方法，科学写作，拨款准备，以及成为一名 来自一个代表性不足的群体的独立大脑研究科学家。拟议的计划包括 与Joseph Cheer博士、Seth Ament博士、Brian Polster博士、UMSOM教员和 NIDA IRP的Marisela Morales博士。此外，西北大学的Rajeshwar Awatramani博士 芝加哥将成为这个项目的顾问。这项提议的短期目标是加强Dr。 多明格斯-洛佩兹关于线粒体新陈代谢和单细胞转录组学的知识应用于 多巴胺能神经回路。从长远来看，这将使多明格斯-洛佩兹博士能够获得受保护的时间 培训和研究活动，建立新的合作关系，并从事他的新的独立研究 从而产生了竞争性的拨款建议。多明格斯-洛佩兹博士获得的数据表明，延长的 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，并降低谷胱甘肽的水平。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应激的微电路 是长期接触冰毒引起的。建议的目标是1)识别VTA多巴胺微电路 编码寻找冰毒行为和2)编码VTA多巴胺神经元的代谢特性 寻找冰毒的行为。确定负责冰毒成瘾特性的特定大脑回路是一种 开发治疗策略以帮助吸毒者从冰毒上瘾中康复的第一步。

Project Summary/Abstract This proposal is submitted to support the transition of Dr. Dominguez-Lopez from a mentored trainee to an independent investigator in the neurobiology of drug addiction, specifically studying the dopamine microcircuits controlling drug-seeking behavior. Dr. Dominguez-Lopez will work under the mentorship of Dr. Mary Kay Lobo at the University of Maryland School of Medicine (UMSOM), investigating the role of dopamine neurotransmission in the ventral tegmental area (VTA) in methamphetamine (METH) self-administration behavior. Dr. Lobo is a recognized expert in motivated behavior and dopamine neurotransmission in the context of drug abuse. Dr. Lobo’s laboratory combines mouse models of drug self-administration with mitochondrial metabolism, molecular biology, genetics, 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 Drs. Joseph Cheer, Seth Ament, Brian Polster, faculty members of UMSOM, and Dr. Marisela Morales from NIDA IRP. In addition, Dr. Rajeshwar Awatramani from Northwestern University in Chicago will be a consultant in this project. The short-term objective of this proposal 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. 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 resistant to mitochondrial oxidative stress induced by chronic METH exposure. The proposed aims are 1) Identifying VTA dopamine microcircuits encoding METH-seeking behavior and 2) Metabolic characteristics of VTA dopamine neurons encoding METH-seeking behavior. Identifying the specific brain circuits responsible for METH addictive properties is a first step to developing therapeutic strategies to help addicts recover from METH addiction.