Abstract： Objective To investigate the expression of endoplasmic reticulum stress-related protein activating transcription factor 4 (ATF4, also known as CAMP-response element protein 2) in rat brain after rapid eye movement (REM) sleep deprivation. Methods Using a modified multiple platform method, REM sleep deprivation for different time lengths was induced in 4 groups of rats (n=10, for 6, 12, 24, and 72 h, respectively), with 10 normal rats as the cage control and another 10 as the tank control groups. Immunohistochemistry and Western blotting were performed to detect ATF4 protein expression in the hippocampus and frontal lobe of the rats. Results No ATF4 was detected in the cage control group. ATF4 expression was detected in the brain tissues of the rats in the tank control group, and the expression peaked after REM sleep deprivation for 12 h, followed by gradual declination as the sleep deprivation was prolonged to 24 and 72 h. Conclusion REM sleep deprivation can induce endoplasmic reticulum stress. The timing of endoplasmic reticulum stress onset and the course of its development following sleep deprivation are almost identical in the frontal lobe and hippocampus of rats.