Using Mice to Model Human Disease: Understanding the Roles of Baseline Housing-Induced and Experimentally Imposed Stresses in Animal Welfare and Experimental Reproducibility

SIMPLE SUMMARY: Scientific research into the causes, progression, and treatment of disease is dependent on the use of animal models. However, many scientists say that they cannot repeat published experiments. Studies designed to investigate the scope of this problem have reported that less than half of the experiments could be successfully repeated. Some reasons are the incomplete description of the experimental protocol, difficulties in identifying and obtaining the reagents and animals models used, and other issues in the actual experimental design and interpretation. However, another important facet of animal research that contributes to these differences is overall animal welfare, which directly impacts experimental outcomes. Mildly cool housing temperature causes chronic stress in mice and has been identified as a factor that can alter experimental outcomes, including experiments involving immunity. This review considers how chronic stress (inadvertently imposed on mice by housing conditions and intentionally by researchers studying effects of stress) both compromise animal welfare and consequently impact experimental outcomes. Increasing awareness of how differing levels of chronic stress can underlie different outcomes in similar experiments will improve animal welfare and experimental reproducibility and should also improve translatability of discoveries to the clinic. ABSTRACT: Mice are the most common animal used to study disease, but there are real concerns about the reproducibility of many of these experiments. This review discusses how several different sources of chronic stress can directly impact experimental outcomes. Mandated housing conditions induce an underappreciated level of chronic stress but are not usually considered or reported as part of the experimental design. Since chronic stress plays a critical role in the development and progression of many somatic diseases including cancer, obesity, and auto-immune diseases, this baseline stress can directly affect outcomes of such experiments. To study the role of stress in both physical and psychiatric diseases, there has been a proliferation of protocols for imposing chronic stress on mice. For somatic diseases, biomarkers can be used to compare the models with the disease in patients, but to evaluate the validity of psychiatric models, behavioral tests are carried out to assess changes in behavior and these tests may themselves cause an underappreciated degree of additional stress. Therefore, it is important for animal welfare to reduce baseline stress and select the most humane protocols for inducing and assessing chronic stress to obtain the most reliable outcomes.