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The central function of the striatum and its dopaminergic (DA) afference in motor control and integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptor- and D2 receptor (D1-SPNs and D2-SPNs), respectively, regardless of SPNs co-expressing these two receptors (D1/D2-SPNs). Here, after developing an approach that enables to target these hybrid SPNs, we demonstrated that, although these SPNs are rare, they play a major role in guiding the motor function of the other two main populations and convey a DA-mediated antagonistic motor brake. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 co-expressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops.

D1/D2 striatal output promotes dopamine-induced motor inhibition