Phrenic motor neuron degeneration compromises phrenic axonal circuitry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury

Charles Nicaise, Tamara J Hala, David M Frank, Jessica L Parker, Michèle Authelet, Karelle Leroy, Jean-Pierre Brion, Megan C Wright, Angelo C Lepore

Research output: Contribution to journalArticle

Abstract

Respiratory dysfunction is the leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). Injuries targeting mid-cervical spinal cord regions affect the phrenic motor neuron pool that innervates the diaphragm, the primary respiratory muscle of inspiration. Contusion-type injury in 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. In an attempt to target the phrenic motor neuron pool, two unilateral contusion injury paradigms were tested, a single injury at level C4 and a double injury both at levels C3 and C4, and animals were followed for up to 6 weeks post-injury. Both unilateral cervical injury paradigms are reproducible with no mortality or need for breathing assistance, and are accompanied by phrenic motor neuron loss, phrenic nerve axon degeneration, diaphragm atrophy, denervation and subsequent partial reinnervation at the diaphragm neuromuscular junction, changes in spontaneous diaphragm EMG recordings, and reduction in phrenic nerve compound muscle action potential amplitude. These findings demonstrate significant and chronically persistent respiratory compromise following mid-cervical SCI due to phrenic motor neuron degeneration. These injury paradigms and accompanying analyses provide important tools both for understanding mechanisms of phrenic motor neuron and diaphragm pathology following SCI and for evaluating therapeutic strategies in clinically relevant cervical SCI models.
Original languageEnglish
Pages (from-to)539-52
Number of pages14
JournalExperimental neurology
Volume235
Issue number2
DOIs
Publication statusPublished - Jun 2012

Fingerprint

Nerve Degeneration
Contusions
Motor Neurons
Diaphragm
Spinal Cord Injuries
Wounds and Injuries
Phrenic Nerve
Respiratory Muscles
Mortality
Neuromuscular Junction
Denervation
Inhalation
Action Potentials
Atrophy
Axons
Respiration
Animal Models

Keywords

  • Animals
  • Axons
  • Cervical Vertebrae
  • Diaphragm
  • Disease Models, Animal
  • Female
  • Motor Neurons
  • Nerve Degeneration
  • Nerve Net
  • Phrenic Nerve
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Paralysis
  • Spinal Cord Injuries

Cite this

Nicaise, Charles ; Hala, Tamara J ; Frank, David M ; Parker, Jessica L ; Authelet, Michèle ; Leroy, Karelle ; Brion, Jean-Pierre ; Wright, Megan C ; Lepore, Angelo C. / Phrenic motor neuron degeneration compromises phrenic axonal circuitry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury. In: Experimental neurology. 2012 ; Vol. 235, No. 2. pp. 539-52.
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Phrenic motor neuron degeneration compromises phrenic axonal circuitry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury. / Nicaise, Charles; Hala, Tamara J; Frank, David M; Parker, Jessica L; Authelet, Michèle; Leroy, Karelle; Brion, Jean-Pierre; Wright, Megan C; Lepore, Angelo C.

In: Experimental neurology, Vol. 235, No. 2, 06.2012, p. 539-52.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phrenic motor neuron degeneration compromises phrenic axonal circuitry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury

AU - Nicaise, Charles

AU - Hala, Tamara J

AU - Frank, David M

AU - Parker, Jessica L

AU - Authelet, Michèle

AU - Leroy, Karelle

AU - Brion, Jean-Pierre

AU - Wright, Megan C

AU - Lepore, Angelo C

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/6

Y1 - 2012/6

N2 - Respiratory dysfunction is the leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). Injuries targeting mid-cervical spinal cord regions affect the phrenic motor neuron pool that innervates the diaphragm, the primary respiratory muscle of inspiration. Contusion-type injury in 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. In an attempt to target the phrenic motor neuron pool, two unilateral contusion injury paradigms were tested, a single injury at level C4 and a double injury both at levels C3 and C4, and animals were followed for up to 6 weeks post-injury. Both unilateral cervical injury paradigms are reproducible with no mortality or need for breathing assistance, and are accompanied by phrenic motor neuron loss, phrenic nerve axon degeneration, diaphragm atrophy, denervation and subsequent partial reinnervation at the diaphragm neuromuscular junction, changes in spontaneous diaphragm EMG recordings, and reduction in phrenic nerve compound muscle action potential amplitude. These findings demonstrate significant and chronically persistent respiratory compromise following mid-cervical SCI due to phrenic motor neuron degeneration. These injury paradigms and accompanying analyses provide important tools both for understanding mechanisms of phrenic motor neuron and diaphragm pathology following SCI and for evaluating therapeutic strategies in clinically relevant cervical SCI models.

AB - Respiratory dysfunction is the leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). Injuries targeting mid-cervical spinal cord regions affect the phrenic motor neuron pool that innervates the diaphragm, the primary respiratory muscle of inspiration. Contusion-type injury in 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. In an attempt to target the phrenic motor neuron pool, two unilateral contusion injury paradigms were tested, a single injury at level C4 and a double injury both at levels C3 and C4, and animals were followed for up to 6 weeks post-injury. Both unilateral cervical injury paradigms are reproducible with no mortality or need for breathing assistance, and are accompanied by phrenic motor neuron loss, phrenic nerve axon degeneration, diaphragm atrophy, denervation and subsequent partial reinnervation at the diaphragm neuromuscular junction, changes in spontaneous diaphragm EMG recordings, and reduction in phrenic nerve compound muscle action potential amplitude. These findings demonstrate significant and chronically persistent respiratory compromise following mid-cervical SCI due to phrenic motor neuron degeneration. These injury paradigms and accompanying analyses provide important tools both for understanding mechanisms of phrenic motor neuron and diaphragm pathology following SCI and for evaluating therapeutic strategies in clinically relevant cervical SCI models.

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KW - Diaphragm

KW - Disease Models, Animal

KW - Female

KW - Motor Neurons

KW - Nerve Degeneration

KW - Nerve Net

KW - Phrenic Nerve

KW - Rats

KW - Rats, Sprague-Dawley

KW - Respiratory Paralysis

KW - Spinal Cord Injuries

U2 - 10.1016/j.expneurol.2012.03.007

DO - 10.1016/j.expneurol.2012.03.007

M3 - Article

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VL - 235

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EP - 552

JO - Experimental neurology

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SN - 1090-2430

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