We do not enter into the world with impressive knowledge of ourselves and our surroundings. We can’t survive alone, let alone dance or do martial arts with grace and efficiency. We don’t know how to interact best with different types of people we encounter. We don’t know how to accelerate our ability to get better at something. We acquire these skills by learning, and by virtue of this capability have the potential to do great things.
Today, important events happened that are worth learning. Tonight, when you sleep, your brain will process that stimulation – the sites, sounds, thoughts, emotions, facts, and so on – into memories that you can access at a moment’s notice in the future. It’s amazing when you think about it: Experiences become parts of who we are.
How much do you know now that you didn’t know 10 years ago?
Learning and accessing information is so routine that it’s easy to forget the processes that make it possible. As it turns out, sleep plays vital roles in these processes. In this interview, I speak with someone who has made, and continues to make, significant contributions to help the world better understand how all this magic works. My guest is Marcos Frank, PhD, Interim Chair of the Department of Biomedical Sciences in the Elson S. Floyd College of Medicine at Washington State University. I hope you enjoy this discussion as much as I did!
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Transcript
| Marcos Frank: | There are things that are going on while you’re sleeping, mechanisms that are activating that are part of this complete process that makes the brain change itself in light of new experience.
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| HumanOS. Learn. Master. Achieve.
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| Dan Pardi: | Greetings, everyone. This is Dan Pardi, and I am very excited to have with us today Professor Marcos Frank from Washington State Univeristy. Now, Marcos and I have known each other for probably ten years. We met at a off-site, I don’t even know how to describe this. It’s like a sleep campout for adults. It’s actually like a mentorship program where younger scientists come and get to interact with older, well-known scientists in the sleep field and help develop their career.
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[00:01:00] |
I was fortunate enough to go that, a place called Lake Arrowhead in Southern California. Anyway, Marcos and I had a chance to meet there and got along really well. Since that time, whenever we’re at the big sleep meeting, the Associated Professional Sleep Society’s meeting, which is the yearly US-based sleep conference, we get together and hang out, and a really nice friendship has developed.
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| To kick things off, Marcos, tell us how you got into the sciences in the first place, and what your career path has been like.
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| Marcos Frank: | It was a twisty path. It began because as a undergraduate student at the UC Santa Cruz, I was interested in dreaming, actually. That got me thinking more about what the mind and brain is doing during sleep. Dream are quite difficult subject matter or science. It’s very hard to actually do scientific work on dreams since you don’t have the dream itself. You have reports that people make to you.
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| That got me into thinking how can we study other aspects of sleep, make it a little bit easier to measure and to control, and I realized as I started getting into those questions that there were lots of questions about sleep that were still not answered. It was true then, just now over 20 years ago, and it’s just as true now. Fundamental questions, why do we sleep? What is it that makes us sleepy in the first place?
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| [00:02:00] | These are things that scientists have been grappling with for over a hundred years in the modern era, but we still don’t have conclusive answers to those questions. That got me going, and then as a graduate student at Stanford, I pursued those ideas more, looking at very basic questions about how does sleep change during early life? How does it affect the brain in early life?
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| That led to questions about, well, does sleep actually do things to the developing brain? Does it actually help the developing brain change its connections? In other words, as you mentioned, does it influence brain plasticity? That really was the launching pad for my career, because after doctoral work and the Univeristy of California San Francisco, where I work with essentially someone that had worked with the grandfather of visual neuroscience.
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This person was Torsten Wiesel and David Hubel at Harvard. The person I worked for was a post doc with them, and for those that don’t know, Hubel and Wiesel won the Nobel Prize for their work about brain plasticity in this part of the brain. I was in a great lab to combine measurements of brain plasticity with sleep, and that’s what we wound up doing. The work from there really launched my career, first at Univeristy of Pennsylvania, where I was there for about 11 years.
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| After getting promoted there, I was approached from people like Washington State Univeristy, where they already had a concentration of great sleep researchers, to join their group. It was an offer I couldn’t refuse, and now part of this very brand new medical school, one of the first new medical schools that’s been launched in a long time in the United States. It is quite exciting. We’re doing a lot of interesting things. My recent interests, although they’ve moved away from dreams, they’re still very much embedded in these fundamental questions about what sleep is doing.
