It is widely accepted that the adult mammalian central nervous system (CNS) is unable to regenerate axons. In addition to physical or molecular barriers presented by glial scarring at the lesion site, it has been suggested that the normal myelinated CNS environment contains potent growth inhibitors or lacks growth-promoting molecules. 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 technique that minimizes scarring 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.

The neural cell adhesion molecule (NCAM) can influence a number of diverse intercellular events, including junctional communication, the association of axons with pathways and targets, and signals that alter levels of neurotransmitter enzymes. These pleiotropic effects appear to reflect the ability of NCAM to regulate membrane-membrane contact required to initiate specific interactions between other molecules. Such regulation can occur through changes in either NCAM expression or the molecule's content of polysialic acid (PSA). When NCAM with a low PSA content is expressed, adhesion is increased and contact-dependent events are triggered. In contrast, the large excluded volume of NCAM PSA can inhibit cell-cell interactions through hindrance of overall membrane apposition.

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