Dissecting Circuits Underlying Obsessive Compulsive Disorder in Humans and Mice

描述（由申请人提供）：候选人要求支持一个为期5年的培训和研究计划，以开发一种新的翻译方法，用于解剖强迫症（OCD）的大脑机制。她的长期目标是在患者中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，候选人将建立在她以前的经验，在基础神经科学研究和焦虑症的临床治疗，在焦虑症研究诊所和综合神经科学部在哥伦比亚大学，本提案的环境进行多学科项目。她的培训计划包括：1）开发OCD临床表型和神经回路及其对小鼠模型的适用性方面的专业知识; 2）识别与OCD神经回路不同组成部分相对应的人类生物标志物的培训; 3）学习与OCD相关的小鼠行为范例; 4）开发光遗传学/光纤技术方面的专业知识;以及5）负责进行研究的培训。这些短期职业目标的完成将通过一个强大的和支持性的机构环境，包括临床和基础神经科学导师;在其他机构强大的多学科顾问关系;和严格的培训计划，包括相关的课程。 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。为了补充她的培训计划，她提出了两个在人类和小鼠中并行的项目，这些项目将使用多层次调查来解构强迫症中的行为成分，并将它们与底层电路联系起来。这两个项目的目的是：1）确定与功能失调的CSTC回路相对应的人类强迫症的可靠行为指标，也可以在小鼠中进行研究; 2）使用光遗传学/光纤技术调节CSTC回路的活性，以测试CSTC回路功能异常导致小鼠强迫症相关行为的假设。目标1的完成将确定哪些行为指标是临床相关的，因此在她的小鼠研究中作为OCD相关行为的读数是有用的。这两个项目将提供与OCD神经机制相关的新数据。初步研究证明了这种方法的可行性。通过进行这些项目，候选人将学习最先进的方法，用于评估强迫症的行为组成部分，用于构建组织特异性转基因小鼠，以及用于调节清醒行为动物的神经回路。在K 08完成后，候选人将拥有成为独立翻译研究员的经验和技能。 公共卫生相关性：强迫症（OCD）是一种慢性致残性疾病，终生患病率为2-3%，是疾病相关残疾的主要原因。需要更好地了解功能失调的电路如何导致强迫症症状，以指导新治疗方法的开发。候选人提案的高潮是开发一种双向方法，用于桥接小鼠和人类研究，以便临床研究的结果可以显著影响基础研究的方向，而动物研究的结果可以导致治疗的显著改善。

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.