Department of Physiology, University of Toronto, 3206 Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Department of Medicine, University of Toronto, 3206 Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Sci Rep. 2023 Jul 29;13(1):12299. doi: 10.1038/s41598-023-39562-z.
Pharyngeal muscle activity and responsiveness are key pathophysiological traits in human obstructive sleep apnea (OSA) and strong contributors to improvements with pharmacotherapy. The thyrotropin-releasing hormone (TRH) analog taltirelin is of high pre-clinical interest given its neuronal-stimulant properties, minimal endocrine activity, tongue muscle activation following microperfusion into the hypoglossal motor nucleus (HMN) or systemic delivery, and high TRH receptor expression at the HMN compared to rest of the brain. Here we test the hypothesis that taltirelin increases HMN activity and/or responsivity to excitatory stimuli applied across sleep-wake states in-vivo. To target hypoglossal motoneurons with simultaneous pharmacological and optical stimuli we used customized "opto-dialysis" probes and chronically implanted them in mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT-ChR2, n = 12) and wild-type mice lacking the opsin (n = 10). Both optical stimuli applied across a range of powers (P < 0.001) and microperfusion of taltirelin into the HMN (P < 0.020) increased tongue motor activity in sleeping ChAT-ChR2 mice. Notably, taltirelin increased tonic background tongue motor activity (P < 0.001) but not responsivity to excitatory optical stimuli across sleep-wake states (P > 0.098). This differential effect on tonic motor activity versus responsivity informs human studies of the potential beneficial effects of taltirelin on pharyngeal motor control and OSA pharmacotherapy.
咽肌活动和反应性是人类阻塞性睡眠呼吸暂停（OSA）的关键病理生理特征，也是药物治疗改善的主要贡献因素。促甲状腺激素释放激素（TRH）类似物 taltirelin 因其具有神经元刺激特性、最小的内分泌活性、经舌下神经核（HMN）微量灌注或全身给药后舌肌激活、以及与大脑其他部位相比 HMN 上高 TRH 受体表达而引起高度的临床前关注。在这里，我们测试了这样一个假设，即 taltirelin 可以增加 HMN 的活动和/或对兴奋性刺激的反应性，这些刺激是在体内睡眠-觉醒状态下施加的。为了用同时的药理学和光学刺激来靶向舌下运动神经元，我们使用定制的“光透析”探针，并将其长期植入表达仅在胆碱能神经元上的光敏感阳离子通道的小鼠（ChAT-ChR2，n=12）和缺乏光感受器的野生型小鼠（n=10）中。在一系列功率下施加的两种光学刺激（P<0.001）和 taltirelin 微量灌注到 HMN（P<0.020）都增加了睡眠中的 ChAT-ChR2 小鼠的舌运动活动。值得注意的是，taltirelin 增加了强直背景的舌运动活动（P<0.001），但对睡眠-觉醒状态下的兴奋性光学刺激的反应性没有影响（P>0.098）。这种对强直运动活动与反应性的差异作用为人类研究 taltirelin 对咽肌控制和 OSA 药物治疗的潜在有益影响提供了信息。
