Détermination des facteurs bénéfiques et néfastes à la récupération locomotrice à la suite d’une section spinale complète chez la souris

Locomotor spinal networks contribution to locomotor recovery has been described in various animal models of spinal cord injury (SCI). It is now assumed that these networks are plastic and will re-express, to some extent, locomotion by hosting activity-dependent adaptation similar to those observed in motor learning and memory. Thus, locomotor training promotes behavioral recovery mediated by locomotor spinal networks after a SCI, including after a complete transection and disconnection from the brain. In addition to training, various factors can exert beneficial or detrimental influence on locomotor spinal networks activity and plasticity, including factors associated with the traumatic origin of spinal injury itself or its pharmacological treatment. In order to direct plasticity toward adaptation and promote recovery, the influence of such factors must be clarified. The objectives of the present thesis is to determine the contribution of training to recovery in two specific conditions of rehabilitation: 1) in presence of musculoskeletal inflammation related to the traumatic etiology of SCI and 2) in combination with a pharmacological intervention, administration of the 5HT agonist buspirone, used in preclinical studies to facilitate locomotor activity.  The first condition, the presence of musculoskeletal inflammation, is frequently observed in patients after a SCI and is associated with poor functional recovery. Considering the role of spinal networks in sensory processing and the selective recruitment by nonnociceptive and nociceptive afferents of reflex pathways implicated in locomotion, the impact of inflammation on locomotor recovery must be determined. In a model of complete transection in mice, we evaluate the impact of lumbar muscle inflammation induced by intramuscular complete Freund adjuvant (CFA) injection on locomotor recovery mediated by spinal networks, with or without locomotor training. Our results show that lumbar muscle inflammation hindered locomotor recovery (study 1). In a second experiment, we examined if CFA injection changed sensory transmission to spinal cord by measuring the evolution of Hoffmann reflex frequencydependent depression, which is progressively attenuated after spinal transection. We found that lumbar muscle inflammation induced a short term suppression of the Hoffmann reflex frequency-dependent depression, thereby altering spinal excitability (study 2). However, this short term change in excitability did not match the temporal course of locomotor deficits and     iv  central neuroinflammatory response as measured with the enhanced presence of microglia in spinal cord, suggesting that inflammation-induced locomotor deficits rely at least partially on mechanism independent of spinal excitability (study 3).  The second condition under investigation, the use of buspirone to enhance locomotor recovery after a SCI, shows great therapeutic potential. Results from a preclinical trial on SCI patients show that it can enhance locomotor activity, but it is not known if it does so by reactivating dormant descending pathways or locomotor spinal networks. Using our model of complete transection in mice, we showed that buspirone strongly activates locomotor spinal networks and allow near full expression of locomotion on day 2 post-transection (study 4). However, this facilitation was associated with limited long term effect when combined with training. Improved long term effect of buspirone depending on residual function after transection (partial vs absent function) caused by different lesion paradigms (hemisection preceding transection vs transection only) suggests that buspirone promotes recovery by enhancing use-dependent plastic changes.  In conclusion, this thesis describes two conditions that influence locomotor recovery mediated by spinal networks oppositely. These findings give new insights on the role of locomotor spinal networks plasticity in recovery after a SCI including spinal transection and provide evidence both beneficial and detrimental factors contributes to functional rehabilitation.

Keyphrases: section, locomotion, inflammation, Spinal cord, Transection, Plasticity, Central pattern generator, Serotonin, Neuromodulation, Hoffmann reflex, Frequency-dependent depression, Sensory afferents