Restoration of locomotor function following stimulation of the A13 region in Parkinson’s mouse models

Parkinson’s disease (PD) is characterized by extensive motor and non-motor dysfunction, including gait disturbance, which is difficult to treat effectively. This study explores the therapeutic potential of targeting the A13 region, a heterogeneous region of the medial zona incerta (mZI) containing dopaminergic, GABAergic, and glutamatergic neurons that has shown relative preservation in PD models. The A13 is identified to project to the mesencephalic locomotor region (MLR), with a subpopulation of cells displaying activity correlating to movement speed, suggesting its role in locomotion. We show that photoactivation of this A13 region can alleviate bradykinesia and akinetic features, while increasing turning in a mouse model of PD. These effects combine disease-specific rescue of function with a possible gain of function. We identified areas of preservation and plasticity within the mZI connectome using whole-brain imaging. Our findings suggest a global remodeling of afferent and efferent projections of the A13 region, highlighting the zona incerta’s role as a crucial hub for the rapid selection of motor function. The study unveils the significant pro-locomotor effects of the A13 region and suggests its promising potential as a therapeutic target for PD-related gait dysfunction.