Changes in miRNAs in the dorsal root ganglion after CNS injury and intramuscular neurotrophin-3 treatment

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.颅脑与脊髓损伤常会损害脊髓内的感觉运动加工过程，并降低机体运动能力。本研究证实，对大鼠锥体部位的皮质脊髓通路进行完全横断，会引发痉挛症状加重、脊髓单突触与多突触反射亢进，以及运动功能受损。在损伤后临床可行的时间点实施肌内注射神经营养因子3（Neurotrophin-3）治疗，可减轻此类痉挛相关体征。本研究发现，神经营养因子3可减轻痉挛性运动障碍，并改善神经生理学层面的感觉运动调控功能。此外，脊髓内抑制性与兴奋性突触的平衡，以及运动神经元膜上维持正常反射所需的离子转运蛋白水平，均恢复至正常水平。本研究还发现，神经营养因子3可通过肌肉来源的感觉传入纤维转运至背根神经节（dorsal root ganglia）。通过对颈髓6-8节段的全部背根神经节进行全基因组小RNA测序，本研究分析了双侧锥体切断术后10周时传入神经元内的微小RNA（miRNA）表达变化。大量表达失调的基因均与轴突导向及神经可塑性相关。肌内注射神经营养因子3治疗可使多数上述基因表达恢复正常，这可能是其恢复脊髓反射、促进运动功能恢复以及调节脊髓内分子标志物水平的机制之一。上述结果表明，神经营养因子3是一种可针对痉挛症的根本病因进行治疗的疗法，而非仅能缓解其症状。