Obsessive compulsive disorder (OCD) is characterized by intrusive thoughts and compulsive behaviors that reduce the anxiety generated by these obsessions. Understanding the pathological and molecular features of this disorder remains a considerable challenge in neuropsychiatry research. The goal of this research is to investigate how changes in large-scale neural activity patterns in neural circuits occur leading to, during, and the resolution of abnormal compulsive behaviors. Longstanding theory indicates that abnormal repetitive behaviors result from imbalances in the direct and indirect striatal pathways as well as increased orbitofrontal cortex (OFC) activity. However, until recently it was not possible to test this theory. Newly available head mounted in vivo microscopes allow us to simultaneously visualize Ca2+ signaling in hundreds of neurons within deep brain structures in awake-behaving mice. Using this imaging technology in combination with tools for circuit-specific manipulation, we can begin to test the OFC, the direct, and indirect striatal pathways. To examine how neural activity evolves with perseverative behavior we will visualize activity in the OFC and its targets in the ventromedial striatum (VMS). These areas are targeted because they show structural and functional abnormalities in MRI studies. Calcium activity will be visualized in the OFC or VMS with either D1 or D2 specificity. We will compare neuronal activity in mice engaged in abnormal repetitive behaviors to examine the relationship between D1+ and D2+ striatal activity patterns and perseverative behaviors. Longitudinal data sets can then be analyzed for changes in network activity and links with behavior over hours, weeks, or months. OFC and VMS D1/D2 cellular activity associated with behavior will be studied using three different approaches (pharmacological, transgenic, and optogenetic) and time scales. 1) Mice will receive injections of pharmacological agents to induce transient perseverative behavior. 2) SAPAP3 knockout mice (a transgenic OCD model) will be studied longitudinally as perseverative behaviors develop over months. 3) OFC-VMS projections will be optogenetcially stimulated to induce perseverative behavior over weeks with calcium imaging before, during, and after stimulation.
Obsessive compulsive disorder (OCD) and its characteristic perseverative behaviors are disabling, prominent, and notoriously treatment resistant. It is a leading cause of illness-related disability with 2-3% lifetime prevalence, yet the underlying biology of OCD is relatively unknown. A better understanding of how dysfunctional neural circuits lead to obsessive thoughts and compulsive behaviors is necessary to develop new treatments. Knowledge gained from this project will be broadly applicable to other severe psychiatric disorders with perseverative thought patterns and actions such as autism, schizophrenia, and addiction.
