النص 🔗
Nicholas Weiler (00:11):
Welcome back to From Our Neurons to Yours from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science.
(00:30):
This week, we are going to be talking about sleep, the brain's insulation, and neurodegenerative disease, but before we get into that, I wanted to just share in the time since we last released an episode, we've been doing some thinking about the show. We've had some great conversations with audience members about what works, what doesn't work, what they'd like to see more of, and we're going to try a few new things this season, which I hope you enjoy, and if you do, let us know. If you don't, let us know.
(00:57):
The first is a short segment we're going to do here at the top of the show, which we're calling Updates from Wu Tsai Neuro. Sometimes there's just a little something, a news story or some happening going on here that catches my attention, which we want to share with you just to give you a little behind-the-scenes glimpse into things that are going on at the institute and in the field, so let's give this a go.
(01:22):
Today, I want to tell you a short story about a study that came out recently from the lab of Rob Malenka, who's been on the show a couple of times, that touched on a really interesting topic: how did dopamine and serotonin, these two well-known neurotransmitters, how do they work together to allow animals to learn about their environments and decide what to do?
(01:45):
To me, this touched on a higher-level question of what guides our behavior? What motivates us? Scientists have noticed for a while that dopamine and serotonin both seem to play some kind of role in allowing animals to learn about rewards, like what is going to predict where I'm going to get an exciting treat? Do I go around this corner to the left or do I go down this corner to the right? Do I follow the sound of this music or do I go where I know that there are some red lights flashing? What lets you learn what is going to lead to a good outcome for you?
(02:18):
Both of these chemicals seem to be involved, but scientists weren't really sure how or whether one of them might matter more than another, and part of the reason is that they couldn't see them both acting at the same time. You have some experiments where you can look at dopamine, you have some experiments where you can look at serotonin, but it's really hard to look at both, and that's exactly what this research team did. They genetically created a mouse where they could see the activity of both the dopamine and the serotonin systems at the same time. So then they were able to see that, well, actually, when an animal is learning about a reward, dopamine goes up and serotonin goes down, so that not only they both change, but they change in opposite directions.
(02:57):
The researchers were then able to take it one step further. They use this technique called optogenetics, which basically lets scientists control different groups of neurons using light, and they could turn off either the dopamine system, or the serotonin system, or both. Unsurprisingly, if you turn both of them off, the animal is not able to make these connections. It's like there's a sound and then there's a reward, but I don't see the connection.
(03:20):
But surprisingly, neither of the two systems were enough on their own to let the animal learn really at all. Dopamine wasn't enough. Serotonin wasn't enough. Only when both of them were active could the animal learn effectively. And to be clear, there was some learning with dopamine, there was some learning with serotonin, but it was pretty slow and it took a lot of training. But when both of these systems were active, the animal was able to learn quickly and robustly.
(03:46):
So the thing that the researchers emphasize from this is we know that these are molecules that are really important for diseases. Dopamine is really central in addiction. It drives individuals towards abusive behavior, towards drugs, towards things that stimulate that system that says, "Go out and get this now." And serotonin, we know, is really important in major depression. One of the major lines of treatment against major depression is SSRI, selective serotonin reuptake inhibitors, that basically keep more serotonin in the brain.
(04:17):
And so this study that shows how much these two things work together raises some really interesting questions about, well, what's the relationship between addiction and depression? One way to think about it might be addiction is a disorder of going out and getting a short-term reward at the expense of long-term consequences, and depression could be seen as losing the ability to see the long-term benefits of anything, right? Nothing seems worthwhile. Nothing gives you pleasure. These are different kinds of things people could experience during depression. But if dopamine and serotonin don't work on their own but are working together and balancing one another out, what this means is that future efforts to treat these disorders could focus on making sure the balance is working rather than trying to treat dopamine or serotonin on its own.
(05:05):
So I'm looking forward to seeing what comes of this next, and we'll keep you updated on the show.
