Dissecting Circuits Underlying Obsessive Compulsive Disorder in Humans and Mice

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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.