Stressed out: providing laboratory animals with behavioral control to reduce the physiological effects of stress

Abstract

Hans Selye would have made a horrible laboratory animal technician. This budding young 1930s scientist accidently discovered stress physiology and the negative effect chronic exposure has on the body because of his extremely poor rat handling skills 1 . As a result, we know for a fact that husbandry affects the quality of animal models. Despite this knowledge, most labs continue to ignore stressful experiences in rodent models, often because of time or financial costs. Today's researchers and animal technicians of course receive more training and animal welfare oversight than Dr. Selye, but the slow rate of progress in minimizing general stress in the laboratory is disheartening. In addition to the obvious animal welfare ramifications of this lack of advancement, animal models in general show poor predictive validity in terms of translational outcomes in human clinical trials. Roughly 90% of compounds (for example, drugs or other therapeutics) that are 'successful' in animal trials fail in FDA human trials; the majority of these failures are a result of a lack of efficacy 2 . There are certainly many variables that contribute to this failure to translate, including reliance on measures that lack biological or psychological homology, translation of human clinical measures, or simple environmental effects 3 . In addition, we widely assume that strain differences and genetics are a large, if not the largest, influence on mouse behavior. However, in a retrospective study of influences on thermal nociception, strain only accounted for 27% of data variability 4 . On the other hand, environmental factors alone accounted for as much as 42% of data variability in the same study, and the identity of the experimenter actually had more effect on behavior than the genetics of the animal. Other examples highlight even more marked ratios, with enormous effects on experimental power and false discovery rates if not properly accounted for in data analysis 3,5 . Yet there is a substantial lack of research and funding available to determine how the laboratory environment affects animal physiology and behavior, particularly as it relates to characteristics of the human disease being modeled.Temperature as an example of environmental stress Many aspects of the laboratory environment are stressful to rodents and do not accurately reflect human physiology. An animal's environment can include both physiological and social stressors that require an animal to adapt to maintain allostatic balance. Thermal stress, for example, is a known stressor in the laboratory that affects temperature regulation and metabolism and results in poor modeling of human conditions in mouse models. Laboratory mice experience some degree of thermal stress under all recommended housing temperatures 6,7 (typically between 20-26 °C), but are prevented from adequately using many of their behavioral adaptations for thermoregulation and must therefore rely on thermogenic processes. At 23 °C, a mouse's metabolic rate is 60% higher than its metabolic rate at thermoneu...

Introducing Therioepistemology: the study of how knowledge is gained from animal research

“…Similarly, the complexities of human diagnoses are ignored or glossed over at our peril 17,48,49,54,55 . A recurrent theme of this paper, and this special issue, is that the role that good animal wellbeing plays in good science also cannot be ignored 26,[41][42][43][56][57][58] . Furthermore, factors that are controlled or standardized have also been widely shown to affect both the model and scientific outcomes, from the infectious agents we choose to exclude 59 , to the choice of bedding materials [60][61][62] and enrichment [63][64][65] , to cage changing practices 66 , to handling technique 58 , to the identity 31 or sex 67 of the experimenter.…”

“…This is particularly important in the case of mice, which are highly adapted to living cryptically as human commensals-in fact, their stealth adaptations rely on using sensory ranges such as ultraviolet and ultrasound that we don't detect and being active when we aren't. Furthermore, as discussed elsewhere in this special issue 41 , the critical issue for well-being and model quality is control, not of the animal, but by the animal. Through overengineering animal housing we take away an animal's control of its environment, which in turn makes it fundamentally abnormal 41,72 .…”

“…Furthermore, as discussed elsewhere in this special issue 41 , the critical issue for well-being and model quality is control, not of the animal, but by the animal. Through overengineering animal housing we take away an animal's control of its environment, which in turn makes it fundamentally abnormal 41,72 . This argument is traditionally a stress-psychology one, although it has recently been expanded to immunology.…”

“…Regardless, investigators may be unaware of the role well-being plays in human health, and as such be unaware of the potential impacts of animal well-being issues on their animal models. As discussed above, improving well-being often adds to the model, not just because we are normalizing the animal's biology 41 , but because we can now model the effects of clinically relevant variables like social support in cancer 96,97 , or educational level and cognitive demand, as modeled by enrichment in mice, in preserving function in Alzheimer's disease 103 .…”

Effects of adaptation to handling on the circadian rhythmicity of blood solutes in Mongolian gerbils

“…There are many factors such as temperature, humidity, light intensity, noise, handling, cage movement, dietary schedules and transportation that may affect experimental results by producing stress in laboratory animals . If the animals have not adapted to the new environment at the procedure of experiment, their physiological state may not have returned to normal, and the biomedical research results obtained may be influenced by even quite small physiological changes .…”