帕金森病又名震颤麻痹，是典型的神经退行性疾病之一。患者核心临床症状为运动迟缓，肌强直，姿势异常与静止性震颤；其特征性病理改变为黑质多巴胺能神经元特异性丢失及路易小体形成。多年的研究表明帕金森病的确切病因不明，病理发生机制不清而且无法治愈。现代生物医学的发展使研究者逐渐意识到帕金森病发病机制及治疗策略的深入探索不仅需要基础研究与临床调查的支撑，更重要的是利用理想的动物模型为平台开展多学科交叉的探索。非人灵长类帕金森病动物模型因进化上与人类极其接近的亲缘关系以及能够复制出酷似帕金森病患者的运动症状和病理表现而被认为是探索该病病理发生机制与治疗或干预手段必不可少的平台，尤其是MPTP（1-甲基-4-苯基-1，2，3，6-四氢吡啶）诱导的帕金森病猴模型被公认为经典。然而MPTP模型存在难以避免的弊端，主要表现在建模动物的运动症状不稳定，动物个体对MPTP毒性反应的差异很大以及基本生理状况不佳而死亡等。这些问题不仅导致大量珍贵资源的浪费，而且限制了基础研究的深入开展。本论文从建立新型非人灵长类帕金森病动物模型入手，针对解决上述问题而设计出科学有效的实验方案，即直接利用MPTP的毒性代谢物MPP+（1-甲基-4-苯基阳离子）进行慢性侧脑室注射或急性偏侧黑质内给药损毁的方法，成功建立了症状稳定，个体差异小且基本生理状况良好的慢性和急性帕金森病猴模型，为帕金森病的病理损伤机制及多巴胺通路功能的研究提供了重要基础。在建模研究的同时，我们兼顾帕金森病动物模型的治疗及其机制研究。以MPTP诱导的帕金森病猕猴模型为平台，我们利用新近兴起的无创脑刺激术——经颅直流电刺激直接兴奋帕金森病猕猴模型的初级运动皮层探索其疗效。结果表明经颅直流电刺激存在显著的治疗效果，并且多次治疗后存在累积效应，即累积刺激量是控制其疗效的核心因素。进一步的研究发现该疗效可能是通过激活运动皮层及黑质的神经元而补偿因多巴胺能神经元丢失引起的运动控制回路调控的异常，最终改善帕金森病猕猴的运动症状。; Parkinson’s disease (PD), it is also called paralysis agitans, which is a typical neurodegenerative disorder. The key symptoms of PD patients are bradykinesia, rigidity, postural instability and tremor, and the characteristic pathological changes are specific loss of dopaminergic neurons in substantia nigra (SN) and the appearance of Lewy body. For decades, much research has indicated the etiology of PD is not clear, the pathogenesis of PD is not fully understood, and there is no method to cure PD eventually. The development of modern biomedical research makes the researchers to be aware of the importance of ideal PD animal models for widely interdisciplinary study in addition to the understanding of basic and clinic research data. Non-human primates PD model is widely regarded as essential basis for PD research because of extremely oncoming inheritance and the best copy of Parkinsonian symptoms, especially the MPTP (1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) induced PD monkey model. However, the MPTP model has obvious defects including the unstability of PD symptoms, the large variance of individual animal to the MPTP toxity, and poor general conditions, which have obviously restricted the further research of PD and wasted of precious resources meanwhile. Here, we firstly proposed the experimental strategy to solve the problem, which is chronic administration of intracerebroventricular MPP+ (1-Methyl-4-phenyl-pyridine) injections and acute lesion by MPP+ injection in the substantia nigra. The results showed that we have successfully established the new PD monkey models with stable PD symptoms, small individual variance to MPP+ administration and good general conditions, which will be helpful for the pathogenesis research of PD and exploration of the dopaminergic pathways’ function. On the other hand, we also studied the effects and mechanisms for the treatment of PD animal models induced by MPTP. We used the noninvasive method---transcranial direct current stimulation (tDCS) to active the primary motor cortex (M1) of PD monkeys, and found that tDCS was significantly effective to improve Parkinsonian symptoms, and the accumulated stimulation would significantly control the treatment effects of tDCS. The underlying neuronal mechanisms of tDCS treatment might be the activation of neurons in the M1 and SN which could restore the abnormal activities of motor controlling pathways.
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