Development of swallow evoked potentials as a novel tool to investigate swallowin

吞咽诱发电位的开发作为研究吞咽的新工具

• 批准号: 7883020
• 负责人: TERESA E LEVER
• 金额: $ 13.28万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883020
• 关键词: Adult; Affect; Age-Months; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Area; Brain Stem; Cell Nucleus; Cessation of life; Childhood; Control Animal; Deglutition; Deglutition Disorders; Dehydration; Development; Electric Stimulation; Electrodes; Evoked Potentials; Future; Goals; Histopathology; Human; Impairment; Individual; Knowledge; Lead; Lesion; Life; Longevity; Malnutrition; Measurement; Measures; Methods; Morphology; Motor; Mus; Pathogenesis; Peripheral; Phenotype; Population; Protocols documentation; Quality of life; Reflex action; Relative (related person); Research; Research Proposals; Sensory; Signal Transduction; Source; Stimulus; Structure of superior laryngeal nerve; Symptoms; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Translational Research; United States; Vacuole; Vagus nerve structure; Work; effective therapy; improved; innovation; insight; mouse model; nervous system disorder; neuromechanism; neuropathology; novel; public health relevance; relating to nervous system; research study; respiratory; response; stem cell therapy; tool

DESCRIPTION (provided by applicant): The broad, long-term objective of this research proposal is to gain a better understanding of the neuropathology of swallowing impairment (dysphagia) in neurological diseases. Several mouse models currently exist that are suitable and readily available for translational research in neurological diseases. However, relatively little is known about the swallowing function of these mouse models because experimental methods to evaluate the function of the individual neural components of the swallow reflex circuit have not yet been developed. The purpose of the proposed research is to develop an experimental protocol for using brainstem evoked potentials recorded in response to stimulation of the superior laryngeal nerve in mice to quantify the function of the individual sensory, central integration, and motor components of the swallowing reflex circuit. Three specific aims will serve this purpose. Specific Aim 1 will test the hypothesis that it is possible to record swallow evoked potentials (SwEPs) in mice. The optimal stimulus and recording parameters will be identified using 3-4 month old wild-type (C57BL/6J) mice. Waveform morphology (i.e., number of positive and negative peaks, peak-to-peak amplitudes, and peak latencies) will be compared relative the following variables: electrode placement, filter settings, signal amplification, signal averaging, stimulus rate, and stimulus amplitude. Specific Aim 2 will evaluate the utility of the SwEP testing protocol established in Specific Aim 1 to phenotype the swallowing function of a transgenic mouse model of amyotrophic lateral sclerosis (ALS; SOD1-G93A) and nontransgenic littermates at four time points: 1, 2, 3, and 4 months of age. Specific Aim 3 will begin to investigate the generator sources for the SwEP peaks. Histological and immunohistochemical methods will be performed on a subset of animals from Specific Aim 2 to identify the brainstem nuclei (and subnuclei) that are activated during swallowing; these regions also will be investigated for evidence of histopathology (vacuoles). The findings will guide future lesioning experiments and near-field recording studies directed toward positive identification of generator sources of SwEP response peaks. These three specific aims will permit: 1) objective quantification of dysphagia in SOD1-G93A transgenic mice, 2) description of the time-course of neurogenic dysphagia in this strain, and 3) identification of the central neural correlates for dysphagia in this animal model of ALS. The knowledge gained from this work will directly extend the scientific knowledge of normal swallowing and the pathogenesis of dysphagia in ALS. In addition, the SwEP testing protocol established by this work has the potential to be used to identify additional mouse models of dysphagia for various neurological diseases, as well as to quantify the effect of various treatments (e.g., pharmacological agents, stem cell therapy, etc.) on the function of the individual neural components of the swallow relay circuit in these animal models. Thus, development of this experimental protocol in mice may ultimately lead to novel and effective treatment options for dysphagia in humans with neurological diseases. PUBLIC HEALTH RELEVANCE: Neurogenic dysphagia (i.e., swallowing impairment caused by neurological disorders such as Lou Gehrig's disease) affects approximately 500,000 individuals, including pediatric and adult populations, annually in the United States. Common symptoms include malnutrition, dehydration, and respiratory complications, all of which may result in a poor quality of life and contribute to death in affected individuals. Few effective treatments for neurogenic dysphagia have been identified; therefore, neurogenic dysphagia is certainly an important area for research that has the potential to benefit hundreds of thousands of individuals living within the United States, as well as many more living beyond these borders, who are afflicted by various neurological diseases.

描述（由申请人提供）：这项研究建议的广泛长期目标是更好地了解神经系统疾病中吞咽障碍（吞咽困难）的神经病理学。目前存在的几种小鼠模型适用于神经疾病的转化研究。然而，对于这些小鼠模型的吞咽功能，相对较少，因为尚未开发出评估燕子反射回路单个神经成分功能的实验方法。拟议的研究的目的是开发一种实验方案，用于使用小鼠刺激上喉神经的刺激，以量化吞咽反射回路的单个感觉，中心整合和运动成分的功能。三个具体目标将达到这个目的。具体目标1将检验以下假设：可以记录小鼠中吞咽诱发的电位（SWEP）。最佳刺激和记录参数将使用3-4个月大的野生型（C57BL/6J）小鼠识别。波形形态（即，正和负峰的数量，峰值峰值幅度和峰延迟）将进行以下变量进行比较：电极放置，滤波器设置，信号放大，信号平均，刺激速率和刺激幅度。具体目标2将评估特定目标1中建立的SWEP测试方案的实用性，以表型表型在四个时间点：1、2、3和4个月，在四个时间点：1、2、2、3和4个月，在四个时间点上的转基因小鼠模型（ALS; SOD1-G93A）和非转基因同窝式吞咽功能。特定的目标3将开始研究SWEP峰的发电机源。组织学和免疫组织化学方法将在特定目标2的动物子集上进行，以识别吞咽过程中激活的脑干核（和亚核​​）；这些区域还将进行研究以获取组织病理学（液泡）的证据。这些发现将指导未来的病变实验和近场记录研究，该研究针对SWEP响应峰的发电机源积极鉴定。这三个具体目的将允许：1）在SOD1-G93A转基因小鼠中对吞咽困难的客观定量，2）在这种菌株中神经源性吞咽困难的时间顺序的描述，以及3）鉴定该ALS动物模型中吞咽困难的中枢神经相关性。从这项工作中获得的知识将直接扩展正常吞咽的科学知识和ALS吞咽困难的发病机理。此外，这项工作建立的SWEP测试方案有可能用于鉴定各种神经疾病的吞咽困难的其他小鼠模型，以及量化各种治疗方法（例如，药理学剂，干细胞疗法等）对这些动物模型中燕子相对的单个神经成分的功能的影响。因此，在小鼠中的这种实验方案的开发最终可能导致神经系统疾病人类吞咽困难的新颖有效的治疗选择。 公共卫生相关性：神经源性吞咽困难（即，由Lou Gehrig病等神经系统疾病引起的吞咽障碍）每年在美国每年在包括儿科和成人人群在内的大约500,000名患者。常见症状包括营养不良，脱水和呼吸并发症，所有这些都可能导致生活质量差，并导致受影响的个体死亡。几乎没有发现神经源性吞咽困难的有效治疗方法。因此，神经源性吞咽困难无疑是研究的重要领域，有可能使数十万居住在美国的人受益，以及超越这些边界以外的更多生活，这些人遭受了各种神经系统疾病的困扰。