(05:12):
Okay, so onto today's main event. Today, we're going to talk about sleep, and I'm very excited about this. Sleep is one of my favorite topics. I enjoy sleeping. I'm sure many of you do as well. And sleep remains one of the most mysterious aspects of not only neuroscience, but of our daily lives. I mean, we spend a third of our lives passed out unconscious, and it is absolutely critical.
(05:38):
I mean, you've probably heard many of these benefits of sleep. It's when our brains are taking the experiences of the day and deciding what to keep as memories and what to throw away. It's when we are clearing the junk out of our brains to keep them healthy and operating well. It's when a
Load full transcript
lot of brain development is happening. It's when a lot of growth is happening, and when we don't get it, bad stuff happens. And if you're getting bad sleep night after night, your mental function is going to start slowing down. The world gets fuzzy around you, your decision-making is impaired. And there's a lot of science that says not only is it bad for you on a day-to-day basis, but it actually increases your risk of a whole host of diseases, high blood pressure, heart disease, diabetes, the list goes on and on.
(06:26):
One area that I actually hadn't heard very much about, and I think it's because it's pretty new, is linking sleep problems to higher risk of Alzheimer's disease and other neurodegenerative diseases. Think about what happens as we age. It's almost a trope or a stereotype that older people nap more. I know a lot of people who complain about increasing trouble getting sleep during the night as they get older, and a lot of people who end up needing to nap a lot during the day. And it turns out that these disruptions to our normal 24-hour circadian sleep patterns could be an early warning sign of Alzheimer's disease.
(07:04):
Now, if you think about this, this leads to sort of the chicken-and-egg problem. Is the issue that, as we age, our sleep gets messed up and that leaves our brains open to the development of Alzheimer's disease? Or could it be the case that because sleep is controlled by the brain, is there something going wrong in the brain that these sleep problems are just an early glimpse that something is awry and maybe an opportunity, a preventative opportunity, that if we see these sleep disruptions, maybe that's a time to go and see what can be done early rather than waiting until more serious symptoms arise?
(07:41):
To take us through this question, we're joined once again by Erin Gibson. Erin is an assistant professor of psychiatry here at Stanford, and she's been on the show before to talk about the importance of our circadian rhythms for our health, but one thing her lab is very interested in is the substance myelin, which is basically the insulation of our nerve cells. It's very important for the speed and accuracy of our brain signals, and it turns out it's very closely linked to some of these neurodegenerative disorders. And Erin is going to tell us about the latest in the field and in her lab helping us to understand this relationship, so let's get right to the conversation.
(08:22):
Erin Gibson, welcome back to From Our Neurons to Yours.
Erin Gibson (08:25):
Thanks for having me.
Nicholas Weiler (08:27):
I want to start off by talking about naps. This is a personal topic for me. I love a good nap, I keep a list of my all-time favorite naps, but for some years now, researchers have been linking napping, at least as we get older, to a higher risk of neurodegenerative diseases like Alzheimer's and Parkinson's, and in general, to cognitive decline as we age.
(08:49):
So I'd love for you as an expert in circadian biology, as someone who's researching neurodegeneration in the brain, to tell us a little bit about what is the science saying here? Is napping more as we age a bad sign for our brains?
Erin Gibson (09:04):
Yeah, no, it's a really interesting question, and a lot of this was spurred by a finding a number of years ago that suggests that what we call increased sleep fragmentation. So the way I like to describe sleep fragmentation is think about like a baby, right? When a baby is born, they will sleep all day, anytime of day, they'll be up at night. There's no real consolidation of their sleep. And as you age, humans especially are very good at consolidating our sleep, so we sleep the majority of the time during the night. So we have this one really large consolidated bout of sleep and we don't really nap anymore.
(09:41):
But as you start aging, you kind of revert a little bit back to the way you were as a kid where you start sometimes having more daytime sleepiness and an increase in napping during the day. And what the field has started to acknowledge is that when you have too much active-phase napping, it tends to be associated with higher risks of neurodegenerative diseases. And one of the strongest links is with Alzheimer's disease in which it's been shown that this increased sleep fragmentation or this increased propensity to nap is associated with a higher risk of Alzheimer's disease. And this can sometime precede the normal pathophysiology we associate with Alzheimer's disease, like memory deficits, a decade or more.
