Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior
bioRxiv Preprint Server – July 06, 2020
Source: bioRxiv
Summary
Ketamine rapidly reduces symptoms in Obsessive-Compulsive Disorder (OCD). To understand this therapeutic effect, researchers used a mouse model of compulsive behavior, finding ketamine boosts activity in a specific fronto-striatal circuit. Significantly, activating this circuit with light technology reversed compulsive grooming. This reveals ketamine's effective control of compulsive behavior via this pathway, offering vital insights into its therapeutic effects for OCD.
Abstract
Obsessive-Compulsive Disorder (OCD), characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), is associated with dysfunction in fronto-striatal circuits. There are currently no fastacting pharmacological treatments for OCD. However, recent clinical studies demonstrated that an intravenous infusion of ketamine rapidly reduces OCD symptoms. To probe mechanisms underlying ketamine’s therapeutic effect on OCD-like behaviors, we used the SAPAP3 knockout (KO) mouse model of compulsive grooming. Here we recapitulate the fast-acting therapeutic effect of ketamine on compulsive behavior, and show that ketamine increases activity of dorsomedial prefrontal neurons projecting to the dorsomedial striatum in KO mice. Optogenetically mimicking this increase in fronto-striatal activity rescued compulsive grooming behavior in KO mice. Conversely, inhibiting this circuit in wild-type mice increased grooming. These studies demonstrate that ketamine increases activity in a fronto-striatal circuit that causally controls compulsive grooming behavior, suggesting this circuit may be important for ketamine’s therapeutic effects in OCD.