Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the combination of episodes of motor and vocal tics. Post-mortem studies show reproducible cellular abnormalities in the basal ganglia of TS patients, including significant changes in the population size of different group of interneurons. Among these changes, a 50-60% loss of cholinergic expressing GABAergic interneurons of the striatum has been observed. Interestingly, cholinergic interneurons are thought to play a key role in coordinating adaptive responses in part by disrupting and/or reorienting ongoing behavior. This assumption comes from their connectivity within the corticobaso-thalamo-cortical loop, and their physiological responses to behaviorally significant stimuli. However, there are no experimental data showing that changes in cholinergic interneurons activity regulate behavioral adaptation, and consequently no data supporting the hypothesis that their loss might be causally linked to TS. Therefore, in order to better understand the function of striatal cholinergic interneurons, our project aims at characterizing their electrophysiological response in behaving animals, and the effects of their inactivation. To achieve these goals, we will use an optogenetic approach in ChAT-Cre transgenic mice to transiently inhibit cholinergic interneurons in the striatum. In a maze, these animals will be trained to perform a ‘cued’ simple reaction time task. In order to receive a reward, animals will be trained to quickly react to a light signal and make a correct turn towards one of the two arms of the maze. An unpredictable conflicting stimulus will prompt the animal to inhibit its ongoing response and switch to the opposite arm to receive the reward. To assess the role of striatal cholinergic interneurons, we will characterize their electrophysiological responses to the various stimuli presented in the task. We will then determine the behavioral effects of the disruption of their responses by means of reversible transient optogenetic inhibition. Sebastien N. Lopez, Ph.D. & Tibor Koos, Ph.D. Rutgers University, Newark, NJ Award: $40,000 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2013-2014