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Why So Thirsty?

Suppose you are marooned in the great Sahara Desert with no water and are very thirsty. Being inspired by Newton’s apple story, instead of worrying about water, you wonder why you are thirsty—you wonder what kind of neurons in your brain are responsible for thirst. But how do you figure out exactly what neurons in your brain deal with thirst when a human brain contains billions of neurons? While I cannot say whether Allen and colleagues (Science, September 2017) came up with this question after suffering from severe water deprivation, their recent research does address this question. Their research also highlights how cutting-edge tools, available in molecular biology, genetics, and electrophysiology, can help scientists to address questions like this.
The researchers did not have to start from scratch—from previous research, they knew the approximate area of the brain that dealt with thirst. This area, called the median preoptic nucleus (MnPO), an area in the hypothalamus, has been shown to integrate and relay thirst information to other brain regions. However, the MnPO harbors different groups of neurons and regulate, beside thirst, other functions such as body temperature, sleep, cardiovascular function, and sodium balance. So, if the MnPO is indeed responsible for thirst, how do you identify which group of neurons in MnPO specifically invokes thirst response?
To address this issue, the researcher took advantage of a genetically modified mouse line: in these mice, the neurons in the MnPO can be labeled when they become active. The researchers deprived one group of animals of water and looked for labeled cells. Compared to the control group, which was not water deprived, much more neurons in the MnPO were labeled in the water-deprived mice. Interestingly, although the MnPO is also known to regulate responses to heat, subjecting the mice to heat activated a different group of neurons in the MnPO compared to the thirst experiment. Thus, these experiments demonstrated that a specific cell population in the MnPO activates in a water-deprived animal. Moreover, these cells, unlike other groups of neurons in the MnPO, make receptors of a protein that has long been implicated in regulating water balance. Therefore, it is possible that these receptors enable MnPO neurons to detect water levels in an animal.
Now comes the critical part: if these neurons are indeed responsible for driving water consumption in thirsty animals, then we can predict that 1) activation of these neurons would cause water-satiated animals to continue seeking water, and 2) inactivation of these neurons would reduce water consumption even in thirsty animals. To answer this question, the researchers used a technique that enabled them to either activate or inhibit these neurons with light (this technique is called optogenetics). They found that, as we predicted, when they artificially silenced these MnPO neurons with light, the water-deprived mice did not seek water. Conversely, when they activated these neurons in water satiated mice, the mice drank more water. In other words, the results match our predictions very well.
Traditionally, scientists relied on patients with brain injuries or ablation studies in mice, to figure out if the injured or ablated brain region is responsible for performing a particular task. The idea is that if the subject fails at a task because of the injury or ablation, then that area must be responsible for that task. While we learned greatly from those studies, they were not very precise. For example, if you take out an area where there are different groups of neurons, how can you tell what group does what? This research by Allen and colleagues not only demonstrates how far we have come from those days of ablation studies but also showcases the powerful biotechnology tools contemporary neurobiologists have at their disposal. Furthermore, thanks to them, now we know which group of neurons in the MnPO is responsible for thirst, so if we ever find ourselves without water in the Sahara, we can fully concentrate on finding water.

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