Naked Mole-Rats in "space"

Mole Rats in Space (aka Space Escape) is a fun cooperative boardgame developed by Peacable Kingdom a series of games designed to encourage cooperative play. Players must cooperate to help naked mole-rats avoid the snakes that invade their space station. Hey, it could happen. We enjoy playing it my house.

The concept of the game has inspired me to summarize the main concepts of our article published today in the journal Current Biology.

Let’s suppose you and your extended family of 50 members were selected to spend a year on the international space station. When you get to the space station, you find around 20 empty rooms, all equally spacious and comfortable, waiting for you. How would your family settle in? If you are an African naked mole-rat, you’d find a nice comfortable room somewhere in the middle of the space station, lie on the floor, and invite your 50 relatives to pile on top of you.

African naked mole-rats can take stuffy environments. Previous work has shown that they can survive in a room without any oxygen for nearly 20 minutes, far longer than any other land-dwelling mammal. They use a number of different tools they have developed in their 35 million years living underground in East Africa. These tools allow their bodies to use alternative strategies for energy when oxygen is unavailable, behaving like plants in some ways. They also have built up a tolerance to stuffiness. Under a pile of 50 of your relatives, you’d experience low oxygen and high carbon dioxide due to the exhaled breath of your kin. Naked mole-rats can take high carbon dioxide, they don’t show the same panic response that most other mammals do when it gets high.

OK, so naked mole-rats can tolerate tough environments, but why do they do create tough environments when they don’t need to? Why not spread out and use all of the rooms? We asked this question in a recent study where we examined how the brain functions in naked mole-rats when they are exposed to the stuffy air conditions we found in their nest, normal room air, or the air that a naked mole-rat would likely encounter if it ventures out of its burrow and goes aboveground on a typical day in East Africa.

We found that when we take the naked mole-rat out of the stuffy environment, and exposed them to the surface environment (normal air heated to 42 degrees Celsius) they began to show a panic response, started breathing faster, and eventually had an epileptic seizure, indicating that the brain was overwhelmed in this environment. Adding the stuffiness back into the heated air prevented this effect.

Normal air at room temperature did not trigger seizures, but naked mole-rats did demonstrate something very peculiar in this environment: diazepam (think valium, a drug known for strong sedative properties) triggered the same seizures. When animals received the same dose of diazepam in the nest environment, they went to sleep.

Here’s where it gets interesting, we partnered with Kai Kaila and Martin Puskarjov at the University of Helsinki and we think we’ve found the exact mechanism that drives this effect.

Looking at the genome of the naked mole-rat, we find a rare change to a particular transporter that helps neurons maintain inhibition. This transporter, known as KCC2, is important in brain development. Human infants have weak brain inhibition like naked mole-rats, but this resolves during early childhood, around the time when KCC2 function increases. Naked mole-rats are the only species in all studied mammals to have a histidine instead of an arginine in a particular position (site 952) on the KCC2 gene (called the R952H variant), but it is seen in humans too. Two out of every 1000 humans have the R952H variant. The rate is higher in people with febrile seizures, [idiopathic epilepsy](https://doi.org/ 10.15252/embr.201438840), autism, and schizophrenia.

These experiments also give some indication for why naked mole-rats might choose to pile on in the space station: they have a very weak ability to keep the brain inhibited (or calm). Carbon dioxide has been known for centuries to suppress brain activity, and so we think the naked mole-rat might not just tolerate the stuffy environment of the colony nest, but depend on it for balanced brain function. This may explain why naked mole rats are one of only two of the over 5000 mammalian species that stay in the colony nest their whole long lives (over 30 years!). Most naked mole-rats never go off and start their own family; they are eusocial like insect societies which have a queen and many workers.

The variant may also be telling us something important about what is needed for a mammal to become eusocial. A dependence upon the nest environment may drive an animal to return to the colony nest rather than go and start its own family. If this is true, and it is partially driven by the KCC2 mutation, we’d expect to see that the only other eusocial mammal, the Damaraland mole-rat, has a mutation in the same part of the gene. This is exactly what we see. A look at the Damaraland mole-rat genome shows a cysteine instead of an arginine at this location (R952C). While it is not terribly surprising that two close relatives have similar genes, it is striking that the only two mammals that do not have an arginine in site 952 of the KCC2 are the only eusocial mammals on Earth.

Based on this, we wonder whether mammalian eusociality has evolved in these two African mole-rat species because they become more anxious when they leave the nest and venture near the surface air. Thus, rather than run off and start their own families, they return to the nest and help raise their siblings. Perhaps humans with variations in KCC2 functioning are more comfortable in the stuffy room on the space station.