A new study has demonstrated how and which activities outside of the brain contribute to feeling thirsty. The discovery offers a rich neurobiological clarification for a phenomenon that each of us has experienced many times in our lives.
The study identifies previously unknown body-to-brain pathways that work together to govern this fundamental sensation. For this study, Chris Zimmerman (postdoctoral fellow at the Princeton Neuroscience Institute) has received the 2020 Eppendorf & Science Prize for Neurobiology.
The study reveals that signals arise from the mouth and gut, providing “predictive” information to brain neurons that use these signals to satiate or convey thirst upon eating or drinking.
Zimmerman said, “What we have learned about the thirst system should improve our understanding of the brain systems that become dysfunctional in eating disorders, such as obesity and anorexia nervosa, and motivation disorders such as addiction and anhedonia, for example, which could someday lead to new therapies for these diseases.”
In the 1950s, Bengt Andersson proposed an answer to the question: where does this sensation come from? He suggested that our brains might contain an “osmosensor” governs thirst, which consists of a group of cells that sense when dehydrated by directly monitoring the blood’s osmolarity.
For the experiments, he systematically infused salt into the brains of goats to locate this osmosensor. He ultimately discovered a small area within the hypothalamus where even minute amounts of salt triggered immediate, voracious drinking. Subsequent studies established that Andersson’s osmosensor encompasses the subfornical organ (SFO), a brain region that is distinctively suited to detecting blood osmolarity because it lies outside the blood-brain barrier.
Zimmerman noted a few unresolved gaps in Andersson’s study. For one, considering how long it takes for ingested food or water to enter the bloodstream, it’s a mystery how a gulp of (often cold) water can immediately quench thirst, or how we can crave a drink shortly after a few bites of food. These quick changes in thirst sensations suggest that the sensory cue is regulated on a moment-by-moment basis, operating on a timescale that’s quicker than the passage of information through the bloodstream.
Zimmerman said, “The traditional model for how these brain structures function, as simple dehydration sensors, was entrenched and written into the textbooks. Demonstrating that thirst neurons also receive ‘predictive’ sensory information from the rest of the body led us to rewrite these traditional models.”
To explore this phenomenon, Zimmerman and his team started by suggesting stimulating and recording calcium movement in mice’s brains using optical fibers to pinpoint precisely how SFO neurons sense thirst. They affirmed that the thirst neurons could detect a lack of hydration levels by monitoring increases in particle concentration in the blood. In any case, incredibly, the thirst neurons likewise diminished activity when the mouse drank water and increased activity with food intake, suggesting that thirst neurons’ regulation happened even before chemicals from food and fluids infiltrated the blood.
Zimmerman thus postulated that the second set of signals — in addition to input from the bloodstream — might feed into the SFO to help the brain dynamically manage a sense of thirst in real-time. Aiming to detect these signals and their origins, he and his team traced the flow of water through the oral and digestive tracts in mice.
They found that as soon as water entered the mouth, the body triggered a near-instantaneous cell signaling pathway that closely tracked the volume of water ingested and inhibited thirst signals from the SFO accordingly.
Zimmerman said, “Cold water was particularly effective at inhibiting SFO neurons during this process, which may explain why we find cooler drinks, especially thirst-quenching and pleasurable.”
Further mouse experiments where water was directly delivered through an opening on the stomach wall to model the swallowing of fluid revealed a similar body-to-brain signaling pathway in the gut. Once water entered the gut, the body transmitted rapid measurements of real-time particle concentrations in the gut via the brain’s vagus nerve.
In light of these discoveries and upheld by additional cell imaging examinations, scientists built a potential model for how the body-to-brain signaling pathway coordinates thirst sensation. They suggest that layers of signals emerge from the mouth, gut, and blood and combine in the SFO.
Here, thirst neurons integrate the array of information from various sources to monitor the body’s hydration level, manage the appropriate level of thirst sensation, and provide guidance on whether to continue ingesting water or food. A parallel series of investigations likewise recommended that the body-to-brain regulation of thirst neurons controls downstream signals to change hormone release and emotions.
Zimmerman explained, “There may be instances when overwriting the cues related to satisfying thirst is necessary. For one, patients are asked not to consume water before undergoing surgery — a common hospital practice. In rare instances, when thirst becomes pathological, patients must overwrite the cue of drinking water to avoid increases in blood pressure and stress in the kidneys. In both cases, doctors prescribe sucking on ice chips and popsicles, or wetting the mouth, triggering the immediate signaling pathway to cope with thirst sensation.”
- Christopher A. Zimmerman. The origins of thirst. DOI: 10.1126/science.abe1479