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态的电压成像分析

• 批准号: 10597209
• 负责人: Xue Han
• 金额: $ 39.6万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597209
• 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; behavioral study; design; dopaminergic neuron; imaging study; insight; millisecond; motor disorder; mouse model; nervous system disorder; neural circuit; novel; pre-formed fibril; segregation; 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：与运动有关的纹状体网络动态的电压成像分析，帕金森氏病 和大脑刺激 概括 深脑仿真（DB）通过长期传递高频电流模拟 植入电极。 DBS已获得FDA批准管理多种脑部疾病，包括帕金森氏症 疾病（PD），癫痫，必需树和强迫性疾病。但是，治疗性 DBS的机制在很大程度上尚不清楚。有许多有趣的假设，但实验证据 有限。在过去的20年中，DBS越来越多地使用DBS，为PD提供了独特的机会 来自患者的各种基底神经节脑结构的记录，并积累证据表明 夸张的病理局部场电位（LFP）Beta振荡（〜10-30Hz） 电路是PD的签名。使用在STN中记录的夸张的LFP Beta振荡作为目标特征，A 最近的研究表明，闭环DBS可以在减轻灵长类动物PD模型中更有效， 强调使用病理β振荡作为PD的生物标志物的潜力。 PD的特征是将纹状体的SNPC多巴胺神经元变性。事实 DBS有效地管理电动病理突出显示PD涉及神经回路的定义可以是 通过电刺激改变以实现治疗作用。该提议的核心目标是研究 使用新型的单细胞电压，与PD有关的神经回路动力学和DBS的治疗机制 最近在Han博士实验室开发的成像技术。具体来说，我们将研究个人 纹状体神经元的子阈值膜电压和尖峰模式与散装纹状体LFP振荡有关 在健康和多巴胺耗尽的PD条件下自愿运动期间，DBS如何改变这些 互动。这种理解将为单个神经元之间的关系提供重要的见解 亚阈值膜电压动力学（突触输入的度量）和尖峰输出，并提供直接 实验证据将病理LFP振荡与单个神经元生物物理学联系起来，DBS如何影响 这些关系。我们认为，这种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。