All hands on deck: the importance of additional pathways in mediating recovery in spinal cord injury.

Abstract

Functional improvement after spinal cord injury (SCI) is thought to be limited by 3 major factors. First, the development of an impenetrable glial scar around the injury site limits functional recovery. Second, there is increasing evidence of the expression of growth-inhibiting molecules such as Nogo-A and its receptors. Third, it is widely accepted that most adult central nervous system neurons have limited intrinsic regenerative capacity. Despite these impediments, some limited recovery does exist in both human and animal models of SCI. In a recent study, Siegel et al1 attempted to determine the importance of redundant descending pathways and functional plasticity in mediating recovery after SCI. Similar to others, they found 3 major types of motor functions with differing capacities for functional recovery after bilateral pyramidotomy, which in effect causes degeneration of the corticospinal tract, the major descending motor pathway in humans and mice. Seeking a behavioral task that shows gradual improvement over time but remains significantly impaired, the authors looked at skilled locomotion using grid-walking analysis. Wild-type mice showed initial and sustained deficits compared with sham-lesioned mice. Moreover, ngr1−/− mice recovered significant function compared with wild-type mice. Armed with these data, the authors attempted to find mechanisms for this functional plasticity. They were able to show convincingly that both the rubrospinal tract (red lines in the Figure, A and D) and the rubrospinal pathways showed increased de novo projections after bilateral pyramidotomy in wild-type mice (Figure, B and E) and that the plasticity-enhanced ngr1−/− mice had even more of these new connections (Figure, C and F). In addition to these known pathways, the authors were also able to identify a previously undescribed connection between the red nucleus and the nucleus raphe magnus (red stippled lines, Figure), which is the originating nucleus of yet another descending motor pathway, the raphespinal tract. The authors also illustrate that this pathway shows plasticity-induced augmentation after bilateral pyramidotomy. Using a combination of both genetic and pharmacological tools, the authors show that transiently silencing these accessory motor pathways does not affect skilled locomotion in the intact central nervous system, suggesting that these pathways play a different role in the face of spinal cord injury.Figure: Bilateral pyramidotomy-induced rubral sprouting drives spontaneous recovery of function after complete corticospinal tract (CST) lesion. A through E, summary schematics show the origin and termination pattern of the CST (green lines), rubrospinal tract (RST; from the red nucleus; red lines), and the raphespinal tract (RPST; from the nucleus raphe magnus; blue lines) in the brainstem (A) and spinal cord (D) of adult intact mice. bPyX (B, C) results in spinal degeneration of the CST and retraction of CST terminals from the spinal cord in both ngr1+/+ (E) and plasticity-sensitized ngr1−/− (F) mice. Lesion-induced de novo connections (red stippled lines) formed between the red nucleus and premotor brainstem nuclei (B; basilar pontine nuclei and nucleus raphe magnus) and motor neurons in the spinal cord (E) after complete ablation of the CST in adult ngr1+/+ mice initiate spontaneous functional recovery. bPyX-induced sprouting of rubral connections in the brainstem (C) and spinal cord (F) is enhanced in ngr1−/− mice, significantly elevating spontaneous recovery of function. Republished with permission from Siegel et al (Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury. J Neurosci. 2015;35[4]:1443-1457) 1.The authors have described the roles of “minor” motor pathways in mediating functional recovery after spinal cord injury, attesting to the grand complexity of neural circuitry that exists in the brain and spinal cord. The ability to know these pathways and to enhance neural plasticity will certainly lead to a better understanding of how to “repair” the injured spinal cord.