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

该基金将建立新的独立研究者研究适应不良的神经可塑性诱导的 长期使用可卡因和海洛因等成瘾药物。该项目将由Ethan安德森博士领导;一个 精力充沛，充满激情和富有成效的研究人员，致力于发展独立的研究职位 研究药物成瘾。该项目将在南卡罗来纳州医科大学（MUSC）进行， 该研究所以培养高质量的研究人员而闻名，专门研究药物成瘾。博士 安德森将在MUSC接受克里斯科万博士和彼得卡利瓦斯博士的指导。这些导师成功地 受过训练的科学家，他们已经在主要大学担任教职，并且是行为科学方面的专家。 药物成瘾模型，由于长期使用药物而导致的脑中的生物化学、分子和结构变化， 以及研究这些成瘾机制的新工具的产生。整个项目将采用 2种新颖和创新的方法来调查和扭转可卡因和海洛因的负面影响 成瘾背后的形态和行为变化该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C β 1（PLC）作为减少人类阿片类药物使用的潜在新靶点。2)反向 可卡因通过选择性靶向和 光遗传学上移除最近被可卡因激活的树突棘。这将决定是否直接 因果关系之间存在逆转这些形态的大脑变化和改变成瘾 行为安德森博士的科学培训计划将侧重于学习3项新技能：1）光遗传学 与新的体内脊柱复位技术，2）海洛因自我管理行为，和3）克隆和 构建新型病毒载体所必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（Eric Nestler博士， David Self、Arthur Riegel和Jacqueline McGinty）和考恩博士提供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单独会面， 准备未来的R01应用程序，每年在研讨会和1 - 2次会议上进行演示，出版1 每1 - 2年发表一篇论文，并在药物成瘾和尖端分子生物学方面进行教学。这 格兰特将为安德森博士铺平道路，以实现他的潜力，成为一个富有成效的，R01资助， 在成瘾研究领域的独立科学家，让他学习新的科学技能，生产 高影响力的数据，从他的顾问和导师那里接受优秀和广泛的培训， 在MUSC的特殊训练场学习。

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.