Regeneration of adult axons in white matter tracts of the central nervous system

It is widely accepted that the adult mammalian central nervous system (CNS) is unable to regenerate axons1. In addition to physical or molecular barriers presented by glial scarring at the lesion site2,3,4, it has been suggested that the normal myelinated CNS environment contains potent growth inhibitors5,6 or lacks growth-promoting molecules1,7. Here we investigate whether adult CNS white matter can support long-distance regeneration of adult axons in the absence of glial scarring, by using a microtransplantation technique8 that minimizes scarring9 to inject minute volumes of dissociated adult rat dorsal root ganglia directly into adult rat CNS pathways. This atraumatic injection procedure allowed considerable numbers of regenerating adult axons immediate access to the host glial terrain, where we found that they rapidly extended for long distances in white matter, eventually invading grey matter. Abortive regeneration correlated precisely with increased levels of proteoglycans within the extracellular matrix at the transplant interface, whereas successfully regenerating transplants were associated with minimal upregulation of these molecules. Our results demonstrate, to our knowledge for the first time, that reactive glial extracellular matrix at the lesion site is directly associated with failure of axon regrowth in vivo, and that adult myelinated white matter tracts beyond the glial scar can be highly permissive for regeneration.