Rat Model of Brain Stimulation in Parkinsonian Condition

在过去的十年中，脑深部刺激(DBS)被用于临床治疗帕金森病(PD)。然而，DBS治疗作用的神经机制尚不清楚。DBS方法是基于专门在灵长类动物模型上进行的实验而发展起来的。关于DBS治疗效果的许多关键问题需要使用啮齿动物模型来解决。这项建议针对三个目标：第一，建立帕金森病症星形胶质细胞的啮齿动物模型。大鼠将受到单侧注射6-羟基多巴胺破坏黑质纹状体多巴胺系统，从而形成跑步机运动任务所揭示的帕金森病运动缺陷。跑步机将交替开启和关闭20秒。10个刺激电极的阵列将被植入丘脑底核(STN)和黑质网状部(SNR)。在跑步机步行阶段将应用高频刺激(HFS)。将测量HFS对运动的改善，并比较不同刺激参数下STN和SNR刺激的效果。第二个目的是通过监测和比较相同神经元在10天多巴胺耗竭期间的活动，了解运动障碍发展过程中基底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SNR。在行为性大鼠中，将同时记录细胞外尖峰活动。这项研究将检验这一假说，即在多巴胺耗竭期间，基底节的直接和间接通路将以不同但相关的方式做出反应。第三个目的是在上述行为模型中研究DBS治疗作用的神经机制。除了植入上述基底节区域的电极外，还将增加8个刺激电极，以靶向STN和SNR。将记录和分析在行为有效的HFS期间所有四个基底节区域的神经元反应，以揭示HFS对运动行为的影响以及与之相关的基底节神经元活动的变化。这项研究旨在探讨DBS治疗帕金森病的基本机制，从这项实验中获得的信息将对改善DBS对帕金森病和其他运动障碍的效果产生直接影响。

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.