Tourette syndrome (TS) is thought to result from primary genetic/developmental abnormalities, long-term compensatory phenomena, and secondary consequences that influence duration and outcome. Here, we focus on identifying common neurobiological abnormalities and genetic systems that are altered in the basal ganglia and connected brain regions that are involved in the generation of motor and vocal tics associated with TS. Our approach involves comprehensive and multifaceted characterization of gene expression. The goals of this study are to: 1. Conduct RNA sequencing of the caudate/putamen (Cd/Pt) of adults with documented persistent TS symptoms and matched controls; analyze differential gene expression and gene splicing; and perform gene network analyses. This will extend our preliminary data suggesting down-regulation of interneuron-related genes and up-regulation in inflammatory/immune-related genes in the striatum of TS. 2. Conduct parallel analyses of cortical regions both previously implicated and presumed unaffected in TS in order to discover whether differential gene expression signatures are limited to the Cd/Pt, extend to implicated brain regions, or represent global alterations in TS. 3. Conduct parallel analyses of the Cd/Pt in young/adolescent TS cases in order to reveal relationships between neurobiological abnormalities and life history of the disorder. These studies will characterize two levels of regulation that might underlie differences in gene expression profile between TS and controls: mRNA levels and their splicing into different types of transcripts. This study is the first high throughput RNA sequencing analysis of the TS brain, and will provide the means to perform integrative analyses of DNA regulatory elements in the future. The long-term aim is to interpret the nature of the genetic risk by focusing on the neurobiological mechanisms of the disorder. Understanding the regional specificity and time of onset of the neuronal abnormalities may help understand whether they are causing the symptoms or are part of the long-term compensatory mechanisms. Flora M. Vaccarino, M.D., Jessica B. Lennington, Ph.D., and Gianfilippo Coppola, Ph.D. Yale Child Study Center, New Haven, CT Award: $149,301 Tourette Association of America Inc. – Research Grant Award 2014-2015