Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS

Mueller, Marissa; Thompson, Rebecca; Osman, Kate L; Andel, Ellyn; DeJonge, Chandler A; Kington, Sophia; Stephenson, Zola; Hamad, Ali; Bunyak, Filiz; Nichols, Nicole L.; Lever, Teresa E.

doi:10.1007/s00455-022-10442-4

Cited by 5 publications

(5 citation statements)

References 64 publications

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“…In humans, videofluoroscopy swallow studies (VFSS) are used to diagnose and monitor swallowing dysfunction (Martin-Harris and Jones, 2008). Recent efforts have adapted VFSS for use in rodents (Lever et al ., 2015; Mueller et al, 2022; Welby et al, 2020). Here, we used VFSS to analyze mice in which we eliminated selected subtypes of vagal sensory neurons, the ablation of which revealed marked esophageal dysmotility.…”

Section: Discussionmentioning

confidence: 99%

“…The 2-5 s video clips were then imported into a custom VFSS analysis software (JawTrack™, University of Missouri) for subsequent frame by frame analysis. The software allows for the semi-automated extraction of many swallowing parameters such as lick rate (number of jaw open/close cycles per second, calculated for 2-5 s long video clips and then averaged), lick interval (time between successive lick cycles throughout a 2-5 s long video clip, and then averaged), swallow rate (number of swallows in each second of a 2-5 s video clip, then averaged), swallow interval (time between successive swallows throughout a 2-5 s video clip, then averaged), lick-swallow ratio (number of jaw open/close cycles between each successive swallow pair throughout a 2-5 s video clip, then averaged), pharyngeal transit time (bolus travel time through the pharynx for each swallow, then averaged), esophageal transit time (bolus travel time through the esophagus, then averaged), jaw closing velocity (speed at which the jaw closes during each jaw cycle throughout a 2-5 s video clip, then averaged) and jaw opening velocity (speed at which the jaw opens during each jaw cycle throughout a 2-5 s video clip, then averaged) (Mueller et al ., 2022; Welby et al ., 2020).…”

Section: Methodsmentioning

confidence: 99%

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Prox2+ and Runx3+ neurons regulate esophageal motility

Lowenstein

Ruffault

Misios

et al. 2022

Preprint

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Sensory neurons of the vagus nerve monitor distention and stretch in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we used genetically guided anatomical tracing, optogenetics and electrophysiology to identify and characterize three vagal sensory neuronal subtypes expressing Prox2 and Runx3. We show that these neuronal subtypes innervate the esophagus and stomach where they display regionalized innervation patterns. Their electrophysiological analysis showed that they are all low threshold mechanoreceptors, but possess different adaptation properties. Lastly, genetic ablation of Prox2+ and Runx3+ neurons demonstrated their essential roles for esophageal peristalsis and swallowing in freely behaving animals. Our work reveals the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain, and could lead to better understanding and treatment of esophageal motility disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prox2+ and Runx3+ neurons regulate esophageal motility

Lowenstein

Ruffault

Misios

et al. 2022

Preprint

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“…Detailed information on radiation doses is provided in table S11. VFSS testing was performed with mice positioned in the lateral plane of a custom miniaturized fluoroscope (LabScope, Glenbrook Technologies) using established protocols (35,(54)(55)(56)(57)(58)(59)(60)(61). Briefly, after overnight water restriction (12 to 14 hours) to motivate participation, individual mice were subjected to ~2 min of low-dose radiation (~30 kV and ~0.2 mA at a source-image distance of 6 to 7 cm) using our miniaturized fluoroscope (LabScope, Glenbrook Technologies).…”

Section: Emg Recordingmentioning

confidence: 99%

Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma

Islam,

Gleber-Netto,

Mulcahy

et al. 2024

Sci. Transl. Med.

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The incidence of human papilloma virus–mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH + ) and CGRP + sensory–afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43 + ) and immature cholinergic (ChAT + DCX + ) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP + nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP + and cholinergic (ChAT + ) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP + and ChAT + neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

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“…LabScope, Glenbrook Technologies, Randolph, NJ) [27][28][29][30]. Prior to testing, rats underwent behavioral conditioning tasks for several weeks to ensure familiarity of the test environment and food/liquid test items.…”

Section: Plos Onementioning

confidence: 99%

“…Three non-overlapping 5-second episodes of drinking and 5 episodes of fully consumed pellets were extracted from the raw video for subsequent analysis using a custom VFSS analysis software, JawTrack™. This software performs semi-automated analysis of jaw motion and bolus flow dynamics to calculate several swallowing outcome measures [29,30]. Drinking-based outcome measures include lick rate (i.e., number of licks per second; measured in cycles per second or Hertz, Hz), swallow rate (i.e., number of swallows per second; measured in Hz), inter-swallow interval (i.e., time between sequential swallows; seconds), and pharyngeal transit time (i.e., time between the swallow onset and swallow end frames; measured in milliseconds, ms).…”

Section: Plos Onementioning

confidence: 99%

Radiation induced changes in profibrotic markers in the submental muscles and their correlation with tongue movement

King,

Kaissieh,

Haxton

et al. 2023

PLoS ONE

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Swallowing impairment is a major complication of radiation treatment for oropharyngeal cancers. Developing targeted therapies that improve swallowing outcomes relies on an understanding of the mechanisms that influence motor function after radiation treatment. The purpose of this study was to determine whether there is a correlation between radiation induced changes in tongue movement and structural changes in irradiated submental muscles, as well as assess other possible causes for dysfunction. We hypothesized that a clinically relevant total radiation dose to the submental muscles would result in: a) quantifiable changes in tongue strength and displacement during drinking two months post treatment; and b) a profibrotic response and/or fiber type transition in the irradiated tissue. Sprague-Dawley adult male rats received radiation to the submental muscles at total dose-volumes known to provoke dysphagia in humans. A clinical linear accelerator administered 8 fractions of 8Gy for a total of 64Gy. Comparisons were made to sham-treated rats that received anesthesia only. Swallowing function was assessed using videofluoroscopy and tongue strength was analyzed via force lickometer. TGFβ1 expression was analyzed via ELISA. The amount of total collagen was analyzed by picrosirius red staining. Immunofluorescence was used to assess fiber type composition and size. Significant changes in licking function during drinking were observed at two months post treatment, including a slower lick rate and reduced tongue protrusion during licking. In the mylohyoid muscle, significant increases in TGFβ1 protein expression were found post radiation. Significant increases in the percentage of collagen content were observed in the irradiated geniohyoid muscle. No changes in fiber type expression were observed. Results indicate a profibrotic transition within the irradiated swallowing muscles that contributes to tongue dysfunction post-radiation treatment.

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Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS

Cited by 5 publications

References 64 publications

Prox2+ and Runx3+ neurons regulate esophageal motility

Prox2+ and Runx3+ neurons regulate esophageal motility

Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma

Radiation induced changes in profibrotic markers in the submental muscles and their correlation with tongue movement

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