Vestibular nucleus stimulation for ameliorating locomotor dynamics in a Parkinsonian mouse model

Postural and locomotor dysfunction represent axial symptoms of Parkinson's disease (PD), which remain poorly treated by medication and deep brain stimulation. Whilst non-invasive neuromodulation of the vestibular system via the vestibular nucleus complex (VNC) offers a novel therapeutic avenue, the underlying circuits are still poorly characterized. Here we show that the mouse VNC feeds extensive Vglut2-defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs and receives substantial input from the sensorimotor cortex. Optogenetic activation of excitatory VNC neurons at sub-symptomatic intensities increased cFos-based activity in basal ganglia-associated and brainstem motor targets. Unbiased pose dynamics and motion analysis respectively showed enhancement of behavioural modularity and locomotion with threshold-level stimulation. In a mouse model of PD, the latter further favored naturalistic gait patterns through improved motor coordination. Our data identify excitatory VNC processes as candidates for therapeutic targeting of axial motor dysfunction in the context of PD.