How a new kind of brain plasticity could help make sense of addiction

This week, we talk with Michelle Monje and Rob Malenka about recent findings on the role of myelin plasticity in opioid addiction
Nicholas Weiler
Michelle Monje, the Milan Gambhir Professor of Pediatric Neuro-Oncology

This week, we're diving into recent research that sheds light on a new form of brain plasticity involving changes in the insulation of nerve fibers — called myelin.  It turns out that myelin plasticity is implicated in a number of serious conditions, from epilepsy to drug abuse and addiction.

Rob Malenka, the Nancy Friend Pritzker Professor of Psychiatry and Behavioral Sciences

We're excited to bring back two previous guests on the show to share their insights on this previously unknown form of plasticity:  Stanford psychiatry professor Rob Malenka (S1 E1 - Psychedelics and Empathy),  a pioneer in the study of synaptic plasticity and addiction, and pediatric neuro-oncologist Michelle Monje (S1 E12 - Brain Fog), who made some of the very first observations of myelin plasticity in the brain, essentially founding this field.

Together, they discuss their recent findings on the role of myelin plasticity in opioid addiction and its implications for understanding addictive behaviors.

Get ready to nerd out as we uncover a new angle on our brain's remarkable capacity for change.

Listen to the episode to learn more!

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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. 
 

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Episode Transcript

Nicholas Weiler:

We've talked a lot on this show about plasticity, the ability of our brains to change and adapt. In a way, it's our human superpower. We can adapt to learn the language, the survival mechanisms, the culture of whatever society we find ourselves in. We are lifelong learners and our ability to learn and grow is rooted in the plasticity of our brains. Of course, plasticity can have a dark side. We can also learn to act in ways that are bad for us or for our communities. Whether simple bad habits like eating too much sugar and scrolling on our phones, or more serious self-destructive or antisocial behaviors, post-traumatic stress, anxiety and depression, violence or drug abuse. In the wrong circumstances, maladaptive behaviors like these can become so fixed, they seem impossible to undo.

This is where neuroscience is so important. These learned behaviors aren't just abstractions. They're rooted in the physical malleability of our brains. And understanding plasticity brings with it hope and the potential for change. For decades, neuroscientists have focused on one type of plasticity, synaptic plasticity, as the fundamental source of learning in the brain. Think of it this way, anytime we learn anything, what we're doing is making connections between old ideas and new ones, between the present and the past, between the outside world and our knee jerk reactions to it. It turns out that this is very literally what's going on in the brain. Learning and plasticity, strengthen or weaken the physical connections or synapses between nerve cells, shifting the balance of electrical activity across brain circuits and ultimately altering our behavior.

Now, all this is certainly true, but it's not the whole story. Recently researchers have discovered there's a fundamentally different kind of plasticity operating in the brain. Zoom back from the synaptic junctions between brain cells, and it turns out that the wiring that connects them has the potential for plasticity as well. Many nerve fibers are wrapped in this fatty substance called myelin that acts as insulation a lot like on an electrical cable. We won't get into the biophysics here, but myelin helps shuttle electrical impulses from one brain cell to another at high speed. Think about how fast you react when you stub your toe. Electrical impulses travel several feet from your toe to your brain and back in the blink of an eye.

What the new research shows is that myelin itself can change in response to brain activity. This means that not only do the strengths of connections in the brain change as we learn, but the speed of different nerve pathways may change as well. And this in turn changes the all important timing of signaling in our brains. Now, I know all of this may be getting pretty technical. It's infrastructure day in the brain, but it turns out that myelin plasticity is implicated in a number of serious conditions. Epilepsy, for example, as well as today's topic, drug abuse and addiction. So whether we want to treat misfired brain circuits or help people escape the cycle of addiction, we need to have a richer understanding of this previously unknown form of plasticity in our brains.

Today, I'm excited to bring back two previous guests on the show whose work perfectly overlaps to answer this question. Rob Malenka is a psychiatry professor at Stanford who's a pioneer in the study of synaptic plasticity. We spoke with him on our very first episode about plasticity and psychedelics. Michelle Monje is a Stanford neuro oncologist and researcher who made some of the very first observations of myelin plasticity in the brain, essentially founding this field. We spoke with her last year on the show about myelin's implication in long Covid and brain fog. Ready to nerd out? Let's go. 

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science.

Michelle, Rob, thank you so much for coming on From Our Neurons to Yours.

Rob Malenka:

It's my pleasure. Thanks for having us.

Michelle Monje:

Wonderful to join you.

Nicholas Weiler:

I'm so glad to have both of you on the show. Rob, your work has taught us a tremendous amount about how our brains learn at the synaptic level and the implications for addiction, particularly in recent years. And Michelle, you've been so central to this new field studying a new form of brain plasticity involving changes in the insulating myelin around nerve fibers that can change the speed of neural signaling, not just the strength of neural signaling. And now you have a new paper together showing a role for this myelin plasticity in opioid addiction.

