Les lésions de la moelle épinière (LM) sont une cause importante de déficits moteurs et sensoriels, incluant des difficultés à la marche et le développement de douleur. Chez l’humain, une lésion incomplète résulte fréquemment en une incapacité totale de générer des mouvements volontaires. Les conséquences de la perte d’autonomie liée aux difficultés à la marche sont majeures tant pour l’individu que son entourage. Ce constant a conduit au développement d’un pôle thérapeutique et de recherche qui s’intéresse à l’optimisation de la fonction par l’entraînement. Toutefois, les résultats cliniques ne sont pas satisfaisants.
En contraste avec ce qui est observé chez les patients ayant une LM, l’entraînement locomoteur sur tapis roulant engendre d’importantes améliorations fonctionnelles dans plusieurs modèles animaux de LM. Il a d’abord été démontré chez le chat, et plus récemment chez le rat et la souris, que l’animal peut générer le patron locomoteur avec ses pattes postérieures comprenant des phases de support et de balancement adéquatement coordonnées en alternance inter-membre, et ce, même après une section spinale complète. Ce phénomène surprenant est médié par la réexpression de réseaux locomoteurs comprenant un générateur de patron central (CPG) et différentes voies réflexes situés dans la moelle épinière lombaire. De plus, l’entraînement sur tapis roulant accélère cette réexpression locomotrice par des mécanismes d’adaptations plastiques induits par l’activation des réseaux locomoteurs spinaux par les afférences sensorielles.
Les résultats présentés dans cette thèse ajoutent des connaissances sur le potentiel de récupération locomoteur à la suite de différents types de lésions (hémilésion, section) chez la souris. La transposition des découvertes concernant l’adaptation plastique des réseaux locomoteurs spinaux en utilisant le paradigme de double lésion depuis le chat et le rat à la souris est une découverte importante dans le domaine. En montrant qu’une souris ayant récupéré un patron de marche normal après une hémilésion conservait une capacité locomotrice résiduelle du côté de l’hémilésion après une section complète subséquente, nous avons démontré que la souris représente un bon modèle pour étudier la contribution d’adaptations plastiques à la récupération locomotrice médiée par les réseaux locomoteurs spinaux. Cela justifie l’utilisation
de ce modèle dans des études visant à déterminer les composants cellulaires du CPG par une approche génétique et permet d’appliquer les découvertes à d’autres modèles animaux.
Les études de cette thèse ont permis d’identifier deux facteurs qui influencent la récupération locomotrice à la suite d’une section spinale. En premier lieu, nous avons observé dans une première étude, puis confirmé dans une seconde étude, que l’inflammation des muscles lombaires atténue la récupération locomotrice médiée par les réseaux locomoteurs spinaux et que l’entraînement peut prévenir cet effet. En mesurant l’excitabilité du réflexe-H par de stimulations électriques répétées, nous avons montré que l’inflammation des muscles lombaires altère temporairement le recrutement des motoneurones par les afférences Ia en désinhibant la voie réflexe. Ce mécanisme est possiblement impliqué dans l’effet observé au début de la réaction inflammatoire. Toutefois, le déficit locomoteur est probablement causé au moins partiellement par un autre phénomène, incluant l’activation persistante de microglie dans le renflement lombaire par un mécanisme indépendant de KCC2. Ces découvertes ont des implications translationnelles évidentes. Des observations chez les patients LM suggèrent que différents facteurs associés à la lésion ou à son traitement peuvent influencer la récupération fonctionnelle (Dvorak et al., 2017). Notamment, les blessures musculosquelettiques associées à l’étiologie principalement traumatique des LM pourraient diminuer le pronostic de récupération (Noonan et al., 2012). Nos résultats supportent ces observations et proposent que les réseaux locomoteurs spinaux soient influencés par l’inflammation et que l’entraînement locomoteur prévienne cet effet. En deuxième lieu, nous avons démontré que la buspirone, un médicament approuvé par le FDA pour le traitement de l’anxiété, active fortement les réseaux locomoteurs spinaux et permet d’engendrer la locomotion dès le jour 2 après une section spinale chez des souris auparavant complètement paraplégiques. De plus, la buspirone améliore la récupération à long terme associée à l’entraînement en facilitant les adaptations plastiques. Considérant les résultats encourageants d’études précliniques sur la buspirone pour améliorer la locomotion chez les patients ayant une LM, ces découvertes ont des retombées importantes en proposant une contribution des adaptations plastiques spinales à la récupération locomotrice.
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