Researchers created knock-in mice carrying the yak version of the RETSAT gene in place of the mouse version, then compared them to normal wild-type mice under low-oxygen conditions mimicking high altitude. Using a Morris water maze learning task, wild-type mice failed to improve over repeated trials under hypoxia, while RETSAT knock-in mice learned rapidly, showing their brains kept functioning normally. Brain slice analysis confirmed this at the tissue level: wild-type mice lost myelin under hypoxia, similar to what happens in multiple sclerosis or in humans who spend too long at extreme altitude, while the RETSAT knock-in mice maintained normal myelin levels.
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The Morris water maze works by having mice swim to find a submerged platform using visual cues on the surrounding walls, with faster times on later trials indicating spatial learning.
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The hypoxia chamber was set to mimic oxygen levels found at roughly 5,000 meters, comparable to the Tibetan Plateau.
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The hosts frame this as the foundational experiment a researcher would run first to establish whether RETSAT has any real role in brain health before pursuing deeper mechanistic work.
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58:56do they actually prove that, right? They actually prove that by engineering a genetic knockin mouse model. Okay. >> So, you can take these mouse models that are in the lab and you can take the redstat yak version >> and replace the redstat mouse version with the redstat yak version. So now these genetic mouse models have the redstat yak version. You got a control and you've got the the yak version. >> We're basically just changing the genetic ingredients and seeing what comes out at the end. >> Yeah. Yeah. And we're trying to see, okay, does this thing play a role in protecting brain health? This is like the first thing that you do if you're a grad student that's assigned to this project. Is there a there there can then
59:36turn into this massive neuron paper? Turns out yes. The way they did it was really quite simple. They had the wild type which is the control and they had the red statin mice and they exposed these knock-in mice and the control mice to hypoxia. They put it in a chamber where it mimicked the amount of oxygen that's there at 5,000 m or whatever the Tibetan plateau is. You subject it to something called a Morris water maze which is the imagine you've got like a circular sort of water tank and you've got a single spot of a platform just under the water so the mouse can't
1:00:16actually see where the where the platform is. But if it gets to the platform it gets like cheese or something. It's got to swim around and it's only seeing the cues of the walls. Like there's like patterns on the walls that tell it where it is in the water maze. Now, pretty soon if you're a smart mouse and everything is working, you're going to do a random walk, random swimming to figure out where the platform is. And then once you're on the platform, you're going to notice um given the cues on the outside where I am. And then the subsequent trials, I'm going to be way faster, right? What they noticed was that the wild type under hypoxia did not learn. But and and that
1:00:57that's why you see um the wild type as the days go by the amount of time that it takes to get to the platform stays the constant. >> But the the ones with the red stat >> Yeah. >> very rapid learning. >> Yeah. >> Right. So the brain is functioning normally for the ones with red stat. What this shows is one, the rat statin thing is working and two, the rat stat is crucial for brain functioning in low oxygen environments. So, we've done our job in creating a biological model that I can now use in the lab to manipulate and understand what exactly is going on here. >> Yeah. >> Right. >> That's that's the that's the main idea. >> We were able to replicate what happens in nature in a lab, which means we can then make it repeatable.
1:01:38>> Yeah. Exactly. >> For our own purposes. >> Yeah. Now the second hypothesis is that the ret I mean this was all a behavioral assay. What about the myelin? Is it actually doing the thing that the myelin is doing? And yes you can go in and look at the the the brain slices and see if you stay in the myelin >> the wild type has in normal oxygen environments the wild type has certain amount of myelin. Yes. >> And if you look in the hypoxy environment the wild type does not have that myelin. So clearly the myelin is getting degraded >> which is what happens in MS. >> Which is what happens in MS. And what happens in normal individuals when they go to Tibet and hang out for way too long, like if you go to Mount Everest, that's why you need oxygen is because this is happening, right? But for the
1:02:19ones with red stat, you've got normal amounts of myelin. So the second hypothesis is also making sense that the red stat has something to do with the maintenance of myelin in low oxygen environments. Is that clear? >> Very much so. >> Okay. So now we're going to move on and understand how is RESTAT doing that. Okay. So we know that the red stat has something to do with myelin maintenance
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