Zebrafish as a Model Organism for Post-Traumatic Stress Disorder: Insights into Stress Mechanisms and Behavioral Assays

The zebrafish (Danio rerio) has emerged as a powerful model organism for investigating the mechanisms of post-traumatic stress disorder (PTSD), offering unique advantages in translational relevance, genetic trackability, and cost-effectiveness. As a logical continuation of our recent systematic review, this manuscript critically examines the spectrum of experimental strategies used to model PTSD in zebrafish, with a focus on the comparative efficacy and validity of acute, chronic, and complex stress paradigms. Among these, 14-15-day chronic unpredictable stress (CUS/UCS) protocols are identified as the gold standard, reliably inducing core PTSD-like phenotypes-such as anxiety-like behavior, cortisol dysregulation, and neuroinflammatory gene activation. We discuss the influence of environmental, developmental, and genetic factors on stress responses, and highlight the importance of standardized behavioral and molecular endpoints for model validation. While alternative paradigms-including acute, social, pharmacological, and predator-based models-offer mechanistic insights, their translational relevance remains limited without further refinement. We conclude by outlining future directions for zebrafish-based PTSD research, emphasizing the need for protocol harmonization, integration of multi-modal readouts, and exploration of individual variability to enhance the translational value of this model system.