Voltage imaging analysis of striatal network dynamics related to movement, Parkinson's disease and deep brain stimulation

与运动、帕金森病和深部脑刺激相关的纹状体网络动力学的电压成像分析

• 批准号: 10588371
• 负责人: Xue Han
• 金额: $ 8.81万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588371
• 关键词: Address; Affect; Anatomy; Basal Ganglia; Biological Markers; Biophysics; Brain; Brain Diseases; Cells; Chronic; Clinical Research; Corpus striatum structure; Deep Brain Stimulation; Disease model; Dopamine; Dopamine Receptor; Electric Stimulation; Electrophysiology (science); Epilepsy; Essential Tremor; Event; FDA approved; Frequencies; Functional disorder; Future; Goals; Image; Imaging Techniques; Implanted Electrodes; Individual; Link; Measures; Membrane; Mental disorders; Modeling; Motor; Movement; Mus; Neurons; Obsessive-Compulsive Disorder; Optics; Output; Oxidopamine; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Primates; Resolution; Structure; Structure of subthalamic nucleus; Synapses; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; alpha synuclein; base; behavioral study; design; dopaminergic neuron; imaging study; insight; millisecond; motor disorder; mouse model; nervous system disorder; neural circuit; novel; pre-formed fibril; voltage

Title: Voltage imaging analysis of striatal network dynamics related to movement, Parkinson’s disease and deep brain stimulation Summary Deep brain stimulation (DBS) delivers high frequency electrical current stimulation through chronically implanted electrodes. DBS has been FDA approved for managing several brain disorders, including Parkinson’s disease (PD), epilepsy, essential tremor, and obsessive compulsive disorders. However, the therapeutic mechanisms of DBS remain largely unknown. There are many intriguing hypothesis, but experimental evidence has been limited. The increasing use of DBS for PD over the past 20 years has offered a unique opportunity to record from various basal ganglia brain structures in patients, and accumulating evidence suggests that exaggerated pathological local field potential (LFP) beta oscillations (~10-30Hz) in the cortical-basal ganglia circuit are a signature of PD. Using exaggerated LFP beta oscillations recorded in STN as a target feature, a recent study showed that closed-loop DBS could be more effective in alleviating akinesia in primate PD models, highlighting the potential of using pathological beta oscillations as a biomarker for PD. PD is characterized by degeneration of SNpc dopamine neurons that project to the striatum. The fact that DBS is effective at managing motor pathologies highlights that PD involves neural circuit deficits that can be altered by electrical stimulation to achieve therapeutic effects. The central goal of this proposal is to study the neural circuit dynamics related to PD, and the therapeutic mechanisms of DBS, using a novel single cell voltage imaging technique that was recently developed in Dr. Han’s lab. Specifically, we will examine how individual striatal neurons’ subthreshold membrane voltage and spiking patterns relate to bulk striatal LFP oscillations during voluntary movement in healthy and dopamine-depleted PD conditions, and how DBS alters these interactions. Such understanding will provide important insights into the relationship between individual neurons subthreshold membrane voltage dynamics (a measure of synaptic inputs) and spiking outputs, and provide direct experimental evidence linking pathological LFP oscillations with single neuron biophysics, and how DBS affects these relationships. We believe that such insights will help establish oscillation based biomarkers for brain disorders, and facilitate future DBS designs.

标题：与运动、帕金森病相关的纹状体网络动力学的电压成像分析 和深部脑刺激 概括 深部脑刺激（DBS）通过长期的高频电流刺激 植入电极。 DBS 已获得 FDA 批准用于治疗多种脑部疾病，包括帕金森氏症 疾病（PD）、癫痫、原发性震颤和强迫症。然而，治疗 DBS 的机制仍然很大程度上未知。有许多有趣的假设，但实验证据 已受到限制。过去 20 年来，DBS 在 PD 中的应用越来越多，这为我们提供了一个独特的机会： 来自患者各种基底神经节大脑结构的记录，并且积累的证据表明 皮质-基底节中病理性局部场电位 (LFP) β 振荡 (~10-30Hz) 夸大 电路是PD的签名。使用 STN 中记录的夸张的 LFP beta 振荡作为目标特征， 最近的研究表明，闭环 DBS 可以更有效地缓解灵长类 PD 模型的运动不能， 强调了使用病理性β振荡作为PD生物标志物的潜力。 PD 的特征是投射到纹状体的 SNpc 多巴胺神经元变性。事实是 DBS 可有效管理运动病理学，强调 PD 涉及神经回路缺陷，可通过 通过电刺激改变，从而达到治疗效果。本提案的中心目标是研究 使用新型单细胞电压研究与 PD 相关的神经回路动力学以及 DBS 的治疗机制 韩博士实验室最近开发的成像技术。具体来说，我们将研究个人如何 纹状体神经元的阈下膜电压和尖峰模式与大量纹状体 LFP 振荡有关 在健康和多巴胺耗尽的 PD 条件下进行随意运动期间的变化，以及 DBS 如何改变这些变化 互动。这种理解将为了解单个神经元之间的关系提供重要的见解 亚阈值膜电压动态（突触输入的测量）和尖峰输出，并提供直接 将病理性 LFP 振荡与单神经元生物物理学联系起来的实验证据，以及 DBS 如何影响 这些关系。我们相信，这些见解将有助于建立基于振荡的大脑生物标志物 疾病，并促进未来的 DBS 设计。