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

摘要 阻塞性睡眠呼吸暂停(OSA)是一种日益严重的睡眠相关呼吸障碍，其患病率 中年人为10-15%，老年人为32%-62%。阻塞性睡眠呼吸暂停患者反复上呼吸道 由于睡眠时上呼吸道扩张肌的活动受到抑制而导致的虚脱，导致反复发作 低氧，频繁的应激性唤醒和睡眠不足。OSA对健康有重大影响，因为它 与心血管、代谢和神经认知疾病的关系，包括发展的危险因素 阿尔茨海默病和老年人死亡率的增加。 脑干去甲肾上腺素(NA)系统在维持上呼吸道张力中起着重要作用 (UA)清醒时保持呼吸道通畅的肌肉。因此，睡眠期间NA释放的减少 这在很大程度上导致了夜间UA肌肉张力的丧失，这是阻塞性睡眠呼吸暂停综合征的主要神经原因。 研究表明，衰老对NA系统有不利影响。然而，几乎没有什么信息 关于脑干NA神经元控制UA肌的年龄相关变化，这可能是一个基础 老年人口中阻塞性睡眠呼吸暂停综合征患病率的增加。 在拟议的项目中，我们将使用一种新的分子遗传学方法，这种方法将允许特定类型的细胞 记录时脑干A1/C1、A5、A7和Corelueus下核NA神经元的激活 膝舌肌(GG)，一种主要的UA扩张肌，在幼年(3-14岁)自然睡眠和清醒时的活动。 4月龄)和老年(16-20月龄)表现为DBH-CRE小鼠。我们将在1)中确定与年龄相关的变化 A1/C1、A5、A7和SUBC神经元激活GG肌的能力；2)A1/C1、A5、A7神经元的作用 和SUBC神经元对NREM睡眠和REM睡眠中GG肌电活动的抑制；3) 这些核团和其他脑干核团中NA神经元的数量；4)轴突及其终末的密度 这些神经元来自A1/C1、A5、A7和SUBC神经元，投射到舌下运动神经元和其他UA运动神经元。 这项拟议的工作将揭示尿失禁肌肉的有效性降低的神经基础 老年人在睡眠期间保持尿酸开放。这项研究的结果将填补我们在 了解老年人阻塞性睡眠呼吸暂停的发病机制，为 老年阻塞性睡眠呼吸暂停的病理学转化研究为临床制定预防和/或治疗策略 老年患者阻塞性睡眠呼吸暂停的处理。

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.