When postdoctoral researcher Matthew Zipple releases lab mice into a large, enclosed field just off Cornell University’s campus, a remarkable transformation occurs. The mice, accustomed only to the confines of a cage slightly larger than a shoebox, rear up on their hind legs, sniff the air, and begin to bound over the grass. This new environment marks the beginning of their journey as “rewilded” mice, and a recent study by Cornell researchers has revealed that this novel setting significantly alters the mice’s behavior, reversing established anxiety patterns.
The study, published on December 15 in Current Biology, involved rewilding multiple cohorts of lab mice over a two-year period. The researchers found that the mice’s fear response, as measured by a classic anxiety assay, was notably reduced and even reversed after just one week in the field.
Understanding the Rewilding Effect
Senior author Michael Sheehan, an associate professor of neurobiology and behavior at Cornell, explained the significance of the findings. “We release the mice into these very large, enclosed fields where they can run around and touch grass and dirt for the first time in their lives,” he said. “It’s a new approach to understanding more about how experiences shape subsequent responses to the world, and the hope is that what we learn from these mice will have more generalizability to other animals and to ourselves as well.”
To assess anxiety, the researchers utilized the elevated plus maze, a common and humane method. The maze consists of two arms: one enclosed by walls, providing a sense of safety, and another open and elevated, where the mice feel exposed. Traditionally, mice spend less time in the open areas after initial exposure, indicating a fear response.
The Cornell team exposed groups of lab mice to the maze before rewilding half of them. In subsequent trials, the rewilded mice exhibited a significantly diminished fear response compared to those remaining in the lab.
“The rewilded mice show either no fear response or a much, much weaker response,” said Zipple, first author and a Klarman Fellow in the College of Arts and Sciences.
Implications for Behavioral Research
The study’s findings have broader implications for behavioral research with mice, challenging the adequacy of traditional lab environments. The research highlights a longstanding debate regarding the translation of findings from mouse models to human health.
“What we show is that yes, this is an example where the lab animal doesn’t generalize more broadly, but we also provide a solution that’s different, which is to study a real organism that’s living in a real environment,” Zipple noted.
Sheehan and his team are eager to explore further questions using the field setup. Potential areas of inquiry include determining the precise duration needed in the field to reverse a fear response and examining whether the age of the mice influences the outcome.
“This opens a lot of possibilities for asking interesting questions about how our library of experiences shapes our response to novel experiences, because I think that’s essentially what anxiety is – when you have an inappropriate response to something that isn’t actually scary,” Sheehan said.
Broader Reflections on Anxiety
While the research does not directly address human behavior, it offers intriguing parallels. Sheehan speculates that the rise in anxiety among young people may be linked to increasingly sheltered lifestyles, drawing connections between modernity and the findings of the study.
“There are conversations around modernity and our own lives that are echoed in this research that make it really interesting,” Sheehan reflected.
Daniel Chang Kuo ’23 is a co-author of the study, which received external funding from the National Science Foundation and the National Institutes of Health.
