Dissecting Circuits Underlying Obsessive Compulsive Disorder in Humans and Mice

描述（由申请人提供）：申请人要求资助一项为期5年的培训和研究计划，以开发一种新的翻译方法来解剖强迫症（OCD）的大脑机制。她的长期目标是在患者身上使用可靠的行为指标，将强迫症症状与人类特定的大脑通路联系起来，并使用小鼠模型来了解这些通路中的分子和功能变化如何相互作用，从而产生功能失调的行为。在拟议的培训计划中，候选人将根据她之前在基础神经科学研究和焦虑症临床治疗方面的经验，在哥伦比亚大学焦虑症研究诊所和综合神经科学部门执行一个多学科项目，这是本提案的环境。她的培训计划包括：1)发展强迫症临床表型和神经回路方面的专业知识，并将其应用于小鼠模型；2) OCD神经回路不同组成部分对应的人类生物标志物识别训练；3)学习与强迫症相关的小鼠行为范式；4)发展光遗传/光纤技术专业知识；5)负责任的研究行为培训。包括临床和基础神经科学导师在内的强大和支持性的机构环境将使这些短期职业目标的完成成为可能；与其他机构建立了紧密的多学科咨询关系；以及包括相关课程在内的严格的培训计划。候选人的研究计划建立在几条证据的基础上，这些证据表明强迫症症状是由皮质-纹状体-丘脑-皮质（CSTC）回路功能障碍引起的。为了补充她的训练计划，她提出了两个并行的项目，在人类和老鼠身上进行，将使用多层次的调查来解构强迫症的行为成分，并将它们与潜在的回路联系起来。这两个项目的目的是：1)确定与CSTC回路功能失调相对应的人类强迫症的可靠行为指标，并可在小鼠中进行研究；2)利用光遗传学/光纤技术调节CSTC回路的活性，以验证CSTC回路功能异常导致小鼠强迫症相关行为的假设。目标1的完成将决定哪些行为指标与临床相关，从而有助于在她的小鼠研究中读出与强迫症相关的行为。这两个项目将为强迫症的神经机制提供新的数据。初步研究证明了这种方法的可行性。通过进行这些项目，候选人将学习评估强迫症行为成分的最新方法，构建组织特异性转基因小鼠，以及调节清醒行为动物的神经回路。在完成K08后，候选人将具备成为一名独立翻译研究者的经验和技能。

DESCRIPTION (provided by applicant): The candidate requests support for a 5-year program of training and research to develop a novel translational approach for dissecting the brain mechanisms underlying obsessive-compulsive disorder (OCD). Her long-term goal is to use reliable behavioral indicators in patients to link OCD symptoms to specific brain pathways in humans, and use mouse models to understand how molecular and functional changes in these pathways interact to produce dysfunctional behavior. In the proposed training program, the candidate will build upon her previous experience in basic neuroscience research and clinical treatment of anxiety disorders to perform a multidisciplinary project in the Anxiety Disorders Research Clinic and the Division of Integrative Neuroscience at Columbia University, the environment for this proposal. Her training plan includes 1) developing expertise in the clinical phenotype and neural circuitry of OCD and its applicability to mouse models; 2) training in identification of human biomarkers corresponding to different components of OCD neural circuits; 3) learning mouse behavioral paradigms related to OCD; 4) developing expertise in optogenetic/ fiberoptic technology; and 5) training in responsible conduct of research. Completion of these short-term career goals will be enabled by a strong and supportive institutional environment including clinical and basic neuroscience mentors; strong multidisciplinary consultant relationships at other institutions; and a rigorous training plan including relevant coursework. The candidate's research plan builds on several lines of evidence which indicate that OCD symptoms result from dysfunction in the cortico-striato-thalamo-cortical (CSTC) circuit. To complement her training program, she proposes two parallel projects in humans and mice that will use multilevel investigation to deconstruct behavioral components in OCD, and link them to underlying circuits. The aims of the two projects are: 1) to identify reliable behavioral indicators of OCD in humans that correspond to dysfunctional CSTC circuits and can also be studied in mice; and 2) to modulate activity in CSTC circuits using optogenetic/ fiberoptic technology to test the hypothesis that abnormalities in CSTC circuit function lead to OCD-related behaviors in mice. Completion of Aim 1 will determine which behavioral indicators are clinically-relevant and therefore useful as readouts of OCD-related behaviors in her mouse studies These two projects will provide new data relevant to the neural mechanisms of OCD. Preliminary studies demonstrate feasibility of this approach. By conducting these projects, the candidate will learn state-of-the art methods for assessing the behavioral components of OCD, for constructing tissue-specific transgenic mice, and for modulating neural circuits in awake-behaving animals. At completion of the K08, the candidate will have the experience and skills to become an independent translational investigator. PUBLIC HEALTH RELEVANCE: Obsessive Compulsive Disorder (OCD) is a chronic, disabling disorder with 2-3% lifetime prevalence, and is a leading cause of illness-related disability. A better understanding of how dysfunctional circuits lead to OCD symptoms is needed to guide development of new treatments. The culmination of the candidate's proposal is to develop a bi-directional approach for bridging mouse and human research, so that findings from clinical studies can significantly impact the direction of basic research, and findings from animal studies can lead to significant improvements in treatment.