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| Dan Pardi: | Marcos, a lot of the work that you’ve done has been with a model called ocular dominance. Can you tell us about that?
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| Marcos Frank: | Right. The model you’re referring to was the kind of plasticity that David Hubel and Torsten Wiesel discovered, and partly because of their discoveries with this model, that’s what got them the Nobel Prize. What it refers to is the fact that an animal such ourselves, that have eyes that face forward, the parts of the brain that processes information with two eyes has neurons, brain cells, that are activated by inputs from either the left eye or the right eye.
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| [00:04:00] | These form actual columns of neurons, anatomically distinct columns of cells span the entire cerebral cortex up and down. These columns are plastic. They can change their shape in response to experience.
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| Dan Pardi: | You’re using this term plastic or plasticity. Tell us more about what that means.
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| Marcos Frank: | It means that the connections that are within these columns are changing, too. The strength of the actual, physical connections between neurons, or these electrochemical connections between neurons, those change. The synapses themselves are changing, and then that’s followed by very large-scale anatomical changes that actually change the shape of these columns. All of that is plasticity, basically.
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| What was shown now some 40, 50 years ago was that if visual is blocked in one eye during a critical period of development, the neurons that were on the column that served that eye would shift their response to the open eye. It was this huge plastic rearrangement that occurs in light of this change in vision. This was not some arbitrary experimental manipulation, because at the time there was great debate about when to take cataracts out of a child’s eye.
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| [00:05:00] | What they noticed is that if you wanted long enough, you waited for the child to be, let’s say 10 or 12 years old and did the surgery, which was an easier surgery for the child, there were these long-lasting irreversible problems with vision in these patients. They had problems with basically with their stereo vision, and it never could be reversed. That led to this idea that there might be a period of time early in life where these circuits were being shaped by experience.
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| If you messed with that experience early in life, you cause these irreversible changes. That’s led to the studies in animals models that then reveal that indeed that’s true, that there is this plasticity that was going on in the visual cortex, visual system that was critical and essential for the normal refinement of the circuitry that allows us to have binocular vision as adults.
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What also makes this very important is that this type of plasticity, ocular dominance plasticity, it was one of the first that had been described in the intact brain in humans and animals as they actually experienced their environment, because prior to that, most of what we knew about plasticity in the brain came from what we would call reduced preparations. Cultured neurons, slices of brain that are maintained in a dish, and although lots can be learned by those reduced preparations, it’s a long way from that to what the intact brain actually does.
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| You’re losing a lot when you take cells out of the brain and culture them. You cut the brain, you’re cutting away all the normal things that normal come into the slice of brain. It was one of the few in vivo models of plasticity that was discovered, and consequently over the last 50 years, we learned a tremendous amount about it. We know a lot about the cellular molecular mechanisms that govern it, kinds of experience that drive it, and as we are finding out lab, that experience is not the only factor that’s important.
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| There are mysterious offline processes that occur during sleep that are very important for the full expression of this plasticity in the brain.
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| Dan Pardi: | When you say offline, are you referring to the period when an animal or a human is asleep versus when they’re awake?
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| Marcos Frank: | Exactly. That shorthand is saying there are things that are going on while you’re sleeping, mechanisms that are activated that are part of this complete process that makes the brain change itself in light of new experience.
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Dan Pardi: |
So among other learnings of this type of research, we can gather that the type of stimulation a young brain receives is important to ultimately how it develops.
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| Marcos Frank: | That’s right, and basically what we’ve learned is that this is but one of many so-called critical or sensitive periods in brain development. It turns out that almost every sensory system that’s been examined in any detail exhibits these periods of time when essentially animal, or the person, the child, the baby is expecting to receive a certain level of sensory input so that the brain can then adjust itself and develop the strength of these connections so it can operate properly in the world.
