Mind & Matter
Mind & Matter
Visual System, Visual Impairments & Cures, Amblyopia, Neuroplasticity, Critical Periods & Metaplasticity, Ketamine & Psychedelics | Mark Bear | #150

Visual System, Visual Impairments & Cures, Amblyopia, Neuroplasticity, Critical Periods & Metaplasticity, Ketamine & Psychedelics | Mark Bear | #150

Download, watch, or listen to M&M episode #150

About the guest: Mark Bear, PhD is a Professor of Neuroscience at MIT, where his lab studies the visual system, neuroplasticity, and the pathophysiology of amblyopia and visual impairments.

Episode summary: Nick and Dr. Bear discuss: the visual system in the brain, from the retina to visual cortex; critical periods of brain development; mechanisms of neuroplasticity; metaplasticity; amblyopia and visual impairments; ketamine & psychedelics; and more.

*This content is never meant to serve as medical advice.


Full AI-generated transcript below. Beware of typos & mistranslations!

Mark Bear 3:35

I'm a neuroscientist I'm currently hold the position of pick our professor of neuroscience at MIT. And we have been studying how experience modifies the brain for the duration of my career. And a lot of our recent work is really focused on trying to apply some of the knowledge that we've gained to correct mishaps of development that arise either from poor visual or experience or gene mutations.

Nick Jikomes 4:11

And so when we think about the visual system, obviously, this is a sensory system that our body has that detects light. We have different sensory systems that affect different aspects of the physical environment in the retina of the eyeball. How is how is the nervous system actually detecting those photons? And what are some of the key features of those sensory neurons have that enable them to do that?

Mark Bear 4:35

That's a That's a deep topic. And I will just tell you right off the bat, Nick, that I take a lot of what goes on in the retina for granted, for better or worse. Because most of our studies are focused on the cerebral cortex, which is the first place in the ascending visual pathway where information from the two eyes is combined. So we're very interested In the neural substrate of bind ocular vision, it's why, why we see one world with two eyes. And we can also see stereo, stereo scopic depth. But to answer your question, there photo pigments in the retina and specialized cells called photoreceptors, and they absorbed these photons. And there's a chemical change that ultimately results in a change in the voltage across the membrane of those photoreceptors. And as a result of that, membrane voltage change, there is a change in the release of a neurotransmitter, which is glutamate, common amino acid, glutamate. And then glutamate tickles the most direct pathways tickling another cell type in the retina called bipolar cells. And bipolar cells, in turn, talk to retinal ganglion cells and the retinal ganglion cells are the first cells in the retina that generate nerve impulses that then sweep up the optic nerves. And so it's the retinal ganglion cell activity. That is how we see. That's how the information gets from the eye into the brain.

Nick Jikomes 6:16

So you said, you said that the visual cortex, which is going to be a number of synapses away from the retina, that's the first place that information from both eyes gets combined. And, and as you said, you know, we see one visual scene, I have one image in my mind right now. And yet, I've got these two channels of information coming from my left eye and my right eye. Can you give us a basic sense for what what is some of the key architecture and circuitry that is enabling that that that is the reason for why I have one image even though I've got these two separate channels of visual information?

