Inhibitory microcircuitry coordinates striatal function

描述（由申请人提供）：纹状体缺陷，基底神经节的主要输入核，是许多神经和运动障碍的基础。肌张力障碍是继帕金森氏症和特发性震颤之后的第三种最常见的运动障碍。肌张力障碍的许多治疗都集中在基底节区，包括深部脑刺激、多巴胺能激动剂或毒蕈碱乙酰胆碱受体拮抗剂。纹状体中的大多数神经元（约95%）是刺突神经元（SPNs），其余5%是gaba能或神经调节中间神经元，它们对局部纹状体网络施加强大的影响。一类纹状体gaba能抑制性中间神经元，即parvalbumin阳性的快速spike中间神经元（FSIs）的缺陷会导致肌张力障碍和运动障碍。在大脑皮层和海马体等其他大脑结构中，fsi与纹状体中的fsi非常相似，它们对于前馈抑制至关重要，前馈抑制是一种微电路，可以使神经元回路反应的时间变快，并扩大其动态范围。然而，纹状体中的fsi是否起着类似的作用尚不清楚。我假设FSIs是纹状体前馈抑制的主要来源，并且通过machr对前馈微电路的调节深刻地影响与肌张力障碍相关的运动行为。在Anatol Kreitzer博士的指导下，我将通过（）使用生理学、药理学和光遗传学直接测量FSIs对急性切片制备中皮质纹状体前反馈抑制的贡献来验证这一假设，(2)定义调节

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.