After a dorsal root crush injury, centrally-projecting sensory axons fail to regenerate across the dorsal root entry zone (DREZ) to extend into the spinal cord. We find that chemogenetic activation of adult dorsal root ganglion (DRG) neurons improves axon growth on an in vitro model of the inhibitory environment after injury. Moreover, repeated bouts of daily chemogenetic activation of adult DRG neurons for 12 weeks post-crush in vivo enhances axon regeneration across a chondroitinase-digested DREZ into spinal gray matter, where the regenerating axons form functional synapses and mediate behavioral recovery in a sensorimotor task. Neuronal activation-mediated axon extension is dependent upon changes in the status of tubulin post-translational modifications indicative of highly dynamic microtubules (as opposed to stable microtubules) within the distal axon, illuminating a novel mechanism underlying stimulation-mediated axon growth. We have identified an effective combinatory strategy to promote functionally-relevant axon regeneration of adult neurons into the CNS after injury.

背根挤压损伤后，中央突出的感觉轴突无法跨背根进入区（DREZ）再生并延伸到脊髓。我们发现，在损伤后抑制环境的体外模型中，成年背根神经节（DRG）神经元的化学遗传学激活可改善轴突生长。此外，在体内挤压后 12 周内，每天重复对成年 DRG 神经元进行化学遗传学激活，可增强轴突再生，穿过软骨素酶消化的 DREZ 进入脊髓灰质，其中再生的轴突形成功能性突触并介导感觉运动任务中的行为恢复。神经元激活介导的轴突延伸取决于微管蛋白翻译后修饰状态的变化，表明远端轴突内存在高度动态的微管（而不是稳定的微管），阐明了刺激介导的轴突生长的新机制。我们已经确定了一种有效的组合策略来促进损伤后成年神经元功能相关的轴突再生到中枢神经系统。