Mark Bear 6:50

Sure, yeah. It's, it's, it's a miracle of, of development and evolution, that these sort of these two rather independently developing structures that you eyes, giving rise to connections that somehow find their way into the brain, and they make a first relay in the part of the brain called the thalamus. And then these thalamic and in the thalamus, in most species, the information from the two eyes remains segregated. And then that information goes from thalamus through a projection to the visual cortex, which is, you know, the you can see it from the surface of the brain where the visual cortex is. And that is the it's neurons in the visual cortex of the first place where you find responses to stimulation of either eye. So there were strictly speaking by knock your now, just to contemplate for a second, how amazing it is, is that there, there's a mapping of points of visual space that talked to ganglion cells and either AI, and somehow those ganglion cells or the output of those ganglion cells, finds its way on a single target in the visual cortex. And the precision of these connections, while it's essential that these connections be precise, to serve by not your vision, and it sort of led to LED human weasel who were the real pioneers in studying the sending visual pathway to ask the question, is there a role for visual experience in this in the development of these very precise connections? And to test their hypothesis, they did a very simple manipulation of visual experience and many labs are still doing it today is temporarily depriving one eye vision during infancy or early early childhood or in animal models very early after birth. And the eyes opened, and they asked what's the consequence of growing up with an imbalance in the activity from the two eyes? And what we know and virtually every species that uses both eyes, ranging from mouse to man is that there is a very dramatic change in anatomy and the physiology of the visual cortex So that most cortical neurons serve only the eye that was non deprived, and that the private eye connections are lost or greatly weakened. So that paradigm, which was introduced in 1963, has been used repeatedly to gain insights into the very basic question of how does experience modify the brain That's how I got into it. It was a very basic just a basic science question is, well, how does experience modify the brain? Here's the system where the modifications are profound, and dramatic and easily studied. And so maybe we can get under the hood and find out what's going on. But I should also mention that this experimental paradigm of deprived and when I envision occurs in nature, rather frequently in humans, where an infant may be born with an uneven refraction in the two eyes so that they can't form a crisp image and both eyes at the same time. So there's an imbalance, where they may be born with the eyes that drift apart or drift together a condition called strabismus, or in the most severe cases, they may be born with a cataract in one eye. So the consequences in a human are just what we would predict from the animal studies, which is that there is a profound loss of visual acuity in one of the eyes, if it was the deprived guy, that input is greatly diminished at the level of the cortex. And there is a profound impairment in vision and stereopsis. So what's cool about this area is is that not only do we have some deep, basic science questions to address, we also have some pretty clinically relevant questions to address as well. So to answer your question, the rambling answer is very simple question. Which is that how does this how is this convergence normally organized, and there, it's interesting that it really depends on the species. Or put another way, the evolutionary history of the, of the species. So what we've learned about monkeys and humans and some carnivores like cats, is that the information arrives in the cortex. Initially, there's a intermingling of the inputs materialize, but then they segregate out into these structures called ocular dominance columns. So part of the cortex Act actually still conserves this information from right or left on. And then it's those neurons within the cortex that converge on to other neurons that bring the information together. So in the human weasel showed that one of the consequences of monocular deprivation was a really dramatic, spectacular change in the dimensions of these ocular dominance columns. So that the, the area of Cortex serving the non deprived it expanded, and the area of Cortex serving the deprived diet contract. So we can have a beautiful picture of what's going on at the anatomical level. I should say that ocular dominance columns exist in humans, cats, and monkeys, are not universally shared by all species. So I'll give you an extreme counter example is, is a tree shrew. And in the same layer, what we see like your dominance columns, and overall monkeys, what you see in a tree shrew is instead of there being columns, their stripes, so it's same solution of keeping the information segregated, but Well, same objective, but different solution, sort of 90 degrees off. Similarly, I should say, in other species, particularly in rodents, we don't see any accurate columns at all, we see the intermingling of the two why's really at the first relay in the cortex. So there's many different substrates of this by not Eurovision. But one thing that is in common and all these species is that early deprivation disrupts these connections.

Nick Jikomes 14:12

So the visual system, you know, our eyeballs are the organ that detect the light, we've got special pigment proteins in the retina, that have evolved to be able to sense the presence of photons within the visible spectrum. You've got these two channels of information your left or your right eye, those channels are separate than they first converge in the visual cortex, the primary visual cortex, which would be all the way in on the backside of the brain. And the fact that we have one visual scene means that somehow we're combining these two separate streams of information in a way that gives us that that one unified scene, and we're not seeing double vision all the time. And that's first happening in the cerebral cortex and that amounts to cells in the cortex that sends information from one eye, and cells that say As information on the other eye, then converging and projecting and sending information to cells that

Mark Bear 15:05

that are hooked up to both. Exactly right.

