Elson S. Floyd College of Medicine, Department of Translational Medicine and Physiology, Washington State University, Spokane, WA United States; Sleep and Performance Research Center, Washington State University, Spokane, WA United States.
Elson S. Floyd College of Medicine, Department of Translational Medicine and Physiology, Washington State University, Spokane, WA United States.
Brain Behav Immun. 2024 Nov;122:325-338. doi: 10.1016/j.bbi.2024.08.014. Epub 2024 Aug 10.
Prostaglandins (PGs) play a crucial role in sleep regulation, yet the broader physiological context that leads to the activation of the prostaglandin-mediated sleep-promoting system remains elusive. In this study, we explored sleep-inducing mechanisms potentially involving PGs, including microbial, immune and thermal stimuli as well as homeostatic sleep responses induced by short-term sleep deprivation using cyclooxygenase-2 knockout (COX-2 KO) mice and their wild-type littermates (WT). Systemic administration of 0.4 µg lipopolysaccharide (LPS) induced increased non-rapid-eye movement sleep (NREMS) and fever in WT animals, these effects were completely absent in COX-2 KO mice. This finding underscores the essential role of COX-2-dependent prostaglandins in mediating sleep and febrile responses to LPS. In contrast, the sleep and fever responses induced by tumor necrosis factor α, a proinflammatory cytokine which activates COX-2, were preserved in COX-2 KO animals, indicating that these effects are independent of COX-2-related signaling. Additionally, we examined the impact of ambient temperature on sleep. The sleep-promoting effects of moderate warm ambient temperature were suppressed in COX-2 KO animals, resulting in significantly reduced NREMS at ambient temperatures of 30 °C and 35 °C compared to WT mice. However, rapid-eye-movement sleep responses to moderately cold or warm temperatures did not differ between the two genotypes. Furthermore, 6 h of sleep deprivation induced rebound increases in sleep with no significant differences observed between COX-2 KO and WT mice. This suggests that while COX-2-derived prostaglandins are crucial for the somnogenic effects of increased ambient temperature, the homeostatic responses to sleep loss are COX-2-independent. Overall, the results highlight the critical role of COX-2-derived prostaglandins as mediators of the sleep-wake and thermoregulatory responses to various physiological challenges, including microbial, immune, and thermal stimuli. These findings emphasize the interconnected regulation of body temperature and sleep, with peripheral mechanisms emerging as key players in these integrative processes.
前列腺素（PGs）在睡眠调节中起着至关重要的作用，但导致前列腺素介导的促睡眠系统激活的更广泛的生理背景仍然难以捉摸。在这项研究中，我们探索了潜在涉及 PGs 的睡眠诱导机制，包括微生物、免疫和热刺激以及通过短期睡眠剥夺引起的稳态睡眠反应，使用环氧合酶-2 敲除（COX-2 KO）小鼠及其野生型同窝仔（WT）。全身给予 0.4μg 脂多糖（LPS）诱导 WT 动物非快速眼动睡眠（NREMS）和发热增加，这些效应在 COX-2 KO 小鼠中完全缺失。这一发现强调了 COX-2 依赖性前列腺素在介导 LPS 诱导的睡眠和发热反应中的重要作用。相比之下，促炎细胞因子肿瘤坏死因子-α诱导的睡眠和发热反应在 COX-2 KO 动物中得到保留，表明这些效应独立于 COX-2 相关信号。此外，我们研究了环境温度对睡眠的影响。适度温暖环境温度的促睡眠作用在 COX-2 KO 动物中受到抑制，导致 30°C 和 35°C 环境温度下 NREMS 显著减少，与 WT 小鼠相比。然而，两种基因型之间的快速眼动睡眠对适度冷或暖温度的反应没有差异。此外，6 小时的睡眠剥夺诱导睡眠反弹增加，COX-2 KO 和 WT 小鼠之间没有观察到显著差异。这表明，虽然 COX-2 衍生的前列腺素对于环境温度升高的促眠作用至关重要，但对睡眠剥夺的稳态反应是 COX-2 独立的。总体而言，这些结果强调了 COX-2 衍生的前列腺素作为各种生理挑战（包括微生物、免疫和热刺激）的睡眠-觉醒和体温调节反应的介导物的关键作用。这些发现强调了体温和睡眠的相互调节，外周机制成为这些整合过程中的关键参与者。
