Basal Ganglia Neurophysiology during DBS in Rats

描述（由申请人提供）： 帕金森病（PD）是一种退行性神经系统疾病，影响着全世界数百万患者。脑深部电刺激（DBS）方法的重新使用为治疗PD提供了新的机会。改善治疗的关键问题是充分理解DBS治疗效果的神经机制。在这项拟议的研究中，我们的实验室开发的两个独特的技术：慢性多通道单单位记录和DBS大鼠模型，将被用来研究在多个基底节区的神经反应，在行为有效的DBS在帕金森病大鼠模型。第一个目标是建立帕金森病条件下DBS的啮齿动物模型。将在进行跑步机运动和肢体使用不对称测试的多巴胺损伤大鼠中评价DBS的作用。单侧多巴胺损害后，会出现踏车行走时的运动障碍和垂直探索行为时前肢使用不平衡。然后将应用丘脑底核（subthalamic nucleus，HFS）和黑质网状部（substantia nigra pars reticulata，SNr）的高频刺激（High frequency stimulation，HFS）来缓解这些运动异常。通过多巴胺标记物的免疫组织化学染色检测基底神经节中多巴胺耗竭的程度，该结果将与运动缺陷的严重程度和DBS效应相关。其次，将检查多巴胺损伤后和行为有效HFS期间的基底神经节神经反应。在进行这些行为测试的大鼠中，将在64通道记录系统中同时记录纹状体苍白球、黑质和SNr中的单个神经活动和局部场电位。多巴胺损伤后的神经反应将有助于我们理解帕金森综合征的病理生理过程，而行为有效HFS期间的神经反应将揭示DBS如何恢复多巴胺损伤后被破坏的基底节神经回路的正常信息处理。将与Biographic Inc.合作，对记录和刺激技术进行几项重要改进。以实现高频刺激和无伪影记录的最佳条件。本研究的目的是探讨DBS治疗PD的神经机制，为进一步提高DBS治疗PD的临床效果提供理论依据。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a degenerative neurological disorder affecting millions of patients all around the world. Renewed use of the deep brain stimulation (DBS) method provides a new opportunity for treating PD. A key issue to improve the treatment is to fully understand the neural mechanisms underlying the therapeutic effects of DBS. In this proposed study, two unique techniques developed in our laboratory: the chronic multiple-channel single unit recording and rat model of DBS, will be employed to study the neural responses in multiple basal ganglia regions during behaviorally effective DBS in rat model of Parkinsonism. A first objective is to establish a rodent model of DBS in Parkinsonian conditions. The effects of DBS will be evaluated in dopamine lesioned rats performing treadmill locomotion and limb use asymmetry tests. Locomotor d deficits during treadmill walking and imbalance usage of forelimb in vertical exploratory behaviors will develop after unilateral dopamine lesion. High frequency stimulation (HFS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) will then be applied to alleviate these motor abnormalities. The degree of dopamine depletion in the basal ganglia will be detected by immunohistochemical staining of dopamine marker and this result will be correlated with the severity of motor deficits and DBS effects. Second, the basal ganglia neural responses following a dopamine lesion and during behaviorally effective HFS will be examined. Single neural activity and local field potential in the striatum globus pallidus, STN and SNr will be recorded simultaneously in a 64 channel recording system in the rat performing these behavioral tests. Neural responses following dopamine lesion will help us to understand the pathophysiologic process of developing Parkinsonian syndromes while the neural responses during behaviorally effective HFS will shed light on how DBS can restore normal information processing in the basal ganglia neural circuits that are disrupted following dopamine lesion. Several important improvements on recording and stimulation techniques will be made in cooperation with Biographic Inc. to achieve optimal conditions for high frequency stimulation and artifact free recording. The goal of this study is to explore the basic neural mechanism underlying the therapeutic effects of DBS and the knowledge obtained form this study will help us to improve the clinical treatment of PD with DBS method.