Upper Airway Dysfunction and Discoordination are Reversed by Isometric Tongue Exercise in a Novel Rodent Model of Hypoglossal Motor Neuron Loss

Abstract

Motor neuron diseases (e.g., amyotrophic lateral sclerosis, pseudobulbar palsy, and Kennedy’s disease) result in life‐threatening alterations in upper airway function (i.e., swallowing and breathing) primarily due to degeneration of hypoglossal (XII) motor neurons, which leads to ventilator and/or feeding‐tube dependence. Despite its critical importance, upper airway function has seldom been studied in motor neuron diseases; thus, effective treatments remain to be discovered. Since genetic rodent models of motor neuron loss develop global symptoms (e.g., limb dysfunction, etc.), we have developed an inducible model of only XII motor neuron death in order to study targeted therapeutic interventions to enhance the functional capacity of spared XII motor neurons to improve functional outcomes. We have previously found that adult male rats intralingually injected with cholera toxin B conjugated to saporin (CTB‐SAP) have XII motor neuron loss and decreased XII motor output, degenerative changes in the XII nerve and genioglossus, and decreased tongue motility and swallowing rate. We hypothesize that deficits in upper airway function and coordination are reversed by using a translational, non‐invasive therapeutic strategy of tongue resistance exercise training in CTB‐SAP rats. To test our hypothesis, we intralingually injected adult male rats with CTB‐SAP or control (CTB unconjugated to SAP), and then studied the following parameters +/‐ isometric tongue exercise (n=3‐7/group): 1) swallowing function via videofluoroscopic swallow studies and force lickometer testing; 2) breathing function via whole‐body plethysmography; 3) XII motor output at baseline and in response to a maximal ventilatory challenge in anesthetized and ventilated rats via in vivo neurophysiology; 4) coordination of swallowing and breathing in anesthetized rats via evoked swallowing electrophysiological recordings; and 5) structural changes via magnetic resonance imaging. Thus far, our data suggests that tongue exercise in CTB‐SAP treated rats remarkably preserves tongue strength and motility and swallowing and breathing patterns/coordination, and reduces structural degeneration in the brainstem and tongue (p<0.05 vs. controls). In conclusion, tongue exercise appears to preserve upper airway function and coordination in the face of XII motor neuron degeneration. Studies are now underway to understand the underlying mechanism of tongue exercise‐induced neuroplasticity in spared XII motor neurons. If successful, this work will identify behavioral (tongue exercise) and molecular strategies for future translational studies to prolong and/or improve upper airway function and coordination in patients with motor neuron diseases to significantly improve their quality and duration of life.