Inhibitory microcircuitry coordinates striatal function

描述（由申请人提供）：纹状体（基底神经节的主要输入核）的缺陷是许多神经和运动障碍的基础。肌张力障碍是第三种最常见的运动障碍，仅次于帕金森病和原发性震颤。肌张力障碍的许多治疗集中在基底神经节，包括深部脑刺激，和多巴胺能激动剂或毒蕈碱乙酰胆碱受体（mAChR）拮抗剂的管理。虽然纹状体中的大多数（~95%）神经元是棘投射神经元（SPN），但剩余的5%是GABA能或神经调节中间神经元，它们对局部纹状体网络产生强大的影响。一类纹状体GABA能抑制性中间神经元（小清蛋白阳性快速尖峰中间神经元（FSI））的缺陷导致肌张力障碍和运动障碍。在其他大脑结构中，如皮质和海马，FSI与纹状体中的FSI非常相似，这对前馈抑制至关重要，前馈抑制是一种微电路，可以锐化神经元电路响应的时间并扩大动态范围。然而，我们还不知道纹状体中的FSI是否也起着类似的作用。我假设FSI是纹状体前馈抑制的主要来源，并且mAChRs对这种前馈微回路的调制深刻地影响了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FSI对急性切片制备中皮质-纹状体前馈抑制的贡献，（2）定义调制 纹状体前馈微电路的mAChR，和（3）使用在体内生理学和药理学来探索潜在的机制，肌张力障碍和运动障碍引起的纹状体mAChR激活。基于mAChR有效抑制皮质-纹状体前馈抑制的初步证据，我假设mAChR对纹状体网络的去抑制导致网络活动紊乱。此外，我推测，这种混乱的网络活动导致增加的异常不自主运动的特点mAChR诱导的肌张力障碍和运动障碍。通过探索这些现象中涉及的微电路机制和mAChR亚型，我的目标是建立从纹状体FSI到皮质-纹状体前馈抑制，到mAChR调制，到肌张力障碍的机制性因果联系。这种机制可以解释为什么mAChR拮抗剂在治疗人类患者的肌张力障碍中是有效的，并可能提供新的治疗方式的见解，以利用这些药物的有益作用，同时限制其使人衰弱的副作用。

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.