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

在舌下运动神经元变性的新型模型中利用舌头运动增强神经可塑性并保留上呼吸道功能

• 批准号: 10433920
• 负责人: TERESA E LEVER
• 金额: $ 52.91万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433920
• 关键词: Activities of Daily Living; Adult; Aerobic; Affect; Amyotrophic Lateral Sclerosis; Aspiration Pneumonia; Back; Behavior; Behavioral; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Cholera Toxin; Clinical; Conflict (Psychology); Data; Deglutition; Deglutition Disorders; Dependence; Development; Disease Progression; Disease model; Electrophysiology (science); Enteral Feeding; Exercise; Fibrinogen; Fluoroscopy; Functional disorder; Future; Goals; Histologic; Hypertrophy; Immunohistochemistry; Impairment; Injections; Kennedy Syndrome; Knowledge; Lead; Life; Limb structure; Lung; Magnetic Resonance Imaging; Modeling; Molecular; Motor; Motor Cortex; Motor Neuron Disease; Motor Neurons; Motor output; Movement; Muscle; Nerve; Neuronal Plasticity; Neurons; Palliative Care; Pathologic; Pathology; Patients; Pattern; Pharmacology; Physical Exercise; Pilot Projects; Plethysmography; Pneumonia; Pseudobulbar Palsy; Quality of life; Rattus; Resistance; Respiratory Failure; Role; Structure; Synapses; Testing; Therapeutic; Tongue; Transmission Electron Microscopy; Up-Regulation; Vascular Endothelial Growth Factors; Ventilator; Whole Body Plethysmography; Work; cell motility; dysphagia rehabilitation; effective therapy; exercise training; functional outcomes; genioglossus muscle; improved; in vivo; interdisciplinary approach; motor neuron degeneration; neuroimaging; neuron loss; neurotrophic factor; novel; orofacial; preservation; repaired; resistance exercise; respiratory; response; targeted treatment; translational study; treatment effect; white matter

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.

运动神经元疾病（例如，肌萎缩性侧索硬化症/ALS，假卵瘫痪和肯尼迪氏病） 导致上呼吸道功能的威胁生命的改变（即吞咽和呼吸）。 降压（XII）轴内的变性。这包括口腔区域的上运动神经元（UMNS） 一级运动皮层（MIO），脑干中的下运动神经元（LMN）和舌肌。 尽管其重要性至关重要，但在运动神经元疾病中很少研究上呼吸道功能。因此， 有效的治疗仍有待发现。这项研究的基本目标是了解如何 XII轴退化会损害吞咽和呼吸的功能和协调，并损害 确定舌头运动是否（以及如何）在XII运动神经元死亡的新模型中定义了XII轴是否改变。 这种独特的模型是通过内在注射霍乱毒素B与糖蛋白结合（CTB-SAP）的注入来引起的。 导致XII运动神经元死亡，XII运动输出降低，XII神经的退化性变化和 Genioglossus（由XII神经支配的肌肉），舌头运动和吞咽相应的相应减少 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试点数据 建议在CTB-SAP治疗的大鼠中进行舌头运动可以明显地保留舌头的力量和运动能力 以及类似于对照的吞咽和呼吸模式/协调。在这里，我们将测试中央 假设可以在XII运动神经元面前保存上呼吸道功能/协调 通过利用舌头运动的治疗潜力来上调神经可塑性来退化 通过较低的XII轴运动神经元中神经营养因子的表达。我们将在我们的 新颖的CTB-SAP大鼠模型，使用抗拒舌式锻炼的转化，非侵入性理论策略 训练和一种涉及全身的多学科方法，视频吞咽 研究，力滤光度测试，XII神经和诱发的吞咽电生理记录，体内 药理操作，组织学评估（免疫组织化学和传播电子学 显微镜）和神经成像（磁共振成像）。室内后提出了两个具体目标 CTB-SAP注射以确定：1）XII轴改变了吞咽和呼吸模式/协调方式 退化; 2）舌头运动对XII轴的影响定义了神经营养因素的作用。自从 大多数运动神经元疾病发育的患者上呼吸道功能障碍会导致呼吸机和/或喂养 管依赖性，我们的远程目标是制定新的策略来增强免疫力的功能能力 XII运动神经元可改善功能结果。如果成功，这项工作将确定行为（舌头） 运动）和分子（例如，神经营养因素）以后的翻译研究策略 运动神经元疾病患者的气道功能可显着改善生命的质量和持续时间。