Ten years of unpredictable chronic stress in zebrafish: a systematic review and meta-analysis

The zebrafish (Danio rerio) is a model animal that is being increasingly used in neuroscience research. A decade ago, the first study on unpredictable chronic stress (UCS) in zebrafish was published, inspired by protocols established for rodents in the early 1980s. Since then, several studies have been published by different groups, in some cases with conflicting results. We conducted a systematic review to identify studies evaluating the effects of UCS in zebrafish and meta-analytically synthetized the data of neurobehavioral outcomes and relevant biomarkers. Literature searches were performed in three databases (PubMed, Scopus, and Web of Science) and a two-step screening process based on inclusion/exclusion criteria. The included studies underwent extraction of qualitative and quantitative data, as well as risk of bias assessment. Outcomes of included studies (n = 38) were grouped into anxiety/fear- related behaviour, locomotor function, social behaviour, or cortisol level domains. UCS increased anxiety/fear-related behaviour and cortisol levels while decreased locomotor function, but a significant summary effect was not observed for social behaviour. Despite including a significant number of studies, the high heterogeneity and the methodological and reporting problems evidenced in the risk of bias analysis make it difficult to assess the internal validity of most studies and the overall validity of the model. Our review thus evidences the need to conduct well-designed experiments to better evaluate the effects of UCS on the behaviour of zebrafish.