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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.

睡眠呼吸暂停综合症通常与自主神经、心血管、代谢紊乱和认知障碍等并存疾病有关。在美国，睡眠呼吸暂停综合症的发病率在普通人群中从2%到4%不等，高达15%。在患有脊髓损伤(SCI)的人中有更大的可能性。更多的调整涉及到唤醒的主要神经功能调制机制。阈值(AT)、化学反射、对低氧和高碳酸血症(CS)的敏感性以及上呼吸道通畅率是三项指标。关键的影响因素是导致睡眠呼吸暂停加重的因素。控制这些因素的确切神经调节剂是什么？这些变量是谜，但有一种可能性是5-羟色胺(5-羟色胺)和它的主要靶标受体。因此，5-羟色胺的可塑性下降。神经元可能也是呼吸暂停、呼吸暂停、上呼吸道通畅和最终保持呼吸稳定的原因。在完好无损的脊髓和脊髓损伤(SCI)动物中，我们将进一步探讨5HT在调节脊髓损伤中的重要作用。可能会加剧正常小鼠和脊髓损伤小鼠睡眠呼吸暂停的因素。我们的提案中有1%的目标是进一步研究睡眠呼吸暂停对健康的影响。 5HT将由美国电话电报公司和美国儿科学会共同努力，最终确定呼吸障碍对睡眠的影响。AIM 2将继续探索。无论是在脊髓损伤后5-羟色胺水平和/或受体亚型的修改，它们都与在脑损伤中的修改密切相关。美国儿科学会和美国儿科学会导致患者出现换气不足，导致上呼吸道和肌肉功能迟钝，并增加了患者的呼吸功能。呼吸暂停事件的频率和持续时间将不会决定是否需要修改5-羟色胺的水平和/或水平。受体亚型：在脊髓损伤后，受体亚型与上呼吸道塌陷能力的增加密切相关。我们需要进一步探讨这些因素。关系是不麻醉的，是自发的，呼吸是完整的，而不是SCI，是色氨酸和羟基酶，是敲除。 (TPH2-/-)基因和野生型基因(TPH2+/+)的小鼠将不再就业。由于TPH2基因的大量缺乏，导致了的进一步枯竭。中枢神经系统5-羟色胺，而中缝和神经元则保持完好。我们将继续测量呼吸参数。在TPH2+/+小鼠和TPH2-/-小鼠的SCI前后，分别检测了AT和TCS的变化。这些呼吸事件在睡眠中也不会被检测到。通过脑电监测，呼吸暂停和呼吸暂停事件将不会通过呼吸监测和隔膜呼吸而被发现。肌电图仪，在监测膝舌肌和肌肉活动的同时，也将被用来检测膝舌肌的变化。上呼吸道肌肉功能在损伤前和损伤后恢复。我们的测试结果将不能确定是否需要在5HT中进行修改。调制，无论是通过遗传性呼吸衰竭还是脊髓损伤，都会导致上呼吸道和肌肉的AT、CCS和肌肉的改变。功能的发挥最终决定了稳定的呼吸。