Nucleus accumbens synaptic mechanisms of opiate reward and aversion

伏隔核突触阿片奖赏和厌恶机制

• 批准号: 9215667
• 负责人: Patrick Rothwell
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215667
• 关键词: Acute; Advisory Committees; Affect; Analgesics; Animals; Applications Grants; Area; Award; Behavior; Behavioral; Brain; Brain region; Chronic; Clinical; Complex; Corpus striatum structure; Data; Development; Dopamine D2 Receptor; Dose; Drug Addiction; Drug Exposure; Drug abuse; Elements; Exposure to; Future; Goals; Injectable; Interruption; K-Series Research Career Programs; Learning; Mediating; Mentors; Minnesota; Modification; Molecular; Monitor; Morphine; Motivation; Naloxone; Neurobiology; Neurons; Nucleus Accumbens; Opiates; Opioid; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Preparation; Property; Protocols documentation; Public Health; Research; Research Personnel; Research Training; Rewards; Role; Scientist; Slice; Source; Specificity; Supervision; Synapses; Synaptic plasticity; System; Training; Transgenic Mice; Universities; Viral; Whole-Cell Recordings; Withdrawal; Work; addiction; base; behavioral pharmacology; behavioral response; brain cell; career; career development; cell type; drug of abuse; experience; experimental study; in vivo; innovation; interest; new technology; optogenetics; osmotic minipump; postsynaptic; preference; presynaptic; psychostimulant; public health relevance; synaptic function; tool

DESCRIPTION: My career goal is to obtain an independent academic position at a respected research university, studying the effects of opiates on striatal synaptic function and behavior, and training future scientists in this area. I developed a passionate interest in this topic during my doctoral studies at the University of Minnesota, where I used behavioral pharmacology to investigate the rewarding and aversive properties of abused drugs, and studied how drug exposure affects synaptic function in the nucleus accumbens (NAc). As a postdoctoral scholar at Stanford University, I have worked with Drs. Robert Malenka and Thomas Sudhof to develop and expand my training in the molecular basis of NAc circuit function. A primary goal of this career development award is to obtain additional training in optogenetic approaches to studying NAc circuitry that will help launch my independent career. My career development in addiction research and training in optogenetics will be supervised by Dr. Malenka at Stanford, with additional support from Dr. Sudhof and Dr. Karl Deisseroth. I will learn to perform optogenetic stimulation of specific NAc synaptic connections in brain slice preparations, while performing whole-cell recordings from identified subtypes of NAc medium spiny neurons, allowing precise definition of synaptic connections based on presynaptic source and postsynaptic target. I will also learn to stimulate specific NAc circuit elements in vivo to examine the impact on behavioral responses. During the mentored phase of this award, I will focus on the synaptic mechanisms of morphine reward, as well as synaptic modifications of NAc circuitry caused by chronic intermittent morphine exposure. During the independent phase of this award, I will extend this analysis to chronic continuous opiate administration, and examine the synaptic and behavioral consequences of opiate withdrawal using optogenetic approaches. My training and career development in opioid pharmacology will be facilitated by an Advisory Committee of established researchers in this area, who will be involved in both the mentored and independent phases of this award. Significant components of this proposal include parallel study of the same NAc circuit elements in opiate reward and aversion, as well as direct and controlled comparison of intermittent and continuous opiate exposure. These different temporal patterns of opiate administration are associated with distinct neurobiological, behavioral, and clinical outcomes. These experiments will lay the groundwork for future grant applications focused on the molecular mechanisms of opiate effects on NAc circuitry. I hope that my research in this area will benefit public health by guiding efforts to reduce abuse of prescription painkillers.

产品说明：我的职业目标是在一所受人尊敬的研究型大学获得独立的学术职位，研究阿片类药物对纹状体突触功能和行为的影响，并培养这一领域未来的科学家。我对这个话题产生了浓厚的兴趣， 我在明尼苏达大学攻读博士学位，在那里我用行为药理学研究了滥用药物的奖励和厌恶特性，并研究了药物暴露如何影响突触功能的神经核（NAc）。作为斯坦福大学的博士后学者，我与Robert Malenka博士和托马斯Sudhof博士合作，开发和扩展了我在NAc电路功能分子基础方面的培训。这个职业发展奖的主要目标是获得光遗传学方法的额外培训，以研究NAc电路，这将有助于启动我的独立职业生涯。我在成瘾研究和光遗传学培训方面的职业发展将由斯坦福大学的Malenka博士监督，并得到Sudhof博士和Karl Deisseroth博士的额外支持。我将学习在脑切片制备中执行特定NAc突触连接的光遗传学刺激，同时从已识别的NAc中等多刺神经元亚型执行全细胞记录，从而基于突触前来源和突触后靶点精确定义突触连接。我还将学习在体内刺激特定的NAc电路元件，以检查对行为反应的影响。在这个奖项的指导阶段，我将专注于吗啡奖励的突触机制，以及慢性间歇性吗啡暴露引起的NAc电路的突触修饰。在这个奖项的独立阶段，我将把这个分析扩展到慢性持续阿片类药物给药，并使用光遗传学方法研究阿片类药物戒断的突触和行为后果。我在阿片类药物药理学方面的培训和职业发展将由该领域的知名研究人员咨询委员会提供便利，他们将参与该奖项的指导和独立阶段。该建议的重要组成部分包括阿片类药物的奖励和厌恶，以及直接和控制比较的间歇性和连续的阿片类药物暴露相同的NAC电路元件的平行研究。这些不同的阿片类药物给药的时间模式与不同的神经生物学，行为和临床结果。这些实验将奠定基础，为未来的拨款申请集中在阿片类药物对NAc电路的影响的分子机制。我希望我在这一领域的研究能够通过指导减少处方止痛药滥用的努力来有益于公共卫生。