Cortico-subthalamic projections send brief stop signals to halt visually-guided locomotion

Goal-directed locomotion requires control signals that propagate from higher-order areas to regulate spinal mechanisms. The cortico-subthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task where head-fixed mice run to a visual landmark then stop and wait to collect reward, and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our modeled behavioral strategy indicates a switching point in behavior or a sudden change from running to stopping, suggesting a critical neuronal control signal at stop locations. Optogenetic activation of M2 axons in STN leads the animal to stop prematurely. By imaging M2 neurons projecting to STN, we find neurons that are active at the onset of stops when executed at the landmark but not when executed spontaneously elsewhere. Our results suggest that the M2-STN pathway can be recruited during visually-guided locomotion to rapidly and precisely control the mesencephalic locomotor region (MLR) through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, MLR and STN, we find that the cortico-subthalamic projections potentially control MLR activity by differentiating an M2 error signal to ensure fast input-output dynamics.