Abstract Obstructive sleep apnea (OSA) occurs exclusively during sleep due to reduced tongue motor activity. Withdrawal of excitatory inputs to the hypoglossal motor nucleus (HMN) from wake to sleep contributes to this reduced activity. Several awake–active neurotransmitters with inputs to the HMN (e.g. serotonin [5-HT]) inhibit K+ leak mediated by TASK-1/3 channels on hypoglossal motoneurons, leading to increased neuronal activity in vitro. We hypothesize that TASK channel inhibition at the HMN will increase tongue muscle activity in vivo and modulate responses to 5-HT. We first microperfused the HMN of anesthetized rats with TASK channel inhibitors: doxapram (75 μM, n = 9), A1899 (25 μM, n = 9), ML365 (25 μM, n = 9), acidified artificial cerebrospinal fluid (ACSF, pH = 6.25, n = 9); and a TASK channel activator terbinafine (50 μM, n = 9); all with and without co-applied 5-HT (10 mM). 5-HT alone at the HMN increased tongue motor activity (202.8% ± 45.9%, p < 0.001). However, neither the TASK channel inhibitors, nor activator, at the HMN changed baseline tongue activity (p > 0.716) or responses to 5-HT (p > 0.127). Tonic tongue motor responses to 5-HT at the HMN were also not different (p > 0.05) between ChAT-Cre:TASKf/f mice (n = 8) lacking TASK-1/3 channels on cholinergic neurons versus controls (n = 10). In freely behaving rats (n = 9), microperfusion of A1899 into the HMN increased within-breath phasic tongue motor activity in wakefulness only (p = 0.005) but not sleep, with no effects on tonic activity across all sleep–wake states. Together, the findings suggest robust maintenance of tongue motor activity despite various strategies for TASK channel manipulation targeting the HMN in vivo, and thus currently do not support this target and direction for potential OSA pharmacotherapy.

中文翻译：

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舌下运动神经元池中 TASK-1/3 通道的调节以及对舌头运动输出的影响和对体内兴奋性输入的反应：对阻塞性睡眠呼吸暂停药物治疗策略的影响

摘要 阻塞性睡眠呼吸暂停 (OSA) 仅在睡眠期间发生，原因是舌头运动活动减少。从清醒到睡眠，对舌下运动核 (HMN) 的兴奋性输入的撤回导致这种活动减少。几种具有输入到 HMN 的清醒活性神经递质（例如血清素 [5-HT]）抑制由舌下运动神经元上的 TASK-1/3 通道介导的 K+ 泄漏，导致体外神经元活动增加。我们假设 HMN 处的 TASK 通道抑制将增加体内舌肌活动并调节对 5-HT 的反应。我们首先用 TASK 通道抑制剂对麻醉大鼠的 HMN 进行微灌注：多沙普兰（75 μM，n = 9）、A1899（25 μM，n = 9）、ML365（25 μM，n = 9）、酸化人工脑脊液（ACSF， pH = 6.25，n = 9)；和 TASK 通道激活剂特比萘芬 (50 μM, n = 9)；所有有和没有共同应用的 5-HT (10 mM)。在 HMN 单独使用 5-HT 会增加舌头运动活动（202.8% ± 45.9%，p < 0.001）。然而，HMN 的 TASK 通道抑制剂和激活剂都没有改变基线舌头活动（p > 0.716）或对 5-HT 的反应（p > 0.127）。胆碱能神经元上缺乏 TASK-1/3 通道的 ChAT-Cre:TASKf/f 小鼠（n = 8）与对照（n = 10 ）。在行为自由的大鼠 (n = 9) 中，将 A1899 微灌注到 HMN 中仅在清醒时增加呼吸内阶段性舌头运动活动 (p = 0.005)，但不会增加睡眠，对所有睡眠 - 觉醒状态的强直活动没有影响。一起，