ABSTRACT The circuit mechanisms that cause dystonia are poorly understood. A prominent hypothesis is that dystonia is caused by aberrant plasticity within motor structures, especially cortical-basal ganglia circuits. The lack of a suitable animal model is a critical barrier to progress. Our preliminary data indicate that we have developed a strategy to generate the first rodent model of human task specific dystonia by uniquely combining genetic and behavioral manipulations. This strategy is based on observations suggesting that dystonia requires “two hits”: a genetic predisposition to abnormal plasticity and a plasticity-inducing environmental trigger (e.g., repetition of specific dexterous movements as with musician's dystonia). We modeled the genetic predisposition with our established model of DYT1 dystonia, caused by inherited mutation in the gene encoding torsinA. TorsinA mutant “Dlx-CKO” mice do not show abnormal movements at baseline, but exhibit selective abnormalities of striatal cholinergic interneurons (ChIs), providing a substrate for striatal dysfunction. Strikingly, Dlx-CKO mice trained to repetitively perform a dexterous paw reaching task develop abnormal, phasic, dystonic-like movements. In contrast, these mice do not develop abnormal movements after repetitively performing a non-dexterous rotarod task. This proposal will focus on establishing the validity and utility of this long-sought model of dystonia. We hypothesize that abnormal function of ChIs in the setting of repetitive dexterous limb movements causes abnormal striatal activity which leads to task- specific dystonic-like movements in Dlx-CKO mice. We will test this hypothesis with three Specific Aims. In Aim 1, we will define the necessary and sufficient behavioral conditions for these mice to develop abnormal movements, and attempt to extend our findings to DYT1 knock-in mice. In Aim 2, we will examine striatal electrophysiology as these movements develop. In translational Aim 3, we will use chemogenetic technology to selectively manipulate ChI activity in Dlx-CKO mice to determine whether modulation of this specific cell type can suppress dystonic-like movements and to define the striatal mechanism of these effects. Successful completion of these Aims will establish a unique model of task specific dystonia with high construct, face and predictive validity. This model will exert a powerful impact on the dystonia community by allowing detailed study of network mechanisms in dystonia and suggesting novel therapeutic approaches. More generally, this model will improve understanding of normal interactions between extrapyramidal and pyramidal motor systems, with broad relevance for a range of movement disorders.