Vestibular circuit stimulation for retuning locomotor dynamics in Parkinson's disease

Postural and locomotor dysfunction represent axial symptoms of Parkinson’s disease (PD), remaining poorly treated by medication and deep brain stimulation. Non-invasive neuromodulation of the vestibular system, centered on the vestibular nucleus complex (VNC), offers a novel therapeutic avenue. However, the underlying circuits remain ill-explored. In this study, we found that the VNC in mice feeds extensive Vglut2 -defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs, but not the mesencephalic locomotor region. Optoactivation of excitatory VNC neurons below the threshold for vestibular symptoms promoted activity in these basal ganglia-brainstem axis targets. Unbiased analysis of pose dynamics revealed global enhancement of behavioural transitions and locomotion, confirmed by regular kinematic analyses. Therapeutically, it enabled resynchronization of naturalistic gait patterns and improved locomotor performance, but not capacity, in parkinsonian mice. Our data identify excitatory VNC circuit processes for therapeutic retuning of motor dysfunction in the context of PD.