Respiratory function after selective respiratory motor neuron death from intrapleural CTB–saporin injections

Nichols, Nicole L.; Vinit, Stéphane; Bauernschmidt, Lorene; Mitchell, Gordon S.

doi:10.1016/j.expneurol.2014.11.011

Cited by 27 publications

(63 citation statements)

References 59 publications

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“…The lack of evident functional impairment using EMG during ventilatory behaviors suggests that assessment of higher force behaviors (i.e., airway occlusion or sneezing) and normalization to maximum force may be needed to reveal a change in EMG amplitude after partial injuries to the phrenic motoneuron pool as seen after spinal cord contusion or other models of toxic motoneuron death. 58 Overall, these results are consistent with a large reserve capacity for ventilatory functions of the diaphragm muscle.…”

Section: Minimal Functional Impairment After Unilateral Midcervical Csupporting

confidence: 72%

The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function

Alvarez‐Argote

Gransee

Mora

et al. 2016

Journal of Neurotrauma

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Midcervical contusion injuries disrupt descending ipsilateral excitatory bulbospinal projections to phrenic motoneurons, compromising ventilation. We hypothesized that a unilateral contusion injury at C3 versus C5 would differentially impact phrenic activity reflecting more prominent disruption of ipsilateral descending excitatory drive to more caudal segments of the phrenic motor pool with more cranial injuries. Phrenic motoneuron counts and evidence of diaphragm muscle denervation at individual neuromuscular junctions (NMJ) were evaluated at 14 days post-injury after unilateral contusion injury (100 kDynes). Whole body plethysmography and chronic diaphragm EMG were measured before the injury and at 3, 7, and 14 days post-injury. Contusion injuries at either level resulted in a similarly sized cavity. C3 contusion resulted in loss of 39 ± 13% of ipsilateral phrenic motoneurons compared with 13 ± 21% after C5 contusion (p = 0.003). Cervical contusion injuries resulted in diaphragm muscle denervation (C3 contusion: 17 ± 4%; C5 contusion: 7 ± 4%; p = 0.047). The pattern of denervation revealed segmental innervation of the diaphragm muscle, with greater denervation ventrally after C3 contusion and dorsally after C5 contusion. Overall, diaphragm root mean square electromyography activity did not change ipsilaterally after C3 or C5 contusion, but increased contralaterally (∼ 11%) after C3 contusion only on the first day post-injury (p = 0.026). Similarly, there were no significant changes in breathing parameters during eupnea or exposure to hypoxia (10% O2) - hypercapnia (5% CO2) at any time post-injury. Unilateral midcervical contusions minimally impair ventilatory behaviors despite phrenic motoneuron loss and diaphragm muscle denervation.

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Section: Minimal Functional Impairment After Unilateral Midcervical Csupporting

confidence: 72%

The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function

Alvarez‐Argote

Gransee

Mora

et al. 2016

Journal of Neurotrauma

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“…Five sections at the C 4 –C 5 segmental level from each rat in each group were used for immunohistochemical analyses conducted by a blinded investigator. Location of putative phrenic motor neurons in the ventral horn was validated based on diagrams from The Spinal Cord (Watson et al 2009) and extensive experience in our laboratory retrograde labeling phrenic motor neurons with cholera-toxin B fragment in normal rats (Dale-Nagle et al, 2011; Dale et al, 2012; Nichols et al, 2015). Putative phrenic motor neurons were counted as described previously (Nichols et al, 2013a; Nichols et al, 2014), where the area containing phrenic motor neurons was validated and identified as a discrete cluster of large neurons in the mediolateral C 4 ventral horn (Boulenguez et al, 2007; Mantilla, et al, 2009; Watson et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS

Nichols

Satriotomo

Harrigan

et al. 2015

Experimental Neurology

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron death. Since most ALS patients succumb to ventilatory failure from loss of respiratory motor neurons, any effective ALS treatment must preserve and/or restore breathing capacity. In rats over-expressing mutated superoxide dismutase-1 (SOD1G93A), the capacity to increase phrenic motor output is decreased at disease end-stage, suggesting imminent ventilatory failure. Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal respiratory motor plasticity with potential to restore phrenic motor output in clinical disorders that compromise breathing. Since pLTF requires NADPH oxidase activity and reactive oxygen species (ROS) formation, it is blocked by NADPH oxidase inhibition and SOD mimetics in normal rats. Thus, we hypothesized that SOD1G93A (mutant; MT) rats do not express AIH-induced pLTF due to over-expression of active mutant superoxide dismutase-1. AIH-induced pLTF and hypoglossal (XII) LTF were assessed in young, pre-symptomatic and end-stage anesthetized MT rats and age-matched wild-type littermates. Contrary to predictions, pLTF and XII LTF were observed in MT rats at all ages; at end-stage, pLTF was actually enhanced. SOD1 levels were elevated in young and pre-symptomatic MT rats, yet superoxide accumulation in putative phrenic motor neurons (assessed with dihydroethidium) was unchanged; however, superoxide accumulation significantly decreased at end-stage. Thus, compensatory mechanisms appear to maintain ROS homoeostasis until late in disease progression, preserving AIH-induced respiratory plasticity. Following intrathecal injections of an NADPH oxidase inhibitor (apocynin; 600µM; 12µL), pLTF was abolished in pre-symptomatic, but not end-stage MT rats, demonstrating that pLTF is NADPH oxidase dependent in pre-symptomatic, but NADPH oxidase independent in end-stage MT rats. Mechanisms preserving/enhancing the capacity for pLTF in MT rats are not known.

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“…Bilateral phrenic nerve recordings were made at baseline and during chemoreflex activation in multiple groups, including Harlan rats, wild-type Taconic rats, and end-stage Taconic mutant rats (data obtained from the following studies: Nichols et al, 2013a; 2013b; 2015b). In 6 groups, mean values of integrated phrenic nerve burst peak amplitude were not significantly different between the left and right sides in any group at baseline or during chemoreflex activation (all p>0.05).…”

Section: Resultsmentioning

confidence: 99%

“…Data from some of these groups have appeared in published studies (all studies conducted by N.N. ), and are repeated here to increase the power of our meta-analysis and enable comparisons among rat sub-strains (Nichols et al, 2013a; 2013b; 2015b). …”

Section: Methodsmentioning

confidence: 99%

Quantitative assessment of integrated phrenic nerve activity

Nichols

Mitchell

2016

Respiratory Physiology & Neurobiology

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Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1G93A Taconic rat groups (an ALS model). Meta-analysis results indicate: 1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; 2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ~1.0; and 3) consistently reduced activity in end-stage SOD1G93A rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease.

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Respiratory function after selective respiratory motor neuron death from intrapleural CTB–saporin injections

Cited by 27 publications

References 59 publications

The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function

The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function

Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS

Quantitative assessment of integrated phrenic nerve activity

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