From Our Neurons to Yours

Our plastic brains: learning, memory and aging with the one and only Carla Shatz (Rerelease)

• Wu Tsai Neurosciences Institute, Nicholas Weiler, Carla Shatz • Season 4 • Episode 6

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-- We're re-releasing our conversation with Carla Shatz, one of our favorites from the archive, which comes up all the time on the show in the context of brain plasticity and aging. Enjoy, and see you next time! -NW --
 
When we're kids, our brains are amazing at learning. We absorb information from the outside world with ease, and we can adapt to anything. But as we age, our brains become a little more fixed. Our brain circuits become a little less flexible.

You may have heard of a concept called neuroplasticity, our brain's ability to change or rewire itself. This is of course central to learning and memory, but it's also important for understanding a surprisingly wide array of medical conditions, including things like epilepsy, depression, even Alzheimer's disease.

Today's guest, Carla Shatz, is a pioneer in understanding how our brains are sculpted by our experiences. She's credited with coining the phrase neurons that fire together, wire together. Her work over the past 40 years is foundational to how we understand the brain today.

So I was excited to talk to Shatz about our brain's capacity for change, and I started off by asking about this sort of simple question, why exactly do we have this learning superpower as kids to do things like pick up languages and why does it go away?

Shatz is Sapp Family Provostial Professor of Biology and of Neurobiology and the Catherine Holman Johnson director of Stanford Bio-X.

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Episode Credits
This episode was produced by Webby award-winning producer Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Art by Aimee Garza.

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Nicholas Weiler:

Hey everyone, Nicholas Weiler here. Two things. First, a quick programming note. As we move into summer, we're going to move into an every-other-week cadence while we work on new episodes from the frontiers of neuroscience. We'll have those for you very soon. Second, today, we're going to be doing a release. We're going back into the archives for one of my favorite episodes that we've done. One that's come up over and over in conversations. 

Last June, I talked with neurobiologist Carla Shatz about brain plasticity, why our brains get worse at learning as we get older, and what we can do about it. 

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler. Here's the sound we created to introduce today's episode.

Perhaps that is the sound of the developing brain. When we are kids, our brains are amazing at learning. We absorb information from the outside world with ease, and we can adapt to anything. But as we age, our brains become a little more fixed. Our brain circuits become a little less flexible. You may have heard of a concept called neuroplasticity, our brain's ability to change or rewire itself. This is of course central to learning and memory, but it's also important for understanding a surprisingly wide array of medical conditions, including things like epilepsy, depression, even Alzheimer's disease. Today's guest, Carla Shatz, is a pioneer in understanding how our brains are sculpted by our experiences. She's credited with coining the phrase neurons that fire together, wire together. Her work over the past 40 years is foundational to how we understand the brain today. So I was excited to talk to Carla about our brain's capacity for change, and I started off by asking about this sort of simple question, why exactly do we have this learning superpower as kids to do things like pick up languages and why does it go away?

Carla Shatz:

Oh, I ask myself that question all the time.

Nicholas Weiler:

Me too.

Carla Shatz:

So why does it go away? It's such a perfect example that you just gave, Nick, that is language learning, which as we all know is so effortless during childhood. And then of course we can still learn a language as an adult, but it's, for me anyhow, much more of a struggle. And you kind of want to know why it is. So when you think about the word plasticity, the circuits themselves are composed of billions of neurons that connect with each other, and the connections between neurons are called synapses. It's those synapses and their ability to grow or be lost that really maintains the circuits. And the brain sculpting... I love the word sculpting. During development, it is kind of like a sculpture if you imagine Michelangelo chipping away at a piece of marble and then gradually some beautiful sculpture emerges.

Nicholas Weiler:

It's done by taking away.

Carla Shatz:

It's done by taking away, but actually also have to emphasize that in the brain it's even cooler because it's done by taking away things, but also stabilizing and growing the synapses. So in the case of learning a language, for example, what the brain is doing during developmental critical periods is taking the experience, in this case of hearing the language, and stabilizing and sculpting circuits and synaptic connections that allow the circuits to program into the brain, the language itself. And then it does another cool thing. Those circuits for hearing language, are then connected to circuits for producing language that is our motor circuits. And so the motor output is actually tuning up our vocal cords and all musculature that's needed to produce effortlessly language. So it's a complex process, right? Input, output.

