Chemogenetic dissection of noradrenergic system and sleep apnea.

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， 1993年，成年人口占2-4%。阻塞性睡眠呼吸暂停综合征患者会反复出现上呼吸道塌陷， 睡眠期间上呼吸道扩张肌活动受到抑制，并因此遭受反复缺氧， 频繁的压力性觉醒睡眠剥夺OSA由于其心血管疾病， 代谢和神经认知后遗症。 脑干去甲肾上腺素能（NA）系统通过维持中枢神经系统的功能，在OSA的病理过程中起着重要作用。 保持气道开放的上气道（UA）肌肉紧张。NA系统也是一个主要贡献者， 在快速眼动（REM）睡眠期间，导致UA肌张力丧失的神经元机制。 然而，关于特定NA神经元群之间的功能关系的信息有限 和肌肉。最重要的是，没有试图评估每一个国家的相对贡献， 脑干NA组在NREM和REM睡眠中抑制UA肌活动。 在拟议的研究项目中，我们将使用一种技术组合：慢性间歇性缺氧 (CIH)，OSA的主要致病因素，以及一种新的分子遗传技术， 在每个脑干组（A1，A2，A5，蓝斑， SubC和A7），同时记录在睡眠-觉醒周期中颏舌肌（GG）的活动， DBH-Cre转基因小鼠。我们将1）确定这些NA基团的活性之间的函数关系 和GG肌肉活动和CIH对这种关系的影响; 2）量化每种肌肉活动的相对贡献， NA神经元组对CIH和sham的自然NREM和REM睡眠期间GG活性的抑制作用 3）鉴定每个NA组与神经元和神经元内的传出连接的模式。 舌下神经核是支配包括GG肌在内的UA肌的主要核团， 对控制上气道肌张力重要的部位;以及4）确定CIH诱导的 舌下神经核内起源于不同NA核团的轴突终末出芽。 拟议的工作将根据脑干NA神经元组参与 CIH小鼠和对照小鼠中的UA肌肉的控制。重要的是，它将定量描述 在NREM和REM睡眠期间，NA组的每一个都抑制了小鼠的GG肌肉活动， CIH或假暴露。因此，这项研究的结果将填补我们对这一问题的认识中的一个重大空白。 OSA发病机制的潜在机制，并可能有助于设计药理学或遗传学 预防OSA的治疗方法

Abstract Obstructive sleep apnea (OSA) is a growing sleep-related breathing disorder affecting up to 10% of the adult population compared to 2-4% in 1993. OSA patients undergo recurrent upper airway collapse due to suppression of upper airway dilator muscle activity during sleep, and thus suffer from repeated hypoxia, frequent stressful arousals sleep deprivation. OSA has a major clinical impact due to its cardiovascular, metabolic and neurocognitive sequelae. Brainstem noradrenergic (NA) system plays a critical role in the pathology of OSA by maintaining the tonus of upper airway (UA) muscles that keep airway open. The NA system is also a major contributor to the neuronal mechanisms that lead to a loss of the UA muscle tone during rapid-eye-movement (REM) sleep. However, there is limited information regarding functional relationship between particular groups of NA neurons and UA muscles. Most importantly, there was no attempt to assess relative contribution of each of the brainstem NA group in depression of UA muscle activity during NREM and REM sleep. In the proposed research project, we will use a combination of techniques: chronic intermittent hypoxia (CIH), a major pathogenic factor in OSA, and a novel molecular-genetic technology that will allow a cell-type- specific activation or inhibition of NA neurons in each of the brainstem groups (A1, A2, A5, Locus Coeruleus, SubC, and A7) while recording activity of the genioglossus (GG) muscles during sleep-wake cycles in behaving DBH-Cre transgenic mice. We will 1) determine the functional relationship between activity of these NA groups and GG muscle activity and effect of CIH on this relationship; 2) quantify the relative contribution of each of the NA neuronal groups to the depression of GG activity during natural NREM and REM sleep in CIH- and sham- treated mice; 3) identify the pattern of efferent connections of each of the NA groups to and within the hypoglossal nucleus, a major nucleus innervating UA muscles including the GG muscle, and to other medullary sites important for the control of upper airway muscle tone; and 4) determine the magnitude of CIH-induced sprouting of axonal terminals within the hypoglossal nucleus that originate from different NA nuclei. The proposed work will rank the brainstem NA neuronal groups according to their involvement in the control of UA muscles in CIH and control mice. Importantly, it will quantitatively characterize the contribution of each of the NA group to depression of GG muscle activity during NREM and REM sleep in mice subjected to CIH or sham exposure. Therefore, results of this study will fill a major gap in our understanding of the underlying mechanisms of OSA pathogenesis and may help in designing pharmacological or genetic treatments to prevent OSA.