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• W4378649395 abstract "Amyotrophic lateral sclerosis (ALS) results in debilitating upper airway (swallowing and breathing) impairment that profoundly degrades quality of life while increasing the risk of death by almost eight-fold. The underlying cause has been attributed to degeneration of the hypoglossal lower motor neurons (XII LMNs) that control tongue movement; therefore, treatment efforts are focused on slowing XII LMN degeneration. However, there is growing evidence that ALS is not a pure motor neuron disease – it also affects sensory neurons, including those in the nucleus tractus solitarius (NTS) involved in autonomic regulation of swallowing and breathing. We propose that upper airway impairment in ALS may be more effectively treated using sensorimotor approaches that collectively target XII LMNs and the NTS. Here, we are leveraging a translational mouse model of ALS (low copy number SOD1-G93A; LCN-SOD1) that we have shown develops progressive tongue atrophy, XII LMN degeneration, and “motor” dysphagia (slower tongue motility and swallow rates) resembling human ALS. These mice also show clinicopathological evidence of “sensory” dysphagia, specifically a higher swallow threshold (assessed via electrical stimulation of superior laryngeal nerve afferents) and degeneration of the NTS. Using this model, we have been developing tools and procedures to investigate the therapeutic effects of optogenetic stimulation (opto-stim) of XII LMNs and the NTS during voluntary swallow-related behaviors (drinking, eating, grooming) vs. spontaneous breathing in LCN-SOD1 mice. We have already achieved robust expression of the excitatory opsin channelrhodopsin (ChR2) in XII LMNs via adeno-associated virus delivery into the genioglossus muscle or XII nucleus. ChR2 transfection of XII LMNs was well-tolerated, without adverse effects on swallowing/breathing, general health, and survival. Functionally, XII LMN opto-stim evoked robust tongue protrusion (i.e., genioglossus contraction) in anesthetized mice and slowed lick rate during voluntary drinking in awake mice, which we hypothesize is due to resistive force against tongue movement, similar to resistance exercise. Currently, we are exploring the effects of opto-stim (10 ms pulses at 40 or 80 Hz in trains of 1 s ON/OFF for up to 1 h, 2X/wk) as a tongue resistance exercise in pre-clinical LCN-SOD1 mice. In parallel, we are also developing procedures for targeted opsin expression in the NTS via direct injection vs. pharyngeal mucosa application. We hypothesize that NTS opto-stim, in contrast to XII LMN, will assist swallowing by lowering the sensory threshold to unleash higher swallow rates. We propose these novel sensorimotor opto-stim approaches could ultimately translate into minimally invasive targeted treatments for upper airway impairment in ALS patients. This project is funded by NIH R21 NS123761 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process." @default.
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• W4378649395 date "2023-05-01" @default.
• W4378649395 modified "2023-09-27" @default.
• W4378649395 title "Developing Targeted Optogenetic Stimulation Approaches to Preserve Upper Airway Function in Amyotrophic Lateral Sclerosis (ALS) Using a Translational Mouse Model" @default.
• W4378649395 doi "https://doi.org/10.1152/physiol.2023.38.s1.5731913" @default.
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