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帕金森氏病中的异常可塑性和习得性动作抑制

庄晓曦^*

芝加哥大学神经生物学系，芝加哥，伊利诺州 60637，美国

摘要

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。

关键词： 帕金森氏病; 多巴胺; 纹状体; 中型多棘神经元; 基底节; 皮层-纹状体可塑性; 运动学习; 学习和表现; cAMP通路; 异常可塑性

分类号：R741.02

Aberrant plasticity and “learned” motor inhibition in Parkinson’s disease

ZHUANG Xiao-Xi^*

Neurobiology Department, University of Chicago, 924 East 57th Street Knapp Research Center , Chicago, Illinois 60637, USA

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized by severe loss of substantia nigra dopamine (DA) neurons. The target region of substantia nigra DA neurons is the dorsal striatum. According to the classic model, activation of DA receptors on striatal medium spiny neurons (MSNs) modulates their intrinsic excitability. Activation of D1 receptors makes MSNs in the direct “Go” pathway more excitable, whereas activation of D2 receptors makes MSNs in the indirect “NoGo” pathway less excitable. Therefore increased DA increases the responsiveness of the Go pathway while decreases the responsiveness of the NoGo pathway. Both mechanisms increase motor output. Conversely, diminished DA will favor the inhibitory NoGo pathway. Therefore, DA has direct, “on-line” effect on motor performance. However, in addition to modulating the intrinsic excitability of MSNs “on-line”, DA also modulates corticostriatal plasticity, therefore could potentially produce cumulative and long-lasting changes in corticostriatal throughput. Studies in my lab suggest that DA blockade leads to both direct motor performance impairment and D2 receptor dependent NoGo learning (“learned” motor inhibition) that gradually deteriorates motor performance. NoGo learning is experience dependent and task specific. It is different from blocked learning since NoGo learning impairs future performance even after DA is restored. More recent data from my lab suggest that NoGo learning in the absence of DA arises from increased LTP at the indirect pathway corticostriatal synapses and contributes significantly to PD-like motor symptoms. Our data and hypotheses suggest a novel therapeutic strategy for PD that targets directly signaling molecules for corticostriatal plasticity (e.g. the cAMP pathway and downstream signaling molecules) and prevents aberrant plasticity under conditions of DA denervation.

Key words: Parkinson's disease; dopamine; striatum; medium spiny neurons; basal ganglia; corticostriatal plasticity; motor learning; learning and performance; cAMP pathway; aberrant plasticity

收稿日期：2012-09-21　　录用日期：2012-09-27

通讯作者：庄晓曦　　E-mail: xzhuang@bsd.uchicago.edu

引用本文：

庄晓曦. 帕金森氏病中的异常可塑性和习得性动作抑制[J]. 生理学报 2012; 64 (5): 543-549.

ZHUANG Xiao-Xi. Aberrant plasticity and “learned” motor inhibition in Parkinson’s disease. Acta Physiol Sin 2012; 64 (5): 543-549 (in Chinese with English abstract).