Faculty Opinions recommendation of Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.

Neural circuits of the basal ganglia are critical for motor planning and action selection [1][2][3] .Two parallel basal ganglia pathways have been described 4 , which are proposed to exert opposing influences on motor function [5][6][7] .According to this classical model, activation of the direct pathway facilitates movement and activation of the indirect pathway inhibits movement.However, more recent anatomical and functional evidence has called into question the validity of this hypothesis [8][9][10] .Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown.Here, we directly activated basal ganglia circuitry in vivo, using optogenetic control [11][12][13][14] of direct-and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of D1-Cre and D2-Cre BAC transgenic mice.Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia, and decreased locomotor initiations.In contrast, activation of directpathway MSNs reduced freezing and increased locomotion.In a mouse model of Parkinson's disease, direct pathway activation completely rescued deficits in freezing, bradykinesia, and locomotor initiation.Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.To obtain selective optogenetic control of the direct and indirect pathways in vivo, we targeted striatal MSNs that form the origin of these pathways.We injected an adenoassociated virus (AAV1) containing a double-floxed inverted open reading frame (DIO)