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If experience is abnormal during those times, it can lead to these very abnormal responses that are often irreversible later in life. We’re taking advantage of the fact experimentally that there are these naturally occurring windows where the brain is very, very plastic to understand more generally how experience and also sleep affect plasticity, because what we’ve learned in the visual system is not just true for the visual system. Same sorts of mechanisms are in play in the auditory cortex, in the somatosensory cortex.
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| Other parts of the brain that do other kinds of processing. What we’re trying to learn here are general, basic rules that apply everywhere in the brain and at all times of life, but this is one way to get there, by taking advantage of these naturally occurring periods.
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| Dan Pardi: | What are some of these critical windows in humans?
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| Marcos Frank: | Obviously it’s hard to pin this down as precisely in humans, but there’s definitely a visual critical period like I just mentioned. If children have problems with their cataract in their eye, or lazy eye, for example, and if that’s not corrected within a window of time, in humans that could be between birth and four years of age, then you could have these long-term hard-to-reverse changes in the brain and visual processing.
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We think there may be critical periods for speech and language acquisition. We’re familiar with the idea that it’s easier to learn a language when you’re young than when you’re old. It appears that there may be some actual neurobiological truth to back this up. There is a critical period for language acquisition. Socialization is another one that there seems to be evidence there are windows of developmental time when those parts of the brain that process our ability to interact socially with other animals, or our own species I should say.
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| If we’re not exposed to the right kind of social input at those times, then those social mechanisms don’t develop, either. Audition, hearing. There’s definitely some evidence that beyond language acquisition, that the cortex that processes sound, and other structures in the brain that process sound, they themselves have critical periods of time when they adjust themselves to the sounds that are out there.
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| There’s definitely a lot of evidence, and that’s all true for humans, as well. All of those things seem to be in place in humans.
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| Dan Pardi: | A lot of how our brain develops is in response to the stimulation that it receives, especially during these critical windows of time, but the mechanisms involved and how the stimulation we do receive during the day, whether it’s auditory, so sounds or vision, or even social stimulation, affect how neurons will connect in our brain. This continues to happen throughout life.
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| Earlier you mentioned offline processing. Tell us more about how sleep would affect how our neurons will interconnect.
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Marcos Frank: |
That’s exactly what we’re trying to figure out. The first thing that we found out was that in order to see the full changes that experience can elicit, you need to have a period of sleep. If you look just at what experience alone does, it causes some changes in the circuits, at least the system that we were looking at. If you let in this case animals sleep after that experience, there are much, much more changes in the circuits.
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| It’s as if you put the gas pedal down, and you got more plastic change during sleep. Why is that? The other thing we think is happening, it’s not only that, is that you get more plastic change from the experience, but those changes seem to be more resistant to interference later on. This is a classic description of what’s been called consolidation. In classic studies of memory, the consolidation refers to the fact that memories are very fragile initially, or some memories can be fragile initially.
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Over time, they crystalize and become more resistant to interference. That probably has something to do with plasticity mechanism in those parts of the brain that are generating those memories, and then ultimately retain those memories. Similar happens in the cortex. This would be something in another part of the brain called the hippocampus that’s important for memory, but of things and objects.
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| We think this is more generally true for neurons and their connections, that there are periods of time when experience can cause an initial change, but that change is potentially fragile, and then something happens over time that makes that change more permanent and a larger effect. The question then is, okay, why would you need sleep to do these things? Why can’t you just do this while you’re awake? That’s the million dollar question.
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| That’s exactly what we’re trying to find out now, is why do you need to go into this very bizarre state of consciousness, this very bizarre pattern of activity in the brain in order to accomplish this process? Why can’t you just do it while you’re awake or just sitting quietly? I can’t tell you that we have an answer yet, but we have some clues. One of the things we think is going on is that there really is division of labor in brain cells over time.
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A brain cell is essentially like any other kind of cell in our body, that it’s a eukaryotic cell. It has limited energy resources to do everything at once. What we think is that there are times when the cell is in a more anabolic state. It’s making things, it’s making proteins. It’s making things that help establish its membrane, and we think that there is evidence during sleep that that’s when those events occur.
