Two-tiered inhibition of axon regeneration at the dorsal root entry zone

Glial-derived inhibitory molecules and a weak cell-body response prevent se nsory axon regeneration into the spinal cord after dorsal root injury. Neur otrophic factors, particularly neurotrophin-3 (NT-3), may increase the rege nerative capacity of sensory neurons after dorsal rhizotomy, allowing regen eration across the dorsal root entry zone (DREZ). Intrathecal NT-3, deliver ed at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-l abeled sensory axone across the DREZ and deep into the dorsal horn. However , delaying treatment for 1 week compromised regeneration: although axons st ill penetrated the DREZ, growth within white matter was qualitatively and q uantitatively restricted. This was not associated with an impaired cell-bod y response (GAP-43 upregulation was equivalent for both immediate and delay ed treatments), or with astrogliosis at the DREZ, which begins almost immed iately after rhizotomy, but with the delayed appearance of mature EDI-expre ssing phagocytes in the dorsal white matter between 1 and 2 weeks after les ion, marking the beginning of myelin breakdown. After rhizotomy with immedi ate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsa l gray matter rather than in the degenerating dorsal columns. The ability o f NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmounta ble by NT-3 treatment.