From Our Neurons to Yours

What the other half of the brain does | Brad Zuchero

• Wu Tsai Neurosciences Institute at Stanford University, Nicholas Weiler, Brad Zuchero • Season 7 • Episode 3

Share episode

We've talked about glia and sleep. We've talked about glia and neuroinflammation. We've talked about glia in the brain fog that can accompany COVID or chemotherapy. We've talked about the brain's quiet majority of non–neuronal cells in so many different contexts that it felt like it was high time for us to take a step back and look at the bigger picture. After all, glia science was founded here at Stanford in the lab of the late, great Ben Barres.

No one is better suited to take us through this history and lead us to the frontiers of the field than today's guest, Brad Zuchero. 

A former Barres lab postdoc, and now an emerging leader in this field in his own right, Brad gives us an overview of our growing understanding of the various different kinds of glia and their roles in brain function, and shares the  exciting  discoveries emerging from his lab — including growing evidence of a role for myelin in Alzheimers disease.

Learn More

Get in touch

We want to hear from your neurons! Email us at at neuronspodcast@stanford.edu if you'd be willing to help out with some listener research, and we'll be in touch with some follow-up questions.

Episode Credits

This episode was produced by Michael Osborne at 14th Street Studios, with production assistance by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Initiative for Brain Resilience at Wu Tsai Neuro.

Send us a text!

Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience.

Learn more about the Wu Tsai Neurosciences Institute at Stanford and follow us on Twitter, Facebook, and LinkedIn.

Nicholas Weiler (00:11):

Welcome to From Our Neurons to Yours from the Wu Tsai Neurosciences Institute at Stanford University, bringing you as always to the frontiers of neuroscience.

(00:27):

To introduce today's episode, I want to tell you a story about someone who's no longer with us. Ben Barres was a medical resident in the 1980s, and he was looking at a number of different neurological diseases from epilepsy to Parkinson's disease, sort of everywhere he looked. He was noticing that the brain's non-neuronal cells, the glial cells, seemed to be implicated in many of these disorders. But when he looked around at the research, he realized no one was really paying attention to these cells. The field had been so focused on the neurons, their electrical excitability, the networks they form, their synaptic plasticity, all of these exciting things that have built the field of neuroscience, but no one had really looked at the glia.

(01:21):

They were just thought to play a supporting role. Their name comes from a Greek word that means glue, and that's kind of how they were thought. They were infrastructure and they were kind of boring. But Ben had an intuition that that wasn't the whole story, and that intuition was so strong that he actually backed out of his residency and went into a PhD program to develop the techniques that were needed to actually study these cells and their roles in neurological disease and brain function. He came to Stanford in the early nineties and set up his lab and with discovery after discovery, he used these new techniques to demonstrate just how important glial cells are to how our brains work.

(02:06):

Sadly, Ben passed away from cancer in 2017, but glia science continues to be a major frontier in neuroscience, and many of the leaders in that field come from Ben's lab here at Stanford, or were trained by people who come from his lab. And the insights that are coming out of this field have come up again and again on this show. We've talked about glia and sleep, and we've talked about glia in neuroinflammation. We've talked about it in brain fog that happens after COVID or after chemotherapy. We've talked about it in so many different places that it felt like it was high time for us to take a step back and look at the big picture of what we now understand about the roles of glia in brain function and brain disease.

(02:49):

No one is better suited to take us through this history and lead us to the frontiers of this field than Brad Zuchero. Stanford has an incredibly strong glia science community thanks to Ben, and Brad is one of the emerging leaders in this field. He's a cell biologist by training, and he studies in particular the oligodendrocytes, the cells that make the myelin insulation we've talked about a number of times on the show. Brad's going to give us an overview of our growing understanding of the various different kinds of glia and their roles in brain function, and then share some really exciting new discoveries that are coming out of his lab. As Brad and I started talking, it was clear that Ben's spirit, for want of a better word, his mentorship really lives on in this field and for Brad in particular. In fact, Brad told me that he still gets inspiration from Ben to this day.

