Modeling Stress‐Related Disorders in Zebrafish Using Prolonged Predator Exposure and Prolonged Unpredictable Stress

The neurobiology of human stress-related disorders remains poorly understood, necessitating novel models and new model organisms to advance translational research in this field. Complementing rodent studies, the zebrafish (Danio rerio) is a useful model species for stress-related disorders. Here, we develop two novel experimental models of stress-related brain disorders, based on repeated prolonged exposure to predators or on chronic unpredictable stress in adult zebrafish. The ability of both models to recapitulate human stress in these fish was assessed behaviorally, in the novel tank and the plus maze (anxiety, locomotor, and cognitive tests), as well as by analyzing the baseline levels of cortisol, a common neuroendocrine biomarker of stress. Overall, anxiety-like behavior in the novel tank test was seen in both stressed groups, whereas poor learning and higher anxiety were observed in the plus maze test in predator-exposed fish, paralleling clinical cognitive and affective symptoms. Elevated cortisol in both stressed zebrafish further resembled neuroendocrine deficits seen in stress-related disorders clinically. Finally, the evoked behavioral and endocrine stress symptoms were rescued by treatment with two popular, clinically active antidepressant drugs, fluoxetine and paroxetine. Collectively, these models successfully recapitulated in zebrafish several key aspects of clinical stress-related disorders, further supporting the utility of these fish for translational stress research and anti-stress drug development.