Protracted myelin clearance hinders central primary afferent regeneration following dorsal rhizotomy and delayed neurotrophin-3 treatment

Regeneration within or into the CNS is thwarted by glial inhibition at the site of a spinal cord injury and at the dorsal root entry zone (DREZ), respectively. At the DREZ, injured axons and their distal targets are separated by degenerating myelin and an astrocytic glia limitans. The different glial barriers to regeneration following dorsal rhizotomy are temporally and spatially distinct. The more peripheral astrocytic barrier develops first, and is surmountable by neurotrophin-3 (NT-3) treatment; the more central myelin-derived barrier, which prevents dorsal horn re-innervation by NT-3-treated axons, becomes significant only after the onset of myelin degeneration. Here we test the hypothesis that in the presence of NT-3, axonal regeneration is hindered by myelin degeneration products. To do so, we used the Long Evans Shaker (LES) rat, in which oligodendrocytes do not make CNS myelin, but do produce myelin-derived inhibitory proteins. We show that delaying NT-3 treatment for 1 week in normal (LE) rats, while allowing axonal penetration of the glia limitans and growth within degenerating myelin, results in misdirected regeneration with axons curling around presumptive degenerating myelin ovoids within the CNS compartment of the dorsal root. In contrast, delaying NT-3 treatment in LES rats resulted in straighter, centrally-directed regenerating axons. These results indicate that regeneration may be best optimized through a combination of neurotrophin treatment plus complete clearance of myelin debris.