Remember all those times your parents told you it was rude to sigh? Well, you can discount that advice entirely, because sighing's actually a crucial reflex that keeps our lungs healthy, and researchers have just uncovered the switch in our brain that controls it.
The team identified two tiny clusters of neurons in the brain stem that automatically turn normal breaths into sighs when our lungs need some extra help - and they do this roughly every 5 minutes (or 12 times an hour), regardless of whether or not you're thinking about something depressing.
"Unlike a pacemaker that regulates only how fast we breathe, the brain’s breathing centre also controls the type of breath we take," said one of the researchers, Mark Krasnow, from Stanford University School of Medicine.
"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," he explains. "One button programs regular breaths, another sighs, and the others could be for yawns, sniffs, coughs and maybe even laughs and cries."
The team has now been able to identify for the first time the 'sigh' button, and it's surprisingly simple, bypassing our conscious brain altogether - which in biology suggests that it's one of the most crucial reflexes, just like 'flight or fight'.
"Sighing appears to be regulated by the fewest number of neurons we have seen linked to a fundamental human behaviour," said one of the researchers, Jack Feldman from the University of California, Los Angeles.
So why is sighing so important? It turns out that, without it, the tiny balloon-like sacs in our lungs known as alveoli can collapse and struggle to reinflate themselves.
"A sigh is a deep breath, but not a voluntary deep breath. It starts out as a normal breath, but before you exhale, you take a second breath on top of it," Feldman explained. "When alveoli collapse, they compromise the ability of the lung to exchange oxygen and carbon dioxide. The only way to pop them open again is to sigh, which brings in twice the volume of a normal breath."
This first became clear to scientists when patients started dying in the earliest iron lung devices, which didn't factor in providing people with these extra deep breaths - a design flaw that's since been fixed. "If you don’t sigh every 5 minutes of so, the alveoli will slowly collapse, causing lung failure," said Feldman.
For most of us that's not an issue, but for people who suffer conditions that stop them from breathing deeply - or, at the other end of the spectrum, who sigh so often that it becomes debilitating - it's not so simple. Which is why it's so important to work out how the process is regulated.
To do this, the team worked with lab mice, which sigh up to 40 times an hour. They screened more than 19,000 gene-expression patterns in the animals' brain cells, and eventually honed in on 200 neurons that manufacture and release one of two neuropeptides. These neuropeptides were known to influence breathing in humans, but no one had been able to work out how.
By studying the pathway in mice further, they found that the peptides stimulate a second set of 200 neurons, which then activated the mouse's breathing muscles to produce a sigh.
When the team increased the amount of peptide being produced, the mice started sighing 400 times an hour, instead of 40. Alternatively, they were able to stop the mice sighing altogether when they blocked the peptides.
"These molecular pathways are critical regulators of sighing, and define the core of a sigh-control circuit," said Krasnow. "It may now be possible to find drugs that target these pathways to control sighing."
Further research is needed to confirm that this same pathway exists in humans, but the similarities in the mouse and human systems suggest we're on the right track.
One thing that still remains a mystery, however, is whether emotional sighing works the same way.
"There is certainly a component of sighing that relates to an emotional state. When you are stressed, for example, you sigh more," said Feldman. "It may be that neurons in the brain areas that process emotion are triggering the release of the sigh neuropeptides - but we don’t know that."
We'll have to wait for the answer to that question, but in the meantime, don't feel bad about sighing to your heart's content. Your alveoli will thank you for it.
“You must remember this: a kiss is just a kiss, a sigh is just a sigh.”
Contrary to the words immortalized by the piano singer in “Casablanca,” a sigh is far more than a sigh. Heaving an unconscious sigh is a life-sustaining reflex that helps preserve lung function.
Now a new study by researchers at UCLA and Stanford has pinpointed two tiny clusters of neurons in the brain stem that are responsible for transforming normal breaths into sighs. Published in the Feb. 8 advance online edition of Nature, the discovery may one day allow physicians to treat patients who cannot breathe deeply on their own — or who suffer from disorders in which frequent sighing becomes debilitating.
