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Nucleus accumbens synaptic mechanisms of opiate reward and aversion

伏隔核突触阿片奖赏和厌恶机制

基本信息

批准号：
8820411
负责人：
Patrick Rothwell
金额：
$ 17.48万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-15 至 2016-01-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820411
关键词：
Acute Advisory Committees Affect Analgesics Animals Applications Grants Area Award Behavior Behavioral Beryllium 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 Indium K-Series Research Career Programs Learning Mediating Mentors Minnesota Modification Molecular Monitor Morphine 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 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 in vivo innovation interest new technology optogenetics osmotic minipump postsynaptic preference presynaptic psychostimulant public health relevance research study synaptic function tool

项目摘要

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.

描述：我的职业目标是在一所受人尊敬的研究型大学获得一个独立的学术职位，研究阿片类药物对纹状体突触功能和行为的影响，并培养这一领域的未来科学家。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，在那里我使用行为药理学研究了滥用药物的奖赏和厌恶特性，并研究了药物暴露如何影响伏隔核(NAC)的突触功能。作为斯坦福大学的博士后学者，我曾与罗伯特·马伦卡博士和托马斯·苏德霍夫博士合作，开发和扩展我在NAC电路功能的分子基础方面的培训。这个职业发展奖的一个主要目标是获得额外的光遗传方法方面的培训，学习NAC电路，这将有助于我开始独立的职业生涯。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马伦卡博士指导，苏德霍夫博士和卡尔·戴瑟罗斯博士将提供额外的支持。我将学习在脑片准备中对特定的NAC突触连接进行光遗传刺激，同时从识别的NAC中棘神经元亚型进行全细胞记录，从而能够根据突触前来源和突触后目标精确定义突触连接。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。在该奖项的指导阶段，我将重点介绍吗啡奖赏的突触机制，以及慢性间歇吗啡暴露引起的NAC回路的突触修改。在该奖项的独立阶段，我将把这一分析扩展到长期持续服用阿片类药物，并使用光遗传学方法检查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得到该领域知名研究人员咨询委员会的推动，他们将参与该奖项的指导和独立阶段。这一建议的重要组成部分包括对阿片剂奖赏和厌恶中相同的NAC电路要素进行平行研究，以及对间歇性和持续性阿片剂暴露进行直接和受控比较。这些不同的阿片类药物给药时间模式与不同的神经生物学、行为和临床结果相关。这些实验将为未来的拨款申请奠定基础，重点是阿片类药物对NAC电路影响的分子机制。我希望我在这一领域的研究将通过指导减少处方止痛药滥用的努力来造福公众健康。