How gut neurons communicate with the brain to control thirst
Drinking a glass of water is often enough to quench thirst after exercise. But while the feeling of thirst can be satiated after just a few minutes of consumption, the rehydration process actually takes about half an hour. The delay occurs because the brain receives signals that you drank water before the body is fully rehydrated based on sensing and measuring osmolality levels in the gut. Osmolality represents the concentration of dissolved solids, including sodium and glucose.
Caltech biologist Yuki Oka’s lab has been working to learn more about gut-brain osmolality signaling that regulates thirst, and now his team has uncovered the key sensory pathway that mediates this process.
Oka, Professor of Biology, Chen Researcher and Researcher of Heritage Medical Research Institute; and his lab has collaborated on research with the lab of David Anderson, Seymour Benzer Professor of Biology and Howard Hughes Medical Institute researcher. Anderson is the Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair and Director of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, where Oka is also an affiliate faculty member. An article describing the study appears in the journal Nature January 26.
Blood has a high osmolality when our body is dehydrated, which triggers the feeling of thirst. But because of the delay between when we feel quenched and when the body is fully rehydrated, the gut must detect osmolality changes before they occur in the bloodstream, and it must send that information to the brain.
Once we ingest food and water, the nutrients are absorbed from the intestine to the liver through the specialized blood vessel called the portal vein. During this uptake event, osmolality signals are also sensed by sensory neurons in the gut. In the research, led by postdoctoral researcher Takako Ichiki and graduate student Tongtong Wang, the team looked at how the gut communicates this information to the brain to indicate thirst or fullness.
There are two major sensory pathways from the gut to the brain: the spinal pathways (dorsal root ganglia, or DRGs) and the vagal pathways. In this study, Ichiki used genetically engineered mice to visualize patterns of neuronal activation in these two pathways. She then systematically monitored DRGs and vagal neurons in response to infusions of water, salt or sugar into the mouse gut that mimic normal nutrient ingestion. The team found that vagal neurons, but not spinal neurons, are strongly activated during osmolality changes in the gut. In fact, distinct subsets of neurons were active in response to different liquids.
The next question was: what part of the gut sends osmolality information to the brain? The team looked at the hepatic portal area (HPA), a major blood vessel running through the gut responsible for absorbing the vast majority of nutrients from the gut and transporting them to the liver. They found that the vagal nerves innervating the HPA do indeed carry osmolality signals. Cutting a specific branch of the vagal nerve at the HPA eliminated the ability of vagal neurons to respond to changes in osmolality.
The team further investigated whether vagal nerves directly or indirectly sense osmolality changes in the gut. They discovered that in response to osmolality changes in the gut, a particular peptide, vasoactive intestinal peptide, or VIP, is secreted into the portal vein, which in turn activates the vagus nerves in the HPA area. This explains how the gut translates physical osmolality changes into hormonal signals that encode the osmolality changes.
“We discovered the beginning of a pathway, the HPA-brain axis,” says Oka, who is also a researcher at the New York Stem Cell Foundation. “Details of all molecular connections and mechanisms have yet to be determined.”
Other future research will examine the connections between vagal neurons in the body and regions of the brain known to control thirst. In previous work, researchers in Oka’s lab identified so-called thirst neurons in the subfornical organs (SFO) region of the brain. When animals are thirsty, these neurons are very active; drinking water quickly calms them down. But SFO thirst neurons are not directly connected to any gut neurons, so the team aims to understand how changes in osmolality are communicated to SFO thirst neurons.
“There’s still so much we don’t know about how the nervous system controls basic functions, like thirst and satiety,” says Karen David, Ph.D., program director at the National Institute of neurological disorders and strokes. “This study shows how approaches supported by the BRAIN initiative are being used to uncover how brain circuitry handles this important sensory information.”
The article is entitled “Sensory representation and detection mechanisms of intestinal osmolality change”. Funding was provided by the President and Provost of Caltech, Caltech’s Biology and Bioengineering Division, the New York Stem Cell Foundation, the National Institutes of Health, the Alfred P. Sloan Foundation, the Heritage Medical Research Institute, and the Japan Society for the Advancement of Science. The study was funded by the NIH Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative (R01NS109997, R01NS123918).