Neural Circuitry of Shared Vulnerability to Both PTSD and Addiction

描述（由申请人提供）：本K08提案描述了一个为期5年的培训计划，用于发展成瘾研究的学术生涯。候选人完成了医学博士学位。和博士在神经科学，然后继续完成了在密歇根大学精神病学结构住院医师。他最近被任命为密歇根大学精神病学助理教授，除了基础研究外，他现在还在成瘾治疗服务诊所治疗物质使用障碍患者。候选人在神经科学和精神病学方面的教育和培训使他为这个项目做好了充分的准备，他现在将通过跨部门资源的独特整合来扩展他的科学技能。为了实现完全的研究独立性，他确定了三个关键的培训目标：（1）熟练掌握先进的神经解剖学技术，特别是免疫组织化学，（2）获得显微注射和使用病毒载体实验操纵行为的专业知识，以及（3）学习如何使用光遗传学作为询问影响特定行为的神经回路的工具。K08项目将 密歇根大学精神病学系和分子与行为神经科学研究所。该部门和研究所受益于密切的合作关系，与其他单位，包括生物工程，心理学，放射学，和CTSA资助的密歇根州临床和健康研究所。这种充满活力的研究环境包括充分利用行为测试设施，组织学和显微镜资源，以及动物饲养，它培养了一个不断扩大的翻译精神病学研究人员群体。主要的导师，特里罗宾逊博士，是一个富有成效和资金雄厚的神经科学家谁拥有超过30年的经验与基本成瘾研究，并建立了跟踪记录的指导初级研究人员。候选人还将受益于两个当地的共同导师，斯坦利沃森医学博士，谁率先使用免疫组织化学研究情绪行为，并指导了几个成功的医生，科学家在他的30多年的研究，和吉娜坡博士，麻醉学副教授谁拥有专业知识，在使用光遗传学研究大鼠的行为。Pedro Lowenstein医学博士是该项目的经验丰富的顾问，在病毒载体和转化研究方面具有相当的专业知识。该研究项目的重点是确定共同的神经生物学底物，赋予脆弱性成瘾和经常共同发生的疾病，如创伤后应激障碍。这将通过识别负责对食欲和厌恶条件暗示产生过度情绪和动机反应的神经回路来实现。具体目标包括：1）识别由食欲和厌恶条件线索激活的神经元和回路中的重叠区域，2）测试边缘系统回路中增加的连接是否可以同时减少条件接近和条件恐惧，以及3）使用光遗传学来识别对食欲和厌恶动机反应施加抑制控制的特定途径。拟议的K08项目与NIH和NIDA的使命保持一致。该项目将培养一名有前途的科学家，并帮助澄清成瘾和经常并发疾病的神经生物学途径，这是一个重要的公共卫生优先事项。

DESCRIPTION (provided by applicant): This K08 proposal describes a 5-year training program for the development of an academic career in addiction research. The candidate completed his M.D. and Ph.D. in Neuroscience, and then went on to complete a structured residency in Psychiatry at the University of Michigan. He was recently appointed Assistant Professor of Psychiatry at University of Michigan, where in addition to basic research he now treats patients with substance use disorders at the Addiction Treatment Services clinic. The candidate's education and training in both neuroscience and psychiatry have prepared him well for this project, and he will now expand on his scientific skills through a unique integration of interdepartmental resources. To achieve full research independence, he has identified three key Training Objectives: (1) to gain proficiency in advanced neuroanatomical techniques, particularly immunohistochemistry, (2) to gain expertise in microinjections and the use of viral vectors to experimentally manipulate behavior, and (3) to learn how to use optogenetics as a tool for interrogating neural circuits that influence specific behaviors. The proposed K08 project will take place within the Department of Psychiatry and the Molecular & Behavioral Neuroscience Institute at the University of Michigan. The Department and Institute benefit from close collaborative relationships with other units including Bioengineering, Psychology, Radiology, and the CTSA- funded Michigan Institute for Clinical and Health Research. This vigorous research environment includes ample access to behavioral testing facilities, histology and microscopy resources, and animal housing, and it nurtures an expanding group of translational psychiatric researchers. The primary mentor, Terry Robinson PhD, is a productive and well-funded neuroscientist who has more than 30 years of experience with basic addiction research, and an established track record of mentoring junior investigators. The candidate will also benefit from two local co-mentors, Stanley Watson MD PhD, who pioneered the use of immunohistochemistry to study emotional behavior and has mentored several successful physician-scientists over his 30+ years of research, and Gina Poe PhD, an Associate Professor of Anesthesiology who has expertise in the use of optogenetics to study behavior in rats. Pedro Lowenstein MD PhD is an experienced consultant on this project with considerable expertise in viral vectors and translational research. The research project focuses on identifying common neurobiological substrates that confer vulnerability both to addiction and to frequently co-occurring disorders such as post-traumatic stress disorder. This will be accomplished by identifying neural circuits responsible for generating excessive emotional and motivational responses to both appetitive and aversive conditioned cues. The specific aims include: 1) identifying areas of overlap in the neurons and circuits activated by both appetitive and aversive conditioned cues, 2) testing whether increasing connectivity within limbic circuitry can simultaneously reduce both conditioned approach and conditioned fear, and 3) using optogenetics to identify specific pathways that exert inhibitory control over both appetitive and aversive motivational responses. The proposed K08 project is well-aligned with the missions of the NIH and NIDA. The project will train a promising scientist and help clarify neurobiological pathways to addiction and frequently co-occurring disorders, which is a significant public health priority.