Low-frequency stimulation of the pedunculopontine nucleus affects gait and the neurotransmitter level in the ventrolateral thalamic nucleus in 6-OHDA Parkinsonian rats

Abstract

The pedunculopontine nucleus (PPN) is connected to spinal, cerebellar and cerebral motor control structures and can be activated with external electrodes. Intrinsic cholinergic neuronal degeneration in the PPN is associated with postural instabilities and gait disturbances (PIGD) in advanced Parkinson’s disease (PD). Clinical studies have demonstrated that PPN stimulation may improve PIGD. We investigated this claim and the underlying mechanisms using the 6-hydroxydopamine (6-OHDA) hemilesion model of PD. In this study, gait-related parameters, including the base of support (BOS), stride length, and maximum contact area, were analyzed via CatWalk gait analysis following PPN–low frequency stimulation (LFS) of rats with unilateral 6-OHDA lesions. Additionally, neurotransmitter concentrations in the ventrolateral thalamic nucleus (VL) were measured by microdialysis and liquid chromatography–mass spectrometry (LC–MS). Our data revealed that unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) induced significant gait deficits. PPN–LFS significantly improved the BOS (hindlimb) and maximum contact area (impaired forelimb) scores, whereas no other gait parameters were significantly affected. Unilateral 6-OHDA MFB lesions significantly decreased acetylcholine (ACh) and moderately decreased noradrenaline (NA) concentrations in the VL. PPN–LFS mildly reversed the ACh loss in the VL in the lesioned rats but did not alter the NA levels. Taken together, our data indicate that PPN–LFS is useful for treating gait deficits of PD and that these effects are probably mediated by a rebalancing of ACh levels in the PPN–VL pathway. Thus, our findings provide possible insight into the mechanisms underlying PIGD in PD.