The thirst is governed by two independent pathways in the body and brain to help keep properly rehydrate


After you have exercised on a hot day, a cool glass of water will quench your thirst immediately – even before your body has had a chance to absorb the water.

Yuki Oka, assistant professor of biology and Chen Scholar at Caltech, was curious about why that is, and how the brain processes satiation and pleasure signals related to drinking.

In a new paper, Oka shows that thirst satiation is governed by two independent pathways in the mammalian body and brain.

These pathways work together to help keep animals properly rehydrated.

Here is how it works:

When you are thirsty and you start drinking a glass of water (or any other liquid), the first parts of your body to interact with that liquid are your mouth and throat.

These two areas, known collectively as the oropharyngeal region, are lined with nerves that pass along a drinking signal to neurons in a brain structure called the subfornical organ (SFO).

The Oka lab has previously shown that the activation of neurons in the SFO generates the sensation of being thirsty.

When the SFO receives a drinking signal, it turns off these thirst neurons.

But the process is not finished yet.

The SFO is waiting for a second signal to confirm what it has been told by the throat.

In this new study, the team has discovered that the second signal comes from your gut sensing the osmolality, or concentration of water, in the liquid you have ingested.

Unlike the signals from your throat, which reveal that you gulped some kind of liquid, the gut-derived signals can show whether the liquid you drank contains water, and, if so, if there is enough water to rehydrate you.

If there is enough water, the SFO keeps its thirst neurons deactivated until your body senses that you again have become dehydrated.

However, if the SFO does not get the hydration signal from your gut – maybe because you have been drinking soda instead of water – it turns the thirst neurons back on, and you end up thirsty again.

Vineet Augustine, the first author on the paper and a graduate student in the Oka lab, says this two-fold satiation system is important for driving animals to drink while ensuring they do not drink the wrong thing.

“The gulping signal is important to prevent the ingestion of too much of any liquid that will not hydrate you,” he says.

“If you drank salty water, for example, this gulping signal is like a brake that stops you from continuing to drink until the second signal can make sure that what you drank was water.”

Oka says that the existence of these two pathways that stop drinking before body rehydration has been hypothesized for more than 30 years, but his team was the first to identify neurons in the brain that monitor the liquid-gulping and gut osmolality signals.

The researchers separated the two satiation signals by delivering liquid to the mouth and gut independently using a technique called intragastric infusion, explains Haruka Ebisu, a co-first author of this paper and a postdoc in the Oka lab.

The technique allowed the team to determine if satiation (thirst quenching) directly causes the sensation of pleasure when drinking.

Indeed, when mice drank water they found that there was a robust release of the neurotransmitter dopamine, an indicator of reward-related neural activity. In other words, drinking water is pleasurable to thirsty animals, as expected.

However, this dopamine release was not observed when water was supplied directly to the gut, despite the gut sending thirst satiation signals to the brain.

Oka says that understanding the refreshing feeling that comes from drinking could help researchers understand more problematic pleasure pathways, like those that cause eating disorders in some people.

“As is the case with drinking, we eat because it is pleasurable,” he says.

“Sometimes, even if you are not hungry, you eat because of the pleasure you feel. So, if we can separate these pathways completely, then we can maybe manipulate them individually.

For example, if we could satiate appetite without stimulating the pleasure pathway, we could regulate overeating. We could possibly also reduce anorexia, which may occur because a person gets too little pleasure from eating.”

The paper describing their findings, titled “Temporally and spatially distinct thirst satiation signals,” was published online by Neuron on May 29 and will appear in the July 17 print issue.

Why do we feel thirsty?

Early theories posited that thirst is the local sensation of dryness in the mouth and throat1,2, but we now know that thirst is a homeostatic response to changes in the blood: increases in plasma osmolality36 or decreases in plasma volume7,8 or pressure9 trigger the sensation of thirst, which motivates animals to find and consume water and thereby restore these parameters to their physiological set-points.

The key brain structure for the genesis of thirst is the lamina terminalis (LT), a group of three deep forebrain nuclei that coordinate the homeostatic response to fluid imbalance (described in more detail below).

While the importance of the LT for the control of drinking has been appreciated for decades (reviewed by refs. 1012), our understanding of the underlying circuit mechanisms remains limited.

For example, we still do not know the identity of most of the cell types that reside in the LT; the dynamics of those cells during behavior; or the anatomical pathways by which they transmit information to other brain regions.

This knowledge gap reflects, in part, the complexity of the LT, which contains a diversity of intermingled neural cell types distributed across three small nuclei. While these features have traditionally made the thirst circuit challenging to dissect, the recent application of genetically targeted techniques has led to renewed progress.

The lamina terminalis

Our modern understanding of the neural control of thirst originated with the discovery by Bengt Andersson in the 1950s that infusion of hypertonic saline into the anterior hypothalamus of goats stimulates intense drinking and water retention (antidiuresis)2224.

James Fitzsimons later discovered that infusion of the hormone angiotensin II (AngII) into the same area of rats also produces thirst25,26.

Together, these experiments identified a small forebrain region (the LT) that monitors homeostatic signals of fluid balance (plasma osmolality and AngII) and translates these signals into appropriate counter-regulatory responses.

The LT is composed of three small, interconnected structures that lie adjacent (anterior and/or dorsal) to the third ventricle.

Two of these structures – the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT) – are circumventricular organs, meaning that they lie outside the blood-brain barrier and therefore have direct access to the circulation27.

Information about fluid balance enters the LT primarily through specialized interoceptive neurons in the SFO and OVLT.

Some of these interoceptive SFO/OVLT neurons are intrinsically osmosensitive, meaning that their firing rate increases in response to increases in the tonicity of the extracellular fluid2831, and many of these osmosensitive SFO/OVLT neurons are also activated by the hormone AngII3235.

Additionally, some SFO/OVLT neurons may receive ascending neural signals from peripheral blood pressure sensors (baroreceptors)36,37.

Thus, SFO/OVLT neurons are poised to integrate signals about plasma osmolality, volume, and pressure and then use this information to control thirst.

The third component of the LT is the median preoptic nucleus (MnPO), which cannot access the blood directly and is thought to be an integratory center38.

Together, these three structures form a forebrain hub for the regulation of fluid balance.

Signals detected in the SFO and OVLT are shared with each other and the MnPO through an extensive network of bidirectional projections3943.

Activation of this network then triggers a coordinated set of homeostatic responses that restores fluid balance.

These responses include: behavioral mechanisms that motivate water and sodium consumption (i.e., thirst and salt appetite)4447; autonomic mechanisms that modulate sympathetic outflow and thereby alter blood pressure and heart rate48,49; and neuroendocrine mechanisms that modulate water and sodium retention by the kidneys50,51.

These neuroendocrine responses are mediated primarily by the hormones vasopressin (AVP) and oxytocin (OXT), which are released from specialized posterior pituitary-projecting neurosecretory cells in the paraventricular hypothalamus (PVH) and supraoptic nucleus (SON) that are under direct control of ascending input from the LT (reviewed by refs. 52,53).

More information: Vineet Augustine et al. Temporally and Spatially Distinct Thirst Satiation Signals, Neuron (2019). DOI: 10.1016/j.neuron.2019.04.039

Journal information: Neuron
Provided by California Institute of Technology


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