Modulation of pedunculopontine input to the basal ganglia relieves motor symptoms in Parkinsonian mice

Abstract Locomotion, the ability to move, is driven by central pattern generators in the spinal cord. However, its initiation, selection of gait and arrest are controlled by command centers in the brain stem of which the best understood is the mesencephalic locomotor region (MLR). Stimulation of the MLR can initiate or arrest movement, but its neural projections and the neural circuits that mediate these actions are poorly understood. Here we show that glutamatergic neurons in the pedunculopontine nucleus (PPN), a major part of the MLR, project to the substantial nigra pars reticulata (SNr) where they innervate neurons that send afferents to the ventro medial motor thalamus (VM). Stimulation of this input to the SNr in mice slows voluntary and driven movement by modifying gait, with higher frequencies arresting gait. In Parkinsons disease (PD), a neurodegenerative disorder, the cardinal symptoms are bradykinesia, tremor and rigidity. Using an mouse model of PD, we show that inhibition of PPN input to the SNr rescues bradykinesia. This is the first description of a circuit in the mammalian brain that regulates movement and gait selection. Targeting of this circuit may be a more effective modality for treating the motor symptoms of PD.