“Sighing appears to be regulated by the fewest number of neurons we have seen linked to a fundamental human behavior,” explained Jack Feldman, a professor of neurobiology at the David Geffen School of Medicine at UCLA and a member of the UCLA Brain Research Institute. “One of the holy grails in neuroscience is figuring out how the brain controls behavior. Our finding gives us insights into mechanisms that may underlie much more complex behaviors.”
According to Mark Krasnow, a professor of biochemistry and Howard Hughes Medical Institute Investigator at the Stanford University School of Medicine, the new findings shed light on the network of cells in the brain stem that generates breathing rhythm.
Krasnow lab/Stanford
On each side of the brain stem, a florescent-green marker illuminates the two networks of 200 neurons that control the sighing reflex.
“Unlike a pacemaker that regulates only how fast we breathe, the brain’s breathing center also controls the type of breath we take,” Krasnow said. “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.”
Using a mousetrap model, Krasnow and his colleagues screened more than 19,000 gene-expression patterns in the animals’ brain cells. They found roughly 200 neurons in the brain stem that manufacture and release one of two neuropeptides, which enable brain cells to talk to each other. Still, the scientists did not know which brain cells these neurons communicated with or why.
Conversely, Feldman knew that the same family of peptides, also found in humans, was highly active in a part of the brain that influences breathing and plays an important role in sighing. What he had not identified were the genes or neurons that controlled them.
By joining forces, Krasnow’s and Feldman’s labs discovered that the peptides excited a second set of 200 neurons. These cells increased the rate that they activated the mouse’s breathing muscles to produce a sigh, from roughly 40 times an hour to more than 400 times per hour.
The researchers found that blocking one of the peptides cut the animals’ sighing rate in half. Silencing both peptides halted the mice’s ability to sigh completely.
“These molecular pathways are critical regulators of sighing, and define the core of a sigh-control circuit,” Krasnow said. “It may now be possible to find drugs that target these pathways to control sighing.”
Sighing is vital to lung function, and thus to life, Feldman emphasized.
“A sigh is a deep breath, but not a voluntary deep breath,” he said. “It starts out as a normal breath, but before you exhale, you take a second breath on top of it.”
On average, a person sighs every five minutes, which translates into 12 sighs per hour.
The purpose of sighing is to inflate the alveoli, the half-billion, tiny, delicate, balloon-like sacs in the lungs where oxygen enters and carbon dioxide leaves the bloodstream. Sometimes individual sacs collapse, though.
“When alveoli collapse, they compromise the ability of the lung to exchange oxygen and carbon dioxide,” Feldman said. “The only way to pop them open again is to sigh, which brings in twice the volume of a normal breath. If you don’t sigh, your lungs will fail over time.”
Turning on sighing would be useful in people who cannot breathe deeply on their own. Early artificial breathing devices did not regularly give patients a deep breath, and many patients died. Current ventilators regularly deliver a large inflation of air that mimics a sigh.
“If you don’t sigh every five minutes of so, the alveoli will slowly collapse, causing lung failure,” Feldman said. “That’s why patients in early iron lungs had such problems, because they never sighed.”
The ability to limit the sighing reflex could prove useful in anxiety disorders and other psychiatric conditions where sighing grows debilitating.
The mechanism behind the emotional roots of conscious sighing remains a mystery.
“There is certainly a component of sighing that relates to an emotional state. When you are stressed, for example, you sigh more,” Feldman said. “It may be that neurons in the brain areas that process emotion are triggering the release of the sigh neuropeptides — but we don’t know that.”
The research was supported by the Howard Hughes Medical Institute, National Institutes of Health grants HL70029, HL40959 and NS72211, a Walter V. and Idun Berry postdoctoral fellowship, the NIH Medical Scientist Training Program, and Canadian Institutes of Health Research and Alberta Innovates Health Solutions postdoctoral fellowships.
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