Investigating Habitual Behavior and Dopamine Dysregulation in Tourette Syndrome

Abstract: Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by urges to perform tics which are repetitive, stereotyped, and uncontrollable movements or sounds. The CDC estimates that TS and related chronic tic disorders affect ~1 in 50 children. Despite the high prevalence, the underlying neuropathology is poorly understood. A lack of preclinical animal models is a large reason for this current impasse in TS research. This grant proposes a new way to overcome this barrier using novel mouse models generated in our lab that express orthologous human mutations identified in a high-confidence TS gene, CELSR3. Preliminary data shows these mice exhibit tic-like stereotypies in the open field, with sex-dependent variable expressivity, and also changes to striatal dopamine. Leveraging these novel mice with construct and face validity, I will test the hypothesis that tics are associated with changes to habit formation and dopamine signaling. Habits and tics are highly similar: they are both repetitive, stereotyped, and automated actions that once formed are hard to break. It is proposed in TS that a potentiation of sensorimotor inputs onto striatal circuits regulating habit formation along with potentially weaker engagement of circuits controlling goal-directed behavior may predispose individuals to develop ‘tic-habits’. Further, ‘tic-habits’ may be perpetuated by aberrant DA signaling, which reinforces and motivates these learned behaviors. Human studies have demonstrated that TS probands develop habits quicker, an effect not seen in medicated probands on DA stabilizers (aripiprazole). Additionally, habit reversal therapy is proven to help decrease tics in ~40% of TS subjects, further suggesting a link between habits and tics. However, these findings have yet to be tested and confirmed in animal models, and the neurodevelopmental circuit changes regulating habit formation in TS remain uninvestigated. Similar to human findings, my preliminary data suggests Celsr3 TS mice form habits faster and have difficultly breaking them (akin to difficulty seen in ceasing to tic). Interestingly, some tic-like stereotypies are more pronounced in female mice, suggesting sex-differences need to be explored. Thus, I hypothesize Celsr3 TS mice will demonstrate enhanced habitual responding and changes to DA signaling during early stages of habit formation, which may be influenced by sex. I also hypothesize that these phenotypes will be normalized with aripiprazole, as observed in human subjects. In Aim 1, I will use instrumental learning paradigms to test if habit formation and goal-directed behaviors are enhanced and/or weakened, respectively. Deciphering potential circuit imbalances between these two systems will provide insight into neurodevelopmental circuit changes proposed in TS. In Aim 2, I will use in vivo imaging and fiber photometry to investigate DA signaling while mice form habits. I will also administer aripiprazole to test if I can normalize habitual behavior to control levels. These experiments will be the first to investigate habit formation and DA dysregulation in TS using bona fide TS mouse models with true construct and face validity. These results will help explain the neurobiological basis of tics, helping to improve treatment strategies.