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）：本研究提案的广泛、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。目前存在几种小鼠模型，它们适合并易于用于神经系统疾病的转化研究。然而，对这些小鼠模型的吞咽功能知之甚少，因为尚未开发出评价吞咽反射回路的各个神经成分的功能的实验方法。拟议的研究的目的是开发一个实验方案，用于使用脑干诱发电位记录在小鼠的上级喉神经的刺激，以量化的功能，个人的感觉，中央集成，和吞咽反射电路的运动组件。三个具体目标将有助于实现这一目的。具体目标1将检验以下假设：可以记录小鼠的吞咽诱发电位（SwEP）。将使用3-4月龄野生型（C57 BL/6 J）小鼠确定最佳刺激和记录参数。波形形态（即，正峰值和负峰值的数量、峰-峰幅度和峰值振幅）将相对于以下变量进行比较：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将评价具体目标1中建立的SwEP测试方案对肌萎缩侧索硬化症（ALS; SOD 1-G93 A）转基因小鼠模型和非转基因同窝出生小鼠在4个时间点（1、2、3和4月龄）吞咽功能表型的效用。特定目标3将开始调查SwEP峰值的发生器源。将对特定目标2的动物子集进行组织学和免疫组织化学方法，以识别吞咽期间激活的脑干核（和亚核）;还将研究这些区域的组织病理学证据（空泡）。这些发现将指导未来的损伤实验和近场记录研究，以积极识别SwEP响应峰值的发生器来源。这三个具体目标将允许：1）SOD 1-G93 A转基因小鼠中吞咽困难的客观定量，2）描述该品系中神经源性吞咽困难的时程，和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和ALS吞咽困难的发病机制的科学知识。此外，通过这项工作建立的SwEP测试方案有可能用于识别各种神经系统疾病的吞咽困难的其他小鼠模型，以及量化各种治疗（例如，药理学试剂、干细胞疗法等）对这些动物模型中吞咽中继回路的各个神经成分的功能的影响。因此，在小鼠中开发这种实验方案可能最终导致患有神经系统疾病的人类吞咽困难的新的和有效的治疗选择。 公共卫生相关性：神经性吞咽困难（即，由神经障碍如Lou Gehrig病引起的吞咽障碍）在美国每年影响大约500，000人，包括儿童和成人群体。常见症状包括营养不良、脱水和呼吸系统并发症，所有这些都可能导致受影响个体的生活质量低下并导致死亡。神经性吞咽困难的有效治疗方法很少;因此，神经性吞咽困难肯定是一个重要的研究领域，有可能使生活在美国的数十万人受益，以及更多生活在这些边界之外的人，他们受到各种神经系统疾病的折磨。