The saltiest solution mice will voluntarily drink tastes roughly half as salty as seawater.
The solution briefly sates the brain cells that control thirst, but then - within a minute - they fire up again, telling mice they're still thirsty. A sip of plain water, though, keeps the same cells silent.
"It was something we just couldn't explain," says Howard Hughes Medical Investigator Zachary Knight, a neuroscientist at the University of California, San Francisco (UCSF). How does the brain know so quickly whether thirst has been quenched? There had to be a signal that clued in such thirst neurons, he says - something that told them whether a liquid was too salty, or just right.
After three years of investigation, he and his colleagues have discovered that the missing signal comes from the gut. Their work, reported March 27, 2019, in the journal Nature, reveals how the gastrointestinal tract measures the salt concentration in the intestines and relays this info directly to the brain. By tracking neural activity in living mice, his team watched in real time as these two organs communicated about thirst.
"We've discovered a new way that the gut talks to the brain," says UCSF graduate student Christopher Zimmerman.
Signs of thirst
Scientists have been trying to understand how our bodies regulate thirst for more than a century. Early studies of animals suggested that signals from the body (a parched throat, for instance, or the salt and water content of the blood) could sound a thirst alarm in the brain. In recent decades, researchers have also pointed a finger at the gastrointestinal tract. "But it's really been a mystery what the gut does to regulate thirst - if it's doing anything at all," Knight says.
What's more, he says, no one knew where in the brain thirst signals from the body registered, or how they got there. In 2016, Knight, Zimmerman, and their colleagues decided to take a direct look. Using an optical fiber threaded into the brain, the team watched as a set of neurons rapidly switched off when thirsty mice took a sip of water and the liquid hit the mouth and throat. The work showed that a thirst signal from the throat actually does exist, Knight says.
But one key experiment hinted that there was something more to the story: salt water turned those same neurons off - but only temporarily. "It's like there's another signal telling the thirst neurons, 'This is not rehydrating you,'" Knight says. He, Zimmerman, and colleagues turned toward the gut.
The gut, the team discovered in a series of experiments described in their new paper, has a built-in salt sensor that reports to the brain. When the researchers infused plain water directly into the gut, thirst neurons shut off. An infusion of saltwater kept the neurons active. The team observed a direct link between the saltiness of the fluid in the gut and the strength of the signal in the brain. "What's stunning about the finding is that the gut can so precisely measure salt concentration," Knight says.
A closer look
By mounting miniature microscopes onto the heads of mice, Knight's team pinpointed exactly where in the brain thirst signals from the body are evaluated.
Near the bottom of the brain, inside the hypothalamus, single neurons in the median preoptic nucleus take input from the gut, the throat, and the blood, and calculate whether an animal is thirsty, the team found. "No one had ever observed this happening in a single cell before," Zimmerman says.
The body's thirst-sensing system is relatively simple, Knight says. Working out its details could eventually help scientists figure out more complicated systems, like feeding and regulating body temperature.
He considers his team's method of pairing neural recordings in living animals with techniques to manipulate the body a crucial way to observe what's actually going on in the brain. "This is a prototype of the kind of science we're going to be doing in my lab in the years to come," Knight says.
Christopher A. Zimmerman, et al., "A gut-to-brain signal of fluid osmolarity controls thirst satiation," Nature. Published online March 27, 2019. doi: 10.1038/s41586-019-1066-x