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

Jared M. Cregg; Kevin A. Chu; Lydia E. Hager; Rachel S.J. Maggard; Daimen R. Stoltz; Michaela Edmond; Warren J. Alilain; Polyxeni Philippidou; Lynn T. Landmesser; Jerry Silver

doi:10.1016/j.celrep.2017.09.076

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

Jared M. Cregg, Kevin A. Chu, Lydia E. Hager, Rachel S.J. Maggard, Daimen R. Stoltz, Michaela Edmond, Warren J. Alilain, Polyxeni Philippidou, Lynn T. Landmesser, Jerry Silver

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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. 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.

Original language	English
Pages (from-to)	654-665
Number of pages	12
Journal	Cell Reports
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2017.09.076
State	Published - Oct 17 2017

Bibliographical note

Funding Information:
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.). We thank Jing Qiang You for technical assistance and Thomas (TED) Dick, Philippa Warren, and Christopher Wilson for helpful commentary and discussion.

Publisher Copyright:
© 2017 The Author(s)

Keywords

breathing
diaphragm
phrenic motor neuron
respiration
rodent
spasticity
spinal cord injury

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

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10.1016/j.celrep.2017.09.076

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title = "A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury",

abstract = "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. 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.",

keywords = "breathing, diaphragm, phrenic motor neuron, respiration, rodent, spasticity, spinal cord injury",

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note = "Funding Information: 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.). We thank Jing Qiang You for technical assistance and Thomas (TED) Dick, Philippa Warren, and Christopher Wilson for helpful commentary and discussion. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

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AU - Edmond, Michaela

AU - Alilain, Warren J.

AU - Philippidou, Polyxeni

AU - Landmesser, Lynn T.

AU - Silver, Jerry

N1 - Funding Information: 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.). We thank Jing Qiang You for technical assistance and Thomas (TED) Dick, Philippa Warren, and Christopher Wilson for helpful commentary and discussion. Publisher Copyright: © 2017 The Author(s)

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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