Brad Zuchero (03:40):

But I have a whole email inbox full of what I call Ben's gems. This is my email folder where I saved all these emails because he would write these pages long emails when he had an idea on a bike ride and send it, and nobody had enough time to follow up all of his ideas. But this is something that I keep as a resource and I continually go back and look at because there are ideas that he thought of 15 years ago. Some of them may still be yet to emerge as really important, but it's cool to have.

Nicholas Weiler (04:07):

That's a treasure trove.

Brad Zuchero (04:08):

We need to make an AI version where we can-

Nicholas Weiler (04:12):

AI path-

Brad Zuchero (04:12):

... compile all this together like the Oracle.

Nicholas Weiler (04:16):

Wow. So I'd love to get sort of a whirlwind overview of how our understanding of these glial cells and their importance has changed since Ben got started in his lab at Stanford in '92. My understanding is there are three main types of glial cells in the brain. There are your astrocytes, your microglia, and your oligodendrocytes, which are the thing that you have focused on most in your lab. I know that there was a period where people were saying that 90% of the cells in the brain were glia, but I think more recently we've revised that and said, well, more than half of the cells in the brain are glia. Is that more accurate? Can we say it's something like a little bit more than half?

Brad Zuchero (04:57):

I think it's safe to say it's more than half. You don't make as many enemies saying that.

Nicholas Weiler (05:03):

It's controversial.

Brad Zuchero (05:06):

I mean, it is, and it depends on where you look in the brain. It can vary from brain region to brain region. It depends on how you count. Do you do it by taking microscopy images and counting markers of cells, or do you do it with transcriptomics? All of these different techniques have slight biases. So, I think it's safe to say it's more than half. Depending on where you look, it could be much more than that. Honestly, I don't think it matters. I think what matters is that these cells, they're not just there and prevalent. They actually have really important dynamic, active roles in the nervous system. That's the key part.

Nicholas Weiler (05:38):

Excellent. Well, let's get into that. So let's start with the astrocytes. First, could you describe an astrocyte to me and then tell me a few of the key things we now understand that astrocytes are responsible for in the brain?

Brad Zuchero (05:50):

Sure. So astrocytes are found all throughout our central nervous system through our brain, spinal cord. They tile the entire nervous system. So just like tiles on the floor of the kitchen or the bathroom, they basically occupy space everywhere throughout the entire brain.

Nicholas Weiler (06:07):

Sort of scaffolding in a way.

Brad Zuchero (06:08):

Well, I mean, scaffolding sounds kind of boring, but yeah.

Nicholas Weiler (06:12):

Yeah, fair point, fair point.

Brad Zuchero (06:14):

Yeah, no. So, let me back up a second. So, as a cell biologist, I think a lot about shapes of cells because I think this can really inform our understanding of what cells are actually doing. And one of the really cool things about an astrocyte is single astrocyte, in a mouse, has 100,000 terminal processes, little fingertips sticking out from it. And in the human it's more like 400,000. So one cell is 400,000 little pokey things, little fingertips sticking out that connect all the way back to the cell body where the nucleus is. These are dynamic processes, and intriguingly, many of these processes interact directly with synapses between neurons.

Nicholas Weiler (06:53):

When you say processes, you're talking about these physical outstretched fingers?

Brad Zuchero (06:55):

Yeah, sorry. We call them processes but fingertips. Let's call them fingertips. So, this single cell will have all these fingertips that terminate in many cases at synapses where they can interact directly with synapses, so this is something that's amazing. If you take a step back, the entire brain is full of these cells. Each one of these cells is kind of like a tile. It occupies its own individual space throughout the central nervous system, and so they're everywhere and their terminal fingertips are able to interact with virtually every synapse in the central nervous system.

Nicholas Weiler (07:28):

400,000 fingers and 400,000 synapses.

