Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI

Exp Neurol., 2018 · DOI: 10.1016/j.expneurol.2018.02.007 · Published: May 1, 2018

Spinal Cord Injury Pulmonology Regenerative Medicine & Stem Cells

Simple Explanation

Damage to the spinal cord in the neck area can disrupt breathing by affecting the nerves that control the diaphragm. This study explores a way to repair those damaged nerve connections. The researchers used a virus to deliver a specific protein (cRheb) into nerve cells in the brainstem that control breathing. This protein is known to promote nerve growth. The study found that the protein helped the damaged nerve fibers to regrow, but this regrowth alone wasn't enough to restore normal diaphragm function, suggesting that other factors are needed for full recovery.

Study Duration

15 weeks post-C2 hemisection

Participants

Female Sprague-Dawley rats weighing 250-300 grams

Evidence Level

Not specified

Key Findings

1
Expression of cRheb selectively in rVRG neurons following cervical hemisection SCI stimulates mTOR pathway activation within transduced cells.
2
cRheb expression reduces dieback of injured rVRG fibers and promotes regeneration of this critical population of bulbospinal respiratory axons.
3
Regenerating rVRG axons do not extend back to caudal spinal cord to reinnervate PhMNs and cRheb alone does not promote recovery of diaphragmatic respiratory function after SCI.

Research Summary

This study investigated the potential of cRheb to promote regeneration of injured respiratory axons after cervical spinal cord injury (SCI) in rats. The researchers found that cRheb expression in rVRG neurons stimulated mTOR pathway activation, reduced axonal dieback, and promoted regeneration of injured rVRG axons into the lesion site. Despite axonal regeneration, the regrown fibers did not reinnervate PhMNs, and diaphragm function was not restored, suggesting that additional strategies are needed to achieve functional recovery.

Practical Implications

Targeted Therapies

Modulation of signaling pathways regulating axon growth potential can promote axon regeneration.

Combination Therapies

Combining cRheb expression with strategies that address neuronal-extrinsic inhibitory effects (e.g., CSPGs) may be necessary to coax regrowing rVRG axons back into the distal intact spinal cord.

Clinical Relevance

Optimizing reconnection of the rVRG-PhMN circuitry could significantly improve respiratory function in individuals with cervical SCI.

Study Limitations

1
Regrowth did not occur back into the intact caudal spinal cord to establish synaptic reinnervation of PhMNs.
2
Activation of the mTOR pathway alone may be insufficient to produce robust growth after CNS damage.
3
cRheb stimulation of S6 kinase 1 may induce feedback inhibition of the phosphatidylinositol 3-kinase/mTOR signaling axis.

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