Nicholas Weiler:

I love this idea that it's sort of the brain is sculpting itself to match the sensory input that it's taking in. It's hearing the language, adapting to that, and then figuring out how to produce it.

Carla Shatz:

Yes, exactly. And then rehearsing how to produce it. So it's a mixture of sensory and motor. So Patricia Cole, who has studied babies learning language for years now, has described babies as citizens of the world in the sense that all of the brain circuits that are available for learning all these languages in the world, including understanding and hearing the distinction between R and L and so on, they're all available, but it's really a case of use it or lose it. So they're all there to start with and they can be used. And if they're used, these circuits are then strengthened because the connections grow. If they're not used, so for Japanese, we don't hear the R and L distinction, then that is loss. And you could almost think of this as a kind of a very economical way that the brain has of optimizing and recording its experiences and then getting rid of the connections it doesn't need and hasn't used for a long time. And you keep using the word developmental critical period, I think language learning is a really good example.

Nicholas Weiler:

There's a particular time when you need to learn a language because you need to start communicating. And so that's the time when your brain is set up to do that task, like I need to learn what language I'm speaking.

Carla Shatz:

Actually, that's a really good point too. I think one of the main reasons is we have to communicate in order to survive. So this is an extremely important process. Now, the issue is what do we give up when we have such rapid learning periods? Because the rapid learning periods are essential. These periods are periods when the connections in the brain and the synapses are changing so fast that circuits can become unstable. And in fact, it's known that children can be more prone to epilepsy than adults. So one idea is that the brain sacrifices circus stability for rapidity of changing connections. The connections that are changing that are associated with brain excitations, so then that's why it makes sense that there's this rapid change that could cause instability, that could lead to too much excitation, that could lead even maybe to childhood epilepsy. And as these circuits change, they become stabilized, inhibition kicks in to kind of preserve a balance so that the brain doesn't just go crazy and become over excitable.

Nicholas Weiler:

So there is this balance between learning and stability, in childhood, maybe it's one way and in adulthood we have a different priority.

Carla Shatz:

Right. So first of all, as you learn, I mean, you kind of want many of these really important fundamental circuits to become quite stable. You don't want them to keep changing over time so that you suddenly can't speak your native language anymore. So neuroscientists think that the mechanisms that lead to stabilization of circuits involve plasticity molecules that are really important for maintaining the structure and stability of synaptic connections. Let's imagine that you have a set of connections and you want to make them stronger. How would you do it? Well, a simple idea that in fact happens is that you might give those connections, growth factors that would allow those synapses to grow, and then maybe some kind of even glue or signaling that allow the connections to become firm and not go away.

Nicholas Weiler:

Right, what is physically stabilizing those connections.

Carla Shatz:

That's right.

Nicholas Weiler:

Yeah, Exactly.

Carla Shatz:

And those things could be a kind of glue that glues the connections together. And those are, for aficionados, things like the skeleton of the synapse, the actual physical structure with actin and microtubules, the things that actually keep the synapse firm.

Nicholas Weiler:

Right, proteins that are stabilizing it.

Carla Shatz:

That's correct. Proteins that are stabilizing it. So upstream of all of those proteins are other molecules that are signaling the state of the synapse. So now it's getting a little more complicated, but the really exciting thing is that neuroscientists have discovered some of those upstream molecules that we call plasticity molecules, and those change with age.

Nicholas Weiler:

Interesting.

Carla Shatz:

So that could work in one of two ways, and it does work in both ways. One way is those plasticity molecules could be positive in that as you get older, they're needed for plasticity. So there's lots of positive signals when you're a child, and then they go away. Another possibility is they're plasticity molecules that act as brakes. So instead of accelerators, you have brakes, and those molecules actually put a brake on plasticity, and those could increase as you age. So like a car of the circuits. And both brakes and accelerators are used by the brain.

