GLUTAMATERGIC NEURONS OF THE PEDUNCULOPONTINE NUCLEUS GATE MOTOR BEHAVIORS IN HEALTH AND PARKINSONIAN STATES

Motor symptoms in Parkinson’s disease (PD), such as akinesia and bradykinesia, are caused by the progressive depletion of dopaminergic neurons, leading to dysfunction of the basal ganglia. But recent work points to a deeper involvement of a BG target in the brainstem, pedunculopontine nucleus (PPN), in the development of the motor symptoms. The PPN, part of the mesencephalic locomotor region, is thought to help switch motor states and initiate action. Indeed, the PPN stimulation induces a stopping of different behaviors, suggesting a role in gating motor outputs. By combining fiber photometry, optogenetic, behavioral assessments, we aim to characterize how dopaminergic depletion alters the function of the PPN during behaviors in freely moving mice.
To model PD-related motor deficits, we performed unilateral injections of 6-hydroxydopamine into the medial forebrain bundle, which causes severe loss of dopamine projections and leads to uneven motor symptoms. This approach lets us compare PPN activity between the healthy and dopamine-depleted sides in the same animal during spontaneous movements.
Fiber photometry revealed that glutamatergic PPN neurons exhibit robust calcium transients during locomotion, grooming, and feeding. Following unilateral lesioning, calcium activity was markedly reduced on the dopamine-depleted side, correlated with difficulty initiating movement on a treadmill. Remarkably, optogenetic activation of these neurons continued to induce immediate and reversible movement pauses even after dopamine loss.
Our observations indicate that while dopaminergic depletion diminishes PPN excitability, its capacity to modulate motor output remains intact, emphasizing the PPN as a promising therapeutic target ftarget for restoring motor function in PD.