Rat Model of Brain Stimulation in Parkinsonian Condition

在过去的十年中，脑深部电刺激（DBS）已被用于临床治疗帕金森病（PD）。然而，DBS治疗效果背后的神经元机制尚不清楚。DBS方法是在专门针对灵长类动物模型的实验基础上发展起来的。关于DBS治疗效果的许多关键问题需要通过啮齿动物模型来解决。本课题主要有三个目的：一是建立帕金森病的DBS啮齿动物模型。大鼠单侧注射6-羟多巴胺破坏黑质纹状体多巴胺系统，从而产生帕金森运动缺陷。跑步机将交替开启和关闭20秒。在丘脑下核（STN）和网状黑质（SNr）植入10组刺激电极。在跑步机行走阶段将使用高频刺激（HFS）。将测量HFS对运动的改善效果，并比较使用不同刺激参数的STN和SNr刺激的效果。第二个目的是通过监测和比较同一神经元在10天多巴胺耗竭期的活动，了解运动缺陷发生过程中基底神经节系统的动态神经活动反应。本实验将采用慢性多通道单单元记录技术。64个电极将被植入纹状体、苍白球、STN和信噪比。同时记录有行为的大鼠的细胞外尖峰活动。本研究将验证基底神经节的直接和间接通路在多巴胺耗竭过程中以不同但相关的方式作出反应的假设。第三个目标是在上述行为模型中研究DBS治疗效果的神经元机制。除上述基底节区植入64个电极外，还将增加8个刺激电极，以STN和信噪比为目标。我们将记录并分析在行为有效高强度刺激过程中所有四个基底节区的神经元反应，以揭示高强度刺激对运动行为的影响以及基底节区神经元活动的相关变化。本研究旨在探讨DBS治疗PD的基本机制，本实验获得的信息将对提高DBS治疗PD及其他运动障碍的效果有直接影响。

Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson's disease (PD) during the past decade. The neuronal mechanisms underlying the therapeutic effects of DBS, however, are yet to be clarified. DBS methods have been developed based on the experiments performed exclusively on primate model. Many critical issues regarding the therapeutic effects of DBS need to be addressed using a rodent model. This proposal is aimed at three objectives: first is to establish a rodent model of DBS for Parkinsonian conditions. The rat will be subjected to unilateral 6-hydroxydopamine injection to destroy nigrostriatal dopamine system and thus develop a Parkinsonian motor deficit revealed by treadmill locomotion task. Treadmill will be turned on and off 20 seconds alternatively. Array of ten stimulation electrodes will be implanted in the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). High frequency stimulation (HFS) will be applied during the treadmill walking phase. The improvement on locomotion by HFS will be measured and the effects will be compared between STN and SNr stimulations using different stimulation parameters. Second objective is to understand the dynamic neural activity responses in the basal ganglia system during the development of motor deficit by monitoring and comparing the activities from same neurons cross 10 day dopamine depletion period. Chronic multi- channel, single-unit recording technique will be used in this experiment. Sixty-four electrodes will be implanted in the striatum, globus pallidus, STN, and SNr. Extracellular spike activity will be recorded simultaneously in the behavioral rat. This study will test the hypothesis that direct and indirect pathways of basal ganglia will respond in different yet correlated manners during dopamine depletion. Third objective is to study the neuronal mechanisms mediating therapeutic effects of DBS in the behavioral model described above. In addition to the 64 electrodes implanted in the basal ganglia regions mentioned above, eight more stimulation electrodes will be added to target the STN and SNr. The neuronal responses in all four basal ganglia regions during behavioral effective HFS will be recorded and analyzed to reveal the effects of HFS on motor behavioral and associated changes in basal ganglia neuronal activity. This study is designed to address the fundamental mechanisms regarding the effects of DBS on treating PD and the information obtained from this experiment will have direct impact on improving the effects of DBS on PD and other movement disorders.