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: 10152578
• 负责人: Sergio Dominguez Lopez
• 金额: $ 0.65万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2021-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152578
• 关键词: Affect; Anatomy; Antioxidants; Applications Grants; Axon; Behavior; Behavioral; Bioinformatics; Brain; Cells; Censuses; Characteristics; Chicago; Chronic; Classification; Collaborations; Data; Development Plans; Dopamine; Drug Addiction; Drug Modelings; Educational Models; Electrophysiology (science); Environment; Event; Exposure to; Fluorescence-Activated Cell Sorting; Foundations; Functional disorder; Gene Expression Profile; Genetic; Genetic Recombination; Genetic Transcription; Glutathione; Glutathione Disulfide; Grant; High Pressure Liquid Chromatography; Holly; Homeostasis; Injections; Intake; Knowledge; Label; Laboratories; Location; Measures; Mediating; Medical Research; Mentors; Mentorship; Metabolic; Methamphetamine; Methamphetamine dependence; Methodology; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurobiology; Neurons; Oklahoma; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Pathway interactions; Population; Predisposition; Preparation; Presynaptic Terminals; Property; Quality of life; Reporter; Research; Research Activity; Research Personnel; Research Proposals; Resistance; Resolution; Respiration; Role; Scientist; Secure; Self Administration; Site; Stains; Survival Rate; Synaptic Transmission; System; Tamoxifen; Technology; Testing; Theoretical model; Therapeutic; Time; Training; Training Activity; Underrepresented Populations; Universities; Ventral Tegmental Area; Viral; Virus; Work; Writing; addiction; base; brain research; career; career development; dopaminergic neuron; drug seeking behavior; experience; fighting; genetic profiling; immunocytochemistry; innovation; member; methamphetamine effect; methamphetamine exposure; mitochondrial metabolism; mouse model; neuronal circuitry; neurotransmission; novel; novel therapeutics; oxidative damage; patch clamp; programs; skills; tool; transcriptomics

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.

项目概要/摘要 提交此提案是为了支持 Dominguez-Lopez 博士从受指导的实习生过渡到 毒瘾神经生物学的独立研究者，专门研究多巴胺 控制寻药行为的微电路。 Dominguez-Lopez 博士在 Dr. Dominguez-Lopez 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 甲基苯丙胺（METH）自我调节腹侧被盖区（VTA）的多巴胺神经传递 行政行为。 Beckstead 博士是多巴胺突触传递领域公认的专家 的成瘾。 Beckstead 博士的实验室将自我给药小鼠模型与膜片钳相结合 电生理学和免疫细胞化学，为 Dominguez-Lopez 博士提供动态环境 成为一名经验丰富的科学家。提交的提案纳入了方法学方面的科学培训，以 研究活性线粒体代谢、转录分析、生物信息学和基因标记 神经元群。申请人将接受教育方法、科学写作、资助等方面的培训 从一个独立的大脑研究科学家成为一名独立的大脑研究科学家所需的准备和其他技能 代表性不足的群体。拟议的计划包括与 Holly Van Remmen 博士的指导互动， OMRF 成员 Willard Freeman 博士、Linda Thompson 博士和来自 OMRF 的 Rajeshwar Awatramani 博士 西北大学在芝加哥。此应用程序的短期目标是增强 Dominguez 博士- 洛佩兹将线粒体代谢和单细胞转录组学知识应用于多巴胺能 电路。从长远来看，这将使 Dominguez-Lopez 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，并进行新颖的独立研究，从而 竞争性赠款提案。 Dominguez-Lopez 博士获得的初步数据表明，长期 小鼠自我给药冰毒会导致 VTA 中的多巴胺神经元减少，从而减少多巴胺 细胞兴奋性，增加线粒体耗氧率并降低谷胱甘肽水平。这些 观察结果与吸毒行为的增加同时发生。这项研究计划扩展了这些 研究结果可识别多巴胺回路中提供阻力或的代谢和分子特征 暴露于冰毒的脆弱性。中心假设是 VTA 多巴胺神经元的一个亚群是 负责寻找 METH 的行为，形成抵抗线粒体氧化的微电路 长期接触冰毒引起的压力。拟议的目标是 1) VTA 多巴胺的鉴定 编码 METH 寻求行为的微电路，以及 2) VTA 多巴胺神经元的代谢特征 编码寻求冰毒的行为。识别导致冰毒成瘾的特定大脑回路 特性是制定治疗策略以帮助成瘾者从冰毒成瘾中恢复过来的第一步。