For better research, let mice be mice

The humble mouse finds itself in thousands of laboratories across the world, where it is used to investigate everything from diseases to behaviour.

However, new research reveals that the traditional way it is cared for and raised for scientific purposes may have inadvertently been reducing its efficacy as a research model.

Along the way, the researchers may also have discovered the first glimpse of natural murine vocal communication.

The house mouse (Mus musculus) has the dubious distinction of being a wonderful window into the world of human ills. Its genetics, anatomy (structure) and physiology (function) are usefully similar to that of humans, and it is small and easily cared for, with a high generation rate.

This makes it not only able to provide insight into human conditions, but also cheap and self-replenishing.

These qualities have led humans to become dependent on mice for a great deal of scientific inquiry as they are incredibly useful for understanding mammalian biology and its complex problems.

Many genes implicated in a variety of diseases are shared with human beings and we’ve even gone so far as to develop artificial strains of Mus musculus using genetic manipulation in order to make them more useful for specific research fields. Take, for example, the Oncomouse, also known as the Harvard mouse, which fairly reliably develops cancer and is used in mind-numbing quantities for oncological research.

Among numerous other studies, Mus musculus are used to understand many human disorders of communication as well as other conditions that have acoustic implications such as autism and schizophrenia. The behaviour of mice in response to acoustic stimuli is a starting point to tracking down the genetic underpinnings of these communicative disorders. 

Now a paper published in the journal eNeuro has brought into question one of the staples of experimental protocols in the area: the lifelong isolation of mice used as research models.

Written by Laurel Screven – now a postdoctoral research fellow at Johns Hopkins University but a graduate student at the University of Buffalo when the research was conducted – and Micheal Dent of the University of Buffalo’s Department of Psychology – an expert in the perception of complex auditory stimuli in birds and mammals – it argues that a more naturalistic way of raising research model mice will improve research into murine acoustic behaviour.

Mice are social creatures and have complex and dynamic social structures that depend on the environmental context. Wild mice live in social groups that display huge variation in size and are fiercely territorial, while mice that live in urban settings live in small social groups and have a pronounced social hierarchy. Young are often reared communally by more than one female, which is a far cry from their lives in the laboratories of university psychology departments.

In laboratories, mice, once weaned, are often kept in isolation for their entire lives. “This is not a good model for humans,” says Dent, “because we’re creating these odd worlds for the mice. It’s not natural.” 

The reason for this isolation is that, as part of experimental protocol, the mice have their water supply mildly restricted in the hours leading up to tests and are supplied large amounts of water after. Having the mice isolated allows scientists to control this more accurately.

Dent tells Cosmos that “the males are also known to fight with one another, so they are hard to house together. Of course, if you house a male and a female together you know what is likely to happen, and we like to restrict that as well or we’ll have constant litters of baby mice.”

Nonetheless, Dent and Screven set out to test whether housing mice in such a way as to promote more natural socialisation might affect the way they perceive acoustic stimuli.

Mice call to each other using ultrasonic vocalisations (USVs) and researchers generally see these as falling into three basic categories. These USVs have large variation in frequency, duration and intensity, which produces an overall “shape” to the call, much like the way humans hear words.

To test whether social exposure or deprivation altered the way mice perceive USVs, the researchers separated 11 female mice into social groups of four females who were housed together, or individuals were housed in isolation. They were then trained to discriminate between 18 different USVs and the difference between the two groups was observed.

The research involved training the mice to place their noses in a hole to start the playback of a repeating USV. When the USV changes, the mice are trained to respond by poking the snouts into a different hole.

Their first finding was that socially housed mice are significantly quicker at learning to discriminate between different USVs than the socially isolated mice. This is significant for researchers as it makes data collection a great deal faster and thus makes the process of experimentation considerably more efficient. “Just the finding that the mice train faster when they live together is important for anyone in my line of research wanting to get the data out faster,” says Dent.

Beyond this, they also discovered that more natural socialisation actually changed the way the mice perceived USVs. Socially housed mice used different aspects of the shape of the call to discriminate between USVs compared to isolated mice.

“The importance of that is that the isolated animals likely have a skewed view of the auditory world,” says Dent. “They didn’t have experience hearing mouse calls emitted from mice, so they perceive them in an abnormal way.”

Dent points out that this “is akin to humans needing experience with speech sounds to properly perceive and produce speech sounds”.

Finally, and rather surprisingly, Dent and Screven discovered that the mice themselves also divide USVs into categories. “This is analogous to our words,” says Dent. “When I say boo and you say boo, receivers in the area hear the same word, even though the acoustics of our words are quite different. The mice were doing something similar.”

The significance of this is startling. According to Dent, “we know that mice produce all sorts of utterance types, but we haven’t been able to say that these types are meaningfully different to the mice – until now.”

This is perhaps the first evidence of vocal communication in mice, though Dent is cautious to add that further experimentation is needed. Nonetheless, she points to the work as “the first study to show that this is at least possible”.

Together, these findings have led them to the firm conclusion that “we should not be isolating mice. We should put them together in order to create a more realistic situation, one that’s more applicable to human communication.” This will not only improve the research but may well have a positive effect on the wellbeing of the mice.

This perhaps points, once again, to the need for greater communication between animal behaviour researchers and the field of animal ethics.

While these findings are fascinating, the aims of the ongoing research into the way mice hear and call to each other are loftier still.

“The goal of the research in our lab is to first establish the baseline acoustic communication behaviour of the mice so in the future we can start understanding communication in mice with genetic manipulations,” says Dent. “If we look at the genes found in humans who stutter, for instance, or have high frequency hearing loss, or accelerated age-related hearing loss, we can see what happens when we knock out those same genes in the mice.

“Eventually,” she says, “we can attempt to ‘fix’ the disorders in mice, leading to possible treatments for humans.”