So I'd love to get into what you've found and what it means for understanding of addiction and our brain's capacity for change. Michelle, I think there's a pretty interesting story behind this study in that you had discovered that brain insulation is sensitive to changes in neural activity and could respond by speeding up or slowing down. And then in early 2020, you saw that injecting morphine or cocaine into mice caused increased myelination in the brain's reward circuitry. Do I have that right? Could you tell me about your reaction to that and what happened next to bring you to this new finding?

Michelle Monje:

Yeah, absolutely. You do have that right. We've been studying for a number of years the way that neuronal activity regulates the behavior of the glial cells that contribute to forming the myelin sheath. Increasingly, we understand in certain regions of the brain that these adaptive changes in myelin can alter conduction velocity in a way that broadly promotes circuit coordination and function so you can change the synchrony of arrival of two signals in a way that really affects how the circuit is functioning.

And we had previously studied this in the cortex and cortical projections and wondering whether this plasticity of myelin was operant in other circuits and we're very interested in the dopaminergic reward circuitry. So we had reached out to Rob to collaborate with us on this. And in early 2020, my absolutely brilliant postdoctoral fellow, Belgin Yalcin, together with a postdoctoral fellow in Rob's lab did the first experiment. I remember Belgin bursting into my office in February of 2020, just so excited when she had seen the first evidence that morphine administration caused a burst of oligodendrocyte precursor cell proliferation and the generation of new oligodendrocytes in the reward circuitry.

Nicholas Weiler:

And those are the cells that create this myelin wrapping?

Michelle Monje:

Exactly.

Nicholas Weiler:

All right. And so you've got this first evidence that drugs of abuse, that opioids can change this myelination.

Michelle Monje:

Exactly. And we were so excited. And so the immediate next question was, how does this influence reward learning? And we started to prepare to ask that question and the pandemic began. So eager to begin these experiments could not come into the lab for a period of time. And then when we could, there were supply chain issues, all of the logistical challenges of the pandemic. And I remember Belgin being so motivated to do this experiment, she ended up to make the behavioral chamber in which we were going to test reward learning, she ordered pieces of acrylic online and really strong glue and just made the chamber herself because there was no way to get one professionally made. So she did a very good job and [inaudible 00:07:31]-

Nicholas Weiler:

I mean, going back to the old days, right? Build it yourself and make it... yeah.

Michelle Monje:

Yeah, that's right. Yeah. So as soon as we could reenter the labs in the limited way that we could, these were the very first experiments that were done.

Nicholas Weiler:

And so in this new study, you're showing that morphine causes increased myelination in the brain's reward system in the dopamine system, and that this changes signaling there and that these changes in the strength of myelination or in the extent of myelination, seems to be required for these animals to actually develop a taste for the drug. So this is really a new aspect of what goes on in the brain when animals are exposed to these drugs of abuse that seems to be important for addictive like behavior. Rob, I wonder if you could talk to us a little bit about how you see this potentially interacting with the kind of plasticity you have long studied in the context of addiction.

Rob Malenka:

I think it brings a whole new mechanistic perspective to how circuits are modified, both for adaptive forms of learning and experience dependent plasticity, and more importantly in the context of this study, pathological forms of learning and memory. And I think Michelle beautifully articulated why changes in myelination and how that change in what we call the conduction velocity, how fast the electrical nerve pulses are going down axons, how they're integrated at their targets, how changes in myelination can dramatically affect how circuits integrate that incoming information. It's just another example that what makes the brain so amazing, but also so susceptible to pathological changes is its bewildering array of plasticity mechanisms.

Historically, I have focused at the changes in the strength of communication between nerve cells at these contacts called synapses. Michelle's lab and her work has shown this new mechanism of plasticity. I should say I was surprised that drugs of abuse like morphine caused such robust changes in the proliferation of these nerve cells that produce myelin. I was also pleasantly surprised that if you prevent those changes, you actually influence the release of dopamine in this key target structure. Circuits utilize every mechanism at their disposal to modify their activity, and sometimes it's for the good of the organism and what we need to learn.

I think in Michelle's previous work, she showed that certain forms of motor learning, what I call an adaptive good form of learning and memory, here there's an example of a powerful experience in this case, the experience of being administered morphine has usurped this adaptive mechanism to trigger a pathological form of learning.

Nicholas Weiler:

Rob, I really liked what you said about this being a pathological form of learning, right? It's taking the brain's learning mechanisms and taking them over essentially. It's saying because it's involving the dopamine system, which is so important for motivating behavior and for learning what should motivate behavior, that if you start administering something that hijacks that system, you can motivate any behavior that you want. Michelle, I'd love to hear a little more from you about where this discovery of changes in myelin came from and how those changes get incorporated into the function of brain circuits.