Brad Zuchero (07:32):

Per astrocyte. Right. I mean, just thinking about the potential for what that could mean is kind of staggering. So, these astrocytes are also connected to each other via something called gap junctions, so they're able to directly communicate with each other. You know, if you go back in time to when Ben was starting or before Ben's lab, what people knew about astrocytes was that they were important for kind of passive roles in the central nervous system. So one critical thing is just survival of neurons. If you purify neurons out of the brain before Ben, what you need to have is astrocytes around. It's what's a so-called feeder layer that allows the neurons to survive. So this is a critical function of astrocytes. Maybe it's a little boring, it's just survival of neurons. And it wasn't until Ben figured out ways to keep the neurons alive without the glia that you could then go on to start to figure out what else these astrocytes are actually doing.

(08:23):

Let me make a plug for one more technology, other than immunopanning, that really, really helped our understanding of what glial cells do. And that's sort of continuously emerging technology called transcriptomics. So basically the ability to peer inside an individual cell or a group of cells and say which genes are they expressing right now? So, every cell in our body that has a nucleus has 20,000 genes. It's the same genes, and what makes one cell different from another cell is the specific set of genes that a blood cell will express or a muscle cell will express, or a neuron will express or an astrocyte will express. So if you can see which genes a cell is expressing at a given point in time, you can infer from that what that cell is actually doing, what types of functions it has. And so this is a technology that was developed here at Stanford, starting with gene chips, microarrays moving to RNA-Seq and now single cell RNA-Seq. There's this huge explosion of technology over the last couple of years.

Nicholas Weiler (09:24):

And it really lets you see what program the cell is running.

Brad Zuchero (09:27):

Exactly. That's a good way to put it. What program or which specific cellular functions a cell might be having normally or might get perturbed in a disease context, say. So, to give a flavor, one of the things that they noticed was if you looked at the gene expression profiles of astrocytes, they turned on, or rather, they expressed a set of genes that are thought to be immune-like genes that are important for something called phagocytosis, which is the ability of a cell to eat debris or parts of another cell.

Nicholas Weiler (10:02):

So these are genes that immune cells use to get rid of bacteria or dead cells and stuff?

Brad Zuchero (10:08):

Exactly. And seeing that inside an astrocyte was really puzzling because astrocytes were not thought to be immune-like cells with the ability to phagocytose. But doing this unbiased look at all of the different gene programs that these cells had on normally, it actually suggested that, oh wait, actually astrocytes do seem to have at least the machinery to be able to do this phagocytosis or clearance of debris. To make a long story short, over the course of many years and many papers, the lab and then the people that came from the lab realized that astrocytes actually, they are able to eat debris. But one of the things that they're actually eating is synaptic debris or pieces of synapses. So I just said a few minutes ago that astrocytes have all these terminal fingertips that are closely opposed with synapses, and now we find that actually one of the things they could be doing at those synapses is helping to eliminate synapses or potentially clear waste products at the synapses.

Nicholas Weiler (11:05):

And I think this raises an interesting point, which is I think when we think, "Oh my goodness, they're eating synapses," that sort of sounds bad. But if you think about it, we are born with the most synapses we will ever have, and a huge amount of the development of the brain from infancy into adulthood is not the formation of new synapses, though of course that's also happening, but the sculpting of all of these synapses to identify which connections are important and which connections are extraneous and disposable. So, this idea that astrocytes are in there clearing out, they're doing some of this pruning, and that's fundamental to how the brain is built.

Brad Zuchero (11:42):

Right. I mean, that was beautifully put, Nick. I mean, this is a very common trope in development that you build more than you need. I sort of liken it to a renaissance sculptor quarrying out a giant block of marble and then sculpting it down to Michelangelo's David or something, right? I mean, this is the way that development works, especially in the nervous system, and it's a way that you can achieve specificity and function. And so it turns out that astrocytes are critically important for that sculpting during development. Jumping to microglia, the lab also found that microglia are doing the same thing. So, microglia are the resident immune cell of the nervous system. They were previously thought to really just be playing immune roles.

