How do lab mice behave, if you let them be mice?

While billions of global research dollars are spent studying lab mice as ‘models’, a Cornell University study is the first to shed light on their social behaviour as ‘mice’ beyond the constraints of their shoebox-sized enclosures.

“It was really fun to see the mice get to go outside, actually touch grass, see the sky and experience the sun, which they’ve never seen for 300 generations,” researcher Caleb Vogt tells Cosmos.

The behaviour of lab mice in this natural, more expansive setting was totally unexpected. In some cases it was fundamentally at odds with what happens in the lab, and the interactions of wild mice. 

The findings – published in BMC Biology – likely have global significance for biomedical research involving lab mice.

The study centres on a genetically uniform strain of black lab mice called ‘C57’, a strain commonly used in research.

Associate professor Michael Sheehan explains, C57: “was the strain that the initial mouse genome was published on”. As a result, a lot of research involves C57 mice. 

“All over the world, scientists anywhere can order the same exact genotype of mouse and keep them in what is ostensibly the same exact environment, and do the same exact study,” he says.

For hundreds of generations, C57 mice have been kept in constrained environments. 

In research facilities – unless they come out for an experiment – lab mice live cradle to grave in small enclosures, usually in same sex groups, with unlimited food and controlled temperatures. The mice develop particular behaviours under these constraints. For example, the males will form linear social dominance hierarchies, under an alpha male.

Scientists all over the world are using the mice as models, without knowing if their behaviours are normal for the animals, or a product of their environment.

As Sheehan says, until now: “No one had really asked: What would these mice do, if you just let them be?”

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A drone-view of the experimental set up / Credit: Matthew Zipple

To find out, Sheehan, Vogt and a team of researchers, released C57 mice in groups of 10 males and 10 females, into a large outdoor enclosure roughly the size of a basketball court (38 by 15 metres).

The mice were provided with resource zones (equipped with food and water) and their activity and interactions were monitored for 10 days using radio frequency identification.

To compare, groups of mice derived from genetically wild mice (from upstate New York) were released into a similar outdoor enclosure. 

In the lab, C57 mice are housed in groups at close quarters. In the outdoor experiment, Sheehan says, they were free to interact as they pleased. 

When given that option, C57 mice spent much of their time solo.

“They could move around next to each other and hang out all the time, or there’s a big enough world that they could never spend any time with each other if they really wanted to. And we found that most mice spent about half of their time alone.”

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Most mice spent about half of their time alone / Credit: Cornell University

In the field, the C57 males let go of hierarchical structures, opting instead for territorial behaviour similar to wild mice.

“The males seem to kind of hole up in one of these sort of resource stores … and sort of stay there for long periods of time,” Vogt says.

Meanwhile the behaviour of the C57 females was the most astonishing. 

“The females are just like off in this totally other behaviour space,” Sheehan says, quite unlike wild female mice, and even other mammals.

In the experiment, the wild-derived female mice tended to meet their male and stay put over the 10 days. Broadly similar behaviour to what’s been described in wild mice.

But the C57 females were visiting all of the spaces, and socially interacting with all of the mice almost every single night, Vogt says.

Wild mouse
A genetically wild-derived mouse / Credit: Cornell University

And while studies of wild mice suggest female mice prefer the company of closely-related “sister mice”. The lab derived females – genetically identical – showed no preference at all. 

“In this world of all identical twins … everyone kind of just went about willy nilly,” Sheehan says.

Sheehan says what their study reveals about C57 social behaviour has potentially significant implications for research, particularly in the fields of neuroscience, and pharmacology research designed to affect social behaviour.

The study is an important reminder that a lab mouse is more than a ‘model’; it’s an organism in its own right. And the unnatural limits of the lab constrain their behaviour.

“They live their life, essentially, in a shoebox. And so a lot of the behaviours they may express may not be available,” he says.

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