A SUBTHALAMIC–BRAINSTEM CIRCUIT FOR LOCOMOTOR INITIATION

Locomotion is a fundamental motor behavior that can be initiated volitionally or driven by sensory stimuli, depending on context. Brainstem and spinal cord circuits are ultimately responsible for locomotor command generation and execution; however, how these circuits are engaged by upstream inputs remains unclear. Glutamatergic neurons of the caudal pedunculopontine nucleus (Vglut2-cPPN) are essential for the initiation and speed control of exploratory locomotion. Anatomical studies show that Vglut2-cPPN neurons receive monosynaptic input from basal ganglia output regions, including the subthalamic nucleus (STN) and substantia nigra pars reticulata. Here, we functionally investigated these pathways, focusing on the STN–cPPN projection. Selective optogenetic activation of STN-cPPN neurons elicited forward, symmetric locomotion, whereas optogenetic inhibition disrupted self-paced locomotion. Using viral strategies, we are linking STN-cPPN projections to downstream targets in the medulla. Combining retrograde viral tracing with in situ hybridization, we found that STN-cPPN neurons are a unique STN cell type. The STN is a major target for deep brain stimulation in Parkinson’s disease (PD). We therefore tested whether activation of the STN–cPPN pathway could promote locomotion in a mouse model of acute parkinsonism induced by dopamine receptor antagonism. Activation of STN-cPPN neurons reversed akinesia and reliably promoted locomotion in haloperidol-treated mice. Together, these findings refine current models of basal ganglia organization for locomotor control, placing the STN–PPN pathway as a central node linking basal ganglia output to spinal locomotor circuits. We propose that targeting the STN–PPN pathway may represent a therapeutic strategy for alleviating locomotor deficits in PD.