The circadian clock as an endogenous time-keeping mechanism modulates fundamental life processes from molecular, biochemical, cellular, physiological to behaviorial with a period of approximately 24 hours. Previous studies showed that circadian abnormalities often lead to human moody disorders. However, little is known about any role of circadian protein Period2 (Per2) in depression pathogenesis. Here a series of behavioral assays show that TALEN-generated zebrafish per2 mutant fish display lower locomotor activities, more time staying in the center region of the tank and less time for social interaction, in comparison with wild types, indicating a clear depression phenotype of the per2 mutant zebrafish. Quantitative RT-PCR showed that glucocorticoid receptor (gr) is significantly down-regulated in both the per2 mutant larvae and adult male fish brain. Luciferase reporter assays showed that Per2 can enhance Rorαa-mediated expression of gr, and ChIP assays showed that Per2 binds to the three RORE elements in the gr promoter, suggesting that Per2 positively regulates gr in zebrafish. Further, cortisol, and expression of pomc(proopiomelanocortin) and crh (corticotropin releasing hormone) are significantly up-regulated in the per2 mutant male fish, implicating disruptive activities of the hypothalamic-pituitary-adrenal (HPA) axis of the per2 mutant fish. Taken together, our findings demonstrate that Per2 acts through glucocorticoid receptor signaling to impact activities of the hypothalamic-pituitary-adrenal (HPA) axis and to contribute to depression pathogenesis, shed light on a novel circadian role in moody disorders.