Cyclooxygenase-2 (COX-2)-dependent mechanisms mediate sleep responses to microbial and thermal stimuli.

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 the pro-inflammatory cytokine 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.

Lipopolysaccharide-Mediated Effects of the Microbiota on Sleep and Body Temperature.

Background: Recent research suggests that microbial molecules translocated from the intestinal lumen into the host's internal environment may play a role in various physiological functions, including sleep. Previously, we identified that butyrate, a short-chain fatty acid, produced by intestinal bacteria, and lipoteichoic acid, a cell wall component of gram-positive bacteria induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Building upon these findings, we aimed to explore the sleep signaling potential of intraportally administered lipopolysaccharide, a primary component of gram-negative bacterial cell walls, in rats. Results: Low dose of lipopolysaccharide (1 µg/kg) increased sleep duration and prolonged fever, without affecting systemic lipopolysaccharide levels. Interestingly, administering LPS systemically outside the portal region at a dose 20 times higher did not affect sleep, indicating a localized sensitivity within the hepatoportal region, encompassing the portal vein and liver, for the sleep and febrile effects of lipopolysaccharide. Furthermore, both the sleep- and fever-inducing effects of LPS were inhibited by indomethacin, a prostaglandin synthesis inhibitor, and replicated by intraportal administration of prostaglandin E2 or arachidonic acid, suggesting the involvement of the prostaglandin system in mediating these actions. Conclusions: These findings underscore the dynamic influence of lipopolysaccharide in the hepatoportal region on sleep and fever mechanisms, contributing to a complex microbial molecular assembly that orchestrates communication between the intestinal microbiota and brain. Lipopolysaccharide is a physiological component of plasma in both the portal and extra-portal circulation, with its levels rising in response to everyday challenges like high-fat meals, moderate alcohol intake, sleep loss and psychological stress. The increased translocation of lipopolysaccharide under such conditions may account for their physiological impact in daily life, highlighting the intricate interplay between microbial molecules and host physiology.