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，影响多达10%的 与1993年2-4%的成年人口相比。阻塞性睡眠呼吸暂停患者因以下原因反复出现上呼吸道塌陷 睡眠期间上呼吸道扩张器肌肉活动受到抑制，从而遭受反复缺氧， 频繁的应激性唤醒，睡眠不足。由于其心血管疾病，阻塞性睡眠呼吸暂停综合征具有重大的临床影响， 代谢和神经认知后遗症。 脑干去甲肾上腺素(NA)系统在阻塞性睡眠呼吸暂停综合征(OSA)的病理过程中发挥重要作用。 维持呼吸道通畅的上呼吸道(UA)肌肉的强直。NA系统也是一个主要贡献者 导致快速眼动(REM)睡眠期间UA肌张力丧失的神经机制。 然而，关于特定的NA神经元组之间的功能关系的信息有限 和UA肌肉。最重要的是，没有试图评估每一个 脑干NA组在NREM和REM睡眠中抑制UA肌电活动。 在拟议的研究项目中，我们将使用一种组合技术：慢性间歇性低氧 (CIH)，OSA的主要致病因素，以及一种新的分子遗传技术，将允许一种细胞类型- 脑干组(A1、A2、A5、蓝斑、 SUBC和A7)，同时记录在睡眠-觉醒周期中的膝舌肌的活动 DBH-Cre转基因小鼠。我们将1)确定这些NA基团的活性之间的功能关系 和GG肌肉活动以及CIH对这种关系的影响；2)量化每个 NA神经元群对脑出血和假手术大鼠自然NREM和REM睡眠中GG活性的抑制作用 治疗的小鼠；3)确定每个NA组到和在 舌下核，支配包括GG肌在内的UA肌和其他延髓的主要核。 控制上呼吸道肌张力的重要部位；以及4)决定CIH诱导的 舌下神经核内发芽的轴突终末，起源于不同的NA核。 这项拟议的工作将根据脑干NA神经元组参与 脑出血小鼠和对照组尿酸肌群的控制。重要的是，它将定量地表征 NA各剂量组对小鼠NREM和REM睡眠中GG肌肉活动的抑制作用 真相大白或假曝光。因此，这项研究的结果将填补我们对 阻塞性睡眠呼吸暂停的潜在发病机制，并可能有助于设计药理学或遗传学 预防阻塞性睡眠呼吸暂停综合症的治疗。

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.