5HT modulation of arousal and chemoreflex responses in intact and SCI mice.

5HT 对完整小鼠和 SCI 小鼠的唤醒和化学反射反应的调节。

基本信息

批准号：
10383651
负责人：
Jason H. Mateika
金额：
--
依托单位：
JOHN D DINGELL VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383651
关键词：
Air Animals Apnea Area Arousal Body mass index Brain Stem Breathing Carbon Dioxide Cardiovascular system Cell Nucleus Cognitive Coupled Dorsal Electroencephalogram Electromyography Event Frequencies General Population Genetic Health Hour Human Hypercapnia Hypoventilation Hypoxia Implant Incidence Individual Investigation Knock-out Light Link Measures Metabolic Modification Monitor Motor Motor Neurons Mus Muscle function Neuraxis Neuromodulator Neurons Noise Nonpenetrating Wounds Obstructive Sleep Apnea Oxygen Physiological Property Recovery Reporting Respiratory Diaphragm Role Serotonergic System Serotonin Services Severities Site Sleep Sleep Apnea Syndromes Spinal Cord Spinal cord injury Supine Position TPH2 Telemetry Testing Time Tissues United States United States Department of Veterans Affairs Variant Veterans Work airway muscle circadian comorbidity density genioglossus muscle lung volume mouse model non rapid eye movement pressure receptor relating to nervous system respiratory response time interval ventilation

项目摘要

Sleep apnea is associated with autonomic, cardiovascular, metabolic and cognitive co‐morbidities. The incidence of sleep apnea in the United States ranges from 2‐4 % in the general population, and is up to 15 times greater in individuals with spinal cord injury (SCI). Adjustments in the neural modulation of the arousal threshold (AT), chemoreflex sensitivity to hypoxia and hypercapnia (CS) and upper airway patency are three critical factors that contribute to exacerbation of sleep apnea. The exact neuromodulators that control these variables are enigmatic, but one possibility is serotonin (5HT) and its target receptors. Thus, plasticity of 5HT neurons may account for modifications in the AT, CS, upper airway patency and ultimately breathing stability in intact and spinal cord injured (SCI) animals. We will explore the role of 5HT in modulating the critical factors that exacerbate sleep apnea in intact and SCI mice. Aim 1 of our proposal will examine the impact of 5HT on the AT and CS to ultimately determine the impact on sleep disordered breathing. Aim 2 will explore whether modifications in 5HT levels and/or receptor sub‐types following SCI, are coupled to modifications in the AT and CS leading to hypoventilation, blunting of upper airway muscle function and increases in the frequency and duration of apnea events. Aim 3 will determine whether modifications in 5HT levels and/or receptor sub‐types following SCI, are coupled to increases in upper airway collapsibility. To explore these relationships unanesthetized, spontaneously breathing intact and SCI tryptophan hydroxylase 2 knockout (TPH2‐/‐) and wild type (TPH2+/+) mice will be employed. The absence of TPH2 results in the depletion of central nervous system 5HT, while the raphe neurons remain intact. We will measure ventilatory parameters, the AT and CS before and after SCI in TPH2+/+ and TPH2‐/‐ mice. Breathing events will be detected during sleep via electroencephalograms. Apneic events will be uncovered by monitoring ventilation and diaphragmatic electromyography, while monitoring of genioglossus muscle activity will be used to detect modifications in upper airway muscle function before and after SCI. Our results will establish if modifications in 5HT modulation, either via genetic depletion or SCI, leads to alterations in the AT, CS, upper airway muscle function and ultimately breathing stability.

睡眠呼吸暂停与自主，心血管，代谢和认知合并症有关。这美国睡眠呼吸暂停的发病率从一般人群的2-4％不等，最多15倍脊髓损伤（SCI）的个体更大。唤醒的神经调节调整阈值（AT），化学反射对缺氧和高脑（CS）和上气通畅的敏感性为三导致睡眠呼吸暂停加剧的关键因素。控制这些的确切神经调节剂变量是神秘的，但一个潜力是5-羟色胺（5HT）及其靶受体。那是5ht的可塑性神经元可能占AT，CS，上呼吸道通畅的修改以及最终的呼吸稳定性在完整的脊髓受伤（SCI）动物中。我们将探讨5HT在调节关键的角色中的作用加剧完整和科幻小鼠的睡眠呼吸暂停的因素。我们提案的目标1将检查 AT和CS上的5HT最终确定对睡眠障碍呼吸的影响。 AIM 2将探索 SCI之后的5HT级别和/或收件人子类型的修改是否与修改相连 AT和CS导致不足衰减，上呼吸道肌肉功能的烦恼，并增加呼吸暂停事件的频率和持续时间。 AIM 3将确定是否在5HT级别和/或 SCI之后的接收器子类型耦合以增加上呼吸道可折叠性。探索这些关系一致化，赞助的完整和SCI色氨酸羟化酶2敲除（TPH2 - / - ）和野生型（TPH2+/+）小鼠将被使用。不存在TPH2导致耗尽中枢神经系统5HT，而Raphe神经元保持完整。我们将测量通气参数， TPH2+/+和TPH2 - / - 小鼠SCI前后的AT和CS。睡眠期间将发现呼吸事件通过脑电图。通过监测通气和隔膜，将发现呼吸暂停事件肌电图，同时对Genioglossus肌肉活动的监测将用于检测修饰 SCI之前和之后的上呼吸道肌肉功能。我们的结果将确定是否在5HT中进行了修改通过通用耗竭或SCI调节，会导致AT，CS，上呼吸道肌肉的变化功能并最终呼吸稳定性。