Compulsive motor behaviors reflect a loss of normal adaptive behavioral responsiveness and result in rigid behaviors that range in severity from detrimental to disabling. Obsessive compulsive disorder (OCD) is the prototypical form of such behavioral disorders, but maladaptive compulsions emerge in diverse contexts affecting people across the lifespan. Development of effective therapeutics for compulsivity has been hampered by our lack of understanding of the underlying cellular and circuit mechanisms. In order to address this need, we have assembled a unique set of genetic reagents and developed a novel approach to examine the local striatal circuit. We propose to: (1) test our hypothesis that overactivity of striatal group 1 metabotropic glutamate receptors (mGluRs) drives compulsive-like behaviors in mice, (2) build upon our recent progress of defining a role for mGluR5 dysregulation by determining whether mGluR1 signaling is also dysregulated in mice with OCD-like behaviors, (3) evaluate the integrated effects of abnormal striatal group 1 mGluR signaling on striatal output in mice with OCD-like behaviors and (4) determine whether mGluR-dependent reconfiguration of striatal output is a common mechanism associated with animal models for compulsive behaviors. Together these studies have the potential to be paradigm-shifting by providing the first direct experimental evidence to support a role for striatal group 1 mGluRs in causing compulsive motor behaviors. Such preclinical results will newly direct attention to this highly druggable class of receptors as well as illuminate specific cellular and circuit mechanisms to advance the treatment of related disorders in humans.
Compulsive behaviors are disruptive, maladaptive behavioral responses that occur in diverse conditions and across our life span;arising in conditions such as Obsessive Compulsive Disorder, Tourette's Syndrome, autism, drug addiction, medication side effects and neurodegenerative diseases. Knowledge of the molecular pathways, cellular mechanisms, and circuits that drive compulsive motor behaviors can greatly accelerate development of effective treatments and is at present greatly lacking. This proposal tests the significance of a class of G-protein coupled receptors that was recently found by our group to be dysregulated in an animal model with OCD-like behaviors that are due to striatal dysfunction. The studies proposed have the potential to reveal a new druggable target for the treatment of compulsive disorders and define the effects of receptor dysregulation at the cellular and circuit level. This advance in our understanding of the neural basis for compulsivity will provide important novel opportunities to guide the rational design of therapeutics.
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