Inhibitory microcircuitry coordinates striatal function

描述(由申请人提供)：纹状体的缺陷，纹状体是基底神经节的主要输入核，是许多神经和运动障碍的基础。肌张力障碍是仅次于帕金森氏症和特发性震颤的第三大常见运动障碍。许多治疗肌张力障碍的方法都集中在基底节，包括脑深部刺激和应用多巴胺能激动剂或M胆碱受体拮抗剂。纹状体中的大部分神经元(~95%)是脊髓投射神经元(SPN)，其余5%是GABA能或神经调制中间神经元，它们对局部纹状体网络产生强大的影响。其中一类纹状体GABA能抑制型中间神经元--小白蛋白阳性快速尖峰中间神经元(FSIS)的缺陷会导致肌张力障碍和运动障碍。在皮质和海马体等其他大脑结构中，与纹状体中的FSIS非常相似的FSIS对于前馈抑制是必不可少的，前馈抑制是一种微电路，可以提高时序并扩大神经元电路反应的动态范围。然而，我们还不知道纹状体中的FSIS是否起到了类似的作用。我推测FSIS是纹状体前馈抑制的主要来源，mAChRs对这个前馈微回路的调节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、药理学和光遗传学来直接测量FSIS在急性切片制备中对皮质-纹状体前馈抑制的贡献，(2)定义调制，来检验这一假设 (3)利用体内生理学和药理学方法，探讨纹状体mAChR激活引起的肌张力障碍和运动障碍的机制。我假设，基于mAChRs有效抑制皮质-纹状体前馈抑制的初步证据，mAChRs解除对纹状体网络的抑制会导致网络活动紊乱。此外，我假设这种无组织的网络活动导致异常非自主运动增加，这是mAChR诱导的肌张力障碍和运动障碍的特征。通过探索这些现象涉及的微电路机制和mAChR亚型，我的目标是建立从纹状体FSIS到皮质-纹状体前馈抑制，再到mAChR调节，再到肌张力障碍的机械性因果联系。这一机制可能解释为什么mAChR拮抗剂在治疗人类患者肌张力障碍方面有效，并有可能为新的治疗方式提供洞察，以利用这些药物的有益作用，同时限制其衰弱的副作用。

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.