Nicholas Weiler (10:25):
Wow. So you could see that as a first symptom potentially.
Erin Gibson (10:28):
Yes. We're starting to see that potentially this might be a really early-stage risk factor for neurodegenerative disease. And we've actually published a study back in 2023 in which we looked at sleep fragmentation and genetics causal links associated with increased sleep fragmentation, and we compared that to risk of multiple sclerosis. And we saw a similar thing where there was a causal association with increased sleep fragmentation and increased risk of multiple sclerosis. So it seems to be pretty applicable across a broad range of neurodegenerative diseases.
Nicholas Weiler (11:02):
Now, you said something interesting there, which is in your study, I think you called that a potentially causal link, and that's, I think, an important question. So one, does this excessive daytime napping, is that always paired with not having good quality sleep at night? And two, do we know what the causal direction of this is? Because I could imagine that neurodegeneration could mess with your sleep and messing with your sleep could impact your brain health.
Erin Gibson (11:28):
Yeah, no, exactly. It's the whole chicken or the egg, which is what a lot of a study is trying to understand causality and directionality of these things.
(11:36):
Napping is not necessarily bad. In fact, there's plenty of evidence that having a short nap in the late
afternoon, 2:00 to 4:00-ish PM-ish, is not necessarily bad. A short nap can actually enhance some cognitive features. So you don't want to go too late in the day because then it disrupts your sleep at night. Well, I don't want people to think they take a nap during a day it's a bad thing. It's the frequency of those naps, and the more naps you have during the day, the more impact it's going to have on your quality of sleep at night.
(12:03):
Because there's two things that drive sleep. There's a circadian path, a circadian rhythm. As humans, our body is driven to sleep during the night phase. So we have 24-hour rhythms and they oscillate over this 24-hour cycle, and we have intrinsic rhythms at the cellular level, at the organ level, and then we obviously have environmental 24-hour rhythms, and we entrain or synchronize these intrinsic rhythms with the external environment. And so we have this circadian drive as humans to sleep during the night, but then we also have this potential homeostatic drive in that we have this buildup of a homeostatic need for sleep. And when these two processes intersect at the proper angle basically, that's what initiates sleep.
Nicholas Weiler (12:45):
So it's a combination of, "It's getting dark, it's time to sleep," and, "I haven't slept for 10 hours, I'm getting tired," so those two things pair up. So if you're messing with either of those, if your circadian system is off, it's going to be hard to sleep, or if you sleep a lot during the day, you're getting rid of that sort of buildup of tiredness that you need to fall asleep.
Erin Gibson (13:08):
Exactly. And so then those two things don't align properly and you don't have good quality sleep at night during that consolidated period.
Nicholas Weiler (13:15):
So I have a question about that, which is the last time you came on the show, we talked extensively about why we need to respect these circadian rhythms, why they're so important for our health and for our biology. And as you just mentioned, that's the way our bodies are wired down to the cellular level to follow this 24-hour cycle of day and night.
(13:35):
I think people are probably familiar for the most part these days that getting good sleep is critical for our health, but why is it so important to get good quality sleep at the right time?
Erin Gibson (13:46):
Yeah. So part of that is that sleep is not uniform, right? So we cycle through different stages of sleep, REM sleep, which is when you dream, non-REM sleep, which is the deep sleep that you need that's more associated with regeneration and potentially memory, and so we cycle through sleeps. And the way that this architecture flows throughout our consolidated long-sleep period is that there are certain phases in which we have more non-REM sleep. There are certain phases in which we may have more micro-arousals. There's certain phases we may have more REM sleep.
(14:17):
An so if you start disrupting that total amount of sleep, you're going to disrupt
the architecture, and that architecture is very important to making sure it's quality sleep. If you start taking away that homeostatic drive during the day by napping too much, you may not actually get into some of those deep sleep states as you need in order to actually get the benefits from that stage of sleep.
