Current Projects

We seek to use the experimental power of rodent model systems to better understand the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and related disorders in which the cortico-striatal circuitry is dysfunctional. Recapitulating the pathophysiology of human neuropsychiatric disease in an animal model is both technically and conceptually challenging, and it is critical that model systems be firmly grounded in observations drawn from human disease. This principle undergirds all of our efforts in the lab. We seek observations that may form the basis of informative pathophysiological models in clinical genetics, neuropathology, psychopharmacology, and other fields, both in the Yale OCD Research Clinic and through a broad network of collaborators.

Excessive or compulsive grooming in animal models has been proposed as a behavioral model of the repetitive behaviors seen in OCD and related disorders. Selective serotonin reuptake inhibitors (SSRIs) have been shown to reduce excessive grooming in two proposed animal models; however, how these compounds help is poorly understood. Recently, a transgenic mouse was developed that lacks serotonin neurons in the central nervous system and a high incidence of grooming-related skin lesions in adult male Lmx1b-KO animals was observed under normal vivarium conditions, suggesting that developmental absence of CNS serotonin may lead to grooming abnormalities. We have been assessing grooming in these mice at baseline and are conducting a battery of behavioral tasks to assay phenotypes of potential relevance to OCD and related disorders.

Recent post-mortem findings indicate pathology of cholinergic (ChAT) and parvalbumin (PV) interneuronal populations in the basal ganglia in severe TS. We have achieved the highly specific and effective ablation of both striatal ChAT and PV interneurons using a combination of the local infusion of a recombinant inducible DTR (iDTR) adeno-associated virus (AAV) and CRE transgenic mice and shown behavioral consequences that recapitulate key aspects of TS. With this conceptual background and versatile tool, we are continuing to study the molecular, neurochemical, and behavioral consequences of recapitulating these cellular abnormalities in mouse models.