Proceedings of The Physiological Society

Future Physiology (Leeds, UK) (2017) Proc Physiol Soc 39, PC62

Poster Communications

Rapid and robust recovery of breathing 1.5 years after cervical spinal cord injury

P. M. Warren2,1, S. Steiger3, T. Dick2,6, P. MacFarlane4, W. Alilain2,5, J. Silver2

1. Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom. 2. Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States. 3. Department of Biology, Case Western Reserve University, Cleveland, Ohio, United States. 4. Department of Pediatrics, Case Western Reserve University, Rainbow Babies & Children's Hospital, Cleveland, Ohio, United States. 5. Spinal Cord and Brain Injury Research Centre, University of Kentucky, Lexington, Kentucky, United States. 6. Division of Pulmonary Critical Care and Sleep Medicine, Case Western Reserve University, Cleveland, Ohio, United States.

Methods to restore respiratory function following chronic cervical spinal cord injury (SCI) have not been extensively studied. This represents a major gap in our current understanding as the primary cause of morbidity and mortality following cervical SCI is respiratory motor dysfunction. The loss of this activity after SCI is caused by disruption to supraspinal control of motor pathways. We show that formation of the chondroitin sulphate proteoglycan (CSPG) rich perineuronal net is the major impediment to sprouting and reawakening of the residual cross-phrenic pathway that can lead to restoration of respiratory motor function regardless of time post injury. Indeed, our data demonstrate that robust and rapid recovery of respiratory motor function is possible up to 1.5 years following severe cervical spinal cord hemisection through a combination of enzymatic degradation of perineuronal net associated proteoglycans and rehabilitative conditioning. This is more efficacious then the same treatment applied acutely after trauma. Further, we provide evidence that this recovery is essentially permanent, lasting up to six months following the cessation of treatment. Our combination treatment strategy mitigates these effects through CSPG breakdown by a single intraspinal injection of chrondroitinase ABC and intermittent hypoxia conditioning to increase respiratory drive and synaptic strength. Following conclusion of our treatment strategy, immunohistochemistry has revealed that the extracellular matrix does not reform normally, perhaps suggestive of on-going plasticity. Further, we provide evidence that our combination treatment strategy allows for re-innervation of diaphragm neuromuscular junctions previously denervated due to paralysis induced atrophy. In addition, we provide data describing the ventilatory response of our animals throughout treatment detailing how our recovered animals respond to environmental challenge. We show that these functional physiological changes in response to our treatment strategy are permanent. Collectively, these data demonstrate the significant restoration of diaphragm function and nerve activity at chronic points following cervical SCI due to matrix modification, induction of plasticity and facilitation of drive. Indeed, our results indicate that essentially complete recovery of motor function in this model of spinal cord trauma may not be limited by time after injury.

Where applicable, experiments conform with Society ethical requirements