Nicholas Weiler (12:21):

And this is because the brain has this blood brain barrier, so the regular immune cells mostly are not supposed to get into the brain. They cause too much damage. The brain has its own dedicated immune cells, that's the microglia.

Brad Zuchero (12:34):

That's right. A surprise came from similar work in the Barres lab that microglia are also functional phagocytes that are helping to eliminate synapses in development and as a way to help prune. Now that work, I mean you alluded to the difference between development and disease, right? And you said, "Oh, elimination of synapses, that sounds like a bad thing." Well, you're absolutely right. Beyond development in the context of disease like a neurodegenerative disease, there's massive synapse loss. And so the idea then emerged that, oh, if these glial cells are actually normally engaged in this type of synapse elimination in a beneficial way during development, could it be that in the context of aging or neurodegenerative disease, these developmental pathways are apparently reactivated and now there's emerging evidence that this could be part of the puzzle of what happens in neurodegenerative diseases.

Nicholas Weiler (13:24):

And both microglia and astrocytes, if I understand correctly, they're also linked to brain inflammation, which is something that we've heard a lot about in the context of long COVID and brain fog. In COVID, we've talked with Michelle Monje before on the show about this. These cells can get overactivated, and maybe this is what you're talking about here, where you can start to get inflammation, you can start to get too much synapse pruning and things like that.

Brad Zuchero (13:47):

Yeah, there's absolutely evidence for that. It's interesting, we've known about glial reactivity since over a hundred years now. Early neuroanatomists saw this in the context of disease and injury, but they didn't really know what these cells were doing. Is it beneficial? Is it detrimental? The answer is, it's probably all of these things. It hasn't really been until the modern era where we have these new technologies like the ability to look at the gene expression profiles of these cells that we begin to make sense of what these cells are actually doing in the context of disease.

Nicholas Weiler (14:19):

Great. And not until we understand these fundamentals can we start thinking about developing treatments to help roll them back. So I'd love to devote the final segment of our conversation to talking about the heart of your lab, your favorite glial cell, if you have to pick favorites, which is the oligodendrocytes. Of course, you had to pick the best Scrabble word. So, can you describe for us the oligodendrocytes? So these are the cells, as we've mentioned, that are creating the myelin sheaths around these tiny fibers that neurons send to one another to create their networks. If you had to close your eyes and describe the process of forming these myelin sheaths, how would you paint that picture for listeners?

Brad Zuchero (15:00):

So, this is a cell type, the oligodendrocyte, that if you can picture in your head an octopus with tentacles extending from its center. The center is the cell body in this case of the cell, and the tentacles that come out from this octopus, these are what are going to become myelin sheaths wrapped around axons. So in this case, rather than it being an octopus with only eight tentacles, oligodendrocytes really have many dozens of these processes. And these processes, again, these cellular protrusions or tentacles, if you will, they are incredibly dynamic and during normal development, they reach out and they try to find axons to wrap around. When they find an appropriate axon, they will then spirally wrap themselves around the axon while simultaneously flattening out to make a mature myelin sheath.

(15:47):

Now, hold that thought in your head. We're going to zoom way in now, so ultra structurally. If you take a cross section through a myelinated axon, cut it straight through. What it actually looks like, and I use this analogy all the time, it looks a lot like a roll of paper towels in your kitchen where the central cardboard tube is the axon and the spirally wrapped paper towels that are around that, that is the myelin. So, maybe this is a hard analogy to picture, but take a dozen paper towel rolls, extend the paper out back to a central octopus. This is what the cell actually looks like. There's a central cell body that have extended all these tentacles out to axons that have been wrapped and flattened around the axons. It's just a totally mindblowingly cool, interesting and difficult to imagine cell biology.

Nicholas Weiler (16:35):

That's facts.

Brad Zuchero (16:35):

This why I geek out about this because I'm a cell biologist. I spent my twenties trying to figure out how cells crawl. Then when I came to interview with Ben, he said, "You should check out oligodendrocytes and myelin because this is just a wild extreme cell biology that nobody understands how these cells do this."

