Inhibitory microcircuitry coordinates striatal function

抑制性微电路协调纹状体功能

• 批准号: 8826591
• 负责人: Scott Owen
• 金额: $ 5.42万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826591
• 关键词: Acute; Adverse effects; Agonist; Americas; Animal Model; Anti-Cholinergics; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Chronic; Clinic; Complement; Conflict (Psychology); Corpus striatum structure; Coupled; Deep Brain Stimulation; Defect; Development; Disease; Disinhibition; Dopamine Agonists; Dyskinetic syndrome; Dystonia; Ensure; Equilibrium; Essential Tremor; Functional disorder; Gilles de la Tourette syndrome; Goals; Health; Hippocampus (Brain); Human; Huntington Disease; Interneuron function; Interneurons; Intervention; Knockout Mice; Lead; Link; Measures; Modality; Molecular; Monitor; Motor; Motor Activity; Movement; Movement Disorders; Muscarinic Acetylcholine Receptor; Muscle; Neurons; Parkinson Disease; Parvalbumins; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Preparation; Receptor Activation; Regulation; Reporting; Role; Slice; Source; Structure; Supervision; Synapses; Synaptic Transmission; Testing; Time; abnormal involuntary movement; base; cell type; feeding; improved; in vivo; insight; nervous system disorder; neuronal circuitry; neuroregulation; operation; optogenetics; receptor; research study; response; treatment strategy

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.

描述（由申请人提供）：纹状体中的缺陷，基底神经节的主要输入核，是许多神经系统和运动障碍的基础。肌张力障碍是仅次于帕金森氏病和基本震颤的第三大常见运动障碍。许多有关肌张力障碍的治疗方法都集中在基底神经节上，包括深脑刺激以及多巴胺能激动剂或毒蕈碱乙酰胆碱受体（MACHR）拮抗剂的给药。尽管纹状体中的大多数神经元中的大多数（〜95％）是棘突投射神经元（SPN），但其余5％是GABA能或神经调节性中间神经元，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的缺陷，白蛋白阳性阳性快速刺激性中间神经元（FSIS）导致肌张力障碍和dyskinesias。在其他大脑结构（例如皮层和海马结构）中，FSI非常类似于纹状体中的FSI对于馈送前向抑制至关重要，这是一种微电路，可以使时间升高并扩大神经元电路反应的动态范围。然而，我们未知的纹状体中的FSI是否起着类似的作用。我假设FSI是纹状体中饲喂前向前抑制的主要来源，而MACHR对这种饲喂前路的调节深刻影响与肌张力障碍有关的运动行为。在Anatol Kreitzer博士的监督下，我将使用（）使用生理学，药理学和光遗传学来检验该假设，以直接测量FSIS对急性切片制备中的Cortico-riatico-Striatico-ratiatico for-ford抑制作用的贡献，（2）定义调节 MACHRS的纹状体喂养微电路，以及（3）使用体内生理学和药理学来探测纹状体MACHR激活引起的肌张力障碍和动态障碍的机制。我假设基于初步证据表明，MACHR有效抑制皮质 - 纹状体饲料向前抑制作用，MACHRS对纹状体网络的抑制会导致混乱的网络活动。此外，我假设这种混乱的网络活动会导致异常的非自愿运动，这些运动表征了MACHR诱导的肌张力障碍和运动障碍。通过探测每种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的机械性，因果关系，再到Cortico-Striatico-ratiatico-ratiatico forward forward抑制作用，再到MACHR调制，再到肌张力障碍。这种机制可以解释为什么MACHR拮抗剂有效地治疗人类患者的肌张力障碍，并有可能洞悉新的治疗方式，以利用这些药物的有益作用，同时限制其使其令人衰弱的副作用。