Functional regeneration of respiratory pathways after spinal cord injury

Abstract

Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways. Patients with spinal cord injuries in the neck area often need mechanical ventilators to help them breathe, and impaired breathing is a leading cause of death in these patients. Two factors combine to make recovery difficult. First, an injury above the fourth cervical vertebra disrupts the passage of nerve impulses from the respiratory centre in the brainstem to the phrenic motor nuclei in the spinal cord, and second, in the event of injury, adult spinal cord axons tend not to regenerate. Working in a rat model of spinal cord injury, Jerry Silver and colleagues have identified an upregulation of extracellular matrix molecules that impairs axonal regeneration following injury. Using a strategy of specific extracellular component digestion with chondroitinase, combined with peripheral nerve autografting across the damaged section of the spinal cord, the authors demonstrate a significant recovery of respiratory activity after axon regeneration. This study suggests that regeneration and restoration of diaphragm function may be possible after some types of spinal cord trauma.