A new Nature study from the lab of OEB and MCB’s Hopi Hoekstra reveals that wild mice from different environments use distinct defensive strategies when faced with threats—differences that can be traced to a specific brain region.
“Over the last years, many people have started using visual looming stimuli to study innate defensive behaviors in lab mice, because these looming stimuli proved very effective at triggering escape and freezing behaviors,” says Felix Baier, first author of the study and former Molecules, Cells, and Organisms (MCO) PhD student who studied in the Hoekstra lab. “We were inspired by this work, and wondered how our wild-derived Peromyscus species, from different environments across North America, would behave in this assay.”
To find out, the research team exposed several wild mouse species to simulations of an attacking bird and observed their reactions. “Could we detect natural variation in these behaviors that may be linked to different defensive strategies that these species evolved in their local environments?” Baier asked.
Developing a reliable test for the more active wild mice wasn’t easy. “We spent a lot of time optimising the assay for our wild mice—many escaped in the process—and trying different combinations of species and parameters,” he recalls. “But eventually, we did find a very robust difference in the behavior of two of our focal species.”
The standout was the Oldfield mouse, native to open habitats in the southeastern U.S. Unlike other species that quickly fled the looming stimulus, Oldfield mice froze in place. “It took me some time to understand the potential adaptive significance of this unusual behavior: in open environments with little cover, it is best to rely on your camouflage for as long as possible—you may have only one shot to escape!”
Curious about the neural basis of these behavioral differences, the team examined brain activity across species. “Naturally, we were super curious to find where in the brain evolution fiddled to enact these species differences,” said Baier. “Initially, we thought the differences may even be in the early stages of the visual system—perhaps these mice just see different things.”
That wasn’t the case. Following the behavioral experiments with visual stimuli, the team tested responses to an auditory threat stimulus—and the same species-specific differences emerged. This pointed toward a common central mechanism rather than sensory differences. “We therefore focused on the first brain region that receives input both from vision and hearing, the superior colliculus,” Baier said.
Staining for FOS, a marker of neural activation, the researchers found that the superior colliculus (SC) was activated equally in both species. “This suggested they see the same,” Baier noted.
Furthermore, the team discovered that a brain region, the dorsal periaqueductal gray (dPAG), which had previously been associated with escape decision-making and receives input from the SC, was significantly less activated in the Oldfield mouse.
Collaborators Katja Reinhard and Karl Farrow at the Neuro-Electronics Research Flanders research institute in Leuven, Belgium, then performed electrophysiological recordings during escape and showed that dPAG neurons encode behavioral events differently in the two species.
The team then experimentally manipulated this brain region. “We managed to activate this brain region and triggered similar species differences, and when we silenced the PAG during a looming stimulus, the species behaved alike!” says Baier.
The findings offer rare insight into how evolution can act on the brain’s central circuits to shape behavior. The team explains, “This is intriguing confirmation that evolution really acted in this central brain region, not in the periphery—perhaps capitalizing on the fact that several brain regions are known to contribute to escape, and adjusting the role of one doesn’t prevent the behavior altogether—which would unlikely be adaptive–but raises the threshold for it to get triggered.”
