Neural circuits of the basal ganglia are critical for motor planning and action selection1, 2, 3. Two parallel basal ganglia pathways have been described4, and have been proposed to exert opposing influences on motor function5, 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 hypothesis8, 9, 10. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control11, 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 bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway 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 behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.
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- Supplementary Information (1.1M)
This file contains Supplementary Figures 1-10 with legends and Supplementary Tables 1-2.
- Supplementary Movie 1 (22.5M)
This movie shows the behavioral effect of unilateral stimulation of striatal indirect pathway MSNs on the left side. The text "LASER" appears in the upper left corner when the fiber is illuminated. Note the ipsiversive turning and immobility during laser illumination.
- Supplementary Movie 2 (19M)
This movie shows the behavioral effect of bilateral stimulation of striatal indirect pathway MSNs. The text "LASER" appears in the upper left corner during laser illumination. Note the profound freezing during multiple trials of laser illumination.
- Supplementary Movie 3 (21.3M)
This movie shows the behavioral effect of bilateral stimulation of the direct pathway in a 6-OHDA treated mouse. The text "LASER" appears in the upper left corner during laser illumination. Note the minimal movement and lack of rearing under basal (parkinsonian) conditions. The mouse has been bilaterally treated 5 days prior with 6-OHDA in the striatum to lesion dopamine projections. During direct pathway activation, the animal becomes more alert, moves more rapidly, and rears more often.