Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat

Abstract

The role of the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease is still unclear. Using microrecordings, we investigated the changes occurring in PPN neurons after lesions of the substantia nigra compacta (SNc) and the role of the subthalamic nucleus (STN) in these changes. In normal rats the firing rate of PPN neurons was 10.6 +/- 1.4 spikes/s, the majority of neurons (91%) having a regular firing pattern, 6% irregular and 3% in bursts. In rats with 6-hydroxydopamine lesions of the SNc, the firing rate increased significantly to 18.3 +/- 3.0 spikes/s compared with normal rats. In addition, the firing pattern changed significantly: 70% of the neurons discharged regularly, 27% irregularly and 3% in bursts. In rats with ibotenic acid lesions of the STN, the firing rate decreased significantly to 7.2 +/- 0.9 spikes/s and the firing pattern changed significantly: 50% of the neurons discharged regularly, 43% irregularly and 7% in bursts. The rats with combined SNc and STN lesions showed no change in the firing rate (8.5 +/- 1.0 spikes/s) compared to normal rats. The firing pattern changed significantly: 69% of the cells discharged regularly, 26% irregularly and 5% in bursts. These findings demonstrate that PPN neurons are overactive and more irregular in the 6-hydroxydopamine-lesioned rats, suggesting the implication of this nucleus in the pathophysiology of parkinsonism. Moreover, the fact that STN lesions induced a reduction in the firing rate of the PPN in normal rats and a normalization of the firing rate in rats with 6-hydroxydopamine lesions suggests that this nucleus is under major control of the STN.

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

“…Stimulation in the 10-25 Hz range, generally thought to drive local neuronal activity, is also effectively used in the PPN to ameliorate motor symptoms in PD patients (Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007). However, in contrast to the non-human primate and patient results, rodent studies suggest either excitation of the PPN (Breit et al, 2001(Breit et al, , 2005Jeon et al, 2003), inhibition of the PPN (Florio et al, 2007;Gomez-Gallego et al, 2007), or no change in PPN neuronal activity following dopamine cell lesion (Mena-Segovia et al, 2005;Heise and Mitrofanis, 2006).…”

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine

“…Other inputs in addition to the GP, such as those from cortex, pedunculopontine and parafascicular nuclei (Orieux et al, 2000(Orieux et al, ,2002Breit et al, 2001; but see Ni et al, 2000b) could also be affected by loss of dopamine and play a role in modulating STN firing patterns after dopamine cell lesion. Cortical input to the basal ganglia appears critical as cortical ablation dramatically reduces the incidence of slow oscillations in the GP and STN after dopamine lesion in the anesthetized rat (Magill et al, 2001).…”

“…Phase relationships derived from STN spike-triggered cortical LFP waveform averages indicate that STN spiking is greatest during the trough of the LFPs recorded from within the cortex which coincides with the intervals of increased cortical spiking activity (Goldberg et al, 2004;Parr-Brownlie et al, 2006). Thus, phase relationships support a scenario in which increased oscillatory inhibitory input from the GP converges with antiphase excitatory input from cortex to contribute to changes in STN firing patterns after loss of dopamine.Other inputs in addition to the GP, such as those from cortex, pedunculopontine and parafascicular nuclei (Orieux et al, 2000(Orieux et al, ,2002Breit et al, 2001; but see Ni et al, 2000b) could also be affected by loss of dopamine and play a role in modulating STN firing patterns after dopamine cell lesion. Cortical input to the basal ganglia appears critical as cortical ablation dramatically reduces the incidence of slow oscillations in the GP and STN after dopamine lesion in the anesthetized rat (Magill et al, 2001).…”

Neural network dynamics in Parkinson's disease

“…This result suggests that in PD the neuronal activity of the PPN is suppressed by an excess of inhibition from GPi and SN r leading to the hypoactivity symptoms. On the other hand, Breit et al [31] shows that in anesthetized dopamine depleted rats PPN cells fire more irregularly and in bursts with an increased firing rate as compared to controls (18-20 Hz vs. 10-11 Hz). After lesion of the overactive STN in PD, the activity of the PPN is diminished, suggesting that the PPN is under major control of the STN.…”

“…This figure was almost equal to the average number of spikes per second indicating that the response was not very bursty. We simulate a STN lesion in our model by setting the STN conductance to zero and adjust the GPi conductance to get a firing rate according to experiments of Breit et al [31] (2.9-6.6 Hz). Having the GPi conductance we then adjust the STN conductance to obtain a firing rate of the PPN cell under normal conditions.…”