AudioHelicase Special: Getting a handle on hibernation

Whitehead Institute Member Siniša Hrvatin discusses his research on the neuroscience of hibernation. This story is part of our series on neurobiology research at Whitehead Institute. Click here to see all stories in this collection.

Whitehead Institute · AudioHelicase Special: Getting a handle on hibernation

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Transcript:

Margaux Phares: In the hush of wintertime, the world slows down. Underneath a blanket of snow, some animals curl up for the season. A process as intricate but different than sleep is happening. Their body temperature sinks lower. Their heart rate and breathing slow down. And somehow, in spite of extreme weather conditions or lack of food, they emerge from it when the time is right. While we don’t hibernate, understanding how this state of dormancy works could teach us how to slow things down in a different way.

Phares: Hi, and welcome to Audio Helicase, the podcast of the Whitehead Institute. Here we unwind the science and the people behind some of the Institute’s most exciting discoveries. I’m your host Margaux Phares, Science Communications Officer at the Whitehead. Today we are peering into the neuroscience of hibernation.

Siniša Hrvatin: I mean, I think the biology is really fascinating, which is why I love studying it. But I think there's also really intriguing possible applications.

Phares: That’s Siniša Hrvatin, Member of Whitehead Institute and assistant professor of biology at MIT. He researches hibernation through the intersections of neuroscience, metabolism, and genetics. Hrvatin’s story with this field began in grad school at Harvard University, with an unrelated project.

Phares: His PhD research took place in the lab of Doug Melton, where he studied specialized cells that control blood glucose, or sugar, in mice. In this experiment, some mice were fasted – or not given food – overnight, in order to see what changes when they have low blood glucose. And then, in the following mornings, Hrvatin saw something strange.

Hrvatin: Some animals were, you know, behaving fairly normally. But then other animals seem oddly lethargic and slow moving. And it looked as if they were sleeping, but it was more profound than sleeping. So that's when I first realized this, this is very unusual, I didn't quite appreciate that animals, that mice, do that. And I went on to look into the literature. And it turned out that this has been previously described, and it's called torpor.

Phares: Torpor is a hibernation-like state that helps an animal survive harsh conditions in their environment, like cold weather or lack of food. Two big things happen during both torpor and hibernation: Metabolism slows down, and body temperature drops below normal.

Phares: Metabolism is the orchestra of processes in the body that produce energy living things need. When mice eat, they convert food into fuel, like glucose. Animals typically use a combination of sugars and fats as a fuel source. During torpor, mice usually use fat reserves to survive.

Phares: As for body temperature, it normally stays around 37 degrees Celsius – or 98.6 degrees Fahrenheit – for pretty much all mammals and birds. During torpor, it can drop to as low as 15 degrees Celsius – which is just under 60 degrees Fahrenheit. For reference, humans go into hypothermia below 35 degrees Celsius, or 95 degrees Fahrenheit. For animals that can go into torpor, though, this is normal.

Phares: Not all animals hibernate. But some – such as lab mice – can enter this hibernation-like state of torpor. For mice, torpor does not need to happen during wintertime. In fact, they can briefly enter it any time they can’t find food.

Hrvatin: And yeah they'll chill in the corner like this for a period of time, really trying to conserve energy, actually. So it's an evolutionary mechanism. We believe that when you're fasting an animal it is trying to do its best to survive that period of time. And sometimes the right strategy is going around and searching for food. And other times is, let me just wait and see if I can conserve as much energy as possible.

Phares: These findings were already known in scientific literature decades prior – along with the fact that the brain is responsible for regulating metabolism and body temperature. But, for Hrvatin, observing this in the lab mice was enough to dedicate his career towards the subject.

Hrvatin: In the back of my mind, I’ve been for a while fascinated by space travel, thoughts about hibernation, suspended animation, all these things, but in a very, more childlike, I would say, way. Not really seriously thinking about how one would go about studying these. But I think when I began to appreciate that we have laboratory animal models that could be used to study some of these torpor-like, hibernation-like states, it really made me realize, well, that that is something that we can discover. We could discover how this state is controlled, how animals can enter and how the tissue survives in those states. And maybe then we can apply some of those things to human cells eventually.

Phares: As a postdoc at Harvard Medical School, Hrvatin turned his focus toward the brain. Was a certain part of it responsible for initiating torpor in mice? First, he looked at the brains of mice in different stages of torpor – specifically, which regions were active during those stages.

Hrvatin: And we weren't actually sure if we're going to find a lot of active regions when you're in this cold, you know, state of torpor. But it turns out, there's plenty of regions of the brain that were newly activated as the animals were entering these states.

Phares: Then, the next question his lab asked was: If they genetically labeled neurons that were active during torpor, and they switched on just the right ones, would that make mice go into torpor? Turns out, yes.

