Fight or flee, it’s in the pee

Researchers get a better understanding of how mice smell a rat, or a cat

The smell of a protein found in urine leaves mice quaking with fear when they smell it coming from cats and rats, scientists report in the May 14 Cell. Yet when mice smell the same protein coming from other mice, the odor prompts mouse-on-mouse aggression.

What signals the mice to flee in one instance and fight in the other isn’t clear, but the find suggests that the animals have adapted an existing sensory communication system to interpret the scent of danger.

Most animals are hardwired to recognize predators, says study coauthor Lisa Stowers of the Scripps Research Institute in La Jolla, Calif. Lab mice are terrorized by the scent of cat, even though they — and hundreds of generations of their ancestors — have never met one. To explore which molecules might trigger this innate fear response, Stowers and her colleagues exposed lab mice to the scents of several predators, including a cat, a rat and a snake.

They found that each mammal predator’s scent contained a protein component that signaled danger to mice. Oddly enough, the danger molecule was a variation on a protein that mice make themselves. And when one male mouse smells the molecule on another, there’s frequently a fight.

“It was quite surprising,” says Stowers. “But the more we thought about it, it made sense — how does a mouse evolve the capacity to be afraid of a wide variety of predators, from weasels to ferrets to cats to snakes to rats?”

The question has puzzled researchers for a while, because it would require a lot of resources to maintain the ability to detect a variety of proteins from a variety of potential enemies, many of whom an animal might never encounter.

But a protein that’s made in slightly different versions by many animals would do the trick. For the mice, this fear-inducing molecule is a MUP, or major urinary protein. Despite their name, MUPs are secreted not just in urine, but in milk, saliva and tears. And while scientists aren’t sure what MUPs do for the animals that secrete them, plenty of animals do make them — including cats and rats.

Previous research showed that when a male mouse smells another male’s MUPs, it triggers aggressive, let’s-fight behavior. The new work shows that MUPs can also trigger fear, at least when they’re produced by predators. The mice weren’t concerned by rabbit MUPs. And Stowers isn’t sure if snakes or other reptiles make MUPs at all. The team couldn’t isolate any from the swabbed snakeskin used in the mouse experiments.

It’s not surprising that the mice have tuned an existing sensory system to detect dangerous predators that might be nearby, says sensory biologist Charles Derby of Georgia State University in Atlanta.

“If you are leaking something or releasing something, other species will use that to their benefit,” Derby says.

The work also nailed down the part of the nose mice use to detect MUPs: a specialized clump of cells previously thought to smell only scents from the same species.  

Most noses have cells that that serve as all-purpose odor detectors. But many animals also have specialized clumps of cells near the tips of their noses known as vomeronasal organs, or VNOs. The VNO is known to be important for detecting pheromones, specialized chemical cues that some animals use to communicate with each other.

But the VNO also detects MUPs, Stowers reports. Mice without working VNO sensory neurons weren’t afraid of the swabbed rat, cat and snake scents. One mouse even curled up and went to sleep next to an anesthetized rat, an animal that usually makes mice hide, tiptoe in fear and pump out stress hormones.

The work suggests that the nasal regions of mice and perhaps other animals might not be as specialized as previously thought, at least when it comes to the scent of danger, comments Howard Hughes Medical Institute Investigator Catherine Dulac of Harvard University. “The more redundancy you have in a system, probably the safer you are,” Dulac says.

A multitasking VNO suggests that interpreting the finer points of what an odor means is the purview of the brain, says Dulac. “Somehow the animal has been able to distinguish friend from foe — an animal who can’t make that distinction clearly is dead.” 

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