Nicholas Weiler (16:51):

I think you said they expand their cell membrane, what, 50,000 times or something to wrap around axons?

Brad Zuchero (16:56):

That is an estimate, 25 to 50,000 fold increase in surface area of the cell to go from being a progenitor cell that doesn't have any of these tentacles and myelin wraps to this massively connected, highly wrapped cell. That is wrapping around dozens of different axons all at the same time.

Nicholas Weiler (17:14):

And so the fundamental thing that myelin is doing, and this has been in the textbooks for a long time, is it's forming insulation around these cables essentially to help the electrical signals pass along the cables. We won't get into too much details about this, but the way that neural signals propagate, they need to sort of do this jumping from spot to spot along the axon, the cable, and these distinct sort of wrapped sections allow them to do that.

(17:43):

So, I always thought of myelin when I was first learning about it as like this is why you pull your hand back so quickly if you touch a hot iron or a hot pot on the stove. You need a really, really fast nerve signal, particularly when your axon is going all the way from your fingertip into your spinal cord. That's a super long... That's one cell, and so you need that to be lightning fast. And that's the way I've always thought about myelin. But it's also in the brain, the myelin, which in the brain we call the white matter because it's wrapped in these fatty sheaths, it actually literally makes it look white is almost half the volume of the brain. So what's it doing there? Why do we need such fast conduction of nerve signals in the brain?

Brad Zuchero (18:24):

I mean, we absolutely need speed. That is the textbook model of what myelin is doing. But more than just needing speed, we need precision. Okay, so if you think of the entire brain or the entire CNS as a circuit,

Nicholas Weiler (18:36):

CNS being central nervous system.

Brad Zuchero (18:38):

Sorry, the central nervous system. If you think of the entire central nervous system as a circuit, lots of cables, lots of connections, what you need is for that circuit to have precise signaling and for it to be dynamic and adaptable. Tunable, if you will, to allow for learning to happen. And so beyond myelin just being there to speed nerve signaling, myelin has actually emerged as being really important for being able to tune the overall circuit dynamics. And it does that by not just being hardwired.

(19:10):

So, in your peripheral nervous system like you were talking about, myelin is formed and it's kind of hardwired during development. We have all this myelin, it's formed, it is there to maximally allow for fast nerve signaling, like you said. In the central nervous system, the story is different. There are certain circuits that we absolutely require, and as they come online during development, they're getting myelinated. But then in the adult brain, we actually have a huge capacity for changes to our myelin to allow for us to adapt to new experiences, to learn new tasks. So, myelin isn't hardwired across the entire central nervous system, it's actually dynamic.

(19:48):

This is an idea that really has only emerged in the last decade or so. There have been hints of this from looking at human brain neuroimaging for a while, say, "Oh, if people learn new things, where are the major changes happening in the brain?" And the surprise was, "Oh, it looks like major changes are actually happening in these white matter regions, these highly myelinated stretches." Now we know from really work that's been pioneered by Michelle Monje here at Stanford and Erin Gibson from her lab and Juliet Knowles as well, now the whole field appreciates this idea that myelin is dynamic. We have a huge capacity to add new myelin in the adult brain, to change existing myelin, the patterns of the myelin, the precise properties of the myelin that allow for the nervous system to adapt and to change and to learn. And that's super exciting.

Nicholas Weiler (20:36):

It is incredibly exciting. We've had great conversations with Michelle and with Erin on the show. I'd love to have Juliet on the show as well. Thinking about timing in the brain, I just want to stick on this for just a moment. There are so many things that require timing, and so much of what the brain is about is sort of a prediction machine. This happens, then that happens. Did this cause that or did that cause this? What happened first? What happened next? And so getting all these signals in the right place at the right time so that those time comparisons can happen so that you can learn these connections is just so important.

(21:07):

And so, I want to ask about sort of how this comes to be, how this develops, because to me, another fascinating thing about myelin is that... You know, my wife is in pediatrics and we talk about this all the time, that like when you watch your kids develop, you can really see their abilities to interact with the world changing as they develop, and one big piece of that is myelination.

