The impact of aging on the functional and anatomical coupling between brainstem noradrenergic neurons and upper airway muscles

衰老对脑干去甲肾上腺素能神经元和上呼吸道肌肉之间功能和解剖学耦合的影响

• 批准号: 10202876
• 负责人: Victor Borisovich Fenik
• 金额: $ 28.11万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202876
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid deposition; Anatomy; Arousal; Axon; Brain Stem; Cardiovascular system; Cell Nucleus; Chronic; Clinical; Clinical Management; Clinical Research; Clinical Trials; Coupling; Data; Dilator; Effectiveness; Elderly; Event; Female; Functional disorder; Health; Hypercapnia; Hypoxia; Impairment; Individual; Link; Maintenance; Maps; Mental Depression; Metabolic; Methods; Molecular Genetics; Morbidity - disease rate; Motor Neurons; Mus; Muscarinics; Muscle; Muscle Tonus; Neurocognitive; Neurologic; Neurons; Obstructive Sleep Apnea; Older Population; Pathogenesis; Pathology; Patients; Pattern; Pharmacology; Play; Prevalence; Preventive; Prosencephalon; Public Health; Quality of life; REM Sleep; Recurrence; Reflex action; Reporting; Risk Factors; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Fragmentations; System; Testing; Therapeutic; Tongue; Translational Research; Viral Vector; Wakefulness; Work; age effect; age related; aging population; airway muscle; base; cell type; density; design; experience; experimental study; genetic approach; genioglossus muscle; hypoglossal nucleus; improved; locus ceruleus structure; male; middle age; mortality; mouse model; nerve injury; nerve supply; neurochemistry; non rapid eye movement; noradrenergic; normal aging; novel; older patient; pressure; transmission process

Abstract Obstructive sleep apnea (OSA) is a growing sleep-related breathing disorder with the prevalence rate of 10-15% in the middle-age adults and of 32%-62% in elderly. OSA patients undergo recurrent upper airway collapse due to suppression of activity of upper airway dilator muscles during sleep, which causes repeated hypoxia, frequent stressful arousals and sleep deprivation. OSA has a major health impact due to its association with cardiovascular, metabolic and neurocognitive morbidities, including a risk factor for developing Alzheimer’s disease and increased mortality in older adults. Brainstem noradrenergic (NA) system plays an important role in maintaining the tonus of upper airway (UA) muscles to keep airway open during wakefulness. Therefore, the decrease of NA release during sleep largely contributes to a loss of the UA muscle tone at night, which is a major neurological cause of OSA. Studies suggest that aging has a detrimental effect on the NA system. However, there is little information regarding age-related changes in the control of UA muscles by brainstem NA neurons, which may be a basis of the increased prevalence of OSA in older population. In the proposed project, we will use a novel molecular-genetic approach that will allow a cell-type-specific activation of NA neurons in the brainstem A1/C1, A5, A7 and SubCorelueus (SubC) nuclei while recording activity of the genioglossus (GG), a major UA dilator muscle, during natural sleep and wakefulness in young (3- 4 months) and old (16-20 months) behaving DBH-Cre mice. We will determine the age-related changes in 1) the ability of A1/C1, A5, A7 and SubC neurons to activate the GG muscle; 2) the contribution of A1/C1, A5, A7 and SubC neurons to depression of the GG muscle activity during NREM sleep and REM sleep; 3) the number of NA neurons in these and other brainstem NA nuclei; and 4) the density of axons and their terminals that originate from A1/C1, A5, A7 and SubC neurons and project to hypoglossal and other UA motoneurons. The proposed work will reveal neurological bases of the reduction in effectiveness of UA muscles to maintain UA open during sleep in older individuals. The results of this study will fill a major gap in our understanding of underlying mechanisms of OSA pathogenesis in elderly and lay the groundwork for translational research of OSA pathology in aging to develop preventive and/or therapeutic strategies for clinical management of OSA in older patients.

抽象的 阻塞性睡眠呼吸暂停（OSA）是一种与睡眠有关的呼吸障碍的增长，患病率为 中年成年人为10-15％，较早的成年人为32％-62％。 OSA患者经历了复发的上呼吸道 由于抑制上空气道扩张肌肉在睡眠期间的抑制，这会导致重复 缺氧，经常压力唤醒和睡眠剥夺。 OSA由于它的健康影响很大 与心血管，代谢和神经认知性病的关联，包括发展的危险因素 老年人的阿尔茨海默氏病和死亡率增加。 脑干甲肾上腺素能（NA）系统在维持上呼吸道的泡沫中起着重要作用 （UA）在清醒期间保持气道打开的肌肉。因此，睡眠期间NA释放的减少 夜间在很大程度上导致UA肌肉张力的丧失，这是OSA的主要神经原因。 研究表明，衰老对NA系统有不利影响。但是，信息很少 有关年龄相关的与年龄相关的变化，脑干NA神经元对UA肌肉的控制，这可能是一个基础 OSA在老年人群中的患病率增加。 在拟议的项目中，我们将使用一种新型的分子遗传学方法，该方法将允许特异性细胞类型 记录脑干A1/C1，A5，A7和亚曲线（SUBC）核中Na神经元的激活 在自然睡眠和年轻人的自然睡眠和清醒期间，Genioglossus（GG）的活性（GG）的活性（3-- 4个月）和旧的（16-20个月）行为DBH-CRE小鼠。我们将确定与年龄相关的变化1） A1/C1，A5，A7和SUBC神经元激活GG肌肉的能力； 2）A1/C1，A5，A7的贡献 在NREM睡眠和REM睡眠期间，GG肌肉活动的抑郁症和SubC神经元； 3） 这些和其他脑干NA核中NA神经元的数量； 4）轴突及其末端的密度 源自A1/C1，A5，A7和SUBC神经元，并投影到降压和其他UA运动神经元。 拟议的工作将揭示UA肌肉有效性降低的神经系统基础 在老年人的睡眠期间保持UA开放。这项研究的结果将填补我们的主要空白 了解较早的OSA发病机理的潜在机制，并为 衰老中OSA病理学的转化研究，以开发临床预防和/或治疗策略 老年患者OSA的管理。