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| During sleep we find that there are lots of genes that are turning on during waking, but it’s really during sleep when we see them made into proteins, and for most genetics changes, at least changes that involve genes, it’s often not enough to have the gene made or transcribed. You need to actually have that messenger RNA turn it to protein for it to actually do something in the cell.
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| Now we have evidence that during sleep, there’s a shift into this anabolic condition of the brain cells, so they’re more likely to make proteins, they’re more likely to make membrane, and all those things are really important if you’re trying to go from a very fragile state of circuit to something that’s more permanent.
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| Dan Pardi:
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Let me attempt to translate some of this. I’m trying to learn something for a test the next day, and me studying during the day gets me exposure to the concepts that I’m trying to learn which starts the learning process, but these memories are fragile. At night, due to this strange pattern of brain activity that is sleep, we respond to that stimulation and form new protein, which strengthen the membranes of the neurons that are involved in the formation of these new memories that you’re trying to learn.
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| This stimulation then becomes a part of who we are. It’s actually changed our brain.
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| Marcos Frank: | That’s a reasonable interpretation. Essentially, there are changes in the sleeping brain that are making these experiences more permanent, or strengthening them and preventing them from being erased as easily. That’s one way to think about it. They are all kinds of different circuits that are engaged in a learning task, and how they behave is not uniform. If you’re in one part of the brain, there may be that kind of change with experience, and that kind of change with sleep, but in another part of the brain, the change from experience might be in the totally other direction.
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| Dan Pardi: | When does this process take place during sleep? Are there some stages of sleep that are more important than others for this consolidation of memory?
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Marcos Frank: |
Yeah, that’s another great question, and we also don’t have a full answer to that, either, but we found roles for both rapid eye movement sleep and non-rapid eye movement sleep, at least in the system that we studied. What we think is going on is that each state, for reasons that we don’t understand yet, it is necessary to turn on different sets of biochemical events.
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| During REM sleep, we see one set of enzymes and neurons turn on, but during non-REM sleep, different sets of enzymes are turning on. What’s interesting is that the enzymes that turn on the non-REM sleep can actually trigger those that then turn on in REM. There’s a relationship between the two sleep states, at least on a biochemical level, we think. Which makes sense, because in normal cases, that’s what we see.
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| We see the two sleep states interact during the course of the night, and they cycle with each other and there are interactions between them, so there must be something on a biochemical level that links them, as well. Why helpful need to divide it up like this, it’s not clear yet, but that’s what we’re finding, is that they’re partners in this process, but the partnership is still mysterious.
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| Dan Pardi:
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In reading your latest paper, there are several changes that you have identified that take place during REM sleep. One of these changes is the production of new proteins that are critical to the process of neurons interconnecting, but you also show that the same group of neurons that are activated during daytime experience have heightened activity during sleep. This I guess reinforced the neural patterns present during an experience.
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| I guess it seems like the brain is basically replaying an experience that it had during the day over and over again. Tell us more about that.
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| Marcos Frank: | That’s what we think is going on, and I have to be careful because the term replay has been used specifically for one kind of measurement. It’s been done in hippocampus principally, but if it walks like a duck and it talks like a duck, I think it’s a duck. If you look at that paper carefully, and you look at the activity that you see across many neurons in REM sleep, before the animal has this plastic change or an experience that caused a plastic change, and you look after that, it’s very clear that the activity of the brain during REM sleep after the experience looks like the experience.
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The activity before that experience does not look like that experience. We can quantify that using various kinds of analytical tools, which we did in that paper. We need to look at this much more carefully, and that’s what we’re doing now with many, many more electrodes that allow us to measure for many hundreds of neurons at once to look at this in much, much greater detail.
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| It won’t be enough to show that these neurons replay or reactivate the experience. We also need to know that replay and reactivation actually does something. Just because it turns on doesn’t mean it’s actually doing anything, and so that’s the challenge. That’s been the challenge in the field of so-called replay studies, is that people record wonderful things about these neurons when they go to sleep. They do incredible things, and yet does that incredible dance that these cells actually sum to anything important functionality?
