RESTORATION OF LOCOMOTOR FUNCTION IN A CHRONIC PARKINSONIAN MOUSE MODEL BY SELECTIVE ACTIVATION OF BRAINSTEM COMMAND NEURONS

Locomotor control is organized hierarchically, with brainstem structures operating downstream of the basal ganglia to modulate locomotion. The mesencephalic locomotor region (MLR), comprising the pedunculopontine nucleus and cuneiform nucleus, governs locomotion initiation and speed modulation, whereas the pontine nucleus oralis (PnO) controls locomotor steering. In Parkinson’s disease (PD), degeneration of nigrostriatal dopaminergic neurons causes basal ganglia dysfunction, disrupting downstream motor control and inducing locomotor impairments such as bradykinesia, freezing of gait, and turning deficits. Given the hierarchical organization of locomotor control, MLR and PnO dysfunction may contribute to parkinsonian motor deficits. We therefore hypothesized that targeted activation of these nuclei may alleviate motor impairments in chronic PD. To investigate this possibility, we used the MitoPark mouse model. Compared to acute pharmacological and toxin-based PD models, MitoPark mice more closely recapitulate human PD pathology through a progressive, adult-onset phenotype that advances to chronic stages. MitoPark mice display reduced locomotion and turning frequency, and progressively fail to attain higher speeds (10–20 cm/s and >20 cm/s). Using excitatory DREADDs, we show that bilateral activation of glutamatergic MLR neurons improves locomotor function by restoring the speed profile, reducing time spent at low speeds (2–5 cm/s) and increasing occupancy of higher speed ranges, without improving turning behavior. In contrast, combined bilateral activation of the MLR and PnO restored the speed profile and increased the turning frequency, indicating that MLR activation enhances forward locomotion, whereas PnO activation improves locomotor steering. Together, these findings outline promising brainstem targets for improving locomotor function in PD.