When it comes to mating, female mice must follow their noses. For the first time, scientists have shown that hormones in mice hijack smell receptors in the nose to drive behavior, while leaving the brain completely out of the loop.
According to the study, appearing this week in Cell, female mice can smell attractant male pheromones during their reproductive periods. But during periods of diestrus, when the animals are unable to reproduce, the hormone progesterone prompts nasal sensory cells to block male pheromone signals so that they don't reach a female's brain. During this time, female mice display indifference or even hostility toward males. The same sensors functioned normally with regard to other smells, like cat urine, showing they are selective for male pheromones.
When ovulation begins, progesterone levels drop, enabling the females to once more smell male pheromones. In short, the system "blinds" female mice to potential mates when the animals are not in estrus.
The finding that the olfactory system usurped the brain's role shocked the research team, says lead author Lisa Stowers of the Scripps Research Institute. “The sensory systems are just supposed to sort of suck up everything they can in the environment and pass it all on to the brain. The result just seems wacky to us,” Stowers says.
“Imagine this occurring in your visual system," she adds. "If you just ate a big hamburger and then saw a buffet, you might see things like the table and some people and maybe some fruit—but you simply wouldn't see the hamburgers anymore. That's kind of what happens here. Based on this female's internal-state change, she's missing an entire subset of the cues being passed on to her brain.”
The scientists gathered 8- to 10-week-old female mice and tested them in different phases of their reproductive cycle. The caged mice could investigate one-by-one-inch squares of blotting paper soaked either with male mouse urine or a control. Their behavior was recorded, and the mice were scored for the frequency and duration of their visits to either substance.
The team also used calcium imaging to examine the vomeronasal organ, the sensory structure in mouse noses, and see what it was doing when females caught whiffs of pheromones. They found that the organ has a special subset of neurons with receptors to detect progesterone, and a “gating” mechanism that slams shut when the hormone is present so that male odors aren't passed to the brain. The neurons responded normally to other scents even when progesterone was present.
The results illustrated that the mouse olfactory system is tuned to internal chemical signals as well as external factors and is terrifically effective in its role as gatekeeper. But it's not at all clear why the nose would function in this manner. One idea is that the system evolved to keep females from being distracted during estrus. But mouse brains, like those of most animals, are constantly bombarded with information like smells and sights and have no problem sorting through it all.
“And the female brain already has ways of deciding whether or not she should be attracted to a mate. Her brain knows when she's not supposed to be mating, so she still won't, even if she does scent male pheromones,” Stowers notes.
The team suspects there is instead some underlying physiological reason for why female mice shouldn't detect male pheromones when they have high progesterone levels. One possible answer is that it protects a mouse fetus in some way—notably, progesterone levels are also robust during pregnancy.
More broadly, the finding suggests that not all big decisions are made in the brain, and that disentangling what occurs in the nose from what happens in the brain may not be straightforward, Stowers notes. Internal states like stress or hunger strongly impact how animals interact with the environment, but scientists don't fully understand how decisions based on these states are made in the brain. That makes Stowers wonder if this mouse discovery represents the tip of the iceberg regarding different roles for the olfactory system in mice and other species—including humans, who can distinguish between one trillion different smells.
“It's pure speculation at this point, but we think this will apply broadly, and we don't see why something similar couldn't be happening in humans,” she says. While humans don't sense pheromones in the same way mice do, the team did find the same molecules in the human nose that mice use to detect progesterone and trigger the smell-blocking process. “So it's there, and it's possible,” Stowers notes.
“It's such a cool trick it seems like it would be an advantage to conserve it across evolution and not discard it.”