Abstract
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.
Highlights
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 first sought to determine if activation of adult dorsal root ganglion (DRG) neurons could enhance axonal regrowth in an in vitro model that mimics the gradient of upregulated chondroitin sulfate proteoglycans (CSPG) present at the DREZ after a dorsal root crush[14,15,34]
Similar to what we saw before[14,15], their axons were not able to extend across the rim of the spot, where there is a high concentration of CSPG, unless CSPGs in the substrate were digested with chondroitinase ABC (ChABC) (Fig. 1a–c)
Summary
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 and others have administered the bacterial enzyme chondroitinase ABC (ChABC) to digest upregulated CSPGs after dorsal root crush[14,15] This allows for a limited number of axons to regenerate across the DREZ, indicating that modifying the inhibitory environment alone is not sufficient to obtain robust axon regeneration. We found that increasing the labile microtubule mass in adult DRG neurons by knocking down the microtubule-severing protein fidgetin improves axon regeneration across the DREZ after dorsal root crush[24]. Another avenue that has been explored to increase the intrinsic capacity for axon regeneration is neuronal activation. Activating neurons expressing the excitatory designer receptor exculsively activated by designer drugs (DREADDs) hM3Dq using the receptor’s ligand clozpine-N-oxide (CNO29–31) enhances retinal ganglion cell axon growth after an optic nerve crush[32,33]
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