Rat Model of Brain Stimulation in Parkinsonian Condition

帕金森病大鼠脑刺激模型

• 批准号: 6466054
• 负责人: JING-YU CHANG
• 金额: $ 32.14万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6466054
• 关键词: 6 hydroxydopamine; Parkinson's disease; brain electrical activity; brain mapping; chordate locomotion; disease /disorder model; dopamine; electrostimulus; experimental brain lesion; laboratory rat; lenticular nucleus; nervous system disorder therapy; neural information processing; neural inhibition; neurophysiology; nonhuman therapy evaluation; substantia nigra

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.

在过去的十年中，诊所已使用深脑刺激（DBS）来治疗帕金森氏病（PD）。 然而，DBS治疗作用的基础神经元机制尚待澄清。 DBS方法是根据仅在灵长类动物模型上执行的实验开发的。 关于DBS的治疗效应的许多关键问题需要使用啮齿动物模型来解决。 该提议针对三个目标：首先是为帕金森氏症疾病建立啮齿动物模型。 大鼠将接受单侧6-羟基多巴胺注射以破坏黑质纹状体多巴胺系统，从而形成跑步机运动任务揭示的帕金森氏症运动不足。 跑步机将打开和关闭20秒。 十个刺激电极的阵列将植入丘脑下核（STN）和黑质nigra pars enticulata（SNR）中。 高频刺激（HFS）将在跑步机步行阶段应用。 将测量HFS对运动的改善，并使用不同的刺激参数在STN和SNR刺激之间进行比较。 第二个目标是通过监测和比较相同神经元的活性跨越10天多巴胺耗竭周期，了解运动不足的发展过程中基底神经节系统中的动态神经活动反应。 该实验将使用慢性多通道单单元记录技术。 六十四个电极将植入纹状体，pallidus，STN和SNR中。 细胞外峰活动将同时记录在行为大鼠中。这项研究将检验以下假设：在多巴胺消耗期间，基底神经节的直接和间接途径将以不同但相关的方式做出反应。 第三个目标是研究上述行为模型中介导DBS治疗作用的神经元机制。 除了上述基底神经节区域中植入的64个电极外，还将添加八个刺激电极以靶向STN和SNR。 将记录和分析所有四个基底神经节区域中所有四个基底神经节区域的神经元反应，以揭示HFS对运动行为行为和基底神经神经神经元活性的相关变化的影响。 这项研究旨在解决有关DBS对PD治疗的影响的基本机制，从该实验获得的信息将直接影响改善DBS对PD和其他运动障碍的影响。