The mesencephalic locomotor region (MLR) has been initially identified as a supraspinal center capable of initiating and modulating locomotion. Whereas its functional contribution to locomotion has been widely documented throughout the phylogeny from the lamprey to humans, there is still debate about its exact organization. Combining kinematic and electrophysiological recordings in mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus initiate locomotion and induce running gaits, whereas glutamatergic and cholinergic neurons of the pedunculopontine nucleus modulate locomotor pattern and rhythm, contributing to slow-walking gaits. By initiating, modulating, and accelerating locomotion, our study identifies and characterizes distinct neuronal populations of this functional region important to locomotor command.

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Spinal cord injury (SCI) results in a disruption of information between the brain and the spinal locomotor circuit. Although the spinal cord contains all the neural circuits to generate locomotion, people with SCI are unable to walk due to the absence of descending commands from the brain. Electrical stimulation of supraspinal locomotor centers, such as the Mesencephalic Locomotor Region (MLR), can promote locomotor recovery in acute and chronic SCI rodent models. Although clinical trials are currently underway in SCI patients, there is still debate about the organization of this supraspinal locomotor center and which anatomical correlate of the MLR should be targeted to promote functional recovery. Combining kinematics, electromyographic recordings, anatomical analysis, and mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus contribute to locomotor recovery by enhancing motor efficacy in flexor and extensor hindlimb muscles, and by increasing locomotor rhythm and speed on a treadmill, over ground, and during swimming in mice with chronic SCI. In contrast, glutamatergic neurons of the pedunculopontine nucleus slow down locomotion. Therefore, our study identifies the cuneiform nucleus and its glutamatergic neurons as a therapeutical target to improve locomotor recovery in patients living with SCI.One Sentence SummaryGlutamatergic neurons of the mesencephalic locomotor region contribute to spontaneous locomotor recovery following spinal cord injury and selective activation of a discrete glutamatergic subpopulation in this region can further improve functional outcome in chronic spinal cord injury.

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