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.
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This work was supported by NSF grant DGE-0951783 (to J.M.C.), start-up from the University of Kentucky College of Medicine (to W.J.A.), NIH grant NS101105 (to W.J.A.), start-up from Case Western Reserve University (to P.P.), the Mt. Sinai Foundation (to P.P.), NIH grant NS085037 (to P.P.), NIH grant NS074199 (to L.T.L.), and NIH grant NS025713 (to J.S.).
Supplemental Information includes Supplemental Experimental Procedures and five figures and can be found with this article online at https://doi.org/10.1016/j.celrep.2017.09.076.
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.; and Silver, Jerry, "A Latent Propriospinal Network Can Restore Diaphragm Function After High Cervical Spinal Cord Injury" (2017). Spinal Cord and Brain Injury Research Center Faculty Publications. 18.