Project description:Brain and spinal injury often impair sensorimotor processing in the spinal cord and reduce mobility. We established that complete transection of corticospinal pathways in the pyramids leads to increased spasms, excessive mono- and polysynaptic spinal reflexes and impaired locomotion in rats. Intramuscular neurotrophin-3 treatment at a clinically-feasible time-point after injury reduced these signs of spasticity. We found Neurotrophin-3 reduced spastic movements and improved neurophysiological sensorimotor control. Furthermore, the balance of inhibitory and excitatory synapses in the cord and the level of an ion transporter in motor neuron membranes required for normal reflexes were normalized. We discovered that Neurotrophin-3 is transported in sensory afferents from muscles to the dorsal root ganglia. Using genome-wide small RNA sequencing of the whole cervical level 6-8 dorsal root ganglia, we explored miRNA changes in afferent neurons that were present 10 weeks after bilateral pyramidotomy. Many of the dysregulated genes are involved in axon guidance and plasticity. Intramuscular neurotrophin-3 treatment normalized many of those gene changes and may be one of the mechanisms how reflexes, functional recovery and molecular markers in the spinal cord are restored. This identifies neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.
Project description:Brain and spinal injury often impair sensorimotor processing in the spinal cord and reduce mobility. We established that complete transection of corticospinal pathways in the pyramids leads to increased spasms, excessive mono- and polysynaptic spinal reflexes and impaired locomotion in rats. Intramuscular neurotrophin-3 treatment at a clinically-feasible time-point after injury reduced these signs of spasticity. We found Neurotrophin-3 reduced spastic movements and improved neurophysiological sensorimotor control. Furthermore, the balance of inhibitory and excitatory synapses in the cord and the level of an ion transporter in motor neuron membranes required for normal reflexes were normalized. We discovered that Neurotrophin-3 is transported in sensory afferents from muscles to the dorsal root ganglia. Using genome-wide RNA sequencing of the whole cervical level 6-8 dorsal root ganglia, we explored mRNA changes in afferent neurons that were present 10 weeks after bilateral pyramidotomy. Many of the dysregulated genes are involved in axon guidance and plasticity. Intramuscular neurotrophin-3 treatment normalized many of those gene changes and may be one of the mechanisms how reflexes, functional recovery and molecular markers in the spinal cord are restored. This identifies neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.
Project description:Brain and spinal injury often impair sensorimotor processing in the spinal cord and reduce mobility. Cortical stroke in rats leads to long-term deficits in dexterity and walking. Subcutaneous neurotrophin-3 infusion initiated at a clinically-feasible time-point after injury improved walking and dexterity. We discovered that Neurotrophin-3 is transported in sensory afferents from muscles to the dorsal root ganglia. Using genome-wide RNA sequencing of the whole cervical level 6-8 dorsal root ganglia, we sought gene changes in afferent neurons that were present at two timepoints after stroke.
Project description:Axon regeneration in the central nervous system (CNS) requires reactivating injured neurons’ intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater spouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. These screens are presented here. Biological quadruplicate - Mouse tissue - Naïve Dorsal Root Ganglia (DRG) and 5 day post sciatic nerve crush DRG - x9 strains.