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That’s been the big mystery, and there’s very little evidence it turns out that they do anything. That’s what we need to do. If the classic studies that were done in the rodent hippocampus, and really launched this concept that, “Oh, wow, neuronal patterns of activity present experience replay during sleep.” That study was back in 1994, and since then there’s probably been over 100, maybe 200 studies that have reported similar things like that, but only two studies where they actually attempted to prove that it did anything to memory.
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| Only two, and that was only in the last five years. There’s been none since. You have this incredible story, but what does it add up to? That’s what we want to do, is we want to first verify that this actually occurs in the visual cortex as the cells are actually modeling themselves. The second thing is to say, “Okay, can we alter this pattern some way as that change the plasticity that we see on the individual cell basis?”
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| That’s exactly what we’re trying to do now.
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| Dan Pardi: | Okay, we have over 100 studies that show that replay happens in response to experience during REM sleep, but we only have two studies that have tried to identify if there’s a biological smoking gun. What did those studies show?
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| Marcos Frank:
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What was found was there were two studies that were published back to back, and what they did essentially was they trained these animals on a maze track paradigm, where they learned to turn left or turn right and get rewards. The cells that they recorded from the hippocampus are what are called place cells. They fire when the animal enters a certain part of space. They’re sensitive to where the head is, in terms of the rest of the body.
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| In any case, you have these what are called place maps, or space maps in the hippocampus. They found that these maps would form as the animals were running this track and learning which way to turn and get reward, and then during times when animals were quiet and presumably mostly asleep, they would see events in the hippocampus that normal carry this replay. Just to give you a little more background on that, replay in the hippocampus is akin to signals on a carrier wave in radio.
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| In a radio wave, you have what’s called a carrier wave, and then you have something that rides on top of it that actually has the information of interest. You have these waves of activity in the hippocampus, and on top of that, that’s when this replay occurs. What they did was they electrically interfered with this carrier wave. They just zapped the hippocampus with electricity essentially, and it disrupted the presence of these events that normal carry replay.
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| [00:19:00] | When they did that, the ability of the animal to learn the task was reduced. It took them longer to reach a criterion level of performance when they interfered with the carrier wave of replay during what presumably was sleep.
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| Dan Pardi: | But they were able to learn it?
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| Marcos Frank: | A while, they didn’t learn anything. They did learn, it just took them a little longer to get there. That was true for both of those studies. There was one more study that was done on a rabbit, but it showed something similar to that, so maybe there are three studies done. In any case, even in those studies, they were not looking at replay per se where they were actually measuring this pattern and saying, “Okay, this pattern’s present, and therefore this happened because of that pattern.”
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| They were looking at the hippocampal events in which replay occurs, and they were disrupting those events. It was a little bit indirect in that sense, but still, at least it provided some evidence that if you interfere with this process, it would interfere with something of value to an animal. Obviously, memory.
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| Dan Pardi: | This is suggesting that learning can take place outside of sleep, that sleep might augment the process, but even if these processes are inhibited during sleeps, learning is still occurring. It’s just taking longer for that to happen.
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Marcos Frank: |
That’s true, but to be fair to those studies, it also could be possible that they just didn’t get enough of it. Enough of it leaked out that they couldn’t get it all, but you put your finger on a problem in the field with this, is that not all learning seems to require sleep for the consolidation of those memories.
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| Dan Pardi: | That would make sense.
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| Marcos Frank: | It’s absolutely right. Obviously we can learn while we’re awake, so I think we need to make a distinction between learning and the consolidation of memory. Learning is the actual behavior that we do that will form a memory, but having said that, clearly we can also make memories while we’re awake. They don’t require sleep for us to retrieve them. Why that should be and what kinds of learning and memory are sensitive sleep, and that are not, I don’t think we have a real consensus on that either right now.
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I think most would agree that learning memory tasks that require the hippocampus, which is the same structure that I was just talking about in terms of these studies, those sorts of memories seem to be most sensitive to sleep loss. Other kinds of learning that don’t involve the hippocampus seem more resistant, but it’s not a hard and fast rule. In the human literature, it’s much more complicated. In human studied, you’ll find evidence for all kinds of learning that seem to require sleep for their consolidation, and then sometimes in other studies, people will find exactly the opposite with the same kind of learning tasks.
