Chemogenetic dissection of noradrenergic system and sleep apnea

去甲肾上腺素能系统和睡眠呼吸暂停的化学遗传学剖析

• 批准号: 9381655
• 负责人: Victor Borisovich Fenik
• 金额: $ 32.48万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381655
• 关键词: Adult; Affect; Alpha Cell; Animal Model; Animals; Arousal; Attention; Axon; Brain Stem; Cardiovascular system; Cell Nucleus; Chronic; Clinical; Clinical Research; Data; Diabetes Mellitus; Dilator; Disease; Dissection; Fiber; Genetic; Health; Human; Hypertension; Hypoglossal nerve structure; Hypoxia; Knowledge; Label; Lead; Life; Link; Literature; Maps; Mediating; Mental Depression; Metabolic; Methods; Molecular Genetics; Motor Neurons; Mus; Muscle; Muscle Tonus; Nerve Degeneration; Neurocognitive; Neurons; Obstructive Sleep Apnea; Outcome Study; Pathogenesis; Pathology; Patients; Pattern; Pharmacological Treatment; Pharmacology; Placebos; Play; Pontine structure; Population; Prevalence; Public Health; REM Sleep; Recurrence; Research; Research Project Grants; Risk; Role; Site; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Wake Cycle; Source; Surgical complication; System; Techniques; Testing; Tracer; Transgenic Mice; Viral Vector; Virulence Factors; Withdrawal; Work; airway muscle; axonal sprouting; base; cell type; density; design; genetic approach; genetic technology; genioglossus muscle; hypoglossal nucleus; locus ceruleus structure; neonatal respiratory distress; non rapid eye movement; noradrenergic; novel; prevent; relating to nervous system; tool

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.

抽象的 阻塞性睡眠呼吸暂停 (OSA) 是一种日益严重的与睡眠相关的呼吸障碍，影响高达 10% 的患者 成年人口的比例在 1993 年为 2-4%。 OSA 患者由于以下原因而反复出现上呼吸道塌陷 睡眠时抑制上呼吸道扩张肌活动，从而反复缺氧， 频繁的压力性觉醒、睡眠不足。 OSA 由于其心血管、 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 保持气道开放的上气道 (UA) 肌肉紧张。 NA系统也是一个主要的贡献者 导致快速眼动 (REM) 睡眠期间 UA 肌张力丧失的神经元机制。 然而，有关特定 NA 神经元组之间功能关系的信息有限 和 UA 肌肉。最重要的是，没有尝试评估每个的相对贡献 脑干 NA 组在 NREM 和 REM 睡眠期间 UA 肌肉活动受到抑制。 在拟议的研究项目中，我们将结合使用多种技术： 慢性间歇性缺氧 （CIH），OSA 的主要致病因素，以及一种新颖的分子遗传技术，将允许细胞类型 每个脑干组（A1、A2、A5、蓝斑、 SubC 和 A7)，同时记录睡眠-觉醒周期行为中颏舌肌 (GG) 的活动 DBH-Cre 转基因小鼠。我们将 1) 确定这些 NA 基团活性之间的函数关系 GG 肌肉活动以及 CIH 对这种关系的影响； 2）量化每个的相对贡献 CIH 和假手术中自然 NREM 和 REM 睡眠期间 NA 神经元组对 GG 活动的抑制 治疗小鼠； 3) 识别每个 NA 组与 NA 组以及在 NA 组内的传出连接模式 舌下核，支配 UA 肌肉（包括 GG 肌肉）和其他髓质的主要核 对于控制上呼吸道肌张力很重要的部位； 4) 确定 CIH 诱发的幅度 源自不同 NA 核的舌下核内轴突末端的萌芽。 拟议的工作将根据脑干 NA 神经元组参与的情况对它们进行排名 CIH 和对照小鼠中 UA 肌肉的控制。重要的是，它将定量描述 NA 组的每个小鼠在 NREM 和 REM 睡眠期间均抑制 GG 肌肉活动 CIH 或假暴露。因此，这项研究的结果将填补我们理解的一个重大空白。 OSA 发病机制的潜在机制，可能有助于设计药理学或遗传学 预防 OSA 的治疗方法。