The Emerging Issue of Cold-Stressed Mice

The number of animals used in research each year is in the millions and the majority of these are mice. There are various reasons for this including the fact that mice are cheaper than larger animals, they reproduce faster, they are easy to handle, and the physiology and biochemistry of mice has many similarities with that of humans. Mice even develop many diseases that humans develop like cancer and diabetes. These traits have made mice the animal of choice for gene manipulation studies. As a result, many lines of mice which carry genetic alterations have been developed, and these have proven invaluable for studying disease processes in humans.
 
Normally when researchers decide to employ an animal to study human disease they have to evaluate whether the animal models the disease adequately in humans. However, so many mouse disease models have been already established that most researchers go along with the prevalent practice in the field of employing certain models. And this makes sense, right? Why reinvent the wheel? After all, these models have been used before, they have led to reproducible observations, and key discoveries have been made with them. So, what do researchers do? They feed the mice the right diet, provide them with water, bedding etc. for their cages, and perform the experiments according to ethical guidelines. Researchers also make sure that they understand the variables they are dealing with, use the right controls, and execute the experiments in a competent fashion. What else is there to it?
 
What about the temperature at which the mice are housed? Until recently if you asked researchers this seemingly mundane question they would draw a blank. They would probably answer that you keep the mice at room temperature of course. And comfortable room temperatures are around 20-22 °C. You don’t want to be doing experiments in a very warm environment where you are going to be dripping sweat over everything you are doing, and you don’t want to be doing experiments in a very cold environment where you are going to be shivering. Scientists have to make judicious decisions about what variables to control or keep track of in their experiments. You can’t control or keep track of everything. Why should housing temperature be an issue?

Several physiologists over the years have been sounding the alarm regarding the problem of housing mice at room temperatures, but only recently have their voices captured the attention of a critical mass of scientists. The problem is that housing mice at room temperatures of 20-22 °C is indeed comfortable, but for humans! As I have noted before in this blog, mice have a very large surface to volume ratio, therefore heat exits their body very quickly. This is why mice have a metabolism that is 7 times greater than that of a human. Room temperatures of 20-22 °C feel comfortable to us because at these temperatures we achieve thermoneutrality. This means that at these temperatures our bodies spend the least amount of energy in heating or cooling. However, for mice the temperature of thermoneutrality is around 30-32 °C and this is not a theoretical calculation. If a mouse is placed on a thermal gradient, these are the temperatures they seek.
 
Mice housed at 20-22 °C are under a cold stress. So when researchers use mice housed at room temperature to model human disease, what they are really modelling is said disease on cold-stressed humans! Housing mice at human room temperatures dramatically changes their physiology and biochemistry and therefore the way they respond to disease and to drugs against diseases. For example, immunological responses are impaired in mice housed at room temperature which affects the way they respond to cancers and anticancer drugs. Also, mice housed at human room temperatures are more resistant to obesity and diabetes.
 
The problem now is that millions of experiments ranging from basic science to drug development have been performed on mice housed at human room temperatures! So the question arises as to which of these results are valid? Do millions of experiments need to be repeated?
 
Fortunately, the adaptations of animals like mice to a cold environment are well understood, and this knowledge can be used by researchers to estimate how much housing temperatures are likely to affect experimental results and then proceed to repeat any relevant experiments. In fact, this knowledge may present an opportunity to improve mouse models! It has been observed that many drugs that worked in mice did not work on humans beings, and the reason why this is the case is not clear. Could the housing temperature have had anything to do with it? This remains to be determined. Additionally, the right temperature to house mice may depend on what is being studied. Some phenomena involving increased energy expenditure and other related variables may actually be better modelled in mice housed at cold temperatures. Finally, housing at both cold and thermoneutral temperatures may give us a better understanding of how stress interacts with the variables involved in disease in ways that are relevant to patients. For example, mice bearing tumors tend to prefer significantly warmer temperatures (37-38 °C) than healthy mice, indicating that cancer induces a form of cold stress.
 
This issue of the housing temperatures illustrates the importance of bringing experiences from several fields of science to bear on the methodological procedures to be followed. Scientists may be very smart and very competent, but they all have in depth training in their own field of study, and what may seem like an unimportant variable in one field may be recognized as something to keep under control in another.

Image by Neil Smith available under a creative commons license: Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0).

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