Howard Hughes Medical Institute scientists have identified a circuit in the brains of mice that regulates thirst. When a subset of cells in the circuit is switched on, mice immediately begin drinking water, even if they are fully hydrated. A second set of cells suppresses the urge to drink. The thirst-regulating circuit is located in a region of the brain called the subfornical organ (SFO). "We view the SFO as a dedicated circuit that has two elements that likely interact with each other to maintain the perfect balance, so you drink when you have to and you don't drink when you don't need to," says Charles Zuker, an HHMI investigator at Columbia University who led the research. By doing so, the circuit ensures animals take in the right amount of fluid to maintain blood pressure, electrolyte balance, and cell volume. This work, led by postdoctoral fellow Yuki Oka was published January 26, 2015, in the journal Nature.

Zuker's lab is primarily interested in the biology of taste. Their studies have identified the receptors for the five basic tastes (sweet, sour, bitter, uammi and salt), and shown that the nervous system devotes multiple pathways to sensing and responding to salt. These circuits ensure that salt is appealing to humans at low concentrations, but not at high concentrations. "This is how the taste system regulates salt intake, which is very important for salt homeostasis in the body," says Oka. "But this is just one side of the coin. Salt intake has to be balanced by water intake."

The scientists knew a different mechanism must be responsible for controlling an animal's water intake. "There are no concentration changes for water -- water is water," Oka says. "But when you're thirsty, water is really attractive." Zuker and Oka set out to determine how the brain regulated the motivation to drink.

They began their search in the brain region known as the SFO, which shows increased activity in dehydrated animals. The SFO is one of the few regions of the brain located outside the blood-brain barrier, meaning it has direct contact with body fluids. "These cells might then have the opportunity to directly sense electrolyte balance in body fluids," Zuker points out.

Past experiments in which researchers had elecrically stimulated various circumventricular organs in the brain of mice, including the SFO, had yielded inconsistent results. Oka wanted to find out if their were specific cells in the SFO that triggered drinking behavior. By analyzing genetic markers, he identified three distinct cell types in the SFO: one set of excitatory cells, one set of inhibitory cells, and a third population of supporting cells known as astrocytes.

"If these neurons really mediated key aspects in driving the motivation to drink, then their activation should trigger active drinking, irrespective of the degree of fluid satiety," Zuker says. "And if you silence these populations, you should suppress the motivation to drink, even if you are extraordinarily thirsty."