Optical voltage imaging analysis of the cellular and network mechanisms of deep brain stimulation

深部脑刺激的细胞和网络机制的光电压成像分析

• 批准号: 10558965
• 负责人: Xue Han
• 金额: $ 202.37万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558965
• 关键词: Action Potentials; Adenosine; Area; Axon; Basal Ganglia; Behavior; Behavioral; Biological Markers; Brain; Brain Diseases; Brain region; Cells; Clinic; Clinical; Corpus striatum structure; Deep Brain Stimulation; Development; Disease; Dopamine; Dyskinetic syndrome; Electric Stimulation; Electrodes; Excision; FDA approved; Frequencies; Image; Implanted Electrodes; Individual; Lead; Lesion; Mammals; Measures; Mediating; Membrane; Mental disorders; Morphologic artifacts; Motor Cortex; Movement; Movement Disorders; Mus; Neuroglia; Neurons; Optics; Parkinson Disease; Pathologic; Pattern; Performance; Pharmacology; Physiologic pulse; Process; Site; Study models; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; awake; base; biophysical model; brain tissue; fluorescence imaging; motor deficit; mouse model; nervous system disorder; neural circuit; neuronal cell body; neurophysiology; neurotransmitter release; optogenetics; postsynaptic neurons; recruit; relating to nervous system; side effect; success; theories; therapy outcome; voltage

Optical voltage imaging analysis of the cellular and network mechanisms of deep brain stimulation Deep brain stimulation (DBS) directly stimulates brain tissue via implanted electrodes. DBS has emerged as a well-established therapy, FDA approved for several neurological and psychiatric disorders, and is increasingly explored for a variety of brain diseases. However, the neurophysiological mechanisms of DBS remain largely unknown. DBS therapeutic outcomes and time courses are diverse and depend on the specific disease conditions targeted. Since DBS effect for movement disorders is consistent with pharmacological lesion or surgical removal of the target brain tissue, DBS was first thought to inhibit local neural activity, likely via membrane depolarization induced action potential blockade or glia mediated adenosine release. However, electrode recordings and biophysical modeling studies suggest that electrical pulses can directly excite axons leading to antidromic activation of neurons projecting to the stimulated area or orthodromic activation of downstream postsynaptic neurons. An alternative theory is that DBS entrains or paces neural activity which interferes with individual neuron’s responding to synaptic inputs and thereby creates information lesion that disrupts pathological network patterns. While these theories are attractive, direct experimental testing of the neurophysiological effects of DBS in the brain has been challenging due to electrical interference on electrode-based recordings. Recently, we pioneered the development of a high-performance genetically encoded voltage indicator SomArchon, which allows optical fluorescence imaging of membrane voltage from individual neurons in awake mammals during behavior. In this study, we will measure the real-time neuronal effect of DBS by performing optical membrane voltage imaging using SomArchon, free of electrical stimulation artifact. We will systematically probe the cellular and network mechanisms of DBS in STN, GPi and VIM, the three FDA approved targets for Parkinson’s disease. Our central hypothesis is that DBS creates information lesion both at the stimulation sites and in the connected circuits, leading to potent disruption of pathological network activities, which underlies the therapeutic mechanisms of DBS.

脑深部电刺激的细胞和网络机制的光电压成像分析脑深部电刺激（DBS）通过植入电极直接刺激脑组织。DBS已成为一种成熟的治疗方法，FDA批准用于多种神经和精神疾病，并越来越多地用于各种脑部疾病。然而，DBS的神经生理学机制在很大程度上仍然未知。DBS治疗结果和时间进程是不同的，并取决于特定的疾病条件的目标。由于DBS对运动障碍的作用与靶脑组织的药理学损伤或手术切除一致，因此DBS首先被认为可能通过膜去极化诱导的动作电位阻滞或神经胶质介导的腺苷释放抑制局部神经活动。然而，电极记录和生物物理建模研究表明，电脉冲可以直接激发轴突，导致投射到受刺激区域的神经元的逆向激活或下游突触后神经元的顺向激活。另一种理论是DBS会引起或调节神经活动，干扰单个神经元对突触输入的反应，从而产生破坏病理网络模式的信息损伤。虽然这些理论很有吸引力，但由于对基于电极的记录的电干扰，DBS在大脑中的神经生理学效应的直接实验测试一直具有挑战性。最近，我们率先开发了一种高性能的遗传编码电压指示器SomArchon，它允许在行为过程中对清醒哺乳动物中单个神经元的膜电压进行光学荧光成像。在这项研究中，我们将通过使用SomArchon进行光学膜电压成像来测量DBS的实时神经元效应，没有电刺激伪影。我们将系统地探索DBS在帕金森病的三个FDA批准的靶点-我们的中心假设是DBS在刺激部位和连接的回路中产生信息损伤，导致病理网络活动的有力破坏，这是DBS治疗机制的基础。