Identifying the Molecular Substrates of OCD Using Human Post-mortem Brain and Optogenetics in Mice
Obsessive compulsive disorder (OCD) is a chronic, severe mental illness that affects 2-3% of people worldwide, and is a leading cause of illness-related disability according to the World Health Organization. Brain imaging studies in OCD patients have consistently shown abnormal activity in regions of the brain involved in decision-making (orbitofrontal cortex) and selection of actions (striatum). However, we have no knowledge regarding the molecular changes in these brain regions that contribute to abnormal function in people who suffer from OCD. In this project, we will therefore conduct RNA-sequencing on post-mortem brain tissue from people with OCD and matched unaffected controls to identify OCD-related gene expression changes in the orbitofrontal cortex and striatum. This unbiased approach will allow us to uncover the biological gene networks most affected in OCD patients. In a complementary experiment, we will then determine if expression of these genes is altered in homologous brain regions in a mouse model of OCD, paving the way for future studies to directly determine how changes in gene expression lead to abnormal compulsive behaviors. Together, these experiments will allow us to identify the molecular changes underlying OCD in OCD-relevant brain regions for the first time, with the goal of ultimately developing new treatments.