DESCRIPTION (provided by applicant): Primary dystonias are disabling neurological conditions which begin in the prime of patients' lives. Scientists have identified genes involved i some inherited forms of the disease, but little is known about the pathophysiology, and at present treatments is limited and symptomatic in nature. As the brains of such patients show no neuropath logical abnormalities, it is hypothesized that dystonia is a disease of abnormal circuit activity. This proposal is aimed at dissecting the circuitry of one of the key movement control centers, the striatum, in a mouse model of dystonia. In examining the striatal circuitry, we hope to identify new targets for therapeutic development in dystonia as well as other hyperkinetic movement disorders. We propose to use several novel tools to better understand circuit dysfunction in dystonia. First, we plan to use a new mouse model of a human dystonia, paroxysmal nonkinesigenic dyskinesia (PNKD), which is one of very few animal models that recapitulate the clinical features of human dystonia. Second, we plan to employ a new experimental tool, ontogenetic, which allows researchers to control the activity of specific cell populations in the brain. In Aim 1, we will use ontogenetic and in vivo electrophysiology to identify the pathological firing patterns of striatal neurons in awake-behaving PNKD mice, and for the first time distinguish how differences in the activity of direct-pathway and indirect- pathway neurons contribute to dystonia. In Aim 2, we will use in vitro electrophysiology to determine the cellular and synaptic substrate for the pathological firing patterns identified in PNKD mice in vivo. Finally, in Aim 3, we will take what we have learned from both in vivo and in vitro studies of dystonic mice to determine what aspects of aberrant striatal activity are necessary and sufficient to cause dystonia, by using ontogenetic in behaving animals. We will also ontogenetically modify striatal firing patterns to reduce or eliminate the symptoms of dystonia in PNKD mice. Overall, we are hopeful this line of research will not only shed light on long-held theories about basal ganglia circuit dysfunction in dystonia, but will yield new areas fo therapeutic development. I am a physician-scientist with a strong commitment to a career in academic neurology, focused on identifying the circuit basis of neurological disease. I combine PhD and postdoctoral training in neurophysiology with subspecialty training in behavioral neurology and movement disorders. The career development entailed in this research proposal will bring my skills into mouse models of neurological disease and cultivate cutting-edge neurophysiological and optogenetic techniques as a means of understanding and disrupting abnormal patterns of neural activity. The mentoring entailed in this proposal will provide me the scientific and professional resources to continue my own development as an investigator, enabling me to submit competitive grant applications and lead my own laboratory in the future.

PUBLIC HEALTH RELEVANCE: This career development proposal brings together a candidate with superb prior training in neurophysiology and neurology with a team of mentors and advisors who are extremely accomplished in basal ganglia neurophysiology, mouse models of human movement disorders, circuit level pathophysiology, and the use of optogenetic to understand and treat neurological disease. The research in this proposal will address whether abnormal patterns of neural activity in the basal ganglia produce dystonia in a new mouse model of the human disease.