A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury

• Published in: Cell reports (Cambridge) 2017-10, Vol.21 (3), p.654-665
• Main Authors: Cregg, Jared M., Chu, Kevin A., Hager, Lydia E., Maggard, Rachel S.J., Stoltz, Daimen R., Edmond, Michaela, Alilain, Warren J., Philippidou, Polyxeni, Landmesser, Lynn T., Silver, Jerry
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; breathing; Cervical Vertebrae - physiopathology; diaphragm; Diaphragm - innervation; Diaphragm - physiopathology; Interneurons - pathology; Light; Lumbar Vertebrae - physiopathology; Mice; Motor Neurons - pathology; Nerve Net - physiopathology; Paralysis - physiopathology; phrenic motor neuron; Phrenic Nerve - physiopathology; Respiration; rodent; spasticity; Spinal Cord Injuries - physiopathology; spinal cord injury; Synaptic Transmission - physiology; Thoracic Vertebrae - physiopathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.09.076

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations showed that this spinal network acts independently of medullary circuits that normally generate inspiration, suggesting a distinct non-respiratory function. We further show that this “latent” network can be harnessed to restore diaphragm function after high cervical SCI in adult mice and rats. [Display omitted] •Blockade of inhibition uncovers a spinal cord network that elicits phrenic bursting•Vglut2 interneurons were sufficient and necessary for induction of phrenic bursts•Spinal-cord-derived phrenic bursting is dissociable from bona fide respiration•This propriospinal network can be harnessed to allow diaphragm function after SCI Cregg et al. uncover a spinal network that can direct diaphragm-innervating motoneurons to burst. This network is functionally independent of descending bulbospinal inspiratory circuits, which points to a different physiologic function. Targeting this network restores diaphragm function after cervical SCI.