Severed axonal connections do not spontaneously regenerate, creating a major hurdle for functional recovery following spinal cord injury (SCI). Previous attempts to aid axonal regeneration have failed to show correct reinnervation of specific target sites in the brain. On pp. 1106–1113 of this issue, Alto et al. demonstrate the successful anatomical regrowth of rat hind limb sensory nerve into the brainstem, across the SCI site.
The Tuszynski laboratory has previously shown that a combination of local neurotrophin expression, conditioning peripheral nerve injury, and cell grafts applied to and near a lesion site can provoke the partial regrowth of severed sensory axons after SCI. In these experiments, the lentiviral expression of neurotrophin-3 (NT-3) provided the chemoattractive guidance cue to direct regenerating axons. A bone marrow graft at the injury site provided scaffolding, a kind of cellular bridge, for the regenerating nerve tract. Sciatic nerve preconditioning lesions, a manipulation known to promote axonal regeneration, were also used. The regenerating axons grew into and beyond the spinal cord lesion site, but the regenerated axons in these previous studies did not quite reach their original targets in the brainstem.
Alto et al. now report ascending sensory tracts that successfully reconnect with their correct target site, the nucleus gracilis in the brain stem. To achieve this, the authors moved the injury site to level C1 on the spinal cord (compared with C4 in their earlier work), where the distance to the target site is much shorter (∼2 mm). The picture shows a confocal micrograph of transganglionic labeling of injured sensory axons (cholera toxin B subunit labeling in red) reaching retrogradely labeled target neurons in the nucleus gracilis (Fluorogold labeling in green). To demonstrate the importance of local neurotrophin gradients in coaxing the regenerating axon to the correct site, the authors misexpressed NT-3 at an inappropriate location, the medullary reticular formation, and found regenerating axons being misdirected and inappropriately reconnected.
Disappointingly, despite this successful anatomical reconnection, these rats did not show appreciable functional recovery. Although regenerating axons formed ultrastructures that are consistent with de novo synaptic contacts, the target neurons in the brain stem showed little or no response to electrical stimulation of the sciatic nerve. Despite the lack of functional recovery, this study shows that proper chemotrophic guidance is a crucial step in promoting recovery after SCI. These findings can potentially aid in designing a combinatorial therapeutic strategy for individuals who have lost peripheral functions as a result of spinal cord trauma.
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