Zebrafish models: Charting promising platform and illuminating the depths of depression

Depression, a prevalent mental disorder with significant global health implications, remains a complex and multifaceted challenge. Despite extensive research using traditional animal models and clinical trials, the underlying mechanisms of depression remain incompletely understood, hindering the development of effective treatments. Zebrafish (Danio rerio), with their remarkable genetic and neurobiological similarities to humans, have emerged as a powerful tool for investigating the complexities of depression. Zebrafish exhibit a rich and quantifiable behavioral repertoire, with assays such as the novel tank test, light-dark box, open field, shoaling, maze test, and tail immobilization used to assess depression-like phenotypes. Diverse modeling approaches (including genetic and pharmacological manipulations, chronic stress paradigms, and gut-brain axis studies) have been applied, enabling investigations into the physiological, genetic, pharmacological, and environmental drivers of depression. The integration of zebrafish into depression research offers unique opportunities to advance mechanistic insight and accelerate antidepressant discovery. This review summarizes recent progress, examines current challenges, and outlines future directions to maximize the translational potential of zebrafish depression models.