Nick Jikomes 15:10

And so there's this experience dependence. So we're going to talk about meaning, you know, you talked about how if you if you just shut off vision for a while in early development, by preventing light from getting into one eye, this changes the, the, the structure of the visual system. And so it sounds like if you, if you, you know, stick an electrode into the primary visual cortex, as many people have done over the years, you've got patches of tissue that primary neurons are primarily responding to one eye and patches of tissue where they primarily respond the input from the other eye. But if you deprive one of those eyes in early development, more of that real estate of the cortex is going to be occupied by cells responding to the non deprived die

Mark Bear 15:55

wellsite. And

Nick Jikomes 15:56

so, one question I had before we kind of get into some of the stuff that you work on, and neuroplasticity, and lots of other things is why, you know, what is what is this architecture? And, and some of the things we're going to talk about, what does it say about the why don't we have this architecture hardcoded in the genome?

Mark Bear 16:21

Well, the genome never ceases to amaze me with early development of precise connections in the brain can really be guided very much by instructions that reside in the genome. So I think maybe the our first assumption is that the genetic instructions alone couldn't, couldn't possibly accomplish this was probably a false assumption. And in fact, there was considerable debate several decades ago now about whether these regions of cortex where the inputs of the DUIs are segregated, whether that segregation process requires visual experience or not. So the the earliest data suggested that, just to recap, very early in development, the inputs are intermingled, and then they segregate out to form these ocular dominance domains. And originally, it was thought that that segregation process really dependent on comparison of activity in the left and right eyes. But later work suggests at least in some species, that that striping pattern can occur purely by genetic instructions. So it's sort of we, you can sort of get the there's not going to be a hard and fast answer that's going to apply to every species. I mean, a really great example, honestly, is a crazy experiment. Well, crazy, an exotic experiment, done by someone named Martha Constantine Patton, who was then at Princeton, and was more morphia recently at MIT. And she did an interesting experiment in frog. So frogs have an almost entirely crossed visual pathway. Because the frog eyes are latterly placed on the head. So you take species, especially, you know, reptiles and amphibians, and birds, they don't well, most birds with an ALS. But let's stick to reptiles and amphibians, they have laterally placed eyes, they don't have much of a substrate for monocular vision. So points in space are either seen by the eye on the same side or the eye on the other side. But what Martha did was they she transplanted a embryonic ibid into tadpoles. And, you know, amazing thing about frogs is that ibid could take and form an eye and the connections would go into the brain. And what she discovered was is that they segregated out into these ocular dominance stripes when they went out. So it was sort of no genetics instructions there. It was purely driven by comparison of activity between the supernumerary eye and the and the the animal's normal eye. So long winded way of saying that we can solve a lot of these problems with a generic solution, but in the end, there's no denying the effect of manipulating visual experience in all of these species on all these species. manipulation of visual experience disrupts these connections.

Nick Jikomes 20:04

When you deprive one, I have the ability to sense light. And you see these changes throughout the visual system, these experienced Bennett changes. How important is the specific developmental window in which the deprivation happens?

Mark Bear 20:21

I'm glad you asked that question. So the short answer is, is that the vulnerability to monocular deprivation is very age dependent. And so this is fairly easily mapped out in animal species where you can look at the consequences of early monocular deprivation that is initiated at different ages. And it's been known for a long time again, originating with your weasel, that at a certain age, the cortex is resistant to the effects of manipulating experience. And you know, so this gave rise to this idea of a critical period is a period of postnatal development, where the fine tuning of these connections requires interaction with with experience. And you can ask yourself, you know, why did nature? Why has nature come up with this? Why would you, why would it be advantageous for the cortex to be vulnerable, the deprivation there, as you know, and I think that the deprivation experiments are actually revealing that the brain is trying to make maximal use of the, of the effective inputs that it has at any given time. So, what it's doing is is reallocating neural tissue to a seeing eye or eye that's forming crisp images, and it's disadvantaged in the other eye, because it's not helpful. It's not useful. So it's, it's a matter of, really of, of us making the most of what you've got, and it's interacting with experience to do that. There is a sort of a flip side to this whole thing, which is that, as I mentioned, in humans and human and fence, was this take the most severe example of a cat being born with a cataract in one eye, which is rare, but not ultra rare? And

Nick Jikomes 22:32

can you just remind everyone, what exactly is a cataract? Oh, sure,

Mark Bear 22:35

yes, it's a clouding of the basically, it's a clouding of the lens in the eye. And so it's impossible to form a crisp image on the back of the eye. And cataracts are very common in adults, of course, especially as we get older, and they're quite easily treated their their lenses removed, and it's replaced. And happily, you can develop cataracts, and adulthood, and you can go untreated for a good long time. And there's no lasting deleterious consequences once the cataract is treated. Vision is restored. And that's because you're beyond your critical period, you're no longer vulnerable to this imbalance in visual input. So

Nick Jikomes 23:21

bring a grain retains. The structure is already there, it already knows how to deal with information, both eyes, so you just you just wipe the lens off or replace the lens. And that's right, it goes right back. Things work as they should.

