Future of Preclinical Depression Research: A Perspective of Behavioral Models with Validity and Translational Potential Description

Depression is a complicated mental disorder that has a high rate of occurrence all over the world and still ranks as the main reason for the occurrence of both disability and death. Although a lot has been discovered, the neurobiological mechanisms underlying depression are still not fully comprehended, and the current pharmacotherapies, most of the time, are not enough to bring about the desired results, thus leading to a large number of patients with treatment-resistant symptoms. Animal models, especially those in rodents, are crucial in the entire process of discovering the mechanisms of depression and evaluating new therapeutic strategies. This paper introduces a critical perspective on the different models and behavioral paradigms that are frequently utilized to simulate depressive-like phenotypes such as anhedonia, hopelessness, apathy, cognitive dysfunction, anxiety, and social withdrawal, among others. A major focus is placed on the dimensions of model validity-construct, face, and predictive validity-as well as reliability, which collectively determine the translational potential of animal studies. Importantly, this article focuses on the Species, Strain, and Sex framework as a guiding principle for model selection, emphasizing its value in improving reproducibility and generalizability across studies. Key paradigms such as Chronic Mild Stress (CMS), Learned Helplessness (LH), Chronic Social Defeat Stress (CSDS), and pharmacological models are evaluated in terms of their strengths, limitations, and relevance to human depressive disorders. In addition, behavioral assays, including Forced Swim Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), Sucrose Preference Test (SPT), and social interaction paradigms, are discussed for their utility in assessing depressive-like behaviors and antidepressant efficacy. Finally, the review highlights the need for refinement and innovation in preclinical depression research. A better integration of neurobiological insights with carefully chosen animal models will enhance translational validity, aid the discovery of novel therapeutic targets, and improve clinical outcomes for depressive disorders.