NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord

The regeneration capacity of spinal cord axons is severely limited. Recentl y, much attention has focused on promoting regeneration of descending spina l cord pathways, but little is known about the regenerative capacity of asc ending axons. Here we have assessed the ability of neurotrophic factors to promote regeneration of sensory neurons whose central axons ascend in the d orsal columns. The dorsal columns of adult rats were crushed and either bra in-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) or a vehicle solution was delivered c ontinuously to the lesion site for 4 weeks, Transganglionic labelling with cholera toxin beta subunit (CTB) was used to selectively label large myelin ated A beta fibres. In lesioned rats treated with vehicle, CTB-labelled fib res were observed ascending in the gracile fasciculus, but these stopped ab ruptly at the lesion site, with no evidence of sprouting or growth into les ioned tissue. No CTB-labelled terminals were observed in the gracile nucleu s, indicating that the lesion successfully severed all ascending dorsal col umn axons. Treatment with BDNF did not promote axonal regeneration. In GDNF -treated rats fibres grew around cavities in caudal degenerated tissue but did not approach the lesion epicentre. NT-3, in contrast, had a striking ef fect on promoting growth of lesioned dorsal column axons with an abundance of fibre sprouting apparent at the lesion site, and many fibres extending i nto and beyond the lesion epicentre. Quantification of fibre growth confirm ed that only in NT-3-treated rats did fibres grow into the crush site and b eyond. No evidence of terminal staining in the gracile nucleus was apparent following any treatment. Thus, although NT-3 promotes extensive growth of lesioned axons, other factors may be required for complete regeneration of these long ascending projections back to the dorsal column nuclei. The intr athecal delivery of NT-3 or other neurotrophic molecules has obvious advant ages in clinical applications, as we show for the first time that dorsal co lumn axonal regeneration can be achieved without the use of graft implantat ion or nerve lesions.