How do hunger and thirst work?

By Dr. John Ditraglia

A recent review article in The New England Journal of Medicine begins to answer that question by using new tools available to scientists that can probe small groups of specialty neurons, brain cells.(1)

Imagine trying to figure out how a computer works without knowing the wiring diagram. Of course even with the wiring diagram you and I couldn’t begin to figure anything out but presumably some electrical engineers could. Without a wiring diagram we could try just zapping things on the circuit board. That could do lots of things and undo other things. That is kind of how we have studied the brain so far without a wiring diagram. But genetics gives us an angle that is not available to a caveman trying to figure out a computer. It turns out that brain cells that do specific things, that might be sitting right next to brain cells that do something else, can be detected by seeing which genes are turned on.

Genes make RNA that makes specific proteins that can be detected. Mice can be engineered to have another gene attached to the target gene that will also be expressed whenever the target gene is turned on, thereby tagging it for the next step in this probe. Then those mice can be infected with a virus, like the rabies virus that infects brains, that has also been engineered with a gene for a tool that is usable only by the mouse brain cell genes that have been tagged. Voila. Now we can see which neurons are doing that specific thing among the 10,000,000 neurons in a mouse brain. Now we have a wiring diagram for the first brain cell in a circuit.

The next step in this magical mystery tour is accomplished by manipulating those specific neurons with some more genetic tools that allow us to turn on or off those particular brain cells using light or a drug. Also we can see when they are turned on or off.

Armed with the circuit diagram and a detector and activator of the switch we can watch mice who are starved or dehydrated or amply fed and watered with and without the switch turned on and see what they do.

Using these probes we have found out that food and salt appetite and thirst are actually controlled by an off switch. The switch is normally turned on. Whenever we have had enough to eat or drink the switches are turned off. We have also figured out that there is a “feed-forward” mechanism that happens before the brain can detect the blood chemistry changes that happen when you eat and drink. The even more complicated circuitry of this “feed-forward” thing can predict what’s going to happen by particular behaviors or the feeling of stuff in your stomach that also can activate the off switches for hunger or thirst.

It would seem that the “feed-forward” mechanisms can then be overridden by the backup of the “thermostat.” A thermostat detects the temperature and turns on the heating or cooling systems. But fat stores water and salt concentrations and lots of other systems also have their own -stats – fat-o-stat, hydrostat… The phenomenon of these -stats is called homeostasis and is an important job of the brain in concert with the rest of your body.

If all of this sounds too complicated it’s actually way worse complicated. We’re talking about brain surgery here.

1. Lowell BB. New neuroscience of homeostasis and drives for food, water, and thirst. N Engl J Med 2019;380:459-71.

By Dr. John Ditraglia