PDF(Pubmed)
Abstract：
Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson\'s disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.
摘要：
左旋多巴诱发的运动障碍(LID)是伴随着疾病的进展和左旋多巴的慢性治疗在帕金森病中出现的一种顽固性运动并发症。然而,介导运动障碍的特定细胞组件尚未完全阐明。这里,我们利用活动依赖工具来识别三个大脑区域(苍白球外段[GPe]，丘脑旁核,和丘脑底核），特别包含运动障碍激活的集合。在运动障碍期间观察到GPe中运动障碍激活的亚群（GPeTRAPedinLID）的强度依赖性过度活跃。光遗传学抑制GPeTRAPed在LID中显着改善LID，而在LID中GPetRAPed的再激活会引起左旋多巴关闭状态下的运动障碍行为。LID中GPeTRAPed的同时化学激活和纹状体中另一个先前报道的合奏完全再现了高剂量左旋多巴诱导的运动障碍。最后,我们将LID中的GPeTRAPed描述为GPe中原型神经元的子集。这些发现为未来LID的精确用药和调制提供了理论基础。
