Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice

Charles Nicaise, Rajarshi Putatunda, Tamara J Hala, Kathleen A Regan, David M Frank, Jean-Pierre Brion, Karelle Leroy, Roland Pochet, Megan C Wright, Angelo C Lepore

Research output: Contribution to journalArticle

Abstract

A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.
Original languageEnglish
Pages (from-to)2748-60
Number of pages13
JournalJournal of neurotrauma
Volume29
Issue number18
DOIs
Publication statusPublished - 10 Dec 2012

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Contusions
Motor Neurons
Diaphragm
Spinal Cord Injuries
Nerve Degeneration
Phrenic Nerve
Wounds and Injuries
Muscles
Neuromuscular Junction
Electromyography
Denervation
Transgenic Mice
Action Potentials
Axons
Animal Models
Cervical Cord
Technology
Morbidity

Keywords

  • Action Potentials
  • Algorithms
  • Animals
  • Axons
  • Brain
  • Cell Count
  • Cervical Vertebrae
  • Cholera Toxin
  • Contusions
  • Diaphragm
  • Electromyography
  • Fluorescent Dyes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Neurons
  • Nerve Degeneration
  • Neuromuscular Junction
  • Phrenic Nerve
  • Spinal Cord Injuries
  • Survival

Cite this

Nicaise, Charles ; Putatunda, Rajarshi ; Hala, Tamara J ; Regan, Kathleen A ; Frank, David M ; Brion, Jean-Pierre ; Leroy, Karelle ; Pochet, Roland ; Wright, Megan C ; Lepore, Angelo C. / Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice. In: Journal of neurotrauma. 2012 ; Vol. 29, No. 18. pp. 2748-60.
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abstract = "A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.",
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author = "Charles Nicaise and Rajarshi Putatunda and Hala, {Tamara J} and Regan, {Kathleen A} and Frank, {David M} and Jean-Pierre Brion and Karelle Leroy and Roland Pochet and Wright, {Megan C} and Lepore, {Angelo C}",
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Nicaise, C, Putatunda, R, Hala, TJ, Regan, KA, Frank, DM, Brion, J-P, Leroy, K, Pochet, R, Wright, MC & Lepore, AC 2012, 'Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice', Journal of neurotrauma, vol. 29, no. 18, pp. 2748-60. https://doi.org/10.1089/neu.2012.2467

Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice. / Nicaise, Charles; Putatunda, Rajarshi; Hala, Tamara J; Regan, Kathleen A; Frank, David M; Brion, Jean-Pierre; Leroy, Karelle; Pochet, Roland; Wright, Megan C; Lepore, Angelo C.

In: Journal of neurotrauma, Vol. 29, No. 18, 10.12.2012, p. 2748-60.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice

AU - Nicaise, Charles

AU - Putatunda, Rajarshi

AU - Hala, Tamara J

AU - Regan, Kathleen A

AU - Frank, David M

AU - Brion, Jean-Pierre

AU - Leroy, Karelle

AU - Pochet, Roland

AU - Wright, Megan C

AU - Lepore, Angelo C

PY - 2012/12/10

Y1 - 2012/12/10

N2 - A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.

AB - A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.

KW - Action Potentials

KW - Algorithms

KW - Animals

KW - Axons

KW - Brain

KW - Cell Count

KW - Cervical Vertebrae

KW - Cholera Toxin

KW - Contusions

KW - Diaphragm

KW - Electromyography

KW - Fluorescent Dyes

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Motor Neurons

KW - Nerve Degeneration

KW - Neuromuscular Junction

KW - Phrenic Nerve

KW - Spinal Cord Injuries

KW - Survival

U2 - 10.1089/neu.2012.2467

DO - 10.1089/neu.2012.2467

M3 - Article

C2 - 23176637

VL - 29

SP - 2748

EP - 2760

JO - Journal of neurotrauma

JF - Journal of neurotrauma

SN - 0897-7151

IS - 18

ER -