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， 中年人10-15%，老年人32%-62%。阻塞性睡眠呼吸暂停综合征患者上呼吸道复发 由于睡眠期间上呼吸道扩张肌的活动受到抑制而导致的塌陷，这导致反复的 缺氧、频繁的压力性觉醒和睡眠剥夺。OSA对健康有重大影响， 与心血管、代谢和神经认知疾病的相关性，包括发生 老年痴呆症和老年人死亡率增加。 脑干去甲肾上腺素能（NA）系统在维持上气道紧张性中起重要作用 (UA)保持呼吸道畅通的肌肉。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肌张力的丧失，这是OSA的主要神经学原因。 研究表明，老化对NA系统有不利影响。然而， 关于脑干NA神经元控制UA肌肉的年龄相关变化，这可能是一个基础， 老年人中OSA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， 记录时脑干A1/C1，A5，A7和SubCoreanus（SubC）核中NA神经元的激活 在自然睡眠和觉醒期间，年轻人（3- 10岁）颏舌肌（GG）的活动，主要的UA扩张肌， 4个月）和老龄（16-20个月）行为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和SubC神经元激活GG肌的贡献 和SubC神经元对NREM睡眠和REM睡眠期间GG肌活动的抑制; 3） 这些和其他脑干NA核中NA神经元的数量;和4）轴突及其终末的密度 起源于A1/C1、A5、A7和SubC神经元并投射到舌下神经和其他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学基础， 在老年人睡眠期间保持UA开放。这项研究的结果将填补我们的一个主要空白， 了解老年人OSA发病的潜在机制，并为 老年OSA病理学的转化研究，以制定预防和/或治疗策略， 治疗老年患者的OSA。

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.