Few things are more refreshing than enjoying a cool beverage after spending a day under the hot summer sun. But gulping down a drink does not always quench thirst. Seawater, for example, may look appealing to someone stranded in the middle of the ocean, but taking a swig of it will only worsen dehydration.
Scientists have now discovered that in rodents, signals from both the throat and gut control feelings of thirst. These distinct pathways may explain why consuming a beverage is typically refreshing but does not always sate one’s thirst, according to a study by Yuki Oka, a neuroscientist at the California Institute of Technology, and his colleagues at the California Institute of Technology, published May 29 in Neuron.
Last year, Oka’s team reported that the simple act of gulping activated a circuit in the lamina terminalis, a region near the front of the brain, which ultimately led to the suppression of activity in neurons responsible for generating feelings of thirst. This throat-brain pathway, which the researchers identified in mice, switched on regardless of what an animal consumed—water, saline solution and oil produced similar effects. But the fact that all of these substances were able to inhibit the brain’s “thirst” neurons indicated that there was something missing. After all, if any liquid could satisfy an animal’s thirst, it might not consume enough water to remain hydrated.
According to Oka, behavioral studies in animals dating back decades suggested that there was an additional mechanism in the gut that signaled the presence of water to the brain. So in their latest investigation, Oka’s team set out to map the brain circuits responsible for receiving these signals. By injecting fluids directly into the guts of mice, the researchers discovered that in order for the rodents to feel fully hydrated, this second gut-based circuit needed to be activated. Without these gastrointestinal signals—which, unlike ones from the throat, selectively responded to the presence of water—the brain’s “thirst” neurons quickly revved up again, driving the animals to drink more.
The throat sends an immediate but temporary thirst-quenching signal to the brain once an animal starts gulping. At that point, the body is unaware of what it is consuming, and “you don’t want to make a mistake and keep drinking something that’s dehydrating,” Oka explains. The second signal from the gut then acts as a “checking mechanism” that makes sure to hold the brakes on thirst only if what the body consumed was actually water.
In another study, published earlier this year in Nature, Zachary Knight, an associate professor of physiology at the University of California, San Francisco, and his colleagues also reported that the gut sensed the water content of an ingested fluid and sent a signal that suppressed thirst in the brain. “[It] is rather cool that two separate groups reach the same conclusion at about the same time,” says Charles Bourque, a neuroscientist at McGill University, who was not involved in either investigation.
Over the past few years, a handful of labs have identified two parallel stories explaining the neurobiology of thirst and hunger. While these processes are mediated by distinct populations of cells in the brain, “the logic is very similar in both systems,” Knight says. After drinking and eating, the brain receives a very fast signal from either the throat or mouth that it uses to estimate how much an animal has ingested or what it is going to ingest. Then, after a delay of a couple of minutes, it gets a slower signal from the gut that confirms what was consumed (in the case of hunger, calories, and in the case of thirst, water).
Oka’s team also wanted to know whether both the oral and gastrointestinal signals were rewarding—driving the underlying motivation to drink. To find out, the researchers measured the levels of dopamine, a neurotransmitter involved in generating feelings of pleasure, in the rodents’ brain. Doing so revealed that while the act of drinking both water and saline led to a release of dopamine, gut infusions of those liquids had no effect. In addition, water-deprived mice were willing to press a lever to receive a spurt of water into the mouth but not directly into the stomach. “If the animals like something, they would work for it,” says study co-author Vineet Augustine, a graduate student in Oka’s lab. This finding, he adds, “clearly shows that [water in the gut] is not rewarding even though it is satiating.”
Interestingly, other groups have found that unlike water, nutrients in the gastrointestinal tract do stimulate the brain’s pleasure centers. Ivan De Araujo, a neuroscientist at the Icahn School of Medicine at Mount Sinai, says that this result is not too surprising because work by his lab has shown that water in the gut does not influence behaviors in the same way nutrients do. One reason for this difference, according to De Araujo, may be that water concentrations need to be tightly controlled, while excess energy from food can be stored for later use. In addition, unlike water, there is a wide diversity of nutrients that an animal can consume—and work by De Araujo and others has shown that animals can develop, independent of taste, a set of flavor preferences that hinge on the caloric content in the gut.
But these differences raise some interesting questions. For one, De Araujo wonders what happens when nutrients are consumed in liquid form. “If you are really thirsty, and you buy a can of Coke to quench your thirst, you are putting a lot of sugar in the gut at the same time,” he says. “[This] may somehow mix the two drives and form ambiguous rewards.”
More research is needed to confirm why nutrients in the gut are rewarding, while water is not. Another uncertainty is how, exactly, signals travel from the throat or gut to the brain. Knight’s group began to address this topic in its recent paper by demonstrating that the vagus nerve, a bundle of fibers connecting the brain stem to the major organs in the body, was involved in the process. But there are still open questions about what kind of information is being sent and whether other signals, such as hormones, also play a role.
While most of these studies have been conducted in rodents, researchers think that similar circuits exist in humans. There is some evidence for this idea, such as neuroimaging work in people that have identified activity in the lamina terminalis in response to thirst. In addition, according to Knight, the brain areas under investigation are thought to be evolutionarily highly conserved because they are involved in basic behaviors needed for survival.
Further probing these circuits could help scientists understand what happens when they go awry. For example, elderly people tend to feel less thirst, which can make them vulnerable to dehydration. On the other hand, some individuals experience polydipsia—a condition that causes excessive, unquenchable thirst. This research could also shed light on the mechanisms that underlie many of our behaviors. “Basic drives like hunger and thirst are the reason we do a lot of the things that we do,” Knight says. “So understanding how they’re regulated provides insight into the origin of our own motivations.”