Thèse Mécanismes et Rôle de l'Entraînement Moteur Pendant la Remyélinisation H/F

Doctorat_Gouv

Établissement : Université Paris Cité
École doctorale : Cerveau, cognition, comportement
Laboratoire de recherche : Institut de Psychiatrie et Neurosciences de Paris
Direction de la thèse : Maria Cecilia ANGULO ORCID 0000000207580496
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-06-01T23:59:59

La myélinisation est un processus dépendant de l'activité, appelé myélinisation adaptative. L'activité neuronale, l'expérience et l'apprentissage peuvent stimuler la prolifération des cellules précurseurs des oligodendrocytes (OPC), leur différenciation et la remyélinisation, ouvrant ainsi une voie thérapeutique potentielle pour les maladies démyélinisantes. Ce projet étudie comment différents paradigmes d'entraînement moteur (tâches simples ou complexes sur roue) modulent l'activité oligodendrogliale et la régénération de la myéline après une démyélinisation induite par la cuprizone chez la souris. En utilisant l'imagerie calcique in vivo, des enregistrements par patch-clamp ex vivo et l'immunohistochimie, l'objectif 1 visera à caractériser la signalisation calcique dépendante de l'activité dans les OPC et les oligodendrocytes pendant l'entraînement. L'objectif 2 explorera les mécanismes moléculaires sous-jacents, en se concentrant sur les changements mitochondriaux et protéomiques qui favorisent la myélinisation adaptative. Ce projet permettra de définir comment l'entraînement moteur régule la réparation de la myéline et d'identifier des cibles potentielles pour promouvoir la remyélinisation dans les troubles neurodégénératifs, tels que la sclérose en plaques.

Emerging evidence in animals and humans has shown that myelination is a plastic process driven by neuronal activity and experience, the so-called adaptive myelination. Enhancing neuronal activity or behavioural training could therefore constitute an alternative to promote remyelination in myelin-related diseases. In line with this, findings from the team have shown that neuronal activity promotes the preferential myelination of active axons and enhances myelin regeneration in a preclinical model of remyelination. Moreover, enhanced experience, voluntary exercise and motor learning increases both the proliferation of oligodendrocyte precursor cells (OPCs) and the generation of new OLs in control and after demyelination. This remodelling of myelin appears essential for the consolidation of learning and memory.
The effects of enhanced neuronal activity and behavior on nodal remyelination could partly account for the impact of physical activity on improving many symptoms in disease or on reducing the risk of developing neurodegenerative disorders. In MS patients, both exercise and cognitive training can reduce cognitive deficits and high intensity aerobic exercise can improve clinical outcome. It has even been suggested that exercise could be prescribed as a treatment in early MS stages. Yet, it is unclear whether different motor training paradigms stimulate myelin formation and which motor-driven mechanisms underlie neuronal activity changes and adaptive myelination in health and disease. Since complex motor training involves learning and coordination skills, we could speculate that it has a greater impact on finely tuning myelin production than physical exercise, albeit intense exercise.
Re-establishing an adapted myelin pattern along partially myelinated neurons is a challenge, and adapted physical activity and motor training could modulate this process. Built on the aforementioned studies and considerations, our hypothesis is that simple and complex motor training could differentially modulate adaptive myelination and neuronal plasticity, and that specific motor intervention following demyelination enhances myelin regeneration. Understanding motor-driven mechanisms that stimulate myelination and remyelination may pave the way for the development of new therapies that protect axons in many neurodegenerative diseases.

AIM 1: Motor-driven responses of oligodendroglia during myelin regeneration
We will use the cuprizone (CPZ)-induced model in which CPZ administration causes a global forebrain demyelination that is followed by a progressive spontaneous remyelination after CPZ withdrawal. The CPZ model has the advantage of reproducing many aspects of the MS pathology (increased astrogliosis and microglial activation, decreased OL density). Using this model, we will test how the activity of oligodendroglia in control and following demyelination is modulated in mice running in a regular wheel and in a complex wheel (wheel with rung gaps). Specifically, we will test whether intracellular Ca2+ signals of OPCs and OLs may play key roles during training because they affect OPC proliferation and differentiation and myelination. We hypothesize that simple and complex motor trainings differentially modulate oligodendroglia Ca2+ signals and OPC development in the motor cortex, contributing to myelin formation and regeneration.

AIM 2: Mechanisms of motor-driven responses of oligodendroglia during myelin regeneration
In this aim, we will assess the molecular and cellular mechanisms underlying motor-driven remyelination during simple and complex motor training paradigms. Our unpublished data indicate that mitochondria Ca2+ flux plays an important role in OL regerenation in vivo (Maas et al., BioRxiv). We hypothesize that the activation of neuronal networks during motor behavior promotes mitochondrial Ca2+ signals, enhancing the renewal of OL and myelin regeneration.

AIM 1: To visualize Ca2+ signals from OL lineage cells in vivo, we already set up the protocols to use the Miniscope-V4, a miniature microscope that can be mounted on the head of PDGFRaCreERT;GCaMP6f/f mice to image GCaMP6+ cells in behaving mice. We will train the mice to run on a simple or a complex wheel in control, during demyelination and remyelination while imaging oligodendroglia. In addition to in vivo experiments, we will compare patch-clamp recordings of neurons in motor cortex slices from control mice and mice that have undergone motor training. These recordings will allow us to assess the functional changes induced by motor adaptations. Furthermore, we will perform immunostaining to evaluate the impact of motor training and the potential modulation of OPC proliferation, differentiation, and (re)myelination.

AIM 2: first, we will analyze the number and distribution of mitochondria in OPCs and OLs during simple and complex motor training paradigms in control and demyelinated lesions using a mouse model expressing fluorescent mitochondria. Then, we will use proteomics to identify potential signaling pathways that mediate the effects of neuronal activity on oligodendroglial function and myelin repair. Protein expression profiles should help identifying potential mitochondria-related pathways contributing to activity-dependent OL lineage cell maturation and (re)myelination during motor training. This analysis will help uncovering molecular changes associated with motor training. We will validate protein candidates using Western blot and immunohistochemistry. This approach will provide a foundation for targeting specific pathways aiming at enhancing adaptive (re)myelination using pharmacology in this project and/or genetic manipulations in the future.