Nicholas Weiler:

So as we age, we sort of ease up on the accelerator and push down on the brake a little bit to shift from that period of rapid easy learning to stabilize the circuits. Is that what you're saying?

Carla Shatz:

Yes. Yes, so that's what we think.

Nicholas Weiler:

Your lab and your research has taught us so much about the accelerators and the breaks on plasticity. And we've spoken with Rob Malenka about psychedelics and their ability potentially to enhance plasticity, to help treatment for people with PTSD and with Nolan Williams about using magnetic stimulation in the context of depression in a similar way to adjust brain circuits. By understanding at the molecular level these controls on brain plasticity, what are some of the things we could start to think about in terms of selectively enhancing our ability to learn? I want to come back to the idea of plasticity in Alzheimer's disease and dementia in a minute. But maybe first we could talk about enhancing learning.

Carla Shatz:

I think they're really related to each other, both of these issues. So first of all, when one uses, let's say psychedelics or any kind of external agents that might change brain plasticity and sort of reopen windows, all of those we think have to work through changing the synapses themselves. What I always ask Rob Malenka, "Okay, well, are these plasticity molecules involved? The brakes or the accelerators?" In other words, how do the drugs work? Because eventually they have to work their way down into the synapses. And so can we, without these kinds of drugs, even without psychedelics or whatever, can we go in there with drugs that work directly on the synapses and allow them to become more plastic? Or another way of putting this question would be, can we reopen these developmental critical periods so I can learn French as an adult because I just can't.

Nicholas Weiler:

Right. I've been working on learning German, and it is a challenge.

Carla Shatz:

Yes, it's a total challenge, isn't it? So we now know neuroscientists have discovered a number of these molecules that we would call breaks, where if you remove them in adult mice, if we remove those breaks, the mice, their ability to learn new tasks, including the ones that are so nicely, easily learned during development... Of course, I haven't heard mice speak French as a second language, maybe they speak German, I didn't really [inaudible 00:12:31].

Nicholas Weiler:

That would be a great future episode-

Carla Shatz:

Exactly. But anyhow, so if we actually manipulate these molecules by blocking them and take the breaks off, we can recreate the same sponge-like amazing learning brain that's present in the young mice during their critical periods. And then the amazing thing is when we look in the brain and ask, okay, what happens when we molecularly remove those breaks? Then we see that the synapses do what they do during the young mice, which is they form more rapidly during the learning period, and they're more stable. And that underlies, we think, this superior learning that can be produced by taking one of the breaks off during this adult period.

Nicholas Weiler:

So how could understanding the mechanisms of circuit plasticity lead to new treatments for Alzheimer's and dementia? I know this is something your lab's been very interested in.

Carla Shatz:

Yes. Well, so underlying the fundamental aspect of circuit plasticity are the changes that happen at synapses. The most important point I think to remember is that when you learn, you make new synapses or you strengthen synapses that are associated with that task or learning, and also you remove synapses during critical periods of learning that are not used. So kind of a light bulb went off for me, and that is that Alzheimer's disease is all about loss of synapses. Now, people generally think of Alzheimer's disease at its late stage when you not only lose the circuits and the synapses, but you actually lose the neurons and the brain shrinks. But prior to that late stage, it's known that synapses are lost. Too many are lost. And this is a big problem for cognition because memories are stored in circuits at synapses, and new memories are encoded by forming new synapses.

So if synapses are lost excessively in neurodegenerative disorders such as Alzheimer's, memories are lost. And so we have molecules that are brakes or accelerators. These are molecules that control synapse formation, synapse elimination, and synapse stability. So if we could manipulate those molecules, maybe we could prevent people from getting Alzheimer's, or maybe we could help restore memories. I don't know. But we do know we have these molecules, and one of the molecules is a break that I mentioned before. If you take it off, mice can learn new tasks much more rapidly in adulthood. And the way this break works is it's needed to remove synapses. So if you take this break away, forming synapses is easier for the brain. So it's more like in childhood. So we realize, oh, this molecule is needed for removing synapses. Alzheimer's involves... Too many synapses are removed. So what if we block this break?