(14:42):
And that's, in fact, what we have seen in a paper we published back in 2023 is that the total amount of sleep and the total amount of wake in these mice that had these changes in these insulating cells didn't differ, but the architecture of that sleep differed. So they had fragmented, non-REM sleep. That means they didn't stay in non-REM for very long. So these were mice and mice are a little different than humans, so whether or not that translates into functional deficits is still unknown. But generally, it's not just about the total amount, it's about the architecture of, it's the quality of those bouts of sleep as well that matter.
Nicholas Weiler (15:22):
Got it. And I want to delve into the connection between circadian biology and neurodegeneration. I do want to pause just very briefly. I love this idea of sleep architecture. There's a whole process that needs to happen and that has different phases and the different phases need to happen for different amounts of time, maybe in a particular order. And so you can't just say, "Well, I took 50 naps, and that's the same as," I'm not going to do the math there, "but that's the same as a whole night's sleep."
(15:50):
Are there any other pieces of what needs to happen during sleep that we should be bearing in mind as we start to talk about the things that could go wrong in the brain as a result of interrupted sleep?
Erin Gibson (16:03):
Yeah. One of the things and one of the reasons we're intrigued by sleep in our lab is because when you think of sleep and sleep circuitry, as neuroscientists, we like to get into circuits, a lot of people study addiction by looking at a specific circuit or memory by looking at a specific circuit, when you think about sleep, it's really more of a sleep network. The entire brain, for the most part, is involved in sleep from the front of the brain, the frontal cortex, major white matter tracks, like the corpus callosum that allow information to travel from one hemisphere to the other, all the way back to the back of the brain in the brain stem.
(16:41):
And so in many ways, I think when you have disorders that can affect the entire brain, much like most of our neurodegenerative disorders do and most of our neurological disorders generally, in a weird way, sleep can be a very interesting output measure for brain-wide functioning because it involves the entire brain in terms of the various circuits. And so it's not super surprising that when you look at everything from autism spectrum disorders up through Alzheimer's disease and multiple sclerosis, sleep disturbances are common features.
Nicholas Weiler (17:17):
Right. If something is wrong with the brain, it's probably going to affect sleep.
Erin Gibson (17:21):
Probably. And so the question then becomes a little bit, to your point earlier, is are these deficits in sleep the chicken or the egg? Are they driving these neurological disorders or are they a consequence of the neurological disorders and the brain dysregulation that's associated with them disrupting that sleep network? I personally don't think we have answers to that, but it's a very interesting relationship that might give us some insights into the underlying biology of these various neurological disorders.
Nicholas Weiler (17:51):
Fantastic. Well, let's dive into that. I really want to know what your team is discovering at the frontiers of this field. So let me set this up just for a moment for our listeners, and please correct me if I get any of this wrong.
(18:05):
I mean, research in this area, I'm talking about neurodegenerative disorders, like so many other areas of neuroscience, has traditionally focused pretty exclusively on the neurons, the classic brain cells that neuroscientists have been studying since the late 19th century. They form networks, they send electrical signals back and forth, they communicate with each other with chemical neurotransmitters at special synapses, they have synaptic plasticity. And the classic view of neurodegeneration also focuses on the neurons. Diseases like Alzheimer's are classically characterized by buildups of protein amyloid plaques between the neurons and tau tangles inside of the neurons. And all this junk is thought to ultimately kill off networks of neurons that are responsible for things like memory and, gradually, our whole brain.
(18:55):
But your research focuses on different kinds of brain cells, glial cells. Glia had basically been ignored for a long time, but after the past two decades, we're realizing they do all kinds of important work: clearing out toxins from the brain, acting as the brain's immune system, pulling down fuel from neurons from the bloodstream, pruning synapses, and so on.
(19:16):
The type of cell you focus on makes myelin. And I'm going to continue my possibly overly long intro, but if you want to say any of this in your own words, I would welcome that as well. The kind of glial cell you focus on makes myelin, which is the fatty insulation that goes around nerve fibers and makes up the brain's white matter, and that's basically like the plastic insulation on an electrical wire. Speeds up electrical signals, makes them more reliable.
