Harnessing tongue exercise to enhance neuroplasticity and preserve upper airway function in a novel model of hypoglossal motor neuron degeneration

运动神经元疾病（例如，肌萎缩侧索硬化症/ALS、假性延髓麻痹和肯尼迪病） 导致危及生命的上呼吸道功能改变（即，呼吸和吞咽），主要是由于 舌下神经（XII）轴内的变性。这包括口面部区域的上运动神经元（UMN） 初级运动皮层（MIo），脑干中的下运动神经元（LMN）和舌肌。 尽管上呼吸道功能至关重要，但很少在运动神经元疾病中进行研究;因此， 有效的治疗方法仍有待发现。这项研究的基本目标是了解如何 XII轴变性损害吞咽和呼吸的功能和协调， 确定舌头运动是否（以及如何）改变XII运动神经元死亡的新模型中的XII轴缺陷。 这种独特的模型是通过舌内注射与皂草素缀合的霍乱毒素B（CTB-SAP）来诱导的， 导致XII运动神经元死亡，XII运动输出减少，XII神经退行性变化， 颏舌肌（由XII神经支配的肌肉），以及相应的舌头运动和吞咽减少 速率，从而模仿运动神经元疾病中吞咽困难的方面。此外，我们有令人兴奋的新的试点数据， 提示CTB-SAP治疗的大鼠的舌运动显著地保持了舌的强度和运动性， 以及吞咽和呼吸模式/协调类似于对照。在这里，我们将测试中央 上呼吸道功能/协调可以在XII运动神经元面中保留假设 通过利用舌头运动的治疗潜力来上调神经可塑性， 通过神经营养因子在备用的XII轴运动神经元中的表达。我们将在我们的 一种新的CTB-SAP大鼠模型，采用抗阻舌运动的转化、非侵入性治疗策略 培训和多学科方法，包括全身体积描记术、视频荧光透视吞咽 研究，力舔测试，XII神经和诱发吞咽电生理记录，在体内 药理学操作，组织学评估（免疫组织化学和透射电子显微镜） 显微镜）和神经成像（磁共振成像）。两个具体的目标后，提出了语内 CTB-SAP注射以确定：1）吞咽和呼吸模式/协调如何被XII轴改变 2）舌运动对XII轴缺陷的影响和神经营养因子的作用。以来 大多数患有运动神经元疾病的患者发展上呼吸道功能障碍，导致呼吸机和/或进食， 管依赖，我们的长远目标是制定新的战略，以提高功能能力的备用 第十二运动神经元，以改善功能的结果。如果成功，这项工作将确定行为（舌头） 运动）和分子（例如，神经营养因子）的策略，为未来的翻译研究，以保持上层 气道功能明显改善运动神经元疾病患者的生活质量和生存时间。

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 to preserve upper airway function in patients with motor neuron diseases to significantly improve the quality and duration of life.