UNDERSTANDING DEPRESSION THROUGH ANIMAL MODELS: EXPERIMENTAL AND BEHAVIORAL PERSPECTIVES.

Abstract

Depression is a multifactorial, chronic, and recurrent psychiatric disorder that represents a major global health burden. Despite extensive research, its underlying neurobiological mechanisms remain incompletely understood, largely due to ethical and methodological limitations in human studies. Consequently, rodent models have become indispensable tools for investigating the neurobiology of depression and evaluating potential antidepressant therapies. This narrative review provides a comprehensive and updated overview of the principal experimental models of depression in mice and rats, including stress-based (learned helplessness, chronic unpredictable mild stress, early-life stress, and social defeat), surgical (olfactory bulbectomy), pharmacological, and genetic models. For each model, commonly used induction procedures, behavioral validation methods, neurobiological relevance, and the concepts of face, construct, predictive, and translational validity are discussed together with their major strengths and limitations. Although a formal systematic literature search was not performed, the selection of studies was guided by a focused review of the most widely cited and methodologically robust literature in the field, with an emphasis on recent advances and persistent controversies. The review also summarizes the behavioral paradigms most frequently used to assess depression-like phenotypes, including the forced swim test, tail suspension test, sucrose preference test, open field test, and complementary behavioral assays. Particular attention is given to current discussions regarding the interpretation and translational relevance of several behavioral tests, and the ongoing debate regarding the translational validity of the forced swim and tail suspension tests is explicitly acknowledged. Additionally, methodological issues such as reproducibility and protocol variability are discussed, and the influence of sex differences on model outcomes and behavioral responses is considered, given their growing clinical and preclinical relevance. Although no single animal model fully reproduces the complexity and heterogeneity of human depression, each model contributes to understanding specific neurobiological mechanisms underlying the disorder. A major challenge that remains is the frequent failure to translate promising preclinical findings into effective clinical therapies. Future progress in depression research will likely depend on integrating complementary animal models with multidimensional behavioral assessments while carefully considering these translational limitations to improve the clinical relevance of preclinical findings.