(19:42):
I want to understand what made you think about linking your interest in these cells that make myelin, what led you to connect that to circadian biology and neurodegenerative disease?
Erin Gibson (19:54):
Yeah, so it was a bit of a serendipitous play in life, I guess. I did my PhD in circadian biology, and I was always quite fascinated about this beautiful hierarchy of biological clocks from the cellular level to the organ level, to the whole organism level, and then
synchronizing with the environment. So it biologically was a very beautiful process. The thing that was always intriguing to me about circadian rhythms, they seem a little bit counterintuitive in that you have these broad, dynamic ranges in physiology and function, but the job of this rhythm is to maintain homeostasis, stability. And so that kind of seems counterintuitive.
Nicholas Weiler (20:33):
They're changing all the time in order to keep things the same.
Erin Gibson (20:35):
Exactly. And so I was like most neuroscientists 20-plus years ago, I was a very neurons-focused person, but I was always intrigued by glia because they seem to be these very dynamic cells and so it seemed like the circadian clock would have a big role in these cells. And so I started doing glial work during my postdoc when I was here at Stanford with Michelle Monje, and that's where I got into myelination.
Nicholas Weiler (20:59):
Okay. So you identified these cells that make myelin as potentially really interesting for understanding circadian biology, and ultimately, your lab is supported by the Knight Initiative for Brain Resilience here at Stanford to look at connections between these myelin-making glial cells and what might be going wrong with them in the context of neurodegenerative disease.
(21:25):
So what's the link there and what are some of the findings that you have been coming up with to understand the connections here?
Erin Gibson (21:31):
Yeah. So one, we've been looking at multiple sclerosis, which is one of the most prevalent neurodegenerative diseases, and that is a myelin-focused disorder, right?
Nicholas Weiler (21:40):
It's basically an autoimmune disease that attacks myelin.
Erin Gibson (21:43):
Exactly. So the immune system attacks these myelin-forming glia, and you get a demyelination or these lesions in which you don't have myelination. So that was a very obvious first step for us.
Nicholas Weiler (21:54):
And I'm sorry, what does that do? What's the outcome of that loss?
Erin Gibson (21:57):
So when you get rid of myelin, then the axons themselves can't efficiently send their neural signals. So you get deficits in motor function because the signals can't arise at their location at the proper time or speed, you get eventually cognitive dysregulation as well because once again, the neurons themselves can't efficiently communicate with one another.
(22:21):
That's where we started, but there were two things that have led us into studying other neurodegenerative diseases, and one of the main drivers was that when we disrupted the circadian clock in these myelin-forming glia and we resulted in massive dysregulation of these cells and myelin, and we identified this very interesting non-REM, deep sleep fragmentation, and it really was localized to the wake phase in these mice. And like we said earlier, one of the first risk factors identified in individuals with Alzheimer's are increased napping.
(22:59):
And so around the same time we were publishing
that work, some work came out of Klaus Nave's lab at Max Planck in Germany showing that deficits in myelination precede normal AD pathophysiology. So generally with normal aging, you see decreases in myelination. If you accelerate that process, you actually accelerate the accumulation of plaques in mouse models of Alzheimer's disease.
Nicholas Weiler (23:27):
Let me unpack this for a moment. We're talking about a couple of things. So in your research, you basically disrupted the circadian clock in the brains of mice, but only in the cells that make myelin, and you found that this leads to both problems with myelin production and these disrupted sleep patterns where they're sleeping less and they're waking in times when they normally would be sleeping. So we're seeing that there's something with the circadian biology of these cells that is causing problems with myelin and problems with sleep.
(23:58):
And then this other research coming out of Germany is showing that if you disrupt myelin more, the brain develops more Alzheimer's-like pathology, these clumps of protein that characterize that disease. Do I have that right?
Erin Gibson (24:14):
Yep, exactly.
Nicholas Weiler (24:15):
Okay. And so what are we taking away from this? It seems like there is this connection now between myelin, circadian rhythms, and Alzheimer's disease, but what is your interpretation of all of that?
