Targeting Phospholipase C and Dendritic Spines to Reduce Cocaine and Heroin Motivation

这笔赠款将建立新的独立研究人员，研究由 长期使用成瘾药物可卡因和海洛因。该项目将由伊桑·安德森博士领导； 精力充沛、充满激情和多产的研究人员正在发展一个独立的研究职位 研究毒瘾。该项目将在南卡罗来纳医科大学(MUSC)进行，并 该研究所以培养出专门研究药物成瘾的高素质研究人员而享有盛誉。Dr。 安德森将在MUSC接受克里斯·考恩博士和彼得·卡利瓦斯博士的指导。这些导师已经成功地 训练有素的科学家，曾在主要大学担任教职，是行为方面的专家 药物成瘾模型，慢性药物使用引起的大脑生化、分子和结构变化， 以及研究这些成瘾机制的新工具的产生。此整体项目将采用 2调查和扭转可卡因和海洛因的负面影响的新的创新方法 关于成瘾的形态和行为变化。这个项目的短期目标包括2 目的：1)确定一种新的内源性抗成瘾信号通路的细胞内机制 通过和磷脂酶Cᵧ1(PLC)作为减少人类阿片类药物使用的潜在新靶点。2)反转 可卡因选择性靶向可卡因诱导伏核突触适应不良改变 光基因移除最近被可卡因激活的树突状棘突。这将决定是否直接 这些形态变化的逆转与成瘾改变之间存在因果关系 行为。安德森博士的科学培训计划将重点学习3项新技能：1)光遗传学 利用新的体内脊柱复位技术，2)海洛因自我给药行为，3)克隆和 构建新型病毒载体所需的分子生物学技术。此外，安德森博士将 通过杰出的职业咨询委员会接受出色的职业发展培训(Eric Nestler博士， 大卫·赛尔夫、亚瑟·里格尔和杰奎琳·麦金蒂)和考恩博士和杰奎琳·麦金蒂的具体个人职业培训 卡利瓦斯。个人科学培训将包括与他的导师们单独会面，讨论和 准备未来的R01申请，每年在研讨会和1-2次会议上发表演讲，出版1 每1-2年发表一篇论文，讲授课程内容为毒瘾和尖端分子生物学。这 格兰特将为安德森博士实现他的潜力铺平道路，成为一名多产的、R01可资助的 在成瘾研究领域的独立科学家，让他学习新的科学技能，产生 高影响力数据，通过其顾问和导师的专业知识接受优秀和广泛的培训，以及 在南加州大学特殊的训练场地学习。

This grant will establish new independent investigator studies on maladaptive neuroplasticity induced by chronic use of the addictive drugs cocaine and heroin. This project will be led by Ethan Anderson, Ph.D.; an energetic, passionate, and productive researcher on a trajectory to develop an independent research position studying drug addiction. This project will take place at the Medical University of South Carolina (MUSC), an institute with a stellar reputation for producing high quality researchers that specialize in drug addiction. Dr. Anderson will be mentored Dr. Chris Cowan and Dr. Peter Kalivas at MUSC. These mentors have successfully trained scientists who have gone on to faculty positions at major universities and are experts in behavioral models of drug addiction, biochemical, molecular, and structural changes in the brain due to chronic drug use, and the generation of novel tools to investigate these mechanisms of addiction. This overall project will employ 2 novel and innovative approaches to investigate and reverse the negative effects of both cocaine and heroin on morphological and behavioral changes underlying addiction. The short-term goals of this project involve 2 aims: 1) Determine the intracellular mechanism of a novel, endogenous anti-addictive signaling pathway through and phospholipase Cᵧ1 (PLC) as a potential new target for reducing opioid use in humans. 2) Reverse cocaine-induced maladaptive changes in synapses in the nucleus accumbens by selectively targeting and optogenetically removing dendritic spines recently activated by cocaine. This will determine whether a direct causal relationship exists between reversal of these morphological brain changes and alterations in addictive behavior. The scientific training program for Dr. Anderson will focus on learning 3 new skills: 1) optogenetics with novel in vivo spine reduction technology, 2) heroin self-administration behavior, and 3) cloning and molecular biological techniques necessary for constructing novel viral vectors. In addition, Dr. Anderson will receive excellent career development training via an outstanding career advisory committee (Drs. Eric Nestler, David Self, Arthur Riegel, and Jacqueline McGinty) and specific individual career training from Drs. Cowan and Kalivas. The individual scientific training will include individual meetings with his mentors to discuss and prepare future R01 applications, presentations at seminars and 1-2 conferences per year, the publication of 1 paper every 1-2 years, and didactic course work in drug addiction and cutting-edge molecular biology. This grant will pave the way for Dr. Anderson to achieve his potential to become a productive, R01 fundable, independent scientist in the field of addiction research by allowing him to learn new scientific skills, produce high-impact data, receive excellent and broad-based training with expertise from his advisors and mentors, and study in the exceptional training grounds of MUSC.