Optogenetic dissection of cortico-striatal circuitry underlying obsessive-compulsive behaviors

J. David Gladstone Institutes, San Francisco CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is an anxiety spectrum disorder that affects both cognition and motor behavior. Symptoms include recurrent, persistent worries (obsessions) and ritualistic, stereotyped actions (compulsions) performed to alleviate the anxiety associated with these worries. A large fraction of OCD patients do not respond to currently available treatments, highlighting the need for more basic research into the neural circuits and mechanisms underlying the disorder. Human neuroimaging studies in OCD patients have consistently shown abnormal activity in the frontal cortex and striatum, which are interconnected brain structures implicated in motor control, action selection, and habit formation. Imbalance in striatal motor control pathways is thought to underlie the aberrant repetitive behaviors characteristic of OCD. However, nothing is known about how frontal cortical areas interact with the striatum to contribute to OCD pathology, and how different downstream striatal pathways are affected. The goal of this research is to disentangle the role of specific circuit elements within the fronto-striatal network using optogenetic and pharmacogenetic tools to precisely control the activity of genetically specified cell types. [These tools can be independently targeted to fronto-striatal projection neurons as well as to different populations of downstream striatal neurons. Using well- validated rodent assays for anxiety and compulsive behavior, we will systematically optically control each circuit element in awake behaving animals to identify which cell types causally contribute to OCD-like behaviors. Ex vivo and in vivo electrophysiological techniques will then be used to track the precise cellular and synaptic changes that are associated with the stimulation-induced behavioral change.] This work will suggest targets for development of more specific and effective treatments for OCD.