Article reviews the research on the axon’s response after spina cord injury (SCI), including axonal dieback and degeneration, then discusses the current understanding of intrinsic pathways affecting central nervous system (CNS) axon growth potential. Finally, the authors describe the extrinsic factors that have been identified as inhibitors of axonal regeneration. The mechanisms that underlie recovery after injury of the CNS have rarely been definitively established. Axonal outgrowth has been studied as a basis for plasticity, regeneration, circuit formation, and eventually functional recovery. The attributed functional relevance of axon regrowth, however, will depend on several subsequent conditional neurobiological modifications, including myelination and synapse formation, but also pruning of aberrant connectivity. Despite the ability to revamp axon outgrowth by altering an increasing number of extracellular and intracellular targets, disentangling which axons are responsible for the recovery of function from those that are functionally silent, or even contributing to aberrant functions, represents a pertinent void in our understanding, challenging the intuitive translational link between anatomical and functional regeneration. Anatomic hallmarks of regeneration are not static and are largely activity dependent. Conversion of axonal growth-promoting interventions into functionality is context dependent, relying on both timing and activity.
