Targeted neuromodulation strategies to delay hypoglossal motoneuron death and preserve tongue strength, function, and structure in a mouse model of ALS

项目总结

Project Summary One of the most debilitating consequences of amyotrophic lateral sclerosis (ALS) is swallowing impairment (dysphagia), which is associated with significant morbidity, depression/social isolation, and early mortality. From a neurological perspective, dysphagia in ALS has been attributed to progressive tongue weakness caused by degeneration of brainstem hypoglossal neurons and their axons (hypoglossal nerve) innervating the tongue muscles. Progressive tongue weakness and atrophy ultimately render nearly all ALS patients unable to eat and drink naturally; instead, they must depend on a feeding tube for survival. Despite the multiple life-threatening consequences of dysphagia in ALS, current therapies, including the FDA-approved drugs riluzole and edaravone, have no beneficial effect on swallowing function. Therefore, there is an urgent clinical need to identify effective therapeutic solutions targeting the underlying pathophysiology of dysphagia to preserve swallowing function, and by proxy, significantly extend survival and improve the quality of life for ALS patients. In this project, to address this clinical need, we will leverage a translational mouse model of ALS with dysphagia to explore optogenetic stimulation (opto-stim) as a therapeutic strategy targeting the tongue. The opto-stim treatment is a gene therapy-based approach that has been shown to promote neuronal survival, nerve growth, and muscle reinnervation in nervous system injury. In our approach, we will use opto-stim to selectively “excite” hypoglossal neurons to cause tongue muscle contraction/resistance that mice must overcome to sufficiently protrude the tongue while voluntarily drinking from a waterspout. We hypothesize that this regime, synergistically integrating the benefits of optogenetics and tongue exercise training, has the potential to prevent or slow down the progression of hypoglossal degeneration and associated tongue weakness. To explore the effects of opto-stim treatment, our project is divided into two aims. In Aim 1, we will apply high- and low-frequency opto-stim treatments three times per week in ALS mice, initiated at clinical disease onset (i.e., start of body weight decline), and assess the treatment effect on tongue motility and swallowing function (via fluoroscopy) and lick force (via force-lickometer) from disease onset to end-stage (i.e., 20% weight loss). In Aim 2, we will employ a variety of histological assessments to quantify the corresponding neuroplastic changes in the hypoglossal nucleus neurons, hypoglossal nerve, and the tongue muscles in response to each neuromodulation strategy to establish clinico-pathological correlations. Our results will provide insight into therapeutic effects and mechanisms of optogenetic-based treatment strategies in ALS. Optogenetics has been gaining increasingly significant translational potential and may be particularly beneficial for advanced-stage ALS patients who cannot participate in alternative treatment programs but may still respond to treatment.