Christopher Zimmerman is the recipient of the 2020 Eppendorf & Science Prize for Neurobiology for discovering how the brain estimates our need for water even before information from ingested food or fluids has entered our bloodstream. His research reveals that, upon eating or drinking, signals arise from the mouth and gut, providing "predictive" information to brain neurons that use these signals to satiate or convey thirst.
Zimmerman's work demonstrates how and which activities outside of the brain contribute to feeling thirsty, identifying previously unknown body-to-brain pathways that work together to govern this fundamental sensation.
"The prize-winning research provides an elegant neurobiological explanation for a phenomenon that each of us has experienced many times in our lives," said Peter Stern, senior editor at Science. The work helps explain, for example, how we can quickly feel thirst, how the sensation changes during meals, and why cold drinks have a thirst-quenching power.
"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," said Zimmerman, a postdoctoral research associate at Princeton Neuroscience Institute.
In the 1950s, Swedish scientist Bengt Andersson infused salt into goats' brains to try to identify a single cluster of cells responsible for the sensation of thirst. He located the first "thirst neurons" in a small area of the hypothalamus, which subsequent studies identified as the subfornical organ or SFO. Lying just outside of the blood brain barrier, the SFO is strategically positioned to directly contact the blood vessels and monitor the concentration of dissolved chemicals and minerals in the blood. "The SFO represented the missing link that transforms dehydration signals into the sensation of thirst," Zimmerman writes in his essay.
A few unresolved gaps remained in Andersson's work, Zimmerman noted. 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.
"The traditional model for how these brain structures function, as simple dehydration sensors, was entrenched and written into the textbooks," said Zimmerman. "Demonstrating that thirst neurons also receive 'predictive' sensory information from the rest of the body led us to rewrite these traditional models."
To investigate this phenomenon, Zimmerman and his team began by stimulating and recording calcium activity in the brains of mice using optical fibers to pinpoint just how SFO neurons sense thirst. They confirmed that the thirst neurons could sense dehydration levels by monitoring increases in particle concentration in the blood. However, to their surprise, the thirst neurons also decreased activity as soon as the mouse drank water, and increased activity with food intake, suggesting that regulation of thirst neurons occurred even before chemicals from food and fluids infiltrated the blood.
Zimmerman thus postulated that a second set of signals — in addition to input from the bloodstream — might feed into the SFO to help the brain dynamically manage 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.
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, said Zimmerman.
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 vagus nerve to the brain, the researchers showed.
Using mouth-to-brain and gut-to-brain signaling, SFO neurons can predict how the amount of ingested fluids will impact hydration and adjust their signaling accordingly, said Zimmerman. Eating, too, contributed to this layered signaling system to activate thirst neurons in anticipation of food absorption, the researchers found. If water is unavailable during a meal, additional signaling activates neuronal activity to suppress eating. If water is available, thirst neurons increase their signaling, to help stimulate drinking.
Based on these findings and supported by additional cell imaging experiments, Zimmerman and colleagues constructed a possible model for how the body-to-brain signaling pathway directs the sensation of thirst. They suggest that layers of signals arise from the mouth, gut, and blood and converge in the SFO. Here, thirst neurons integrate the array of information from different sources to monitor hydration level in the body, manage the appropriate level of thirst sensation, and provide guidance on whether to continue ingesting water or food. A parallel series of experiments also suggested that the body-to-brain regulation of thirst neurons controls downstream signals used to adjust hormone release and emotions.
There may be instances when overwriting the cues related to satisfying thirst is necessary, Zimmerman explained. For one, patients are asked not to consume water before undergoing surgery — a common hospital practice. Or in the rare instance 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.
The Eppendorf & Science Prize for Neurobiology recognizes the increasingly active and important role of neurobiology in advancing our understanding of the functioning of the brain and the nervous system. The winner receives $25,000 and publication of his or her essay in the October 2 Science issue.
"Eppendorf wants to reward and highlight the work of young, early-career scientists who are doing exceptional research in neurobiology," said Eva van Pelt, Co-CEO of Eppendorf AG. "Our past winners have gone on to run incredibly successful labs of their own and have become the opinion-leaders in their field."
Tara LeGates is the 2020 finalist for her essay, "The reward integrator: A new synapse emerges as a key regulator of motivation." LeGates received a B.S. in biopsychology from Rider University and her Ph.D. from Johns Hopkins University. She completed a postdoctoral fellowship at the University of Maryland School of Medicine, where she established the importance of the strength and plasticity of synapses in the brain's hippocampus-nucleus accumbens in reward-related behavior. LeGates is now an assistant professor at the University of Maryland Baltimore County. Her lab studies how neuronal circuits integrate information to regulate behavior and their alterations in psychiatric disorders.
Riccardo Beltramo is the 2020 finalist for his essay, "A new primary visual cortex: The postrhinal cortex joins the V1 as a first-order processor of visual information." Beltramo received his undergraduate degree from the University of Turin and his Ph.D. from the Italian Institute of Technology. After his doctoral training, Beltramo joined the Howard Hughes Medical Institute at the University of California San Diego and the University of California San Francisco, where he is completing his postdoctoral work. He studies sensory perception in the mouse visual system, focusing on understanding how cortical and subcortical neural circuits in the brain process visual information to drive behavior.