Robust Regeneration of Adult Sensory Axons in Degenerating White Matter of the Adult Rat Spinal Cord

Abstract

We have recently reported that minimally disturbed adult CNS white matter can support regeneration of adult axons by using a novel microtransplantation technique to inject minute volumes of dissociated adult rat dorsal root ganglion neurons directly into adult rat CNS pathways (Davies et al., 1997). This atraumatic injection procedure minimized scarring and allowed considerable numbers of regenerating adult axons immediate access to the adult CNS glial terrain where they rapidly extended for long distances. A critical question remained as to whether degenerating white matter at acute and chronic stages (up to 3 months) after injury could still support regeneration. To investigate this, we have microtransplanted adult sensory neurons into degenerating white matter of the adult rat spinal cord several millimeters rostral to a severe lesion of the dorsal columns. Regeneration of donor sensory axons in both directions away from the site of transplantation was robust even within white matter undergoing fulminant Wallerian degeneration despite intimate contact with myelin. Along their route, the regrowing axons extended large numbers of collaterals into the adjacent dorsal horn. However, after entering the lesion, the rapidly extending growth cones stopped and became dystrophic within high concentrations of reactive glial matrix. Our results offer compelling evidence that the major environmental impediment to regeneration in the adult CNS is the molecular barrier that forms directly at the lesion site, and that degenerating white matter beyond the glial scar has a far greater intrinsic ability to support axon regeneration than previously thought possible.

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

“…This limited capacity for repair has been attributed, in part, to the nonpermissive environment of the glial scar that forms in the penumbra surrounding the lesion site (Bahr et al, 1995;Davies et al, 1999;Fawcett and Asher, 1999;McKeon et al, 1991;Reier and Houle, 1988). This glial scar is predominantly formed from extracellular matrix (ECM) molecules expressed by reactive astrocytes although macrophages, microglia, oligodendrocytes, invading Schwann cells and meningeal fibroblasts all contribute to production of the scar matrix (Fawcett and Asher, 1999).…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…They approach, but do not come into contact with the newly formed glia limitans at the innermost margin of the glial scar. This was demonstrated in studies by Silver and colleagues, 75,76 in which eGFP-expressing axons from grafted sensory neurons elongated within the degenerating dorsal columns, but halted within a halo of chondroitin sulfate proteoglycan (CSPG) immunoreactivity surrounding a small, previously generated, wound. Sensory axons injured within the dorsal root also regenerate up to the DREZ.…”

Basal forebrain cholinergic cell attachment and neurite outgrowth on organotypic slice cultures of hippocampal formation

“…As described by Davies et al (1999) the GFP expressing transgenic mice were maintained on a C57BL/6N background, with the gene for the GFP protein under control of a chicken L-actin promoter (Okabe et al, 1997). In these animals, virtually all neurons, along with other cells, express GFP.…”