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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要该提议正在提交，以支持Dominguez-Lopez博士从受训者到的过渡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博士在博士的心态下工作。俄克拉荷马州医学研究基金会（OMRF）的迈克尔·贝克斯特（Michael Beckstead）调查了甲基苯丙胺（甲基苯丙胺）自我的多巴胺神经传递行政行为。 Beckstead博士是多巴胺突触传播的公认专家成瘾。 Beckstead博士的实验室结合了鼠标的药物自我管理模型与贴片夹的模型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。提交的提案将科学培训纳入了研究线粒体代谢，转录分析，生物信息学和活性的遗传标记神经元种群。申请人将接受教育方法，科学写作，赠款的培训从一个准备和其他技能的准备和其他技能，成为一名独立的大脑研究科学家代表性不足的组。拟议的计划包括与Holly Van Remmen博士的心理互动， Willard Freeman博士，OMRF成员Linda Thompson博士和来自Rajeshwar Awatramani博士芝加哥西北大学。该应用的短期目的是增强Dominguez-博士洛佩兹对线粒体代谢和应用于多巴胺能的单细胞转录组学的了解界。从长远来看，这将使Dominguez-Lopez博士能够确保受保护的培训时间和研究活动，建立新的合作，并追求他的新颖独立研究，导致竞争性赠款建议。 Dominguez-Lopez博士获得的初步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，形成对线粒体氧化具有抗性的微电路慢性甲基甲基暴露引起的压力。拟议的目的是1）识别VTA多巴胺编码寻求甲基的行为的微电路和2）VTA多巴胺神经元的代谢特征编码寻求甲基苯丙胺的行为。识别负责MET添加剂的特定脑电路属性是制定理论策略的第一步，以帮助吸毒者从甲基成瘾中恢复过来。