Erin Gibson (24:26):
Yeah, so we're doing studies now to actually try to probe that question directly, and we are taking our mouse models in which we can disrupt the circadian clocks specifically in these myelin-forming glia. And we've now crossed them to mice that are a mouse model for Alzheimer's disease that also exhibits similar Alzheimer's disease pathology as well as sleep disruptions that we see in our human patient populations. And so we're starting to really probe directly at how the circadian system within these myelin-forming glia may contribute to the sleep dysregulation we see associated with Alzheimer's disease and also the normal pathology within this disorder.
(25:05):
And so we're still early stages, we don't have the story yet, but one of the things that we have identified and that we're working on is we have this hypothesis that potentially aging in the circadian system at the cellular level may be contributing to this dysregulation of myelin, and that is what's preceding some of these normal Alzheimer's disease pathology.
(25:29):
And what we've found, actually, and this is work that we're hoping to submit for publication in the next month or two, is that when you disrupt the circadian clock in these myelin-forming glia, and you look at these cells... So in our hands, we oftentimes will look at these cells when they're in a mouse on postnatal day seven, which a myelin-forming glia cell from a mouse at this really early developmental stage should be the most peak-functioning cell. So these cells should be young, strong, they should be healthy. And yet when
we disrupt the circadian clock in these cells and we look at them, these cells essentially look like a very old myelin-forming glia.
Nicholas Weiler (26:09):
Interesting.
Erin Gibson (26:10):
So metabolically, they look like an old cell. They're a senescent cell. We oftentimes, senescence is associated with aging. They don't proliferate as much, they don't differentiate as much. And then when we compare those cells to an actual aged myelin-forming glia, so if we look at a 20-month-old myelin-forming glia, they look almost exactly the same.
(26:37):
And so one of the things that we think might be happening in some of these neurodegenerative disorders, at least in the realm of myelin and myelin-forming glia, is that this accelerated aging in the circadian clock causes these cells to age prematurely. They then start functioning not as efficiently, and that leads to a bunch of downstream effects that will then contribute to some of these neurodegenerative features that we typically see.
(27:07):
And so this concept that the circadian system can age is not novel. And one of the reasons we think that individuals, as they age, tend to take more daytime naps and not sleep as well at night is because the circadian system is aging and not running as efficiently on that 24-hour cycle as it did when you were younger, and so we think that might be occurring at the cellular level within these myelin-forming glia.
Nicholas Weiler (27:34):
I find this really interesting, and I just want to make sure that we're on the same page here. What you're hypothesizing is that if there are problems with the circadian systems in the brain, and maybe these are caused just by the normal process of aging, this is one of the things that breaks down as we age, our circadian systems, what you're showing is that that leads to Alzheimer's pathology. Do I have that in the right order or-
Erin Gibson (28:00):
Yeah, yeah.
Nicholas Weiler (28:00):
... are we not sure about how those things connect here?
Erin Gibson (28:02):
We're not exactly sure, but one of the things we're hypothesizing is that this circadian dysregulation is upstream of potentially a lot of these effects.
Nicholas Weiler (28:12):
So the circadian disruption comes before the Alzheimer's pathology is the hypothesis, potentially?
Erin Gibson (28:17):
Yeah, potentially. And so one of the things that we have found is that we can actually rejuvenate these cells if we administer certain pharmacological agents that have been shown to potentially play a role in rejuvenating myelin-forming glia and enhancing myelination, so things like Metformin, or something called NMN, which is a precursor to something called NAD, which plays a role in the metabolism of cells and energy of cells. But we find that we can only rejuvenate these cells that have the circadian clocks disrupted if we give these drugs at certain times of day, and specifically, at the time of day when these processes are supposed to be occurring, but are no longer occurring at that time of day because the circadian clock is dysregulated.
(29:07):
And so what we are hoping to see is that if we can really target these metabolic processes at the time of day that they should be occurring, can we rejuvenate the cells, slow down this aging process or reverse it, and then do we see an improvement in myelin, do we see an improvement in sleep, and whether or not this upstream circadian dysregulation is really driving a lot of this downstream pathology?