So it's almost like, again, we're thinking about reopening a critical period, but here we're just going to block the break. What would happen in Alzheimer's disease? And in a mouse model, you know, scientists can make a humanized mouse model of Alzheimer's disease where genetically they insert some of the genes that put humans at high risk for familial early onset Alzheimer's. Then sadly, at about nine months of age, the mice suffer memory loss, they get these plaques and tangles and the other hallmarks of Alzheimer's disease. And even before that, they lose synapses. And so it really is like human Alzheimer's. When we studied a mouse model like that, and we removed the break that causes synapse loss. So now the brain can't lose as many synapses. We found that the mice did not come down with the cognitive loss, that's so characteristic of Alzheimer's disease. So they were somehow resistant to Alzheimer's.

Nicholas Weiler:

So they're still getting these plaques and tangles in the brain, but they're not losing their memories.

Carla Shatz:

Absolutely. They're getting high levels of these plaques just like the other Alzheimer's model mice, but they're not losing their memories. So we became extremely excited in trying to understand what is the mechanism for this resistance to Alzheimer's? And that's where we are now. What we've discovered is that some of this bad Alzheimer molecules that are produced that are even before the plaques form, so these are called beta amyloid. These bad beta amyloid molecules hijack our receptor, put it into overdrive and force pruning to happen at a higher rate. So when we remove this brake receptor molecule, this overdrive, we think doesn't happen. No, we have to prove a lot of this.

Nicholas Weiler:

Right.

Carla Shatz:

But the really neat thing that's exciting to us is that we find the same molecule in the human brain at synapses, and that's something new that we're working on now. So we want to try to relate the mouse situation to the human condition, at least it suggests that there might be a way forward, which would be completely different from the approaches that are being used now clinically, which are to attack the plaques. Now, let's go back to think about the brain as an extraordinary adaptive machine where circuits are capable of changing throughout life much more in development, but still, obviously, you and I can still learn and remember as an adult. So we have this amazing capacity to change our circuits with learning and experience even in adulthood.

Nicholas Weiler:

Yeah. It's remarkable to think that we now have some understanding of the brakes and accelerators on the process of learning itself that could help us understand when either one of those goes wrong, right? If our brains get too rigid in our thinking or in our behavior, or if we're slipping back into having the accelerator pedal down and things are changing too fast and we're losing synapses that we wanted to keep.

Carla Shatz:

Right. Exactly. And neuroscientists are discovering many, many components now of this braking and acceleration process. And so it's very promising in the sense that if you could sort of save the synapses, maybe this would be a way of treating a lot of disorders that have to do with synapse loss. But then of course, the cosmic question is, when would you try to intervene? I mean, I look at the brain from a developmental neuroscientist standpoint, and I keep thinking to myself much earlier than any of the trials have been done, which kind of maybe also makes things a little more optimistic going forward if even some of these trials that haven't yielded the kind of results people were hoping for, maybe one should really think about the brain as a highly adaptive machine that can compensate for years before you really show up in the clinic with a problem. And so my thought is, at age 50, I would like a checkup on my brain and an intervention if need be, that would help preserve my synapses.

Nicholas Weiler:

Yeah. And I think understanding these systems and the way that learning works opens the door to being able to keep our brains healthy and learning in a healthy way without going overboard. Well, I think that's about all the time we have, unfortunately. I would love to keep this conversation going, and there are so many more topics I'd love to delve into, but we'll have to save those for another episode. And thank you so much for joining us and talking about all these issues.

Carla Shatz:

You're so welcome, and I'm just delighted to be part of this wonderful enterprise. Thank you, Nick.

Nicholas Weiler:

Thanks so much again to our guest, Carla Shatz. For more info about her work, check out the links in the show notes. This episode was produced by Webby Award-winning producer, Michael Osborne, with production assistance by Morgan Honaker. I'm Nicholas Weiler, see you next time.