Hrvatin: And we saw that within minutes of activating the neurons, the body temperature began to drop. And it dropped all the way down to pretty much the levels that we saw in natural torpor. And we also saw that the metabolism was dropping, and the respiration rate and so on.

Phares: This happened even in mice that were already fed, or if they had already gone through torpor.

Hrvatin: We were really surprised actually, that this worked, because it was a little bit of a shot in the dark to be honest, at the beginning.

Phares: The lab narrowed down the brain regions even further. And then, they broke one region down into individual neurons – tens of thousands of them – and found which ones were active during torpor. And then, there it was: a population of neurons peppering the preoptic area. It is not uncommon to find a lot of different functions packed into the same space of the brain, and the preoptic area is no exception. This part of the brain has neurons involved with a number of things – like sleep, thirst, aggression, temperature regulation, metabolism, and now torpor.

Hrvatin: So there are kind of layers and layers of building this, starting from the whole brain, to a region, to a subset of neurons in the region that finally got us to this population of neurons.

Phares: This experiment demonstrated that these neurons in the preoptic area – more specifically, the avMLPA – are necessary to produce aspects of natural torpor. It was a promising start to breaking down such a complex behavior. In January 2022, Hrvatin joined Whitehead as a Member, where he continues to investigate torpor. His lab is split broadly into two areas: the organismal, and the cellular. In the former, he will be following up on questions about how an animal can enter torpor. Questions like:

Hrvatin: What are these neurons sensing in order to initiate the state? How do they know that it's time to enter torpor? Also, how do they actually induce a body-wide change that results in torpor? How do they change the metabolism? How do they lower the body temperature? How do they do these things? Is this through a series of neurons that are connected to them that are sent out to all the different organs in the body that are coordinating these responses? So we're really trying to understand a bit more of the bigger picture of how the brain is controlling the body.

Phares: His group is also venturing in hibernation. They have set up a colony of hibernating hamsters to answer these questions as well. For an animal to enter hibernation, it takes about two to three months of exposure to fall-like or winter-like weather – conditions the lab can simulate. During hibernation, their body temperature – as well as other hibernators – drops to four or five degrees Celsius, which is about how cold it is inside of your fridge. Hibernators stay in this state for a few days. Then, they come out for a day or half a day. Then they go back. And out. And back again. They cycle in these deep torpor states for the entire season.

Hrvatin: Why do they keep on coming out every few days? It's like, it's one of the big mysteries in hibernation, because the energy is generally, the animal’s generally trying to conserve energy. But it spends like 80, or 90% of its energy just coming out every so often. So it must be important for it. But we don't actually understand why that is the case. And then how does it know when to end the whole hibernation season? So, we're trying to think about it from the standpoint of the brain and neurons that control these circuits.

Phares: The other part of Hrvatin’s lab focuses on the cellular level. In hibernation and torpor, the brain coordinates these states of low temperature and metabolism, and many cells in the body go along with it.

Hrvatin: And that's not that trivial, because if you, for instance, take human cells, and you put them in the fridge, they'll generally die within a few days. But you know, if you did the same experiment with cells from hibernators, it's remarkable how much better they are that you can stick the hibernator cells in the fridge and a week, sometimes even longer, two weeks out, they're pretty much fine. So that tells me that there is something in the individual cells that doesn't require the whole body, something in the cells, we call that cell autonomous. So the cell on its own is capable of surviving the cold. And we're trying to figure out what's behind that.

Phares: Getting human cells to survive low temperatures alone may not teach us how to hibernate, but it could nonetheless offer some interesting applications. It’s been long known that cells in a state of low metabolism are more resistant to stressors, such as low oxygen – which can happen during things like heart attacks and strokes.

Hrvatin: So is there a way to induce a cellular kind of hypometabolic state to preserve cells during stroke? That's a question that I think might come out of, out of this research as well.

Phares: Until then, preliminary findings in Hrvatin’s research suggest that similar brain circuits are involved in initiating torpor and hibernation in mice and hamsters.

Hrvatin: And that, that'll be pretty interesting, because then you might begin to ask questions about how have these evolved differently? Or how are they wired? That, you know, one of them requires just a few hours of fasting, and the other one requires months of preparation to enter this state. And of course, they lower temperature to different levels, and so on. But yeah, I'm excited about getting a handle on hibernation.

Hrvatin: I think it's actually a fantastic field for a young scientist to be involved in because it's still so under explored. And, and we understand so little about it that I wouldn't be surprised if we find something pretty surprising and fun and novel. I have high hopes.

Phares: I’m Margaux Phares, and this has been a conversation with Siniša Hrvatin about the neuroscience of hibernation for AudioHelicase. To learn more about the science and people at Whitehead, please subscribe to AudioHelicase and check out wi.mit.edu. Thanks for listening.

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Interview, production, and hosting by Margaux Phares.

Music:

Underwater Exploration by Godmode (CC BY 3.0)