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New paper: "High neural activity accelerates the decline of cognitive plasticity with age in Caenorhabditis elegans". But what does it all mean? Gather round, my lovelies. Here comes a wee explainer thread. https://doi.org/10.7554/eLife.59711
First of all, acknowledgments. The massively talented Qiaochu Li ( @li_qiaochu ) is the first author. Qiaochu came to Edinburgh as a @zje_institute 3+1 MSc student. She stayed to complete her PhD with @EmanuelBusch who is the senior author. Also on the team, @TSpiresJones.
(I couldn't find Twitter handles for the other authors: Daniel-Cosmin Marcu, Ottavia Palazzo, Frances Turner, and Declan King, but please tag them in if you know them)
OK, so what is this paper about? You know how it gets more difficult to learn new things as we get older? What's up with that?
That's a brain question, and as you probably know, brains are quite complicated. We humans have bajillions of neurons [citation missing] and it's all rather ... unwieldy.
Often, what we do in biology when faced with a complicated system is we find another organism with a simpler version of that system system, so we can understand it more easily. We call those organisms "model organisms".
In this study, we use C. elegans, the best model organism [citation missing]
C. elegans is short for "Caenorhabditis elegans", which is fancy science speak for elegant ... erm ... Caenorhabditis. Not important. Among friends, we call them "C. elegans"
What is C. elegans? A teeny tiny worm. What does it look like? Go find a book. Open it on a random page. Find a comma. There you go, that's about the size of a C. elegans. Also, approximately the shape. Not the colour though: C. elegans are actually transparent!
Their transparency makes them useless for typesetting, but really very useful as a model organism, because we can look into their brains! And let me tell you about their brains.
You know how I said humans have bajillions of neurons? Actually, it's something like 100 billion, or 100 000 000 000. Do you know how many neurons C. elegans has?
Three hundred and two!
Three hundred and two!
But despite their adorable tiny little brains, C. elegans are actually quite clever. They have to survive in a complex environment, find food, move around, avoid predators, mate, etc. One important thing they need to be able to do is avoid oxygen.
A bit of oxygen of course is important and needed for survival. But high oxygen concentrations are not that great. Here is the thing: C. elegans would typically live in something like a rotting apple and eat the bacteria there. Quite a low-oxygen environment.
High oxygen would mean you are nearing the surface of the apple, and there, all kinds of dangers await. Predators. Sunshine. The Great Outdoors.
So what C. elegans does when it encounters high oxygen concentrations is, it runs away. Well, inasmuch as worms can run. It will just start moving faster.
It turns out their speed correlates nicely with ambient oxygen: You put them in a high oxygen environment, they speed up, you lower the oxygen a little, they slow down a little, you lower it a little more, they slow down a little more. It's a very robust and precise behaviour.
But now comes the cool part: How much they slow down at intermediate oxygen concentrations depends on what oxygen concentrations they were brought up in!
Imagine a worm brought up at nice low oxygen. If you put them in high oxygen, they will move very fast. If you then lower the oxygen concentration a little bit, they will feel better, but it's still much higher than they are used to. So they slow down a bit, but not much.
In contrast, a worm that has been brought up at high oxygen will move fast in a high oxygen environment. But if you lower the oxygen just a little, even if it's still high, it's better than anything the worm has seen before, so the worm will slow down a lot and just chill.
So, two worms will respond differently to the exact same environmental information, depending on what environment they have been exposed to in the past. And this is - tadaaa! - a form of memory.
What's more, worms can re-learn this type of memory, if you switch them to a different oxygen concentration for an extended amount of time.
So with their teeny tiny 302 neuron brains, worms can remember stuff, and learn new stuff and remember that! (Whereas I, with my bajillion neurons brain, keep forgetting to take the tea bag out of my teacup).
Now, that ability to re-learn the running-away-from-oxygen behaviour declines with age: Older worms find it a bit more difficult to re-learn this than younger worms. Or, as @EmanuelBusch says "It's difficult to teach an old worm new tricks".
Quick aside: by "old" we mean, like, a week. C. elegans are very "live fast, die young". Which, again, makes them an excellent model organism, because we don't have to wait around for them to age.
Here is the important bit though: the ability of old worms to learn new tricks depends on their past oxygen exposure. Worms that grew up in low oxygen are quite good at retaining their ability to learn. Worms that grew up in high oxygen are quite bad at it.
Let's have a closer look at the part of the brain that deals with the oxygen information. Out of the 302 neurons in C. elegans, there are four whose job it is to sense oxygen.
You can measure the activity of those neurons (by measuring the Calcium concentration inside them), and you can see that it tracks pretty much exactly with the speed at which they move in different oxygen environments. More oxygen - more activity, less oxygen - less activity.
So, for an animal that grew up in a high oxygen environment, those neurons would have been active basically all the time. And we think it is exactly that constant high activity that destroys their ability to learn when they get older.
But Mela, I hear you say, that can't be right. First of all, aren't we told we should do Sudokus to keep our brains active precisely to avoid cognitive decline with age? And also, maybe it's the oxygen itself that's harmful, not the fact that the neurons are active?
I will get to the Sudokus later. First, oxygen. You are right. I have already told you worms don't like high oxygen. And oxygen can cause damage to cells. Isn't that why people eat Kale and have anti-oxidant face creams in their fifty-two step evening skincare routines?
So, we did several things in the paper to address this. First, if you expose the worms to high oxygen but "silence" the oxygen-sensing neurons, you also lose the age-related cognitive decline. So, oxygen damage alone cannot explain what is going on.
Second, if we give worms an antioxidant to protect them from oxygen damage, chronic activity of the oxygen sensing neurons will still result in cognitive decline. Third, if we artificially chronically activate those neurons even at low oxygen concentrations, we see the same thing
Therefore, it is really the chronically high activity of the neurons, rather than oxygen damage, that impairs their ability to learn with age. So, neurons that are chronically activated lose their ability to learn new things.
(For neuronal signalling nerds out there, we also did some transcriptomics and knockdown studies to identify possible pathways that are involved. They have to do with how Calcium signals are processed, but further studies are needed to uncover the details.)
OK, so the take-home is: If a neuron is chronically active, it will lose its ability to adapt, and hence the individual loses the ability to learn whatever it is that neuron was responsible for.
But, you say, but Sudoku?!
Here is the thing: What we are talking about here is sustained high activity over a long time period. You spending half an hour on a Sudoku is probably not that. Indeed, it's not that easy to translate what this chronic high activity would look like on a human scale.
But while I am at it: there is also very little evidence that doing Sudokus actually prevents cognitive decline with age. The one thing that has been shown to actually be effective is, I hate to break it to you, exercise. So go out and move, my beautiful friends.
And lest I forget: Emanuel and I are looking for a PhD student through @PrecisionMedPhD If you think that C elegans is The Best, that this is a cool project and that it would be even cooler with some computational modelling - talk to us! https://www.ed.ac.uk/usher/precision-medicine/project-opportunities/21-22-projects/using-modelling-and-c-elegans-to-target-the-molecu
