A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson's disease.
A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson's disease.
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DOI：
10.1016/j.celrep.2012.11.014
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发表时间：
2012-12-27
期刊：
影响因子：
8.8
通讯作者：
Zhuang X
中科院分区：
文献类型：
--
作者：
Beeler JA;Frank MJ;McDaid J;Alexander E;Turkson S;Bernardez Sarria MS;McGehee DS;Zhuang X
多巴胺有助于皮质纹状体可塑性和运动学习。多巴胺去神经支配会极大地改变运动表现，就像帕金森病一样；然而，这些症状在多大程度上反映了运动学习受损尚不清楚。在这里，我们证明了 D2 受体阻断会诱导异常学习，当多巴胺信号恢复时，这种学习会阻碍未来的运动表现，而在阻断期间联合使用腺苷拮抗剂会减弱这种效应。我们假设间接通路的纹状体苍白球细胞中不适当的皮质纹状体增强是异常学习的基础。在这里，我们证明了纹状体苍白球神经元的突触增强是由 D2 阻断诱导的，并通过应用腺苷拮抗剂而减弱，这与行为观察结果一致。基底神经节的神经计算模型概括了行为模式，并进一步将异常学习与间接途径的可塑性联系起来。因此，D2 介导的异常学习可能会导致帕金森病的运动缺陷，并为治疗方法的开发提供新途径。
Dopamine contributes to corticostriatal plasticity and motor learning. Dopamine denervation profoundly alters motor performance, as in Parkinson’s disease; however, the extent to which these symptoms reflect impaired motor learning is unknown. Here we demonstrate a D2 receptor blockade induced aberrant learning that impedes future motor performance when dopamine signaling is restored, an effect diminished by co-administration of adenosine antagonists during blockade. We hypothesize that an inappropriate corticostriatal potentiation in striatopallidal cells of the indirect pathway underlies aberrant learning. Here, we demonstrate synaptic potentiation in striatopallidal neurons induced by D2 blockade and diminished by application of an adenosine antagonist, consistent with behaviaoral observations. A neurocomputational model of the basal ganglia recapitulates the behavioral pattern and further links aberrant learning to plasticity in the indirect pathway. Thus, D2-mediated aberrant learning may contribute to motor deficits in PD and suggest new avenues for the development of therapeutics.
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