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Scientists Identify Thirst-Controlling Neurons

The researchers identified 2 types of neurons that control thirst. This image of a mouse brain shows CAMKII neurons (red), which trigger thirst, and VGAT neurons (green), which inhibit thirst.Lab of Charles Zuker

Thirst—the basic instinct to drink water—regulates the salt and water balance (osmolality) in the body. The brain senses changes in this balance and directs us to drink water when needed. Certain medications and conditions, as well as aging, can interfere with this sensor system. In these cases, people become less likely to notice their thirst and may not drink fluids when needed.

Previous studies have shown that the urge to drink water is encoded in the hypothalamus and associated structures called circumventricular organs. One of these, called the subfornical organ (SFO), is among several regions activated by water deprivation. The SFO lacks the normal blood–brain barrier, so researchers thought it might function as the brain’s osmolality sensor.

A research team led by Drs. Yuki Oka and Charles S. Zuker at the Columbia University Medical Center explored whether neurons in the SFO play a role in controlling drinking behavior. They used a technique called optogenetics, which uses light to activate or inhibit specific neurons. The research, published online in Nature on January 26, 2015, was partly funded by NIH’s �����鶹��Ƶ Institute on Drug Abuse (NIDA) and �����鶹��Ƶ Institute of Neurological Disorders and Stroke (NINDS).

The researchers identified 3 distinct types of cells in the SFO of mice: one that expresses proteins characteristic of excitatory neurons; one that expresses proteins characteristic of inhibitory neurons; and a third that expresses proteins found in neuronal support cells called astrocytes.

When the researchers use optogenetics to specifically activate the excitatory neurons, the mice promptly started drinking water, even when they were already well hydrated. Stimulating these neurons didn’t increase consumption of food or other liquids like mineral oil or honey, showing that those neurons promote thirst specifically. The light-stimulated animals refused to drink water, however, if it contained a bitter compound or high concentrations of salt, showing that these neurons don’t bypass the animal’s aversion to toxic or noxious chemicals.

Activating inhibitory neurons, on the other hand, caused thirsty mice to stop drinking water. Stimulating these neurons didn’t decrease eating in hungry mice or salt consumption in salt-deprived mice. This suggests that the inhibitory neurons of the SFO function as an “off switch” specifically for water consumption.

Together, these findings show that the SFO is a dedicated brain system for thirst. To better understand how the SFO drives drinking behavior, future studies will look at the connections between the SFO and other brain regions activated by dehydration.

“The SFO is one of few neurological structures that is not blocked by the blood-brain barrier—it’s completely exposed to the general circulation,” says Oka, who recently moved to the California Institute of Technology. “This raises the possibility that we may be able to develop drugs for conditions related to thirst.”

—by Brandon Levy and Harrison Wein, Ph.D.