On each side of the brain stem, a florescent-green marker illuminates the 200 neurons that control the sighing reflex. (Stanford/Krasnow lab)

It's a great day for sigh-ence. In a study published Monday in Nature, researchers claim to have found the brain circuit that controls sighing in mice. You probably haven't given much thought to the involuntary exhalations that signal everything from wistfulness to disapproval, but this type of breathing is more than just an emotional cue: It's actually a life-saving reflex.

Sighs — the quick addition of a second inhalation before an exhalation, creating an unconscious deep double breath — can have emotional triggers, but they also happen involuntarily every few minutes regardless of your mood. Some scientists now believe that these sighs serve a monumentally important purpose.

The lungs contain some 500 million tiny, balloon-like structures called alveoli, which all together have the surface area of a tennis court. Alveoli hardly ever collapse, but then again there are a half-billion of them. At that scale, "hardly ever" becomes pretty often. And if enough alveoli collapse, breathing becomes difficult.

It's thought that sighs serve to re-inflate errant alveoli and keep us breathing easy.

(Disney via giphy)

According to the new study, this mechanism could rely on a surprisingly small group of brain cells. Just 200 or so neurons in the brain stem trigger the process that leads to a sigh — at least in rodents, which have brains and respiratory systems quite similar to our own.

"Unlike a pacemaker that regulates only how fast we breathe, the brain's breathing center also controls the type of breath we take," study author Mark Krasnow of Stanford University said in a statement. "It's made up of small numbers of different kinds of neurons. Each functions like a button that turns on a different type of breath. One button programs regular breaths, another sighs, and the others could be for yawns, sniffs, coughs and maybe even laughs and cries."

The work is the result of a fortuitous collaboration between Stanford and University of California at Los Angeles researchers. UCLA's Jack Feldman and his lab had identified a kind of neuropeptide — the protein-like molecules that brain cells use to communicate with one another — that affected sigh rates in mice. Injecting the peptide made the mice go from sighing 40 times an hour to sighing 400 times. Killing cells with the receptor for the peptide made the mice stop sighing altogether, though their regular breathing patterns were unaffected.

Feldman wasn't interested in "pursuing the nitty-gritty work" he'd need to publish the research, so his lab tabled the data. Years later, when a student who had heard Feldman lecture at UCLA ended up in Krasnow's lab, the Stanford researchers took their own look at the sigh reflex, screening for patterns in the brain cells that could be linked back to particular genes. Then Feldman started getting questions from the other lab as the two research groups figured out who knew what.

"They had come up with a set of molecules they thought might be interesting, but of course they wouldn't share the list," Feldman told The Post. When Feldman happened to be in the area and visited the lab, they hinted that they'd found two molecules in particular that seemed highly expressed.

"They wouldn't tell, which was fine by me," Feldman recalled. But as he rushed out the door to the airport, he casually dropped which peptides his lab had worked on and asked them if Stanford's molecules were related.

His phone rang while he was still at the airport, with the Stanford lab eager to pick his brain. They had indeed zeroed in on peptides from the same family, but they didn't know what these molecules did. It was Feldman's turn to say his lips were sealed, and the groups agreed it was time to formally collaborate.

"We did a whole slew of experiments, and we each relied on our own expertise, which was largely non overlapping. That was the fun in all of this," Feldman said.

By working together, they learned that the peptides they'd identified serve to trigger a second set of 200 neurons, which then produces a sigh by controlling breathing muscles. Blocking one of the two peptides identified by Stanford cut sighs in half, and blocking both cut sighing off entirely.

The researchers hope that others will use their work to help those who sigh too much — or not enough. It's possible that patients unable to breathe deeply on their own could benefit from artificial sighs to keep their alveoli inflated, and while there isn't any indication that excess sighing is bad for you, it can cause a lot of stress. Feldman, who is primarily interested in studying how the brain controls behavior, thinks the basic science behind the new paper is just as noteworthy as potential medical applications.

"This greatly interests us because it’s happening on top of the normal breathing rhythm," Feldman explained. "If we can understand how this double breath comes, it could give us a back door into understanding how the basic rhythm is generated."

And breathing, he said, is one of the most fascinating behaviors to study.

"You do it from the time you’re born until you die, and you can't stop," Feldman said. "It works when you’re sleeping, you don't have to think about it at all, it's amazing. It’s amazingly reliable, and we don't really understand the basic neuroscience of it yet."

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