Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

The basal ganglia are a group of subcortical nuclei that regulates motor and cognitive functions 1,2 . Recent identification of neuronal heterogeneity in the basal ganglia suggests that functionally distinct neural circuits defined by their efferent projections exist even within the same nuclei 3-5 . This distinction may account for a multitude of symptoms associated with basal ganglia disorders such as Parkinson’s disease (PD) 6,7 . However, our incomplete understanding of the basal ganglia functional organization has hindered further investigation of individual circuits that may underlie different behavioral symptoms in disease states. Here we functionally define two distinct classes of parvalbumin-expressing neurons in the mouse external globus pallidus (GPe-PV) embedded within discrete neural pathways and establish their contributions to different Parkinsonian behavioral deficits. We find that GPe-PV neurons projecting to the substantia nigra pars reticulata (SNr) or parafascicular thalamus (PF) undergo different electrophysiological adaptations in response to dopamine depletion. Furthermore, counteracting these adaptations in each population can selectively alleviate movement deficits or behavioral inflexibility in a Parkinsonian mouse model. Our findings provide a novel framework to understand the circuit basis of separate behavioral symptoms in Parkinsonian state which could provide better strategies for the treatment of PD.