Abstract
BackgroundInjuries to the spinal cord often result in severe functional deficits that, in case of incomplete injuries, can be partially compensated by axonal remodeling. The corticospinal tract (CST), for example, responds to a thoracic transection with the formation of an intraspinal detour circuit. The key step for the formation of the detour circuit is the sprouting of new CST collaterals in the cervical spinal cord that contact local interneurons. How individual collaterals are formed and refined over time is incompletely understood.Methodology/Principal FindingsWe traced the hindlimb corticospinal tract at different timepoints after lesion to show that cervical collateral formation is initiated in the first 10 days. These collaterals can then persist for at least 24 weeks. Interestingly, both major and minor CST components contribute to the formation of persistent CST collaterals. We then developed an approach to label single CST collaterals based on viral gene transfer of the Cre recombinase to a small number of cortical projection neurons in Thy1-STP-YFP or Thy1-Brainbow mice. Reconstruction and analysis of single collaterals for up to 12 weeks after lesion revealed that CST remodeling evolves in 3 phases. Collateral growth is initiated in the first 10 days after lesion. Between 10 days and 3–4 weeks after lesion elongated and highly branched collaterals form in the gray matter, the complexity of which depends on the CST component they originate from. Finally, between 3–4 weeks and 12 weeks after lesion the size of CST collaterals remains largely unchanged, while the pattern of their contacts onto interneurons matures.Conclusions/SignificanceThis study provides a comprehensive anatomical analysis of CST reorganization after injury and reveals that CST remodeling occurs in distinct phases. Our results and techniques should facilitate future efforts to unravel the mechanisms that govern CST remodeling and to promote functional recovery after spinal cord injury.
Highlights
Injury to the spinal cord leads to a disruption of ascending and descending fiber tracts followed by loss of sensation and voluntary movements below the level of the lesion [1]
Axons arising from all hindlimb corticospinal tract (CST) components sent only very few collaterals into the gray matter of the cervical spinal cord
When we analyzed the contribution of different CST components to the formation of cervical collaterals, we found that, while in absolute number most of the collaterals arose from the main CST, the relative number of new collaterals that emerge per labeled fiber was several-fold higher for the minor dorso-lateral and ventral CST components (Fig. 1 E–P)
Summary
Injury to the spinal cord leads to a disruption of ascending and descending fiber tracts followed by loss of sensation and voluntary movements below the level of the lesion [1]. Detour circuits are formed in the following steps: First, the lesioned CST fibers sprout new collaterals in the cervical spinal cord above the level of lesion. These collaterals extend to the intermediate layers of the cervical gray matter. There they form contacts with different populations of spinal interneurons, including long propriospinal neurons, a population of interneurons that are involved in coupling of forelimb and hindlimb movement [15,16,17,18]. How individual collaterals are formed and refined over time is incompletely understood
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