Brad Zuchero (21:31):

That's right.

Nicholas Weiler (21:31):

It's the development of white matter in different parts of the brain, and so the reason a six-month-old can't walk and the reason a two-year-old can't necessarily hold a pencil, and the reason a 16-year-old probably shouldn't be trusted with certain levels of decision-making or a 12-year-old can't drive a car. I mean, a number of these things have to do with the progressive myelination of different parts of the brain. So I just made up a bunch of those examples, but maybe you can give us a little bit more insight into like, is myelin organizing brain development? Is that a way we can think about this?

Brad Zuchero (22:05):

I think that's absolutely accurate. Actually, one of the cool things that came out maybe, I don't know, 10 years or so ago, was taking a really close look at development of brains comparing humans to our closest primate cousins or chimpanzees. One of the things that came out of those studies was this realization that actually other primates, they myelinate very, very quickly, so faster than we myelinate. So, a chimp when it's born has more myelin per brain area than a human, and that myelin continues to form developmentally. Just like you said, as you're learning new motor tasks and things, the myelin develops really quickly. But the myelin develops so fast and then plateaus in the chimp's brain at about the time that it reaches sexual maturity, so hitting puberty.

(22:52):

Versus in humans, we start much less myelinated and we are progressively adding more and more and more myelin along past sexual maturity into the thirties. There's actually thought to be myelin increases even in the forties and into the fifties, so you're constantly adding new myelin. At first that seemed puzzling, right? Why do we have less myelin? The idea is that so brain function or say intelligence is maybe not just about total amount of myelin, it could be more about the capacity for myelin to be a dynamic regulatable thing.

(23:27):

So, even in a mouse's brain, or mice can learn new things as adults, even in a mouse brain there's many axons that are not fully myelinated normally. But in response to learning something new, you can add new myelin. So, coming back again to your conversation about the peripheral nervous system where you just want to maximize speed, you want to maximize myelin, that's just fundamentally not the way you want the central nervous system to work. You don't just want it to be all the knobs turned up to 11, right?

Nicholas Weiler (23:57):

Right. Right.

Brad Zuchero (23:58):

You want the ability to tune this: to turn the knob down, to turn the knob up. One of the knobs that you can change is the speed of nerve signaling, and you can change that knob by adding, removing, or otherwise modifying the myelin sheaths that are there.

Nicholas Weiler (24:13):

So one of the ways that I think is fascinating that myelin is involved in the development of the brain sort of goes back to some of the early discoveries that Ben Barres made. So, your lab recently had a discovery about myelin playing a fundamental role in activating the electrical properties of sensory neurons. And I think if I understand right, these are the neurons that are communicating from our skin to our spinal cord about touch and pain. Through some of these purification experiments, you were able to find that they're not going to become electrically active if you take them away from the cells that make myelin. I'd love to hear a little bit more about that, but do you imagine that this applies to neurons in the brain as well? I mean, is myelin also permissive of neural signaling in the central nervous system?

Brad Zuchero (24:58):

It's a really great question. We have a little teaser at the end of our paper about this, looking at the central nervous system to see whether this pathway we discovered is actually conserved in the central nervous system like in the periphery. And we have a lot of evidence that that could be the case. But if I may, can I just back up and just sort of tell this-

Nicholas Weiler (25:15):

Yeah, please. I kind of jumped the gun there.

Brad Zuchero (25:16):

Yeah. Yeah. So it's actually a fun story for me to tell because if you ask anyone, "What does a neuron do?" You say, "Oh, this is a cell that is electrically excitable." It can respond to external signals maybe from another neuron or from sensory inputs, and it can fire an action potential. It can have an electrical signal that it transmits throughout the nervous system. That is maybe the fundamental thing about a neuron, and once again, it's something that everyone assumed was a default property of a neuron. This is a process that the neuron turns on on its own as it matures from the stem cell that it came from.

