Impact of tongue exercise on hypoglossal axis survival, structure, and output in a rodent model of hypoglossal motor neuron degeneration.

Abstract

Motor neuron diseases (MNDs) are progressive neurological disorders in which motor neurons necessary for walking, swallowing, and breathing are destroyed. Obstructive sleep apnea (OSA) occurs more commonly in patients with MNDs and may contribute to disease progression. Intralingual injections of cholera toxin B conjugated to saporin (CTB-SAP) mimic hypoglossal (XII) motor neuron loss observed in MND models and result in airway deficits observed in MNDs and OSA, often leading to respiratory failure and death. Using this model, we investigated the effects of a high-repetition/low-resistance tongue exercise paradigm on XII axis survival, structure, and output in adult male Sprague-Dawley rats. Rats were allocated to four experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) ± tongue exercise. Following tongue exercise exposure, we evaluated motor neuron survival in the primary motor cortex and XII nucleus, and glial density in the XII nucleus with immunohistochemistry, ultrastructural XII nerve changes with transmission electron microscopy (TEM), and XII motor output in anesthetized rats using in vivo neurophysiology. Results revealed that) decreased XII motor neuron survival and degenerative changes in the XII nerve (e.g., decreased axon-myelin circularity and convexity) were not impacted by tongue exercise;) tongue exercise increased microglial fractional area and density in the XII nucleus; and) deficits in XII motor output were mitigated by tongue exercise in CTB-SAP rats. These findings provide further evidence that tongue exercise-induced neuroplasticity may be a viable treatment to improve functional outcomes in patients with MNDs and/or OSA.Intralingual injections of CTB-SAP result in decreased XII motor neuron survival and degenerative changes in the XII nerve consistent with what is seen in many MNDs. Although these deficits are not mitigated by tongue exercise, we do observe increased microglial fractional area/density in the XII nucleus of CTB-SAP + exercise rats. In addition, deficits in XII motor output are mitigated by tongue exercise, indicating neuroplasticity despite significant loss of XII motor neurons and XII nerve degeneration.