Why Men Stress Mice


For the second prompt, we will be talking about a discovery that impressed us this year. There are so many cool things that came out, but we thought we’d keep it light and pick something that’s both fun and interesting.

Alright, so you know how neuroscientists sometimes use mice for their experiments? They make them find cheese in mazes or swim to hidden water platforms etc. But before the mouse gets into the maze, for example, someone has to pick it up from its cage and put it there. And because this isn’t the 1800s anymore, that someone can either be a male or a female.

But here’s the catch: sometimes results aren’t reproducible across labs, even though all variables of interest stay the same. Of course, it goes without saying that’s generally not good for science (in fact, we have an entire other post about the reproducibility crisis). Anyway, this prompts the question: if all variables of interest stay the same, what drives the differences in results?

Well, it’s very possible that there are hidden variables which might influence results. In any given experiment, there are factors which could theoretically influence results, such as the ambient room temperature, the amount of sunlight, the type of cage in which mice live, the food they receive, and many others that people don’t explicitly notice. However, unless specifically investigating, let’s say, the effect of sunlight exposure on depressive symptoms in mice, scientists don’t necessarily control for this factor or other similar ones.

And this brings us to one such unexpected factor that was ultimately investigated: the sex of the experimenter handling the mice. This is usually a hidden variable, so most studies don’t pay attention to it. But there are some reports that mice are capable of discriminating between human experimenters by smell, that their performance improves in the presence of familiar experimenters, and that they show stress-induced pain inhibition when exposed to males.

The new study that came out this year builds on that and offers a more comprehensive view of how mice react to male and female experimenters. They found that not only do mice show aversion towards the human male scent and will prefer the female one given the choice, but they were also more susceptible to stress when handled by males. What’s more, this study identified the neural pathway which gets activated in response to the male scent (for those interested: it’s the corticotropin-releasing factor neurons in the entorhinal cortex projecting to the hippocampus).

On top of that, ketamine, an anesthetic and potential antidepressant drug, only produces its antidepressant effects if mice are exposed to the male scent and not to the female one. That implies ketamine needs to be administered shortly after the neural pathway from above has been activated, otherwise it won’t work. This information could turn out to be useful in the treatment of mood disorders, for which ketamine is researched as a therapeutic drug.

Of course, as we always remind you here, we need to wait for a body of evidence to be established before getting overly excited. But this study looks promising in several directions. For one, it highlights the importance of investigating potential hidden variables. It also suggests that studies on mice could benefit from keeping track of the experimenters’ sex. And finally, it provides an interesting direction of research with respect to neural pathways important for ketamine action.

What did you think about this post? Let us know in the comments below.

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Further reading

Georgiou, P., Zanos, P., Mou, T. C. M., An, X., Gerhard, D. M., Dryanovski, D. I., … & Gould, T. D. (2022). Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nature Neuroscience25(9), 1191-1200.

Sorge, R. E., Martin, L. J., Isbester, K. A., Sotocinal, S. G., Rosen, S., Tuttle, A. H., … & Mogil, J. S. (2014). Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature methods11(6), 629-632.

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