电针调控皮层-基底节通路的异常活动在改善帕金森病大鼠运动症状中的作用研究

Previous results have proved that high frequency electro-acupuncture (EA) stimulation could alleviate motor symptoms in parkinsonian rats. However, the mechanisms of EA on the central nervous systems are unclear. Recent studies suggested that stimulation directly activation of cortical neurons can interfere with the abnormal synchronized oscillation in the cortico-basal ganglia pathway, and therefore can facilitate the improvement of movement disorders.. Our preliminary studies indicated that EA could modulate the discharge of cortical neurons and the release of glutamate. In this study, We hypothesized that EA stimulation, which targeted on the abnormal neuronal activities in the motor cortex , can improve motor symptoms through modulation of the balance between the excitatory/ inhibitory cortical neurons medicated by glutamate, and the modulation of abnormal synchronized oscillation in the cortico-basal ganglia pathway. Deep brain stimulation (DBS) or decortication were used as control, EA stimulation targets in the cortex were confirmed by assessing the influence of EA stimulation on the motor behaviors of rats and electrical activity in cortical neurons. Multiunit array were applied to synchronically record the local field potential and spike in the cortex and the cortico-basal ganglia in order to identify the modulatory approaches of EA stimulation. The release of glutamate, the expression of transporter and spine in the dendrite were tested to identified the modulatory substance within the brain. This research could provide insights for the explanation of EA stimulation mechanism, and contribute to the development of the new therapeutic strategy for PD based on the cortex target.

持续的研究已经证实高频电针能有效改善帕金森病（PD）的运动症状，但其中枢作用机制尚不清楚。最新研究揭示，针对运动皮层的治疗能改善PD运动症状，与其干扰了皮层-基底节通路中异常同步化震荡活动直接相关。预实验表明电针能调节皮层神经元放电及谷氨酸的释放，因而提出"电针是以运动皮层为调控靶点，通过对谷氨酸介导的皮层神经元兴奋/抑制的平衡调节，以及对皮层-基底节通路中同步化震荡活动的调控而改善PD运动症状"。以深部脑刺激和去皮层处理为对照，检测电针对大鼠行为学、皮层神经元放电的影响来证实电针的作用靶点；采用清醒动物在体多通道技术，同步记录皮层与基底节各核团的局部场电位和峰电位，分析电针对核团间同步化震荡活动的影响来明确电针的调控途径；检测皮层及核团的谷氨酸释放、囊泡转运体表达、树突棘的改变来明确电针调控的内源性物质基础。本研究可为阐明电针的作用机理提供帮助，也为研发以皮层为靶点的PD治疗提供新策略。

在证实了高频电针能有效改善帕金森病（PD）大鼠模型运动症状的基础上，我们深入探讨其治疗的中枢作用机制。基于本课题原始假说"电针是以运动皮层为调控靶点，通过对谷氨酸介导的皮层神经元兴奋/抑制的平衡调节，以及对皮层-基底节通路中同步化震荡活动的调控而改善PD运动症状 "。我们以6-OHDA单侧损毁造成了PD大鼠模型，通过对电针对PD大鼠的症状改善，表明电针对PD模型的治疗作用；通过对大鼠运动皮层神经元电活动的影响，证实了电针可调节皮层神经元活动，表明电针的可能作用靶点是皮层；对皮层及基底节环路的神经环路的异常放电模式及其同步化为客观指标，明确电针所引起的调节效应，证实了电针的作用途径；通过对神经递质谷氨酸含量的调节，证实了电针的调控作用的脑内物质基础；进一步发现电针对纹状体神经元的结构和功能可塑性的调节作用，明确电针发挥作用的具体分子机制。进而，我们采用化学药物进行去皮层损伤，观察电针治疗对上述行为学、皮质基底节环路电活动、突触可塑性的影响，进一步确认了电针可以调控皮质基底节环路，并以谷氨酸作为脑内的物质基础而实现的治疗效应。本研究通过揭示电针改善PD运动症状的机理，将极大的促进针灸在国际学术界上的科学性和影响力；并以转化医学的理念，探索以皮层-基底节环路为靶点的治疗新新策略，将是PD极具前景的新方向。