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帕金森氏病是一种进行性的神经退行性运动障碍疾病,其主要病理特征是黑质多巴胺能神经元的严重丢失。黑质多巴胺神经元的投射区域为背侧纹状体(多巴胺能神经元发出上行纤维到达纹状体)。根据经典模型,激活纹状体中型多棘神经元(medium spiny neurons,MSNs)上的多巴胺受体调节它们内在的兴奋性。在Go/NoGo调控中,激活D1受体可增强“Go”直接通路的MSNs的兴奋性,而激活D2受体则可降低“NoGo”间接通路的MSNs兴奋性。因此,多巴胺升高既可增强Go通路的反应性,同时又可降低NoGo通路的反应性。这两种机制均可导致运动输出的增强。相反地,减少多巴胺则更倾向于增强抑制性的“NoGo”通路。因此,多巴胺对于运动表现首先具有直接的、实时的调控作用。然而,除了实时调控MSNs的内在兴奋性外,多巴胺尚具有调控皮层-纹状体可塑性的功能,进而对皮层-纹状体通路产生潜在的、累积性的、持久的改变。我们的研究显示,阻断多巴胺在直接损害运动表现的同时,也介导了NoGo学习(一种习得性动作抑制),从而使得运动能力逐渐恶化。这种恶化是潜在的、累积性的和持久的。NoGo学习是D2受体依赖的,它是一种经验依赖性及任务特异性的学习。NoGo学习与“学习过程被阻断”不同,因为NoGo学习对未来运动的损害甚至在多巴胺水平恢复后仍然存在。最近,我们的研究数据表明,在缺乏多巴胺时,NoGo学习起源于皮层-纹状体间接通路中突触的LTP增加,很大程度上参与了形成帕金森样的运动障碍。我们的研究指出了一种针对帕金森氏病的新型治疗策略:即直接针对信号分子来调控皮层-纹状体可塑性(如cAMP通路从及其下游信号分子),进而防止由于多巴胺去神经调控产生的异常可塑性。
Parkinson’s disease is a progressive neurodegenerative dyskinetic disorder whose major pathological feature is the severe loss of substantia nigra dopaminergic neurons. The dorsal striatum (dopaminergic neurons issue upstream fibers to the striatum) is projected in the substantia nigra dopamine neurons. According to the classical model, activation of dopamine receptors on the striatum medium spiny neurons (MSNs) regulates their intrinsic excitability. Activation of D1 receptors enhances the excitability of MSNs in the “Go” direct pathway in Go / NoGo regulation, whereas activation of D2 receptors decreases MSNs excitability in the “NoGo” indirect pathway. Thus, elevated dopamine potentiates both Go pathway reactivity and at the same time reduces the NoGo pathway reactivity. Both of these mechanisms result in increased motor output. Conversely, reducing dopamine tended to enhance the inhibitory “NoGo” pathway. Therefore, dopamine first of all has a direct, real-time regulation of motor performance. However, in addition to regulating the intrinsic excitability of MSNs in real time, dopamine also has the potential to regulate the cortical-striatal plasticity and thereby potentially, cumulatively and persistently alter cortical-striatal pathways. Our study shows that blockade of dopamine mediates NoGo learning, an impaired learning motility, while directly impairing performance and thus worsening athletic performance. This deterioration is potential, cumulative and long-lasting. NoGo learning is D2 receptor-dependent and it is an experience-dependent and task-specific learning. NoGo learning is not the same as learning process blocked because NoGo learns that damage to future motions persists even after dopamine levels have recovered. More recently, our data suggest that in the absence of dopamine, NoGo studied increased synaptic LTP originating in the cortical-striatal indirect pathway, largely involved in the formation of Parkinson-like dyskinesias. Our study points to a novel therapeutic strategy for Parkinson’s disease that directly modulates cortical-striatal plasticity (such as the cAMP pathway and its downstream signaling molecules) directly against signaling molecules, thereby preventing denervation due to dopamine denervation Abnormal plasticity.