Department of Pharmacology and Physiology, the George Washington University, Washington, DC.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Sleep. 2020 Jun 15;43(6). doi: 10.1093/sleep/zsz301.
Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive sleep-related losses of upper airway patency that occur most frequently during rapid eye movement (REM) sleep. Hypoglossal motoneurons play a key role in regulating upper airway muscle tone and patency during sleep. REM sleep activates GABA and glycine neurons in the ventral medulla (VM) to induce cortical desynchronization and skeletal muscle atonia during REM sleep; however, the role of this brain region in modulating hypoglossal motor activity is unknown. We combined optogenetic and chemogenetic approaches with in-vitro and in-vivo electrophysiology, respectfully, in GAD2-Cre mice of both sexes to test the hypothesis that VM GABA/glycine neurons control the activity of hypoglossal motoneurons and tongue muscles. Here, we show that there is a pathway originating from GABA/glycine neurons in the VM that monosynaptically inhibits brainstem hypoglossal motoneurons innervating both tongue protruder genioglossus (GMNs) and retractor (RMNs) muscles. Optogenetic activation of ChR2-expressing fibers induced a greater postsynaptic inhibition in RMNs than in GMNs. In-vivo chemogenetic activation of VM GABA/glycine neurons produced an inhibitory effect on tongue electromyographic (EMG) activity, decreasing both the amplitude and duration of inspiratory-related EMG bursts without any change in respiratory rate. These results indicate that activation of GABA/glycine neurons from the VM inhibits tongue muscles via a direct pathway to both GMNs and RMNs. This inhibition may play a role in REM sleep associated upper airway obstructions that occur in patients with OSA.
阻塞性睡眠呼吸暂停（OSA）是一种常见的疾病，其特征是在上呼吸道通畅性方面反复发作与睡眠有关的丧失，这些丧失最常发生在快速眼动（REM）睡眠期间。舌下运动神经元在调节睡眠期间上气道肌肉张力和通畅性方面起着关键作用。REM 睡眠会激活延髓腹侧（VM）中的 GABA 和甘氨酸神经元，以在 REM 睡眠期间诱导皮质去同步化和骨骼肌弛缓；然而，该脑区在调节舌下运动活动中的作用尚不清楚。我们分别在两性 GAD2-Cre 小鼠中结合光遗传学和化学遗传学方法以及体外和体内电生理学方法，来测试 VM GABA/glycine 神经元控制舌下运动神经元和舌肌活性的假设。在这里，我们表明，存在一条源自 VM GABA/glycine 神经元的通路，该通路通过单突触抑制支配舌突伸肌（GMNs）和回缩肌（RMNs）的脑干舌下运动神经元。表达 ChR2 的纤维的光遗传学激活在 RMNs 中诱导的突触后抑制大于 GMNs。VM GABA/glycine 神经元的体内化学遗传学激活对舌肌肌电图（EMG）活动产生抑制作用，降低吸气相关 EMG 爆发的幅度和持续时间，而呼吸频率没有任何变化。这些结果表明，VM 中的 GABA/glycine 神经元的激活通过直接途径抑制 GMNs 和 RMNs 来抑制舌肌。这种抑制可能在 OSA 患者 REM 睡眠相关的上气道阻塞中起作用。
