by Michelle Frank
figures by Jovana Andrejevic

You’ve undoubtedly experienced the feeling of thirst: it’s a slight itch in the back of your throat, a distracting urge to turn away from whatever you’re doing and find something to drink. It drives you to guzzle water on hot days and to drink something along with your meals. Our need for water is as omnipresent and critical as our need for food or oxygen–it’s an essential cog that keeps our bodies working normally. The craving to pick up a beverage when we’re feeling parched might feel intuitive, but our bodies rely on an intricate set of biological processes to make sure we stay properly hydrated, as consuming both too much or too little water can lead to problems.

What makes us thirsty?

When your body starts to run low on water, a number of changes take place: for one, the volume of your blood decreases, causing a change in blood pressure. Because the amount of salt and other minerals in your body is staying constant as the volume of liquids decreases, their relative concentration increases (the same number of particles in a smaller volume means that the particles are more concentrated). This concentration of particles in bodily fluids relative to the total amount of liquid is known as osmolality, and it needs to be kept in a narrow range to keep the cells in your body functioning properly. Your body also needs a steady supply of fluids to transport nutrients, eliminate waste, and lubricate and cushion joints. To some extent, the body can compensate for water depletion by altering heart rate and blood pressure and by tweaking kidney function to retain more water. For you, though, the most noticeable indication that your body is running low on fluids is likely the feeling of thirst, as you increasingly feel like you need to drink some water.

So how does your body know that these responses are necessary, and how are they coordinated across so many different organ systems? Scientists are still trying to uncover how this process works, but research over the past several decades indicates that a highly specialized part of the brain called the lamina terminalis is responsible for guiding many of these thirst responses (Figure 1). Brain cells within the lamina terminalis can sense when the body is running low on water and whether you’ve had anything to drink recently. When researchers manipulate this brain region, they can also drive animals to seek out or avoid water, regardless of how hydrated that animal might be.

Figure 1: Brain regions controlling thirst. The lamina terminalis (yellow) is a series of interconnected brain structures that act as a central hub to control fluid levels in the body. Some cells in the lamina terminalis are adjacent to large, fluid-filled compartments in the brain, called ventricles (blue). When the body begins to run low on water, the composition of the body’s fluids (including the fluid in the brain’s ventricles) starts to change. The lamina terminalis neurons that border the ventricles can sense changes in the ventricular fluids, giving a snapshot of whether the body has enough water. These neurons also receive messages from other parts of the brain to give an even more complete picture of the body’s water needs.

The lamina terminalis is located towards the front of the brain and occupies a prime location just below a fluid reservoir called the third ventricle. Unlike much of the rest of the brain, many cells in the lamina terminalis aren’t guarded by a blood-brain barrier. This barrier prevents many circulating factors in the blood and other fluids from interacting with cells in the brain, offering the brain protection against potentially dangerous invaders like certain bacteria, viruses, and toxins. However, the blood-brain barrier also cuts the brain off from many circulating signals that might hold useful information about the body’s overall status. Because certain cells in the lamina terminalis lie outside the blood-brain barrier, these cells can also interact with the fluid in the third ventricle to keep tabs on factors that indicate whether the body needs more or less water. In particular, these cells can monitor the fluid in the ventricle to determine its osmolality and the amount of sodium present. 

When other parts of the brain detect information that’s relevant to understanding the body’s water needs, they frequently pass it along to the lamina terminalis, as well (Figure 2). In this way, the lamina terminalis also collects information about things like blood pressure, blood volume, and whether you’ve eaten recently (even before food can cause any change in circulating salt or water levels, your body tries to maintain a balance between these factors by encouraging you to drink water every time you eat). Information from the part of the brain that controls the circadian clock also gets forwarded to the lamina terminalis, encouraging animals to drink more water before sleeping to avoid becoming dehydrated during long periods of sleep. Collectively, this information gives the lamina terminalis the resources needed to make a call about whether the body needs more or less water. In turn, cells in the lamina terminalis project to many other areas of the brain, sending out their verdict about current water needs. Although scientists are still trying to figure out exactly how information from the lamina terminalis affects other brain regions, it’s clear that this output can influence an animal’s motivation to seek out water, as well as physiological factors like kidney function and heart rate (Figure 2).

