Dopamine receptor-expressing neurons are differently distributed throughout layers of the motor cortex to control dexterity.

The motor cortex comprises the primary descending circuits for flexible control of voluntary movements and is critically involved in motor skill learning. Motor skill learning is impaired in patients with Parkinson's disease, but the precise mechanisms of motor control and skill learning are still not well understood. Here we have used transgenic mice, electrophysiology, in situ hybridization and neural tract-tracing methods to target genetically defined cell types expressing D1 and D2 dopamine receptors in the motor cortex. We observed that putative D1 and D2 dopamine receptors expressing neurons (D1+ and D2+, respectively) are organized in highly segregated, non-overlapping populations. Moreover, based on ex vivo patch-clamp recordings, we showed that D1+ and D2+ cells have distinct morphological and electrophysiological properties. Finally, we observed that chemogenetic inhibition of D2+, but not D1+ neurons, disrupts skilled forelimb reaching in adult mice. Overall, these results demonstrate that dopamine receptor-expressing cells in the motor cortex are highly segregated and play a specialized role in manual dexterity. Significance Statement The primary motor cortex (M1) is a command center governing voluntary motor control and performance of fine motor skills. Dopamine (DA) signaling in the M1 is required for skill learning and the underlying synaptic plasticity, although little is known about DA-recipient neurons in the M1. Here, we show that neurons in mouse M1 that express D1 and D2 receptors are arranged into distinct, non-overlapping populations. Furthermore, we show that D2-expressing neurons in M1 control skilled forelimb reaching in adult mice. Overall, our findings reveal distinct circuits for DA receptor-expressing cells in the M1 as well as a unique function for D2-expressing neurons in manual dexterity.