(29:39):
One of the things that is interesting, and we've actually looked at lesions in the brains of individuals with multiple sclerosis, and we do tend to see more dysregulation in circadian genes in these myelin-forming glia in the lesions than in non-lesioned brain tissue.
Nicholas Weiler (29:56):
Interesting. So you can see where there's actually damage, and it looks like there's genetic evidence that maybe there have been circadian disruptions there.
Erin Gibson (30:03):
Yes, specifically in these myelin-forming glia, yeah.
(30:06):
So it's very early, there's a lot more questions, but we really do potentially think that this could be a really novel therapeutic approach for a lot of neurodegenerative diseases, especially those associated with myelin disruption and sleep disruption, that really targeting these cells, but in a very, what we call, chronotherapeutic manner. So not just giving drugs, but giving them at the time of day in which they will be most efficacious could actually not only enhance the efficacy of these drugs generally, but also maybe minimize some of the pathologies associated with these neurodegenerative disorders.
Nicholas Weiler (30:44):
Right. If the circadian timing of myelin formation is off, you need to fix it at the time when it's supposed to be making myelin.
Erin Gibson (30:51):
Yeah.
Nicholas Weiler (30:52):
Great. Well, this research is so exciting because as a field, neuroscience has been trying to come up with solutions for Alzheimer's disease and other forms of neurodegeneration for so long, and there are glimmers of hope, there's certainly treatment, symptomatic treatments, things that make symptoms better in some of these disorders. There are new drugs for Alzheimer's disease. We've talked with Mike Greicius on the show before about questioning how much these really help, but I think there are a lot of people out there who are frustrated that with all the investment we've made, hopefully next year, next five years, it will finally pay off, but it's great to see these different approaches being taken, like, okay, we know that there are these toxic proteins, but what's the role of sleep? When does that start? Maybe that's an earlier way in to try to deal with some of these issues.
(31:43):
To me, that brings us back a little bit to this chicken-and-egg question of does poor sleep cause neurodegeneration or does neurodegeneration cause poor sleep and the poor sleep is a warning sign that something may be wrong in the brain? As
you said, if there's something wrong in the brain, it's going to affect sleep. So I wonder if we could just take the last couple of minutes that we have here and talk a little bit about that.
(32:10):
First, on the sleep-to-neurodegeneration side, is there evidence that treating sleep disruption could help protect our myelin or our brains in general and reduce the risk of neurodegenerative disease?
Erin Gibson (32:27):
I think those studies are really hard to do. Most of these studies are pretty correlative in terms of looking at quality of sleep and then looking at risk factors.
Nicholas Weiler (32:37):
Right, it's hard to tell if the sleep can change the risk.
Erin Gibson (32:40):
Exactly. I mean, I think one of the things that I think it's always important to think about, especially with neurodegenerative disorders, is when we talk about developing those disorders, it's the risk of developing those disorders. And there's very few of these disorders which is you can say, "You're 100% going to get this disorder," right? I mean, Alzheimer's disease, multiple sclerosis, Parkinson's, oftentimes they're multifactorial.
Nicholas Weiler (33:04):
They have many causes.
Erin Gibson (33:05):
And their causes. And so the way that we like to think about it is, is if you have certain risk factors, do you elevate those risk factors by potentially having sleep disruptions? Does sleep dysregulation elevate that risk versus solely it being like a single causal event to them? And so I think that's the way we try to think of it. So whereas if you can mitigate that, can you reduce your risk?
(33:33):
There's no one magic pill that I think is going to cure these disorders. They're just too multifactorial. And there are genetic predispositions that elevate your risk, but none of them make you 100% likely to develop Alzheimer's disease or develop MS. And we know there's environmental factors that elevate your risk, right? But it's like the combination of various risk factors that then puts you on the course to developing it, and if we can figure out which of those risk factors are more dominant and find ways to maybe target those, can we then minimize the risk?
Nicholas Weiler (34:11):
It's a little bit like with cancer where many of the things are, how can we reduce the risk that you're going to get this early? We all have a limited lifespan. If we can just put off these things, if we can give ourselves more time, if we can make these things happen later, if we can lower our annual risk of this being a problem.
