Enterochromaffin Cells Drive Anxiety-Like Behaviors in Sleep-Deprived Mice

Background Sleep deprivation (SD) is a potent trigger of anxiety and poses a substantial threat to mental health. Although accumulating evidence suggests that disrupted intestinal function contributes to abnormal behaviors associated with SD, the specific mechanisms by which the gut-derived signals modulate SD-related anxiety remain poorly understood. Methods Combining behavioral analysis, chemogenetic manipulation, and neuropharmacological approaches in a male mouse model of sleep deprivation (SD), we investigated the circuit mechanism from colonic enterochromaffin (EC) cells to hippocampal neurogenesis. The involvement of vagal afferent signaling was further probed by pharmacological blockade of 5-HT 3 receptors. Results We identified colonic EC cells as critical early responders to SD, whose dysfunction temporally precedes the emergence of anxiety phenotypes. Chemogenetic inhibition of EC cells mimicked the behavioral and neurogenic deficits seen after SD. Conversely, chemogenetic activation of EC cells during SD normalized 5-HT levels, rescued hippocampal neurogenesis, and alleviated anxiety-like behaviors. Mechanistically, 5-HT derived from EC cells activated vagal afferents via 5-HT 3 receptors, thereby promoting hippocampal neurogenesis and reducing anxiety-like behaviors. Conclusion Our findings reveal a key role for colonic EC cells in regulating emotional homeostasis during SD. These results provide novel insights into the mechanisms underlying SD-induced anxiety and highlight potential therapeutic targets for preventing anxiety related to sleep loss.