(25:54):

I created a way to purify sensory neurons. These are, like you said, the neurons that are important for receiving external stimuli. Whether it's heat or pressure, touch, position of your limbs in space, these types of neurons, I figured out a way to purify them away from glia rapidly for the first time. This was back when I was a postdoc with Ben actually, and I just so happened to talk to someone from Justin Du Bois's lab in the Chemistry Department, and they study neural signaling. They were looking for neurons to do some experiments. I said, "Oh, I've got some. I just came up with this new way to purify these sensory neurons. Why don't you give them a try?"

(26:29):

And they came back to me a week or so later, two weeks later, and they said, "Brad, what have you given us? These cells, they're not neurons. Oh, they don't fire action potentials." You can stimulate them with electrical signals, they don't fire action potentials like they normally do. I think there was a period of time we didn't know each other very well, and I thought, "What are they talking about? They don't know what they're doing." And they thought, "What is he talking about? He doesn't know what he's doing." Right?

Nicholas Weiler (26:50):

Right.

Brad Zuchero (26:50):

So we had to think. We looked at them carefully and we said, "No, no, these are definitely neurons." And being in Ben's lab, the realization struck me. I said, "Well, what I did that was different from what everyone else has ever done is I purified these cells away from the glia. So, what happens if we take the glial cells and we put them back?" And sure enough, we did that experiment really quickly and we realized, oh my goodness, if you put the glia back, all of a sudden these cells become electrically excitable again. So they are neurons, they're just neurons with their excitability turned off, kind of like quiet neurons without glia.

(27:23):

And we spent a lot of time, this is something that sort of simmered for a while. I picked this up again when I started my lab in 2017, and the first postdoc came to the lab. She picked this up again, and then together with Justin Du Bois's lab and some awesome people there, we figured out the entire pathway basically. We figured out that glia secrete a molecule that is required for neurons to become electrically excitable during development. We knocked out the whole pathway in vivo in mice and found that without this, their neurons don't develop normal excitability, and then the mice have sensory deficits that match this inability for the neurons to mature.

(28:00):

So, by knowing the pathway and the genes that are important for this pathway, we can then also look in the central nervous system or in other neural types and see that these same pathways at least exist in these other cell types. So, I think it remains totally possible, plausible even, that myelinating glial cells in the central nervous system, the oligodendrocytes actually are contributing directly to the ability of neurons to become excitable or to change their excitability in the context of learning or potentially disease. And that's so exciting.

(28:30):

Quite possibly the most exciting or important roles of glia have yet to be imagined, and I think this discovery from our lab is one example of this. No one in a million years would have thought that neurons wouldn't become excitable on their own and that they needed signals coming from glia to do that. And so, until you look, until you do this naive experiment, or in this case sort of stumble serendipitously onto this, we would have had no idea about this. And so, I think there's still a lot of discoveries like that that remain to be discovered.

Nicholas Weiler (29:03):

Well, fantastic. I would say that that's a fantastic place to end, but I haven't asked you my last question about Alzheimer's. So, we've been talking a lot about development and normal function, but sort of to bring it back to one of the things that was motivating for Ben as we discussed, is on the one hand, we want to understand how this works. At least half of the cells in the brain, they're playing these roles that no one's explored before, and we need to understand them because they're also impacted in many different kinds of brain disease.

(29:31):

And I know that in particular, you're working with Aaron Gibson, who we have also talked with on the show about the role of myelin in neurodegenerative disorders. We were talking with Aaron about problems with circadian clocks and myelin-forming cells contributing to sleep problems and loss of myelin and Alzheimer's. I don't think that we have space here to delve into all of the details here. We're going to have to have you both back and talk more about some of the specifics, but what's your impression about the role of myelin as a victim or a suspect in these neurodegenerative disorders? Is it a cause or is it an effect?

