Plasticity Of Spinal Motor Network Without Corticospinal Connections

Two major aspects were studied in this dessertation by using conditional gene knockout mice: Part One: spinal cord maturatuion and locomotor in mice with an isolated cortex The spinal cord plays a key role in motor behavior. It relays major sensory information, receives afferents from supraspinal centers and integrates movement in the central pattern generators. Spinal motor output is controlled via corticofugal pathways including corticospinal and cortico-subcortical projections. Spinal cord injury damages descending supraspinal as well as asce nding sensory pathways. In adult rodent models, plasticity of the spinal cord is thought to contribute to functional recovery. How much spinal cord function depends on cortical input is not well known. Here, we address this question using Celsr3|Foxg1 mice, in which cortico-subcortical connections(including corticospinal tract(CST) and the terminal sensory pathway, the thalamocortical tract) are genetically ablated during early development. Although Celsr3|Foxg1 mice are able to eat, walk, climb on grids and swim, open-field tests showed them to be hyperactive. When compared with normal littermates, mutant animals had reduced number of spinal motor neurons, with atrophic dendritic trees. Furthermore, motor axon terminals were decreased in number, and this was confirmed by electromyography. The number of cholinergic, calbindin, and calretinin-positive interneurons was moderately increased in the mutant spinal cord, whereas that of reelin and parvalbumin-positive interneurons was unchanged. As far as we know, our study provides the first genetic evidence that the spinal motor network does not mature fully in the absence of corticofugal connections, and that some motor function is preserved despite congenital absence of the CST. Part two: Plasticity of motor networks and function in the congenital absence of corticospinal projections Despite obvious clinical interest, our understanding of how developmental mechanisms are redeployed during regeneration in case of brain and spinal cord injury or degeneration remains quite rudimentary. In animal models of spinal cord injury, although spontaneous regeneration of descending axons is limited, compensation by intact corticospinal axons, descending tracts from the brainstem, and local intrinsic spinal networks all contribute to recovery of motor function. Here, we focused on spontaneous motor compensation and plastic changes that occur in the absence of corticospinal tract, using Celsr3|Emx1 mice in which the corticospinal tract is fully and specifically absent as a consequence of Celsr3 inactivation in the cortex. Mutant mice had no paresis, but they displayed hyperactivity in open- field, and a reduction in skilled movements in food pellet manipulation tests. Rubrospinal projections, calretinin-positive propriospinal projections, connections between calretinin-positive segmental interneurons and motor neurons, and terminal ramifications of monoaminergic projections were significantly increased in Celsr3|Emx1 mice. These observations demonstrate for the first time that the congenital absence of corticospinal tract induces spontaneous plasticity, both at the level of the motor spinal cord and in descending monoaminergic and rubrospinal projections. Such compensatory mechanisms could be recruited in case of brain or spinal cord lesion or degeneration.