Thinking Fast and Slow about Thirst

Out of all motivational states, thirst should have been a simple one to understand. One feels thirsty when one is dehydrated, which can be detected from blood volume and osmolarity. Drinking water hydrates one’s body and quenches thirst. This is a homeostatic model. Intuitive, right? Well, the strange thing about thirst is that it is quenched within seconds to minutes after drinking water, which is too fast for any changes in the blood to happen. This is as if the brain gets hydrated before the body, which makes little sense since there is no specialized canal that passes water from mouth to brain (thank goodness). On the other hand, the buildup of the thirst drive is usually rather slow, meaning that thirst state can change on both a fast and slow time scale. How does it work?

To answer these kinds of questions, Zack Knight’s lab at UCSF uses mice as a model and records the activity of excitatory neurons in a brain region called SFO (referred to as the SFO neurons below). These SFO neurons have been previously shown to drive avid drinking in fully hydrated mice when stimulated optogenetically1. This new work2, led by Zack’s graduate student Christopher Zimmerman, begins by showing that the activity of the SFO neurons behaves exactly as what one expects from the thirst drive. Their activity increases dramatically after the injection of either salt solutions (which increases blood osmolarity) or a drug that reduces blood volume (which normally happens during dehydration). Both phenomena are to be expected from the classic thirst homeostatic model.

The homeostatic model fell apart when Zimmerman et al. found that the SFO neurons’ activity decreased dramatically minutes after a thirsty mouse started drinking and stayed low after (Figure 1). This is in contrast to the blood osmolarity level, which does not start decreasing until later. When looked at in detail, the SFO neurons’ activity starts decreasing when the animal starts licking (i.e. drinking) water. These results suggest that sensory inputs from mouth directly tell the SFO neurons that the animal is drinking water, therefore dampening down the thirst drive in anticipation of a drop in blood osmolarity and an increase in blood volume.

The activity of thirst-encoding SFO neurons drops immediately as the thirsty mouse starts licking. Figure adapted from Zimmerman et al

The activity of thirst-encoding SFO neurons drops immediately as the thirsty mouse starts licking. Figure adapted from Zimmerman et al

If sensory inputs from mouth alone can instruct thirst, one should be able to decrease SFO neurons’ activity without letting the animal drink any water. Indeed, Zimmerman et al. found that oral cooling, a procedure that has been reported to reduce thirst in humans, transiently decreases SFO neurons’ activity in a thirsty mouse. This suggests that thirst drive can change on a fast and a slow scale because it receives two streams of information about water consumption: fast information from the mouth and slow information from the blood.

If fast and slow information about drinking controls SFO neurons’ activity, what happens if these two streams of information are in conflict with each other? To test this, Zimmerman et al. let a thirsty mouse drink high-osmolarity saline, which is mostly water but does not quench thirst, and find that the SFO neurons’ activity initially drops and then recovers during the process. Now, we can explain these results. The fast sensory inputs from mouth get to the SFO first, relaying information about drinking, but then the slow information about blood osmolarity catches up, updating the SFO neurons with the actual osmolarity state of the animal.

When a thirsty mouse drinks high-osmolarity saline, its SFO neuron activity initially drops (fast information about drinking from the mouth) but then recovers (slow information about osmolarity from the blood). Figure adapted from Zimmerman et al

When a thirsty mouse drinks high-osmolarity saline, its SFO neuron activity initially drops (fast information about drinking from the mouth) but then recovers (slow information about osmolarity from the blood). Figure adapted from Zimmerman et al

References:

  1. Oka, Y., Ye, M. & Zuker, C. S. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature520, 349–352 (2015).
  2. Zimmerman, C. A. et al. Thirst neurons anticipate the homeostatic consequences of eating and drinking. Nature537, 680–684 (2016).