Scientists have for more than a century been working to unravel the mechanisms by which our bodies regulate thirst, and until recently it’s been believed that a region of the brain called the hypothalamus triggers thirst sensations when blood hydration drops. Prior work has also demonstrated that sensors in the mouth and throat communicate to thirst neurons in the brain about the volume of liquid being consumed.

Now, studies by researchers at the University of California, San Francisco (UCSF) and the Howard Hughes Medical Institute (HHMI) suggest that this isn’t the whole story. Their work in mice has found that sensors in the gut can detect the hydration value of a liquid, rather than its volume, and report back to the brain on whether the animal needs to keep drinking. “We’ve discovered a new way that the gut talks to the brain,” said UCSF graduate student Christopher Zimmerman, who was working in the laboratory of associate professor of physiology and Howard Hughes Medical Institute Investigator, Zachary Knight, PhD, when he carried out a series of studies in 2016 that set the scene for the latest research. “The hypothalamus is a critical center for keeping our physiology within a healthy range, whether it’s hydration, appetite, making sure we’re the right temperature, or controlling blood pressure—and all of these needs compete with and modify one another,” Knight added. “It has been difficult to study how all of these factors interact in the brain of a living animal, but studies like this are beginning to allow us to investigate this critical question.

Zimmerman is first author of the team’s new paper, which is published in Nature, and titled, “A gut-to-brain signal of fluid osmolarity controls thirst satiation.”

Drinking influences the composition, as well as the volume of blood, and consuming water and salt have opposite consequences for fluid balance, the authors explained. This raises the question of how the brain monitors whether a drink we are consuming is pure water, or might contains salt, for example. And while having a thirst-quenching drink can very quickly start to alleviate our perceived need to drink, it will actually take 10 minutes or more for the body’s hydration levels to increase.

One way in which the brain can keep tabs on our drinking is by monitoring fluids that pass through the mouth and throat. Zimmerman’s 2016 experiments in mice demonstrated that drinking triggered sensors in the mouth and throat to signal and switch off thirst neurons in the hypothalamus. Using optical fibers implanted in the brain, the researchers could see the neurons deactivating when thirsty mice took a drink of water into their mouth and throat. Cold fluids, in particular, triggered a fast shutdown of these thirst neurons. “Classic experiments have demonstrated that drinking temporarily satiates thirst even if the ingested water is immediately drained from the esophagus,” the authors wrote. “… recent work has identified specific populations of forebrain neurons that receive this rapid oropharyngeal signal during drinking.”

While these mouth and throat sensors seemed to be monitoring the volume of fluid being swallowed, but not its composition. “This fast signal from the mouth and throat appears to track how much you drink and match that to what your body needs,” Zimmerman said. “But we also knew that this fast signal couldn’t explain everything.” In fact, when mice in Zimmerman’s original experiments drank salty water the same neurons were switched off, but only temporarily. “It’s like there’s another signal telling the thirst neurons, ‘This is not rehydrating you,'” Knight commented.

During recent years studies have hinted that the gastrointestinal tract may play a role monitoring and reporting to the brain on the concentration of fluids that are ingested. “But it’s really been a mystery what the gut does to regulate thirst—if it’s doing anything at all,” Knight noted. For the studies now reported in Nature, the scientists implanted flexible optical fibers near to the hypothalamus in experimental mice, and monitored the activity of the thirst neurons when thirsty mice drank either pure or salty water, or had the fluids infused directly into their stomachs. “To gain insight into these longstanding questions, we set out to monitor directly the dynamics of thirst-promoting neurons in the brain while simultaneously manipulating the fluids that were ingested or infused into peripheral tissues,” they explained.

The results showed that infusing fresh water directly into the stomach and bypassing the mouth and throat also deactivated the thirst neurons cells, in the same way that taking a drink would do. “This indicates that changes in gastrointestinal osmolarity (but not distension) are sufficient to satiate thirst and conversely, that oropharyngeal cues are not required,” the authors stated.

In contrast, when salt water was infused into the stomach the thirst neurons remained active. And when mice were given a salt infusion and then allowed to drink pure water, their thirst neurons initially switched off in response to the animals drinking, but then reactivated, as if signaling the need to continue drinking to make up for the added salt.

An optical fiber (gray bar) threaded into the brain of a mouse (green) revealed activity of neurons involved in thirst. Scale bar equals 1 millimeter. [C. Zimmerman et al./Nature 2019]
It seems that while the mouth and throat sensors trigger the brain to think that thirst is quenched as a result of drinking, a second set of sensors in the gut can override that initial signaling if they forecast that the drink won’t hydrate the animal. “Interestingly, salt water didn’t drive drinking in well-hydrated mice, just in mice who were already thirsty,” Zimmerman said. “This suggests that signals from the gut are needed to quench thirst, but that you actually need to become dehydrated to trigger thirst in the first place … What’s stunning about the finding is that the gut can so precisely measure salt concentration.” As the team concluded, “these data reveal that osmolarity is precisely measured within the gastrointestinal tract and then communicated to thirst neurons in the brain.”

Further studies demonstrated that the gut signals traveled along the vagus nerve to activate thirst neurons. Optogenetic tests, which enable individual neurons can be switched off using light, showed that these cells, located near the subfornical organ (SFO) in the hypothalamus, then signal to the median preoptic nucleus (MnPO), which results in the thirst sensations and also instructs the kidney to conserve water in the blood. It appears that individual cells in the MnPO can respond to and coordinate signals from the mouth and throat as well as the signals from the gut, and information about bloodstream hydration. “We have shown here that individual, genetically defined thirst neurons in the MnPO integrate information about fluid balance that arises from the oropharynx, gastrointestinal tract, and blood,” the authors concluded.

The authors propose that the overall signaling mechanism occurs in three stages. “First, detection of liquid in the mouth generates a rapid signal that reports the volume of fluid ingested.” This early volume estimate temporarily turns off the thirst neurons. “Next, detection in the gastrointestinal tract generates a second signal that reports the osmolarity of the ingested fluid.” This early estimate of fluid osmolarity acts to keep the thirst neurons switched off if the liquid consumed is water, but reactivates them if the liquid contains substances that will concentrate in the blood. “Finally, absorption of water into the bloodstream alters fluid balance throughout the body, which leads to sustained changes in well-characterized signals (such as blood osmolarity) that are monitored by the brain directly.”

The researchers hope to use the new insights into the roles of the MnPO and SFO neurons to understand whether defective regulation of fluid balance in the body might also explain the foundation of diseases such as high blood pressure.

“This is the first time we’ve been able to watch in real time as single neurons integrate signals from different parts of the body to control a behavior like drinking,” Knight said. “This opens the door to studying how all these signals interact, such as how stress or body temperature influences thirst and appetite.”

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