Lesion of the pedunculopontine nucleus reverses hyperactivity of the subthalamic nucleus and substantia nigra pars reticulata in a 6‐hydroxydopamine rat model

Abstract

The pedunculopontine nucleus (PPN) and the subthalamic nucleus (STN) are reciprocally connected by excitatory projections. In the 6-hydroxydopamine (6-OHDA) rat model the PPN was found to be hyperactive. Similarly, the STN and the substantia nigra pars reticulata (SNr) showed increased activity in Parkinson's disease (PD) animal models. A lesion of the STN was shown to restore increased activity levels in the SNr of 6-OHDA-treated rats. As the STN and the PPN were reciprocally connected by excitatory projections and both structures were shown to be hyperactive in PD animal models, the present study was performed in order to investigate the changes in neuronal activity of the STN and SNr under urethane anesthesia after unilateral ibotenic acid lesioning of the PPN in animals with previous unilateral 6-OHDA lesions of the substantia nigra pars compacta (SNc). The firing rate of STN neurons significantly increased from 10.3 +/- 0.6 spikes/s (mean +/- SEM) to 17.8 +/- 1.8 spikes/s after SNc lesion and returned to normal levels of 10.8 +/- 0.7 spikes/s after additional lesion of the PPN. Similarly, the firing rate of SNr neurons significantly increased from 19.0 +/- 1.1 to 25.9 +/- 1.4 spikes/s after SNc lesion, the hyperactivity being reversed after additional PPN lesion to 16.8 +/- 1.2 spikes/s. The reversal of STN and SNr hyperactivity of 6-OHDA-treated rats by additional PPN lesion suggests an important modulatory influence of the PPN on STN activity. Moreover, these findings could indicate a new therapeutic strategy in PD by interventional modulation of the PPN.

Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson’s disease

“…Several lines of experimental evidence support an integrative role of the SNr on locomotion [14][15][16], which is reciprocally linked to functional brainstem circuitries. SNr activity presented pathologically increased in the 6-hydroxydopamine model, but restituted if the pedunculopontine nucleus was lesioned [17]. Based on these previous findings, we hypothesize on normalization of pathologically overactive SNr activity in our patient.…”

Glutamatergic and cholinergic pedunculopontine neurons innervate the thalamic parafascicular nucleus in rats: changes following experimental parkinsonism

“…Futhermore, bilateral PPN hyperactivity was reported in rats with unilateral nigrostriatal damage (Carlson et al 1999;Breit et al 2001Breit et al , 2008 together with an increased number of cholinergic neurons (García-Rill et al 1995) and augmented release of glutamate (Blanco-Lezcano et al 2005). These data paved the way for appointing the PPN nucleus as a potential surgical candidate for functional neurosurgery (Jenkinson et al 2005;Plaha and Gill 2005;Breit et al 2006). Lowfrequency stimulation (20-25 Hz) of the PPN using deep brain stimulation (DBS) electrodes has proven to be useful for the treatment of akinesia in parkinsonian monkeys (Jenkinson et al 2004).…”

Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats

“…This hypothesis is supported by the recent observation that a lesion of the dorsal raphe nucleus alters neuronal activity of the STN in 6-OHDA rats ). On the other hand, STN activity is also regulated by glutamatergic inputs from the cerebral cortex, thalamus, pedunculupontine nucleus (Breit et al 2006;Lanciego et al 2004;Nambu et al 2000), and also by dopaminergic projections from the substantia nigra (Cragg et al 2004;Hassani et al 1997). We cannot exclude that sarizotan-mediated activation of 5-HT 1A receptors could also modulate some of these afferent projections to the STN and participate in the antidyskinetic effect here reported.…”