Brad Zuchero (30:13):

I think this is maybe the biggest, most important question right now in the field, and I think there's a huge potential for myelin to really be an overlooked suspect in the development of neurodegenerative diseases. So, I'll say a couple of things. One is that we've known for a long time that myelin does more than just speed action potentials. I told you about one example that we just discovered in my lab, but we've known for longer that myelin is actually actively metabolically supporting the neurons that get myelinated. And you can make mutations to genes in oligodendrocytes that don't affect myelin, but that cause neurons to degenerate. So, neurons are absolutely depending on these myelin sheaths and the oligodendrocytes that build them for their normal health. So, that's fact one.

(30:57):

Fact two is a number of papers in the last couple of years from labs who didn't think anything about glia before. These are real, dyed in the wool neuroscientists. They took transcriptomics approaches like we've been talking about, single cell RNA-Seq in this case, to look at what's actually going wrong in Alzheimer's disease in patient samples, as well as in corresponding mouse models. And one after another, these papers came out and they said, "Huh, surprise, surprise. One of the major things that changes and actually changes early in Alzheimer's disease is changes to myelin. Myelin dysfunction potentially, gene expression changes and oligodendrocytes that suggest that these cells are playing a central role and potentially a really early role in the development or progression of Alzheimer's disease.

(31:42):

And this was super surprising, especially to these people, these neuroscientists that hadn't thought about glia before, especially hadn't thought about myelin. So I think this is a huge opportunity right now is that this is emerging as central. It's still a frontier. We know very little about what these cells are actually doing, and it kind of opens up a whole bunch of questions that my lab and others who have been thinking about glia for a long time are poised to answer. So we're really excited about working on that right now.

(32:08):

I should just say that some of the major genes that are linked to Alzheimer's, so for instance APP, amyloid precursor protein. The protein that goes on to make amyloid plaques, this protein is incredibly, highly expressed by oligodendrocytes, so enriched in oligodendrocytes compared to other cell types, but we know almost nothing about what it does inside oligodendrocytes. So, I think there's a potential here that we're going to discover oligodendrocytes have really important early roles in Alzheimer's disease and potentially represent a completely untapped therapeutic target for preventing or reversing cognitive decline and disease. I think this is the space to watch, I would say, Nick. Over the next 10 years, there's so much to learn in this space.

Nicholas Weiler (32:52):

Fantastic. Well, I hope listeners will be able to tune back into this show to hear you tell us exactly what you are discovering. Brad, thank you so much for coming on the show. This has been a fascinating tour of the field, where it's come from and where it's heading. So, thank you so much for coming on the show.

Brad Zuchero (33:07):

Well, thanks so much for having me. Appreciate it.

Nicholas Weiler (33:12):

Thanks again to our guest, Brad Zuchero. He's an assistant professor of neurosurgery at Stanford Medicine and Covert-Matera Families endowed faculty scholar with the Stanford Maternal and Child Health Research Institute, as well as an affiliate of the Wu Tsai Neurosciences Institute. To read more about his work and the legacy of Ben Barres, check out the links in the show notes. Next time on the show, how large language models like ChatGPT could help us understand our own amazing communication abilities.

Laura Gwilliams (33:42):

A lot of people refer to speech and language models as a black box, which yes, we don't know exactly how these systems work. On the other hand, they're kind of the opposite of a black box, because we have access to every single neuron in that system. We can turn the neuron down, we can amplify it, we can turn it off entirely, and we can do that as many times as we want to be able to get a really comprehensive link between the model's neural implementation and the behavioral output.

Nicholas Weiler (34:20):

Join us next time for a great conversation with Laura Gwilliams. If you're enjoying the show, please subscribe and share with your friends. It helps us so much as we grow as a show and work to bring more listeners to the frontiers of neuroscience. We'd also love to hear from you. Tell us what you love or what you'd like to see more of on the show, in a comment on your favorite podcast platform, or send us an email. We're at neuronspodcast@stanford.edu. From Our Neurons to yours is produced by Michael Osborne at 14th Street Studios with production assistance from Morgan Honaker. I'm Nicholas Weiler. Until next time.