Michelle Monje:

Absolutely. So a number of years ago, the idea that neurons in an activity dependent way might regulate the extent to which their axons are myelinated was first proposed by the true pioneer in the glial field, Ben Barres. And then it was supported by some really beautiful in vitro and correlational work, but it remained a very controversial idea. And so we used, at the time, newer techniques in modern neuroscience to stimulate neuronal activity in a very controlled way in cortical projection neurons and see how that changed the behavior of these oligodendroglial myelin forming cells. And what we first discovered was that activity of those cortical projection [inaudible 00:11:56] induced myelin changes that we would predict might alter circuit dynamics and therefore function. And indeed, what we found is that there was an improvement in mouse motor function that depended upon the generation of oligodendrocytes. And we, in trying to untangle the mechanisms that mediate these interactions, found that neurotrophin signaling was a key mechanism.

Nicholas Weiler:

And those are chemicals that cells send between-

Michelle Monje:

Exactly. So the neurons in an activity dependent way release a growth factor that signals to a receptor on the oligodendrocyte precursor cell, and that's one required component of myelin plasticity in the cortex. And so we use that as kind of a molecular handle to specifically block these activity regulated changes in myelin and ask what role they had in various forms of behavior. And we found that there was a role not only in motor function and motor learning, but also in attention and memory encoding. Later, we showed that there was an important role for plasticity of myelin in frontal hippocampal projections, memory consolidation, and spatial learning. Another group had shown that there was an important role in fear learning. And so a number of different cognitive processes were becoming implicated with myelin plasticity having an important role in contributing to those various neurological functions. But we had really focused on the neocortex and on the hippocampus, and we were curious whether other structures exhibited myelin plasticity and how specific that was. So one of our early findings was that not all neurons in the cortex exhibit plasticity or myelin plasticity of the same type.

Nicholas Weiler:

Interesting. So different brain circuits and different projections within brain circuits have different rules about how the myelin can change.

Michelle Monje:

Exactly. And we saw that really clearly in the dopaminergic reward circuitry. So we stimulated neuronal activity in part of the dopaminergic reward circuitry called the ventral tegumental area, or VTA. And VTA projects to the nucleus accumbens, and the signaling of the dopaminergic neurons in VTA signaling to nucleus accumbens is critically important in reward learning and motivated behavior. And what we found was that there was oligodendrocyte precursor cell proliferation, specifically in the VTA, and we saw this with optogenetic stimulation of the dopaminergic neurons. We saw this in response to morphine, we saw this in response to cocaine. So all of these different stimuli that cause action potentials in dopaminergic neurons recruited the establishment of new myelin on the dopaminergic axons. But it was very specific.

Nicholas Weiler:

I mean, it's odd because I think you mentioned in the paper as well that people didn't even realize that there was myelin on dopamine neurons.

Michelle Monje:

Which is honestly one of the reasons that we wanted to look at dopaminergic neurons initially was it just wasn't known and no one really had taken a close look as far as we could tell.

Rob Malenka:

And another interesting observation is Michelle's team saw these changes with morphine, with cocaine, but not with a food reward.

Michelle Monje:

That's right. That's right.

Rob Malenka:

And that's really important because it says that this myelin plasticity plays an important role in certain forms of adaptive motor learning, of hippocampal dependent memory formation. But here it's only being utilized for a pathological form of learning, for these very powerful stimuli of dopamine neuron activity and dopamine release. And that's important because it looks like it's not happening when I have my Krispy Kreme donut in the morning, or when-

Nicholas Weiler:

It depends how much you let Krispy Kreme I imagine.

Rob Malenka:

Yeah. Yes, exactly. And so these mechanisms in this specific case may really be pathological. The reason that's important is maybe in the long run we can target them for therapeutic benefit. And then it also opens the door to explore does this happen with profound stress, for example, that we believe modifies the reward circuitry?

Michelle Monje:

Yeah. And Rob, I'm so glad that you pointed out the food reward, because the way I think about this is you may modify this reward circuitry with heroin or fentanyl, but not every time you have to. And so it takes a strong stimulus and it takes a certain kind of stimulus to modify the circuitry. And this brings up a point that you alluded to earlier, Rob, that we have relevant to learning and memory adaptive changes in myelin, but there are also maladaptive changes in myelin that can really importantly contribute to disease. And this is a very clear example of maladaptive myelin changes that contribute to this drugs of abuse related reward learning. We have a previous example of maladaptive myelination in generalized epilepsy. The increase in activity within the seizure network caused hyper myelination. That was critically important to worsening of the epilepsy syndrome over time. And that blocking the activity regulated myelin changes was therapeutic in those seizure models. And I think this is a second example of those kinds of maladaptive changes in a circuit contributing in an important way to disease states that we may be able to target therapeutically.

