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The hardy souls who manage to push shorts season into December might feel some kinship with the thirteen-lined ground squirrel.

The critter hibernates all winter, but even when awake, it’s less sensitive to cold than its nonhibernating relatives, a new study finds. That cold tolerance is linked to changes in a specific cold-sensing protein in the sensory nerve cells of the ground squirrels and another hibernator, the Syrian hamster, researchers report in the Dec. 19 Cell Reports. The altered protein may be an adaptation that helps the animals drift into hibernation.
In experiments, mice, which don’t hibernate, strongly preferred to hang out on a hot plate that was 30° Celsius versus one that was cooler. Syrian hamsters (Mesocricetus auratus) and the ground squirrels (Ictidomys tridecemlineatus), however, didn’t seem to notice the chill until plate temperatures dipped below 10° Celsius, notes study coauthor Elena Gracheva, a neurophysiologist at Yale University.

Further work revealed that a cold-sensing protein called TRPM8 wasn’t as easily activated by cold in the squirrels and hamsters as in rats. Found in the sensory nerve cells of vertebrates, TRPM8 typically sends a sensation of cold to the brain when activated by low temperatures. It’s what makes your fingertips feel chilly when you’re holding a glass of ice water. It’s also responsible for the cooling sensation in your mouth after you chew gum made with menthol.

The researchers looked at the gene that contains the instructions to make the TRPM8 protein in ground squirrels and switched up parts of it to find regions responsible for tolerance to cold. The adaptation could be pinned on six amino acid changes in one section of the squirrel gene, the team found. Cutting-and-pasting the rat version of this gene fragment into the squirrel gene led to a protein that was once again cold-sensitive. Hamster TRPM8 proteins also lost their cold tolerance with slightly different genetic tweaks in the same region of the gene.

The fact that it’s possible to make a previously cold-resistant protein sensitive to cold by transferring in a snippet of genetic instructions from a different species is “really quite striking,” says David McKemy, a neurobiologist at the University of Southern California in Los Angeles.
As anyone who’s lain awake shivering in a subpar sleeping bag knows, falling asleep while cold is really hard. Hibernation is different than sleep, Gracheva emphasizes, but the squirrels and hamsters’ tolerance to cold may help them transition from an active, awake state to hibernation. If an animal feels chilly, its body will expend a lot of energy trying to warm up — and that’ll work against the physiological changes needed to enter hibernation. For example, while hibernating, small mammals like the ground squirrel slow their pulse and breathing and can lower their core body temperature to just a few degrees above freezing.

Modifications to TRPM8 probably aren’t the only factors that help ground squirrels ignore the cold, Gracheva says, especially as the thermometer drops even closer to freezing. “We think this is only part of the mechanism.”

Scientists also aren’t sure exactly how TRPM8 gets activated by cold in the first place. A detailed view of TRPM8’s structure, obtained using cryo-electron microscopy, was published by a different research group online December 7 in Science. “This is a big breakthrough. We were waiting for this structure for a long period of time,” Gracheva says. Going forward, she and colleagues hope that knowing the protein’s structure will help them link genetic adaptations for cold tolerance in TRPM8 with specific structural changes in the protein.

Cold weather often brings with it hot takes on so-called man flu. That’s the phenomenon in which the flu hits men harder than women — or, depending on who you ask, when men exaggerate regular cold symptoms into flu symptoms. In time for the 2017–2018 flu season, one researcher has examined the scientific evidence for and against man flu.

“The concept of man flu, as commonly defined, is potentially unjust,” Kyle Sue, a clinician at Memorial University of Newfoundland in St. John’s, Canada, writes December 11 in BMJ. Motivated by his own memorable bout of flu, he says, Sue began looking into man flu research and summarizes the work in a review article that’s part of BMJ’s Christmas issue, which traditionally features humorous takes on legitimate research.
There might be a reason men come across as wimps. In the United States, more men than women died from flu-related causes from 2007 to 2010 across several age groups, researchers reported in the American Journal of Epidemiology in 2013. An analysis of data on the 2004 to 2010 flu seasons in Hong Kong found that in children and adults, males were more likely to be hospitalized for the flu than females.

Sue isn’t the first to make a case for man flu. A prevailing explanation for men’s susceptibility says that women have higher levels of the hormone estradiol, which can boost the immune system, while men have higher levels of testosterone, which can sometimes suppress the immune system. However, these hormones interact with the immune system in other ways as well.

“There is some evidence that men make weaker immune responses to some viruses than women, but how this happens and whether it is seen across all viruses is still unclear to me,” notes John Upham, professor of respiratory medicine at Queensland University in Australia.

Sue’s review also cites evidence that women respond better to some flu shots than men do. Sex differences in immune response could have real consequences when it comes to vaccine choice, Upham says.
It’s also unclear what the evolutionary drivers for immune differences between the sexes might be. And studies of how the male and female immune systems respond differently all come with caveats, Sue notes: Such studies are often in mice rather than humans, have limited data or don’t account for health differences such as smoking habits and tendency to go to the doctor. Upham adds that studying differences in flu cases among men in Western versus non-Western societies could reveal the degree to which learned behavior plays a role in “man flu.”

As much as he’d like to help out his half of the species, Sue says, “we cannot yet conclude that this phenomenon is real, but the current evidence is suggestive that it may be.” Not surprising, his review has met just as much skepticism as previous man flu treatises.

Regardless of the possibility that men may be immunologically weaker than women, Sue says, both flu-stricken men and women alike “could benefit from resting in a safe, comfortable place with a recliner and TV.”