Motor neuron diseases (e.g., amyotrophic lateral sclerosis/ALS, pseudobulbar palsy, and Kennedy’s disease) result in life-threatening alterations in upper airway function (i.e., swallowing and breathing) primarily due to degeneration within the hypoglossal (XII) axis. This includes upper motor neurons (UMNs) in the orofacial region of the primary motor cortex (MIo), lower motor neurons (LMNs) in the brainstem, and the tongue muscles. Despite its critical importance, upper airway function has seldom been studied in motor neuron diseases; thus, effective treatments remain to be discovered. The fundamental goals of this study are to understand how XII axis degeneration impairs the function and coordination of swallowing and breathing, and to determine if (and how) tongue exercise alters XII axis deficits in a novel model of XII motor neuron death. This unique model is induced by intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) to cause XII motor neuron death, decreased XII motor output, degenerative changes in the XII nerve and genioglossus (muscle innervated by the XII nerve), and corresponding decreased tongue motility and swallowing rate, thus mimicking aspects of dysphagia in motor neuron diseases. Further, we have exciting new pilot data suggesting that tongue exercise in CTB-SAP treated rats remarkably preserves tongue strength and motility as well as swallowing and breathing patterns/coordination similar to controls. Here we will test the central hypothesis that upper airway function/coordination can be preserved in the face of XII motor neuron degeneration by harnessing the therapeutic potential of tongue exercise to upregulate neuroplasticity via neurotrophic factor expression in spared XII axis motor neurons. We will test this hypothesis in our novel CTB-SAP rat model using a translational, non-invasive therapeutic strategy of resistance tongue exercise training, and a multidisciplinary approach involving whole body plethysmography, videofluoroscopic swallow studies, force lickometer testing, XII nerve and evoked swallowing electrophysiological recordings, in vivo pharmacological manipulations, histological assessments (immunohistochemistry and transmission electron microscopy), and neuroimaging (magnetic resonance imaging). Two specific aims are proposed after intralingual CTB-SAP injections to determine: 1) how swallowing and breathing patterns/coordination are altered by XII axis degeneration; and 2) the impact of tongue exercise on XII axis deficits and the role of neurotrophic factors. Since most patients with motor neuron disease develop upper airway dysfunction leading to ventilator and/or feeding- tube dependence, our long-range goal is to develop new strategies to enhance the functional capacity of spared XII motor neurons to improve functional outcomes. If successful, this work will identify behavioral (tongue exercise) and molecular (e.g., neurotrophic factor) strategies for future translational studies ...