Chronic Unpredictable Mild Stress Model of Depression: Possible Sources of Poor Reproducibility and Latent Variables

SIMPLE SUMMARY: Scientists use animal models to study the mechanisms of human diseases and find new drugs to treat them. Chronic Unpredictable Mild Stress is the best animal model of depression. However, this animal model is very sensitive to even the slightest changes in design. Researchers often have difficulty reproducing the main behavioral and physiological effects of Chronic Unpredictable Mild Stress. Animal behavior is influenced by a wide variety of factors. The better we standardize the Chronic Unpredictable Mild Stress procedure and the more factors we can control; the more reproducible results will be obtained by scientists from different laboratories who are engaged in the study of depression. In this review, we have attempted to identify possible sources of poor reproducibility of this model and have made a number of recommendations that can improve the model by making it more reliable. ABSTRACT: Major depressive disorder (MDD) is one of the most common mood disorders worldwide. A lack of understanding of the exact neurobiological mechanisms of depression complicates the search for new effective drugs. Animal models are an important tool in the search for new approaches to the treatment of this disorder. All animal models of depression have certain advantages and disadvantages. We often hear that the main drawback of the chronic unpredictable mild stress (CUMS) model of depression is its poor reproducibility, but rarely does anyone try to find the real causes and sources of such poor reproducibility. Analyzing the articles available in the PubMed database, we tried to identify the factors that may be the sources of the poor reproducibility of CUMS. Among such factors, there may be chronic sleep deprivation, painful stressors, social stress, the difference in sex and age of animals, different stress susceptibility of different animal strains, handling quality, habituation to stressful factors, various combinations of physical and psychological stressors in the CUMS protocol, the influence of olfactory and auditory stimuli on animals, as well as the possible influence of various other factors that are rarely taken into account by researchers. We assume that careful inspection of these factors will increase the reproducibility of the CUMS model between laboratories and allow to make the interpretation of the obtained results and their comparison between laboratories to be more adequate.