(34:30):
And I think one of the most fascinating things in neurodegenerative disease research is you look at the brains of people who die age 90, age 100, very healthy, cognitively fine, very often you see these buildups of amyloid plaques, like their brains are full of this stuff, but they're fine. And so that's one of the things. I mean, that's why we talk about the Knight Initiative for Brain Resilience, which is what are the things that make our brains resilient against some of the things that go wrong as we get older? And it seems like we're saying that sleep, circadian rhythms, and all of this is a really important one to be looking at.
Erin Gibson (35:04):
Exactly.
Nicholas Weiler (35:06):
Well, the last thing I want to ask about, because we've brought up several times the idea that potentially this disruption of our normal sleep architecture as we age, that we're sleeping less well at night, we're taking more naps during the day, could be considered a warning sign of early-stage, potentially asymptomatic neurodegenerative disease, and I think that's something that's probably very worrisome. We do all know people who are getting older who take more naps. Maybe we know in ourselves we can see this.
(35:35):
So what are some things that listeners might want to know about that? If they have a relative or if they themselves are noticing this, are there now things we can do? Is this now a useful warning sign?
Erin Gibson (35:48):
Yeah. I mean, I think it's a useful warning sign even if it's not for neurodegeneration, right? Generally, quality sleep leads to quality cognition. And so even if you aren't worried about developing a neurodegenerative disease, sleep enhances your brain function. And we know this because individuals who are shift workers, so doctors, nurses who are working night shifts, pilots, tend to have deficits in cognition. And we know that by reestablishing proper sleep patterns, you can override those deficits to cognition.
(36:26):
So we're in a good space, I think, in time because I think everyone agrees sleep is an important biological process, that we should all be doing it properly, and the benefits far outweigh anything we could imagine. And so just having as healthy of sleep hygiene as you can will only ever really enhance brain functioning.
(36:47):
There are things that we can do, and people have heard these sorts of things. Sunlight in the morning is important for entraining your circadian clocks. You do not need to go outside and stare at the sun, which I think people have implied, and you don't need to do that, but getting morning sunlight is good. Minimizing light at night so your body starts getting those cues that it's dark and it's nighttime, "I should go to sleep." This allows your melatonin to start rising, which is that timing cue to our body that night's coming and at night, we, as humans, sleep. Trying not to nap as much during the day. Part of that comes through nutrition. So oftentimes, if you eat a very large lunch, you want that post-nap lunch. So maintaining energy levels and glucose monitoring can actually help to ensure that you don't necessarily feel that need to nap during the day.
(37:42):
So there are behavioral things you can do to enhance the quality of your sleep that are relatively low effort, but can have a big reward.
Nicholas Weiler (37:51):
Fantastic. Well, I am going to take my naps sparingly, but this is really helpful, Erin. Thank you so much for coming on the show and telling us what we are learning about the connection between sleep and our myelin-forming cells and neurodegeneration. We'll look forward to having you back on soon to hear how these things are going.
Erin Gibson (38:14):
Happy to. Thanks for having me.
Nicholas Weiler (38:17):
Thanks again so much to our guest, Erin Gibson. Erin is an assistant professor of psychiatry and behavioral sciences at Stanford School of Medicine. To read more about her work, check out the links in the show notes.
(38:29):
On the next episode of the show, ultrasound.
Kim Butts Pauly (38:32):
The beauty of this technology is that something as big as, say, a hockey puck that you put up against the skull, then we can focus down to a point deep in the brain. The focal spot could be about the size of a jelly bean.
Nicholas Weiler (38:44):
Don't miss this, and other upcoming conversations from the frontiers of neuroscience. Subscribe or follow the show on your podcast platform of choice. And if you're enjoying the show, please help us spread the word and bring more listeners to the frontiers of neuroscience. As always, we'd also love to hear from you. Leave us a comment on your favorite podcast platform, or send us an email at neuronspodcast@Stanford.edu.
(39:06):
From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios with production assistance from Morgan Honaker and research assistance from G Kumar. I'm Nicholas Weiler. Until next time.