Striatal ensembles specify and control granular forelimb actions.

The ability of the brain to control specific fine actions is crucial for survival. The striatum is a critical brain center for both movement and learning, and its dysfunction underlies numerous movement disorders1-9. Whereas activity in the striatum has been classically viewed as invigorating5,10-13 and reinforcing movements12-20, recent studies suggest that striatal activity encodes specific movements21-24. However, it is not known how granular this activity is, and if it indeed controls specific ongoing movements. We designed a task where mice performed two minimally-different forelimb actions, consisting of a push or pull isometric force on an immobile joystick, and imaged the activity of medium spiny neurons (MSNs) in the dorsolateral striatum using 2-photon microscopy. We observed that striatal activity encoded both the preparation and execution of specific actions, even when those actions were not reinforced. Furthermore, both populations of D1 and D2-MSNs - classically viewed as promoting versus inhibiting movement2,3,25 - equally encoded action identity. We developed a closed-loop system to model and stimulate action-specific neural ensembles deep in the brain, using holographic optogenetics through a GRIN lens. Stimulation of action-specific ensembles of both D1- and D2-MSNs increased the force of ongoing actions, but only when the ensemble stimulated was congruent with the ongoing action. These results reveal that specific ensembles of both D1- and D2-MSNs causally control specific ongoing actions, as granular as different muscle co-contractions of the same forelimb. Such granularity provides a mechanistic framework for understanding how striatal dysfunction can produce highly specific movement impairments in Huntington's disease2,9 and dystonia2,6.