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Brain Circuits that Control Drinking

Credit: KariDesign

Credit: KariDesign

By Philip Ryan

Cutting-edge genetic technology has revealed how the “love hormone” oxytocin protects us from drinking too much, and could lead to a better understanding of the brain circuitry underlying mental illnesses.

Neuroscience is in the midst of a major discovery phase. Scientists, in collaboration with neural engineers, have developed an extensive array of genetically-engineered tools that can probe the brain’s secrets in much finer detail than previously imagined. Examples include optogenetics, which can rapidly switch nerves on or off by shining a laser light; designer receptors that can turn nerves on or off for several hours by injecting a corresponding purpose-built drug; and calcium imaging, which can pinpoint actively firing nerves by illuminating them with bright, fluorescent colours. Scientists are using these techniques to construct a detailed map of the brain circuits underlying our most personal inner-workings: how we think, feel and behave.

I have been exploring one of our most fundamental behaviours – drinking. Using genetic techniques, I have located several nodes in the mouse brain that control water consumption, and traced out their connections to construct a brain circuit map. By mapping the circuits underlying basic functions like drinking, I am developing a framework for investigating more complex behaviours, such as those involved in mental disorders.

Oxytocin Is Involved in Drinking

The “love hormone” oxytocin can increase trust and bonding between people, promote uterine contractions during birth, and induce the milk let-down reflex during breastfeeding. It also plays a lesser-known role in controlling drinking, which is why I chose to investigate it.

I targeted a group of oxytocin-responsive nerves in a brain region called the parabrachial nucleus (PBN). This is located in the brainstem, an ancient part of the brain that controls some of our most basic survival functions like breathing. Using technology developed in NASA’s research labs, I implanted a miniature microscope over the PBN to observe individual nerves firing while a mouse was drinking.

What I observed was impressive: when the mouse was dehydrated, the PBN nerves were silent. When the mouse started drinking water, these nerves burst into action, with increasing numbers of nerves firing as the mouse progressively drank more and more.

However, when the mouse ingested a tasty, high-calorie liquid diet, these PBN nerves displayed minimal activity; and when the mouse attempted to drink from an empty bottle, the PBN nerves remained silent. This suggested I had discovered a group of neurons that specifically responded to water.

When I artificially switched on these nerves by injecting a purpose-built drug, mice stopped drinking even if they were dehydrated. Apparently, the mice sensed that they had had enough to drink, even though they had barely touched a drop! When I inactivated the nerves, mice increased their fluid intake.

Constructing a Brain Circuit Map for Thirst

These oxytocin-responsive PBN nerves served as a valuable entry point for mapping out the rest of the brain circuit controlling drinking. Using genetic tracers, I was able to identify discrete inputs and outputs from the forebrain and brainstem, enabling me to piece together key parts of the brain circuitry controlling drinking. I soon hope to target different parts of this brain circuit to treat patients with fluid balance problems, such as in heart failure, kidney failure and liver cirrhosis, where controlling the urge to drink water can be unbearable.

Calibrating the Amount of Water We Drink

One intriguing aspect of drinking is that the body can precisely calibrate the amount of water required to restore fluid balance – and well in advance of water reaching the bloodstream. Signals from the mouth, oesophagus and stomach swiftly inform the brain about the amount of fluid ingested, although the precise nerve signalling pathways remain obscure.

A key player in calibrating the amount of fluid consumed is a brain region called the subfornical organ (SFO). Calcium-imaging studies reveal that “thirst nerves” in the SFO increase their firing rate during dehydration, but these nerves rapidly decrease firing as soon as the mouse begins drinking. The firing dwindles until it reaches baseline levels, which is precisely the moment the mouse stops drinking. In other words, the nerves appear to pre-set their firing pattern to calibrate fluid intake.

Interestingly, cold liquids switch off these thirst neurons faster than warm liquids, which may be why cold liquids seem better at quenching thirst. By contrast, food consumption switches on these nerves, which may explain why we feel thirstier during a meal.

The Pleasure of Drinking

Drinking is not merely functional; it can be extremely pleasurable. The Swedish explorer Sven Hedin (1865–1952) provides an evocative description of being intensely thirsty during a harsh journey through the arid Taklamakan desert in western China:

I stood on the brink of a little pool of water – beautiful water! ... I took the tin box out of my pocket and filled it, and drank. How sweet that water tasted! Nobody can conceive it who has not been within an ace of dying of thirst. I lifted the tin to my lips, calmly, slowly, deliberately, and drank, drank, drank, time after time. How delicious! What exquisite pleasure!

This pleasurable sensation gradually diminishes as we drink more water until our thirst is quenched and we feel pleasantly satiated. This probably involves oxytocin signalling. On the other hand, if we are forced to drink to excess it can feel unbearable. It appears our body deploys pleasure and aversion to regulate the amount of water we consume, helping us maintain our fluid balance – a prime example of the “wisdom of the body”.

Broader Implications

Many laboratories are using genetic tools to research other basic survival instincts, like hunger, satiety, salt appetite and sexual behaviours. These instincts lie at the heart of many of our deepest desires and fears, and genetic tools are providing a window to peer into these subconscious processes. Scientists are developing a neuroscientific appreciation of our most primordial emotions – like hunger, thirst and satiety – and building a picture of their corresponding brain circuits. Research is revealing tantalising links between neuroscience and psychology, which may soon illuminate what goes awry in mental disorders such as addiction and anxiety.

Neuroscience has already unveiled remarkable similarities between basic instincts and complex human psychology. Prof Andrew Lawrence’s team at the Florey Institute in Melbourne have shown that salt appetite, which is critical for survival, engages similar brain circuits to drugs like cocaine. Dr Robyn Brown at the Florey has observed that sugar and fats ramp up synaptic plasticity, strengthening nerve connections just like drug addiction. These and other findings suggest that drugs of abuse hijack key desire circuits in the brain, and explain why junk food can be so difficult to stop eating.

Future Research DIrections

By studying the brain circuits underlying basic behaviours like drinking water or eating salty foods, we are not only understanding more about our internal fluid and salt balance, but also gaining insights into the neural circuitry of complex behaviours. Our growing toolbox of genetic techniques is allowing a more detailed analysis of brain circuits, revealing a brain that is bewilderingly complex but also highly organised.

We hope our research will produce more elegant and targeted therapies for mental illnesses and other conditions. Until then, we are rapidly unlocking more intricate marvels in the brain. It is an extraordinary time to be studying neuroscience, and many more discoveries await!


Dr Philip Ryan is an NHMRC CJ Martin Research Fellow at the Florey Institute of Neuroscience and Mental Health. He completed this work during his postdoctoral studies at The University of Washington, Seattle. This research has been published in Nature Neuroscience (https://tinyurl.com/y8jb7vz9).