Nicholas Weiler:

That's a really interesting point, Michelle. And it sounds like there are sort of different levels of plasticity. There are types of plasticity that are easy to occur in the brain. Most things make the brain change a little bit, but then for more extreme events or stimuli or learning, maybe the circuits are changing in a more fundamental way that we wouldn't want happening all the time, but those are maybe more lasting and more permanent.

Michelle Monje:

That's one way. I think that's a really important set of hypotheses. I think that this is really the first example that I've seen of a place in the brain that undergoes myelin plasticity where there seems to be a threshold level of activity that is required. So thinking about experimental stimulation strategies, for example, if we're trying to mimic what happens during normal experience, or if we don't use any direct stimulation method and we simply change sensory experience, we see evidence of myelin plasticity in those circuits that doesn't necessarily require a pathological or very, very strong stimulus to occur. And I think that second point that there is evidence not only for new myelin establishment, but also there's newer evidence for myelin removal. And so this plasticity of myelin can go both ways. And there's evidence in the literature for myelin being pruned. These myelin changes are not necessarily permanent, but it's not clear yet what regulates the removal or decreases in myelin in various circuits where I do think different rules are likely operant.

Rob Malenka:

Yeah, and let me emphasize that the devil's in the details. Certain circuits have evolved to be perhaps more sensitive to activity and allow activity dependent myelination and demyelination to happen in response to normal patterns of activity because it's really important for those circuits to be malleable and use all the different mechanisms at their disposal. And then there are other circuits, perhaps the reward circuitry we're talking about that have evolved to use a subset of those plasticity mechanisms. And it's only under pathological conditions, they start utilizing something like activity dependent myelination. And maybe for the seizure type of work Michelle was talking about, these circuits are sometimes using activity dependent myelination in an adaptive way and other times in a maladaptive, pathological way.

Michelle Monje:

I think that's exactly right. And the different brain regions really do seem to have different kinds and different extents of myelin plasticity. I want to point out that in corticospinal projections, those are projections that are fairly ideally myelinated and that makes sense. You really want the signal from your brain to your feet to go as fast as it can to run away from the bear, right? Evolutionarily, that makes sense. But in terms of complex motor output and motor learning, there's a place where some plasticity might be really advantageous, and it's those cortico-collosal, cortico-cortical projections that seem to, in that system, exhibit the plasticity. So there's some really interesting subtleties to understand, and we really as a field need to experimentally probe these different circuits and understand the role that myelin changes play potentially in the way those circuits adapt or maladapt.

Nicholas Weiler:

It's just so fascinating to think about, and I love this point that you're both making that different systems in the brain use these rules in different ways. We're now learning more about this whole new domain of ways in which the brain can change, in this case, the speed of signaling as opposed to the strength of connections that Rob has studied and many others for a long time. And so there's this whole new world open to us to better understand the different learning rules the brain has.

Michelle Monje:

Can I make one quick point?

Nicholas Weiler:

Yeah, sure.

Michelle Monje:

The speed is important, but what's important about the speed is probably the synchrony. So what we found in nucleus accumbens was that myelin plasticity was really important for kind of a coordinated sharp peak of dopamine release. And that in the absence of these activity regulated changes, there was sort of a flattened curve, non synchronous release.

Nicholas Weiler:

I see. So you need the myelin to get all the firing to happen at the same time precisely?

Michelle Monje:

Exactly, or to have all the signals arrive at their target at the same time. And in the healthy brain, what we think myelin plasticity is doing is to coordinate a circuit such that there is appropriate synchrony. And we have some really clear evidence in this study that the addition of the new oligodendrocytes and the consequent changes in myelination results in coordinated dopamine release into nucleus accumbens, and that that's important for reward learning.

Nicholas Weiler:

Right, so it's not so much the speed, but really the timing.

Rob Malenka:

It's both. It's probably both. If the speed is slow in some set of axons and fast in the other, you're not going to get the synchrony.

Nicholas Weiler:

Right. You need control over speed to get proper timing.

Rob Malenka:

Right. Exactly.

Michelle Monje:

Exactly.

Rob Malenka:

Exactly.

Nicholas Weiler:

Well, thank you guys both so much for joining us. I think that we're out of time on this topic, but I'd love to keep hearing how this work is progressing.

Rob Malenka:

Thanks for having us.

Michelle Monje:

Yeah. Thanks.

Nicholas Weiler:

Thanks again so much to our guests, Michelle Monje and Rob Malenka. To read more about their new study and their other work, check out the links in the show notes. This episode was produced by Michael Osborne at 14th Street Studios with production assistance from Morgan Honaker. I'm Nicholas Weiler. Until next time.

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