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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Respiratory Physiology and Pathophysiology
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1488951
This article is part of the Research Topic Respiratory Dysfunction in Neurological Disease and Injury: Novel Mechanisms and Potential Therapeutics View all 5 articles

Spinal TNF-α receptor 1 is differentially required for phrenic long-term facilitation (pLTF) over the course of motor neuron death in adult rats

Provisionally accepted
Ryan D Lewis Ryan D Lewis 1Amy Keilholz Amy Keilholz 2Catherine L Smith Catherine L Smith 2Ethan A Burd Ethan A Burd 3Nicole L. Nichols Nicole L. Nichols 2*
  • 1 Grinnell College, Grinnell, Iowa, United States
  • 2 University of Missouri, Columbia, United States
  • 3 Seton Hill University, Greensburg, Pennsylvania, United States

The final, formatted version of the article will be published soon.

    Introduction: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor ; TNF-) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats. Methods: Here, we worked to determine the impact of TNF- in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-) expression; 2) investigating astrocytes (glial cells known to release TNF-) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF- receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats. Results: Results revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p<0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype; p<0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p<0.05) following intrathecal sTNFR1i delivery. Conclusions: This work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them.

    Keywords: Phrenic motor neuron death, breathing, Respiration, plasticity, astrocyte, rat model

    Received: 31 Aug 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Lewis, Keilholz, Smith, Burd and Nichols. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Nicole L. Nichols, University of Missouri, Columbia, United States

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