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

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 总结 脑深部电刺激（DBS）通过慢性脑损伤提供高频电流刺激。 植入电极。DBS已被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、特发性震颤和强迫症。然而，治疗 DBS的机制在很大程度上仍然未知。有许多有趣的假设，但实验证据 是有限的。在过去的20年里，DBS在PD中的使用越来越多，这为以下方面提供了独特的机会： 从患者的各种基底神经节脑结构记录，并积累证据表明， 皮质-基底神经节中过度病理性局部场电位（LFP）β振荡（~10 - 30 Hz） 电路是PD的特征。使用放大的LFP β振荡记录在作为目标功能， 最近的研究表明，闭环DBS可以更有效地缓解灵长类PD模型中的运动不能， 突出了使用病理性β振荡作为PD生物标志物的潜力。 PD的特征在于投射到纹状体的SNpc多巴胺神经元的变性。的事实 DBS在管理运动病理方面是有效的，强调PD涉及神经回路缺陷， 通过电刺激改变以达到治疗效果。这项建议的中心目标是研究 与PD相关的神经回路动力学，以及DBS的治疗机制，使用一种新的单细胞电压 这是韩博士实验室最近开发的成像技术。具体来说，我们将研究如何个人 纹状体神经元阈下膜电压和发放模式与体纹状体LFP振荡的关系 在健康和多巴胺耗尽的PD条件下的自主运动期间，以及DBS如何改变这些 交互.这样的理解将为了解单个神经元之间的关系提供重要的见解 阈下膜电压动态（突触输入的测量）和尖峰输出，并提供直接的 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，这样的见解将有助于建立基于振荡的生物标志物， 疾病，并促进未来的DBS设计。

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.