Experimental PTSD Models in Zebrafish: A Systematic Review of Behavioral, Neurochemical, and Molecular Outcomes

Abstract

Post-traumatic stress disorder (PTSD) is a complex psychiatric condition characterized by persistent behavioral and neurobiological alterations following trauma. Although rodent models are commonly used to study PTSD, zebrafish (Danio rerio) have emerged as a promising alternative due to their genetic similarity to humans, conserved stress response systems, and high-throughput capabilities. This systematic review evaluates 33 experimental studies on zebrafish PTSD models, focusing on behavioral, neurochemical, and molecular outcomes. Chronic unpredictable stress (CUS/UCS) paradigms of 14–15 days were identified as the most reliable for inducing PTSD-like phenotypes, consistently resulting in anxiety-like behaviors, cortisol dysregulation, and gene expression changes. In contrast, acute stress models produced transient effects, and social defeat paradigms showed methodological variability. Chronic models frequently demonstrated neurotransmitter imbalances, oxidative stress, and upregulation of inflammatory and neuroplasticity-related genes. However, the literature revealed challenges, including protocol heterogeneity, limited sex-specific analyses, and constraints in longitudinal biomarker tracking. Future directions include epigenetic profiling, environmental standardization, and cross-species validation. When used with methodological rigor, zebrafish offer a powerful and translationally relevant platform to study PTSD mechanisms and screen novel interventions.