Figure 2: Thirst signals and their effects. Neurons in the lamina terminalis receive many different messages about the body’s water needs. Thanks to their location next to ventricles in the brain, they can directly sense key indicators of water need like sodium levels and osmolality (the ratio of salt particles to a given amount of liquid). They also receive information about what time of day it is from another brain region, as well as cues from the mouth and kidneys. Neurons in the lamina terminalis can pool all of this information to determine whether the body needs more or less water. If it needs more, they can trigger feelings of thirst and appetite suppression. If it needs less, the brain will send signals telling you to stop drinking. The lamina terminalis also sends messages to a brain region called the hypothalamus. In turn, the hypothalamus can affect heart rate or urge the kidneys to retain more or less water.

What makes water so refreshing?

After a while standing outside in the hot sun, a cold drink of water tends to feel instantly refreshing. You might also find that drinking a very sugary beverage feels equally refreshing but leaves you feeling thirsty again later. In both cases, it takes tens of minutes for that drink to have any effect on attributes like osmolality or blood pressure, the body’s main indicators of hydration status. Instead, the brain must rely on some other cue to tell you to stop drinking and give you that instant feeling of refreshment. 

One clue came from the discovery that neurons in the lamina terminalis actually respond to the physical act of swallowing liquids, even before there are any changes in the amount of water in the blood. Researchers in Zack Knight’s lab at UCSF identified a group of neurons in the lamina terminalis whose activity is required for drinking behaviors: when you artificially turn off the activity in these cells, mice no longer drink water, even when they are water deprived. When the researchers recorded the activity of these cells as animals drank water, they found that the cell’s activity decreased in lockstep with each sip of water, far before any physiological changes in blood pressure or osmolality could have an effect. They also found that this change in activity only happened when the mice drank water, not when they drank a salt solution. This study suggests that our brains have a built-in mechanism to compare how much water we need with the amount of water we’re currently drinking, telling us when we’ve had enough and leaving us feeling instantly hydrated. Still, scientists don’t know exactly how the brain can tell water apart from other liquids, or why drinking some non-water beverages can leave you feeling instantly hydrated, as well.

Another group of researchers led by Yuki Oka at Caltech set out to tackle the problem of why we find drinking water so rewarding when we’re thirsty. Neuroscientists have long known that most reward signals are carried by a molecule called dopamine. In order to look at the role that this molecule has drinking behaviors, Oka’s team used a new kind of sensor that glows in the presence of dopamine. By putting this sensor into a mouse’s brain, they were able to record dopamine levels in real time as the mouse went about its tasks (Figure 3).

Figure 3: Drinking water is rewarding. Researchers in Yuki Oka’s group at Caltech conducted a study to see why animals find water rewarding. By using a special kind of sensor that glows in the presence of the rewarding molecule dopamine, they could see what kinds of liquids caused dopamine release. They recorded large spikes of dopamine release when thirsty mice drank both water and salty saline solutions, indicating that mice found both of these liquids rewarding. When researchers injected water into thirsty mice, though, they found no changes in dopamine levels, even though the injected water would also hydrate the thirsty animals.

These researchers looked at dopamine levels after thirsty mice drank water and other liquids. They also recorded dopamine levels after they injected water directly into the gastrointestinal system; this procedure hydrated thirsty animals, but meant that the mice didn’t actually drink any water. Oka’s group found that thirsty mice had a large surge in dopamine levels after drinking either water or saline and that these dopamine changes happened even before drinking would have any effect on blood fluid levels. In contrast, the animals didn’t release any dopamine after water was pumped into their gastric systems, suggesting that it’s the act of drinking itself that’s rewarding—not the feeling of being hydrated. This effect also starts to explain why drinking beverages other than water can be so satisfying, even when they leave you feeling thirsty later: the dopamine spike that comes from drinking liquids when animals are thirsty doesn’t depend on what kind of liquid they’re drinking, even though not all liquids are equally hydrating.

These two studies highlight the varying strategies the brain uses to monitor essential nutrients like water; because no single sensor can tally current water levels and predict future water needs, the brain relies on myriad complementary sensations and cues. As researchers get closer to unraveling the mystery of thirst, they’re sure to identify even more ways that the nervous system accounts for our innate need for water. 


Michelle Frank is a PhD Candidate in Neurobiology at Harvard Medical School.

Jovana Andrejevic is a fourth-year Applied Physics Ph.D. student in the School of Engineering and Applied Sciences at Harvard University.

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