Venue: Centre Broca
Defense in french
Supervisor: Grégory Barrière (INCIA)
Title
Regulation of Motor Behaviors by the Pedunculopontine Nucleus under Physiological and Pathophysiological Conditions
Abstract
The pedunculopontine nucleus (PPN) occupies a key position at the interface between the Basal Ganglia and the brainstem motor networks. The roles of glutamatergic PPN neurons (PPN-Vglut2) to motor control remains to be fully understood, their activation being able to trigger locomotion on one side or to pause ongoing motor behaviors on the other side. Their possible contribution to pathological movements as is the case for instance in Parkinson’s disease (PD) remained to be fully addressed. Here, we combined projection mapping, bilateral fiber photometry recordings, and optogenetic manipulation to better characterize the contribution of PPN-Vglut2 neurons to motor control in healthy mice and after a dopaminergic lesion mimicking part of the symptomatology of PD.
Anatomically, PPN-Vglut2 project extensively and bilaterally (with an ipsilateral predominance), toward the Basal Ganglia and several brainstem regions involved in motor functions such as locomotion, limb and orofacial movements, and even breathing (LPGi, LatRM, IRt, PB/KF). In vivo calcium dynamic recordings revealed that PPN-Vglut2 activity is modulated during different motor behaviors spontaneously generated and remained tightly coordinated on both sides. During treadmill locomotion, PPN-Vglut2 activity is correlated to the instantaneous speed of the animal. However, this movement-related activity contrasted with the effects of their uni- or bilateral optogenetic activation which transiently paused ongoing motor behaviors that resumed at the end of the stimulation. Taking the opportunity to investigate the regulation of respiration, we found that opto-excitation of PPN-Vglut2 reduced the respiratory rate, and in some cases triggered transient apneas. During long protocoles, breathing resumed but remained modulated in amplitude and frequency for the length of the stimulation.
In “PD-like” condition, most characteristics of PPN-Vglut2 activity and effect of manipulation were preserved, even during the course of the L-DOPA treatment where induced rotations and dyskinetic movements could be set on pause with opto-excitation. In contrast, the respiratory response was modified in the parkinsonian condition: its dependence on stimulation frequency was altered by the lesion and was not restored by L-DOPA treatment.
Taken together, these results indicate that PPN-Vglut2 contribution to motor regulation extends beyond the only locomotor behaviors, even influencing automatic motor programs such as breathing. Importantly, the preservation of PPN-Vglut2 function in PD-like condition may be relevant to update the therapeutic strategies targeting the PPN in movement disorders.
Keywords: pedunculopontine nucleus, Vglut2 glutamatergic neurons, motor networks, respiration, Parkinson’s disease.
Publication
Int J Mol Sci . 2023 Sep 29;24(19):14747. doi: 10.3390/ijms241914747.
Jury
M. Guehl Dominique – PU-PH, CNRS, Université de Bordeaux Président du jury
Mme Coizet Véronique – CR, INSERM, Université Grenoble Alpes Rapporteur
Mme Benoît-Marand Marianne – PR, Université de Poitiers Rapporteur
Mme Wyart Claire DR, INSERM, Université de Paris Examinateur
M. Barrière Grégory CR, Université de Bordeaux Directeur de thèse
Membre invité :
M. Mallet Nicolas – CR, CNRS, Université de Bordeaux