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| I do think the evidence is more in favor that sleep is serving some role, undefined role in memory consolidation more generally, but why some memories, not others-
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| Dan Pardi: | Based off of the last findings from your research, what is the next question that you want to tackle?
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| Marcos Frank: | As I mentioned, one of the things we want to do is we want to go deeper into the neural activity that’s present during REM sleep under these conditions, and really try to understand is it true that it’s really replaying and reactivating experience in a broad way, and in a meaningful way? Does that reactivation have any function? For cells that participate in this replay, are they more likely to have more plasticity than ones that don’t?
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Does that replay change depending what part of the brain we’re measuring from? Those are questions that we’re trying to address right now. The other one that’s related to that is the biochemical changes that accompany REM sleep. REM sleep is such a peculiar brain state, not only because of the behavioral aspects that you’re asleep and you’re paralyzed, and you’re often dreaming, and you’re in this weird state of consciousness, and your brain temperature drops, and your autonomic system goes crazy.
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| All these things about REM that are very peculiar, but on a biochemical level, it’s even weirder than that. When you have whole systems of neurochemicals that are normally active during wake all of a sudden just shut off. Then you have others that stay on. It’s like brain has gone into this weird chemical cocktail that’s totally different than what it is during waking.
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| Dan Pardi: | Amazing.
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| Marcos Frank: | Why would you do this? Are you doing it because that is permissive or promotes certain biochemical events over others? Possibly. That’s what we’re thinking. Maybe that’s why certain enzymes are turning on in REM, and only in REM, or mostly in REM. We’re trying to understand that, too. Trying to tease that component apart.
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| Dan Pardi: | All right, I have a fun question here. Since you study learning and memory, is there anything that you do based off of the knowledge that you’ve gained about how these systems work to augment your own memory and learning?
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| Marcos Frank:
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I’ll tell you one thing that clearly does make a difference is anything that you do that would disrupt REM sleep, my opinion would be detrimental ultimately to what sleep is supposed to be doing in your brain in the first place. That would include recreational use of various substances too close to bedtime. Good sleeping habits. Generally, if you do all the right things about sleep, then REM sleep will be present and intact.
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| I’m also very wary because of having kids of medications that might be prescribed to my children, because I have some understanding that some of them could affect REM sleep, and this is something that was touched on in the paper. There’s a very high and alarming rise in the use of what we call psychotropic medications in children, even toddlers. This can include sleeping medications, but it can also extend to antipsychotics, and of course antidepressants, and of course stimulants, which are often used to treat ADHD.
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One thing all these compounds have in common, although they get there by different ways, is that they can profoundly suppress REM sleep. We know from animal studies, it could profoundly suppress REM sleep in developing, in early life, too. It’s not just an adult suppression. It can happen to children. The dirty secret out there is that we know very little about what these drugs actually do to the developing brain.
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| There’s a shocking lack of what we call pre-clinical research in animal models of what these drugs are doing, not just in the short-term, but in the long-term. There’s plenty of evidence to indicate that these drugs can do radically different things in the developing brain than the adult brain. That’s something that I have taken away from this research, is that for my own kids for sure, I’m very cautious.
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| Fortunately it hasn’t come to that, but I’m cautious and on guard when medications are discussed that can affect these things in children.
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| Dan Pardi: | On that note, Maros, I want to thank you for coming onto the show and sharing the details about this subject that affects all of us so intimately. It’s nice to hear the details about it to understand it better, so I appreciate you taking time out of your day and your research to visit with us, and educate us on all the stuff that you’re doing.
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| Marcos Frank: | Thanks, Dan. It’s been a pleasure, as always.
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| Dan Pardi: | Thank you, and likewise. Have a great afternoon.
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| Marcos Frank: | All right, Dan, thanks.
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Thanks for listening, and come visit us soon at HumanOS.me.
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