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

Abstract

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.

Post-traumatic inflammation following spinal cord injury

“…14,48,[71][72][73][74]111 It has been demonstrated that reactive adult astrocytes upregulate the production of laminin and neurotrophin C. 75,76 In addition to the endogenously present myelinassociated neurite growth inhibitory constitutents, reactive astrocytes form an astroglial scar that acts as a physical and/or chemical barrier to axonal regeneration. 8,35,72,77,78 Proximity to the lesion epicentre determines whether the reactive glial environment will be growth supportive or inhibitory. 63 Although the functional role of glial scarring is not completely understood, it has been suggested to be an attempt by the CNS to restore homeostasis through isolation of the damaged region.…”

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

“…Chief of the many ECM molecules that serve to inhibit axonal regeneration are the chondroitin sulfate proteoglycans (CSPGs) (Eddleston and Mucke, 1993;Silver and Miller, 2004) that experience a great increase in expression following SCI (Lemons et al, 1999;McKeon et al, 1991). Both in vitro and in vivo studies have shown that axons do not extend into CSPG-rich ECM (Davies et al, 1997(Davies et al, , 1999McKeon et al, 1991;Meiners et al, 1995;Zuo et al, 1998), and specific CSPGs that inhibit neurite outgrowth have been identified including: aggrecan (Condic et al, 1999), neurocan , phosphocan , brevican (Yamada et al, 1997), versican (Schmalfeldt et al, 2000), and NG2 (Dou and Levine, 1994).…”

Manganese‐enhanced MRI of the optic visual pathway and optic nerve injury in adult rats

“…Unlike axons in the peripheral nervous system, those in the CNS of adult mammals do not regenerate after injury (20,21). Failure to regenerate is attributed to a combination of axon growth arrest by myelin-associated and scar-derived inhibitor molecules (22,23), and to the absence of growth-promoting neurotrophic factors in the adult CNS (24).…”