Dynamics of Corticostriatal Regulation of Repetitive Stereotypical Movements

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pittsburgh
Investigators Name
Homayoun, Houman, MD

Repetitive tics constitute an important aspect of Tourette Syndrome (TS). Although tics are generally believed to result from miscommunication between cortical regions and basal ganglia, the cellular processes underlying their expression are not well understood. Recent evidence suggests that prefrontal cortex (PFC) may play a critical role in the regulation of tic expression. PFC pathology has been implicated in TS as well as in its co-morbid disorders (attention- deficit hyperactivity disorder and obsessive compulsive disorder). PFC is thought to play a critical role in coordinating motor behaviors based on affective and cognitive information. For example, a disruption in the regulatory function of PFC as a result of stress, may reduce regulatory control of PFC over basal ganglia function and cause the emergence of involuntary movements and behaviors. Thus, a better understanding of the factors that govern the interplay between basal ganglia and PFC would help us develop more efficient strategies to treat tics and related behavioral symptoms of TS. In this context, a critical question is how abnormal activity of neuronal networks in the PFC and basal ganglia interact to produce tics. One of the difficulties in addressing this question is that these regional networks consist of a large number of neurons that form distinct functional subsets (ensembles) encoding for different behaviors. To address this problem, we propose to monitor the electrophysiological activity of a large number of neurons simultaneously in basal ganglia and PFC during tic-like behaviors. We plan to use two pharmacological models known to induce stereotypical tic-like behaviors in rats. The first model, based on NMDA receptor blockade, is relevant to tic-like behaviors originating from PFC malfunction. The second model, based on dopamine receptor activation, is a more standard model predictive of the clinical efficacy of available and potential anti-tic therapies. We will characterize the functional interaction between PFC and striatal neurons that are relevant to expression of stereotypical behaviors in these two models. The effects of dopamine antagonists, a standard class of anti-tic drugs, as well as cortical inactivation will be investigated in this interaction. It is anticipated that these experiments will help to identify the role of cortical and striatal neuronal ensembles in the expression and inhibition of stereotypical behavior, and may prove helpful for defining novel functional targets for therapeutic strategies used in Tourette Syndrome. Houman Homayoun, M.D. University of Pittsburgh, Pittsburgh, Pennsylvania Award: $40,000 Tourette Association of America Inc. – Research Grant Award 2005-2006