Of Mice and Men: Do men really cause stress?

When you walk in the door, Fluffy (your dog, cat, or pet of choice) jumps up, greets you, voices their approval.  He can sense you; she can smell you; he loves you.  What you may not realize is that when Fluffy senses the men in your house, she might become a little stressed out.

You may have heard about this research article published in Nature Methods recently.  I saw this story on the news: men induce stress in laboratory mice.¹  I laughed, and then I needed to learn more.  So let us take a brief departure from the seriousness that cancer evokes and discuss how and why men cause stress in mice.

The Science:

This study comes out of Montreal and the laboratory of Jeffrey Mogil.  As a pain geneticist, he studies the factors that determine sensitivity to pain.  His lab staff started to notice and anecdotally reported how their presence might affect the behavior of the laboratory mice.  Could this be true? Or just a researcher’s too-critical eye?  The only way to know for sure was to design some experiments to answer the question: do animals respond differently in response to pain when exposed to male and female researchers?

Measuring pain in mice requires careful examination of animal behavior.  Mogil designed the facial grimace scale describing changes in facial expressions including whisker position, ear position, cheek bulges and eye positions.² See examples of mouse facial expressions in the figure below.  Using this scale, experimenters can score the pain experience of each mouse. 

Figure 1: Facial Grimace Scale (2)

The experimental setup was as follows: researchers induced pain through administration of an inflammatory agent and assessed pain.  As the lab staff suspected there was a significant difference in pain response, except only in the presence of male experimenters not their female counterparts compared to no observer at all.  When males were assessing the pain response, they noticed a significant decrease in the facial grimace scale.  And the gender of the experimenter only matters when the pain is assessed, not during normal handling procedures such as cage cleaning or when the pain was administered.  Like any good science, these results were repeated with a separate measure of a pain response.  This is the first evidence to suggest that the gender of the researcher can affect the results of an experiment – a big deal!

But it gets more interesting.  Let’s switch shirts.  You wear my shirt and I’ll wear yours.  When cotton t-shirts worn by males the night before were placed in the room, the same decrease in facial grimacing effect was seen after pain induction suggesting the response is olfactory in nature.  The same effect was observed with bedding from unrelated male mammals.  The mice can smell men.   Because the affect is olfactory in nature, the experimenters determined which volatile acidic and steroidal compounds were responsible.  The compounds turn out to be male androgens such as testosterone. 

The authors provide and test two possible explanations for this observation: either the mice are consciously inhibiting their pain response or the stimuli (the male androgens) produce a stress-induced analgesia (loss of pain response) (SIA).  SIA is physiological response that involves signals from the spinal cord disseminating to modulatory pathways.  In mice exposed to male t-shirts, the levels of the stress hormone cortisone were significantly higher providing evidence for the latter explanation.  Additionally, the mice exposed to male androgens pooed more.  Yes, increasing amounts of fecal boli signals stress in mice.

The conclusion is clear: male androgens cause a stress response in mice that causes them to feel less pain.   

Where do we go from here:

This robust study describes a phenomenon we might have already observed in nature: animals can smell other animals and this affects their behavior.  Regardless, from the perspective of someone that does animal research, it is not something that we would expect to influence our results.  Perhaps we should think again.

What is particularly interesting in this article is the fact that such behavior change is due to a chemical response.  The significance of this chemical response, particularly in laboratory rodents, is yet to be determined.  If cortisone levels are higher, can this stress hormone affect other processes?  Perhaps tumor growth, for example? 

Of course, it’s essentially impossible to ensure that all laboratories across the world use the same gender of experimenters.  So it’s hard to see what effect this will have on animal research.  However, it might help to understand some discrepancies in between reports.

What is clear: men cause stress . . . . in mice. 

References:

      1.     Sorge RE, Martin LJ, Isbester KA et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents.  Nature Methods.  2014; doi: 10.1038/NMETH.2935

      2.     Langford DJ, Bailey AL, Chanda, ML et al.  Coding of facial expressions of pain in the laboratory mouse.  Nature methods. 2010:7(6):447-452.