Review False Resurrections: Distinguishing Regenerated from Spared Axons in the Injured Central Nervous System

Several recent studies report that axon regeneration can be induced in the mature mammalian nervous system by novel treatments or genetic manipulations. In assessing these reports, it is important to be mindful of the history of regeneration research, which is littered with the corpses of studies that reported regeneration that later proved incorrect. One important reason is the “spared axon conundrum,” in which axons that survive a lesion are mistakenly identified as having regenerated. Here, we illustrate the problem and propose criteria that may be used to identify regenerated vs. spared axons, focusing on the injured spinal cord. J. Comp. Neurol. 459:1–8, 2003. © 2003 Wiley-Liss, Inc. Indexing terms: axon regeneration; spinal cord injury; sprouting; tract tracing On the face of it, a study of axon regeneration in the central nervous system would seem simple to perform. One simply cuts or otherwise damages a population of axons, and then evaluates whether those axons re-grow. In a typical experiment involving spinal cord injury, for example, one would produce a lesion in the spinal cord, wait for some period of time to allow for possible axon regeneration, and then trace particular spinal tracts by using tract-tracing techniques. Numerous studies indicate that there is minimal axon regeneration in normal animals (Schwab and Bartholdi, 1996). The axons that had been cut retract for some distance from the injury and persist as retraction balls, perhaps exhibiting regenerative sprouting into nearby territory. In contrast, several recent studies report that, in animals that receive some treatment or that carry a mutation in a gene that presumably encodes an inhibitor of axon growth, the axons that had been cut regenerate around, beyond, or sometimes even through the lesion site. What could possibly go wrong in such a simple experiment? The answer is that axons are remarkably resilient and can survive displacement and stretch. Because of this resiliency, axons that are revealed by tract tracing at some time point after a lesion may not have been cut in the first place, and treatments or genetic manipulations may reGrant sponsor: Roman Reed Project of the State of California; Grant sponsor: Californians for Cure; Grant sponsor: International Spinal Research Trust; Grant sponsor: Howard Hughes Medical Institute; Grant sponsor: Helen Hay Whitney Fellowship. *Correspondence to: Oswald Steward, 1105 Gillespie Neuroscience Research Facility, College of Medicine, University of California at Irvine, Irvine, CA. E-mail: [email protected] Received 11 November 2002; Revised 6 December 2002; Accepted 12