Spike discharge characteristic of the caudal mesencephalic reticular formation and pedunculopontine nucleus in MPTP-induced primate model of Parkinson disease

Abstract

The pedunculopontine nucleus (PPN) included in the caudal mesencephalic reticular formation (cMRF) plays a key role in the control of locomotion and wake state. Regarding its involvement in the neurodegenerative process observed in Parkinson disease (PD), deep brain stimulation of the PPN was proposed to treat levodopa-resistant gait disorders. However, the precise role of the cMRF in the pathophysiology of PD, particularly in freezing of gait and other non-motor symptoms is still not clear.

Here, using micro electrode recording (MER) in 2 primates, we show that dopamine depletion did not alter the mean firing rate of the overall cMRF neurons, particularly the putative non-cholinergic ones, but only a decreased activity of the regular neurons sub-group (though to be the cholinergic PPN neurons). Interestingly, a significant increase in the relative proportion of cMRF neurons with a burst pattern discharge was observed after MPTP intoxication. The present results question the hypothesis of an over-inhibition of the CMRF by the basal ganglia output structures in PD. The decreased activity observed in the regular neurons could explain some non-motor symptoms in PD regarding the strong involvement of the cholinergic neurons on the modulation of the thalamo-cortical system. The increased burst activity under dopamine depletion confirms that this specific spike discharge pattern activity also observed in other basal ganglia nuclei and in different pathologies could play a mojor role in the pathophysiology of the disease and could explain several symptoms of PD including the freezing of gait. The present data will have to be replicated in a larger number of animals and will have to investigate more in details how the modification of the spike discharge of the cMRF neurons in the parkinsonian state could alter functions such as locomotion and attentional state. This will ultimely allow a better comprehension of the pathophysiology of freezing of gait.

Introduction

Improving therapeutic strategies to treat gait disorders in neurodegenerative diseases requires a better understanding of the pathophysiology at the level of brainstem structures. The caudal mesencephalic reticular formation (cMRF) contains the pedunculopontine nucleus (PPN) (nucleus tegmentalis pedunculopontinus) and the cuneiform nucleus thought to be involved in several functions such as the supra-spinal control of locomotion, postural tone, waking state and sleep (Gut and Winn, 2016; Mena-Segovia and Bolam, 2017; Garcia-Rill, 2015).

In addition to the neurodegenerative process affecting dopaminergic neurons of the substantia nigra pars compacta occurring in Parkinson disease (PD), the loss of cholinergic PPN neurons is thought to be involved in the PD pathophysiology (Braak et al., 2003; Coelho and Ferreira, 2012; Galvan and Wichmann, 2008; Hirsch et al., 1987; Jellinger, 1988; Karachi et al., 2010; Pienaar et al., 2013; Rinne et al., 2008; Zweig et al., 1989). Based on experimental data in Parkinsonian animal models, it was suggested that over-activity of the basal ganglia (BG) output structures (internal segment of the globus pallidus and substantia nigra pars reticulata) could lead to hypoactivity of the PPN and finally could explain akinetic symptoms and rigidity (Aziz and Stein, 2008; Gomez-Gallego et al., 2006; Hamani et al., 2007; Pahapill and Lozano, 2000; Takakusaki et al., 2008). On the contrary, an increased electrophysiological activity of PPN neurons was observed in the 6-hydroxydopamine PD model in rat (Breit et al., 2001), in agreement with a previous metabolic study in rat (Orieux et al., 2000).

Altogether, these results highlighted a potential role of the PPN neurons in the pathophysiology of the PD. In 2005, deep brain stimulation (DBS) of the PPN was proposed as a new therapeutic strategy to treat levodopa-resistant gait disorders in PD such as freezing of gait (Mazzone et al., 2005; Plaha and Gill, 2005). Despite a growing interest in the neurological community, the precise role of the PPN in the pathophysiology of PD and related gait troubles is still lacking (Mena-Segovia and Bolam, 2017; Pienaar et al., 2017). Regarding the overall considerations on the difficulty to study PPN activity in human beings, we initiated experiments in the behaving primate to study PPN activity during locomotion (Goetz et al., 2016a) and to investigate the role of PPN in the pathophysiology of PD. Regarding the lack of precise anatomical delimitation of the PPN in primate and human, we decided to refer to the cMRF to describe the PPN area, assuming that it encompasses the PPN (cholinergic and non-cholinergic neurons) and the cuneiform nucleus (Goetz et al., 2016a).

For several decades, intoxication with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has proved to be a very robust non-human primate model of PD (Fox and Brotchie, 2010; Morissette and Paolo, 2017; Przedborski et al., 2001; Wichmann et al., 2017). This is the model we considered here, with the goal to evaluate the spike discharge characteristics of the cMRF neurons in the PD context. Using micro electrode recording (MER), we investigated how dopaminergic depletion induced by MPTP intoxication could modify the activity of cMRF neurons by evaluating changes in firing rate and pattern. In particular, we tested the hypothesis of a hypoactivity of the MRF neurons in PD because of basal ganglia dysfunction.