DESCRIPTION (provided by applicant): Defects in the striatum, the major input nucleus of the basal ganglia, underlie a number of neurological and movement disorders. Dystonia is the third most common movement disorder, after Parkinson's disease and essential tremor. Many treatments for dystonia are focused on the basal ganglia, including deep brain stimulation, and administration of dopaminergic agonists or muscarinic acetylcholine receptor (mAChR) antagonists. While most (~95%) of the neurons in the striatum are Spiny Projection Neurons (SPNs), the remaining 5% are GABAergic or neuromodulatory interneurons that exert a powerful influence over the local striatal network. Defects in one class of striatal GABAergic inhibitory interneurons, the Parvalbumin-positive Fast-Spiking Interneurons (FSIs), lead to dystonia and dyskinesias. In other brain structures such as cortex and hippocampus, FSIs closely resembling those in the striatum are essential for feed-forward inhibition, a type of microcircuit that sharpens the timing and expands the dynamic range of neuronal circuit responses. It us unknown, however, whether FSIs in the striatum play a similar role. I hypothesize that FSIs are the primary source of feed-forward inhibition in the striatum, and that modulation of this feed-forward microcircuit by mAChRs profoundly influences motor behavior relevant to dystonia. Under the supervision of Dr Anatol Kreitzer, I will test this hypothesis by () using physiology, pharmacology and optogenetics to directly measure the contribution of FSIs to cortico-striatal feed-forward inhibition in an acute slice preparation, (2) defining the modulation of striatal feed-forward microcircuitry by mAChRs, and (3) using in vivo physiology and pharmacology to probe the mechanisms underlying dystonia and dyskinesias induced by striatal mAChR activation. I hypothesize, based on preliminary evidence that mAChRs potently suppress cortico-striatal feed- forward inhibition, that disinhibition of the striatal network by mAChRs leads to disorganized network activity. Furthermore, I hypothesize that this disorganized network activity causes the increased abnormal involuntary movements that characterize mAChR-induced dystonia and dyskinesias. By probing the microcircuit mechanisms and mAChR subtypes involved in each of these phenomena, my goal is to establish a mechanistic, causal link from striatal FSIs, to cortico-striatal feed-forward inhibitio, to mAChR modulation, to dystonia. This mechanism may explain why mAChR antagonists are effective in treatment of dystonia in human patients, and potentially provide insight into new treatment modalities to harness the beneficial effects of these drugs while limiting their debilitating side effects.

PUBLIC HEALTH RELEVANCE: The aim of this project is to understand how mis-regulation of the microcircuitry within a brain structure called the basal ganglia can lead to devastating movement disorders such as dystonia and dyskinesias. Dystonia is the third most common movement disorder in America, after Parkinson's Disease and Essential Tremor, but we understand very little about the underlying origins of this disease or how to treat it. The experiments outlined in this proposal will improve our understanding of the cell types involved in dystonia, and how specific interventions that target these cell types might contribute to treatment of this disorder.