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

脑深部电刺激（deep brain stimulation， DBS）通过植入电极直接刺激脑组织。DBS已经成为一种完善的治疗方法，FDA批准了几种神经和精神疾病的治疗，并且越来越多地用于各种脑部疾病的治疗。然而，DBS的神经生理机制在很大程度上仍然未知。DBS的治疗结果和时间过程是多种多样的，取决于特定的疾病条件。由于DBS对运动障碍的作用与药物损伤或手术切除目标脑组织一致，DBS首先被认为是抑制局部神经活动，可能是通过膜去极化诱导的动作电位阻断或胶质细胞介导的腺苷释放。然而，电极记录和生物物理模型研究表明，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反向激活或下游突触后神经元的正向激活。另一种理论认为，DBS抑制或调节神经活动，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，但由于电极记录的电干扰，对DBS在大脑中的神经生理作用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，它可以在清醒的哺乳动物行为期间对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。我们将系统探讨DBS在STN、GPi和VIM这三个FDA批准的帕金森病靶点中的细胞和网络机制。我们的中心假设是，DBS在刺激部位和连接回路中都产生了信息损伤，导致病理网络活动的严重破坏，这是DBS治疗机制的基础。

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.