Cortico-reticulo-spinal circuits mediate functional recovery after spinal cord contusion

After a spinal cord injury (SCI), only half of affected individuals regain voluntary control of leg movements below the level of the lesion. Anatomical, electrophysiological and imaging data revealed that even the most severe forms of SCI usually spare a small bridge of tissue in the surrounding of the lesion cavity. These bridges contain residual fibers from brain projections that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. However, without therapeutic interventions, these spared fibers will fail to conduct nervous information from brain centers to the spinal circuits below injury, leading to permanent paralysis. It is accepted that spontaneous regeneration of lesioned fibers is limited in the adult nervous system, but hope for motor recovery lies in the capacity of the spared neural motor network to readapt and find compensational routes. In the past, a neuroprosthetic rehabilitation strategy combining electrochemical neuromodulation of the spinal cord during robot-assisted overground locomotion was developed for rats to restore volitional control of the paralyzed legs. Such rehabilitation platforms was developed for rats, enabling large-scale studies prior to pre-clinical trials in non-human primates. However, most innovative tools for the manipulation of specific populations of neurons are currently designed for mice, and these techniques are essential to establish causality between the anatomical reorganization and the observed functional recovery. In the first part of this thesis, we developed a robotic interface with end-effector modules that can be rapidly exchanged between experiments with rats or mice. The functionalities of the robot are tailored to the size and weight of the animal, to the personalized need of assistance and to the type of performed task. Using this platform, the next part of the thesis uncovers the mechanisms enabling motor recovery after a clinically relevant injury model – a severe spinal cord contusion. Such injury leads to permanent leg motor deficits with very little spontaneous recovery. Similar to humans, the modelled contusion injury induce highly variable white matter damage with undefined neural pathway sparing. For the first time, we show that the rehabilitation strategy enabled rats to regain supraspinal control of leg movements that persisted without any neuromodulation even during unpracticed motor tasks. We then investigated the reorganization of the spared circuitry that mediated this functional recovery after contusion. Despite interruption of direct corticospinal projections, we showed that the motor cortex regained adaptive control over the paralyzed legs during neuromodulation of lumbar circuits. We found that the cortical command was relayed through spared glutamatergic projection neurons in the reticular formation. Indeed, due to the distributed spatial topography of reticulospinal projections, the contusion systematically spares a subset of these projections. Extensive training promoted plasticity of the identified cortico-reticulo-spinal pathway mediating a motor cortex dependent recovery of voluntary leg movements. As the anatomy and function of reticulospinal pathways are well-conserved across mammals, this pathway may be recruited by similar therapeutic interventions to improve recovery in humans.