Dopamine Neuronal Microcircuits Controlling Methamphetamine Seeking Behavior

多巴胺神经元微电路控制甲基苯丙胺寻求行为

• 批准号: 10591238
• 负责人: Sergio Dominguez Lopez
• 金额: $ 14.97万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591238
• 关键词: Affect; Anatomy; Applications Grants; Behavior; Bioinformatics; Brain; Cells; Characteristics; Chicago; Chronic; Collaborations; Data; Dopamine; Drug Addiction; Drug Modelings; Drug abuse; Educational Models; Environment; Faculty; Genetic; Genetic Transcription; Glutathione; Grant; Knowledge; Label; Laboratories; Maryland; Mentors; Mentorship; Metabolic; Methamphetamine; Methamphetamine dependence; Methodology; Mitochondria; Molecular; Molecular Biology; Morale; Mus; National Institute of Drug Abuse; Neurobiology; Neurons; Oxidative Stress; Oxygen Consumption; Population; Preparation; Property; Quality of life; Research; Research Activity; Research Personnel; Research Proposals; Resistance; Role; Scientist; Secure; Self Administration; System; Technology; Therapeutic; Time; Training; Training Activity; Underrepresented Populations; Universities; Ventral Tegmental Area; Viral; Work; Writing; addiction; brain research; dopaminergic neuron; drug seeking behavior; experience; fighting; immunocytochemistry; medical schools; member; methamphetamine exposure; mitochondrial metabolism; motivated behavior; mouse model; neuronal circuitry; neurotransmission; novel; novel therapeutics; oxidative damage; programs; skills; transcriptomics

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.

项目摘要/摘要 该建议的提交是为了支持Dominguez-Lopez博士从受训的实习生到 药物成瘾神经生物学的独立研究者，专门研究多巴胺 控制寻求药物行为的微电路。 Dominguez-Lopez博士将在博士的心态下工作。 马里兰大学医学院（UMSOM）的玛丽·凯·洛博（Mary Kay Lobo）调查了多巴胺的作用 甲基苯丙胺（甲基苯丙胺）自我管理的腹侧对盖区域（VTA）的神经传递 行为。 Lobo博士是在动机行为和多巴胺神经传递方面的公认专家 吸毒的背景。 Lobo博士的实验室结合了鼠标自我管理模型与 线粒体代谢，分子生物学，遗传学和免疫细胞化学，提供动态 Dominguez-Lopez博士成为经验丰富的科学家的环境。提交的建议 将科学培训纳入研究线粒体代谢，转录分析的方法中， 活性神经元种群的生物信息学和遗传标记。申请人将接受培训 教育方法，科学写作，赠款准备和其他技能 来自代表性不足的群体的独立大脑研究科学家。拟议的程序包括 指导与Drs的互动。约瑟夫·乔伊（Joseph Cheer），塞思·阿曼（Seth Ament），布莱恩·波斯特 NIDA IRP的Marisela Morales博士。此外，来自西北大学的Rajeshwar Awatramani博士 芝加哥将是该项目的顾问。该提案的短期目标是增强博士。 Dominguez-Lopez对线粒体代谢和单细胞转录组学的了解 多巴胺能圈。从长远来看，这将使Dominguez-Lopez博士能够确保受保护的时间 培训和研究活动，建立新的合作并从事他的新颖独立研究 导致竞争性赠款建议。 Dominguez-Lopez博士获得的数据表明延长 小鼠中的甲基甲基给药会在VTA中产生多巴胺神经元的降低，减少多巴胺 细胞兴奋性，增加线粒体氧的消耗率，并降低谷胱甘肽的水平。这些 观察与寻求毒品的行为同时发生。这项研究建议扩展了 发现在多巴胺回路中识别代谢和分子特征的发现，可提供抗药性或 暴露于甲基苯丙胺的脆弱性。中心假设是VTA多巴胺神经元的亚群是 负责寻求甲基甲基的行为，形成对线粒体氧化应激的微电路 由慢性甲基暴露诱导。提出的目的是1）识别VTA多巴胺微电路 编码寻求甲基的行为和2）编码VTA多巴胺神经元的代谢特征 寻求甲基苯丙胺的行为。识别负责MET添加特性的特定脑电路是一个 制定治疗策略的第一步，以帮助吸毒者从甲基苯丙胺成瘾中恢复过来。