Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment

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 (GPe TRAPed in LID ) is observed during dyskinesia. Optogenetic inhibition of GPe TRAPed in LID significantly ameliorates LID, whereas reactivation of GPe TRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPe TRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPe TRAPed 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.