Mark Bear 23:33

things get interesting. So it's so from on the therapeutic side of this, as I mentioned, so we have unilateral cataract, you're born with unilateral cataract. And the question is, how are we going to save the visual system? And so the of course, the answer is that well, first thing you have to do is really counteract so if you are in a medically well served community, excellent health care. It's noticed early in life and the there you can't delay you have to go in and correct that cataract. And typically, that alone is, well it's necessary but not sufficient to see a recovery. What is additionally done is that the strong eye or the good eye, the intact eye, or we call it the fellow eye, is often patched for periods of time. And the reason is that it sort of forces the other eye to be used by the baby. And so that other writes sometimes is called the lazy eye. So it's forcing the lazy eye to to work. And if you initiate treatment, early enough, you can get a pretty nice recovery. Not necessarily a full recovery by not your vision, but you can get acuity back to that eye that had been deprived by the cataract. But here's the rub the rub is is that that treatment effect is restricted to a critical period. So if you don't do this manipulation early enough, you won't see a recovery. The duration of the critical period sort of depends on the critical period for treatment depends on the cause of the underlying visual condition. By the way, I don't think I've defined in that visual condition. It's called amblyopia. ism. You can practice saying that but amblyopia and that is simply amblyopia is a visual impairment, typically restricted to one eye, for which there is no observable cause in the retina or eye. So it's a it's a visual impairment that is occurring elsewhere in the brain, typically in the visual cortex, and it's not uncommon. So it affects about four or 5% of the population.

Nick Jikomes 26:05

How does that matter? How does that typically manifest in terms of their visual experience if it's untreated?

Mark Bear 26:10

If it's untreated, there they are there? The amblyopic eye is, is not useful. It's not useful.

Nick Jikomes 26:20

So it's like it's like monocular deprivation?

Mark Bear 26:23

It is Yes, exactly. I mean, deprivation is a is a perfect model of what's called deprivation amblyopia, which is that which would be caused by a cataract. And I will say that the, for if amblyopia is caused by deprivation, the critical period in humans is very young, before one year of age. So you don't have a lot of time to hop on this and try to set things right before these connections are formed. And then frozen in place, basically. But

Nick Jikomes 26:59

I'd imagine you know, a six month old baby has no good way of telling us that their vision is impaired. So this is probably often missed.

Mark Bear 27:08

That's true. You know, they the that is totally a very good point. And now there are other more sort of less severe causes of amblyopia, but also insidious. So one is called an isotropy. Trump. And I saw material via I can't even say it. But anyway, it's the it's the uneven refraction. On two eyes. Now, you know, I'm wearing glasses, I need an optical correction. So I can form a crisp image on my eyes. And as you know, if you wear glasses that often your prescription can differ in the two eyes, one I might be weaker than the other eye having to do with differences in the shape of the eyeball, or the curvature of the surface of the eye. Not uncommon, right? refractive errors. But if you have a refractive error errors that are that differ in the two eyes early in development, you set up a situation where you can only really form a crisp image on one retina or the other, but never at the same time. And that is another condition that causes amblyopia. And that's a condition that can go on treating if you don't have you know, eye timely eye exams. So that's why this early neonatal medical care is so important. And it'd be so easily missed if you if you don't have that. Cataracts, of course, are obvious, it's a clouding of the eye. strabismus is obvious because the eyes aren't lined up properly. But you but you're definitely regardless of the cause you're working against the clock. And I think one of the lasting legacies of who will weasels work was recognition that you got to start early, you can't, you know, wait indefinitely for the skull to get hard and then started to be able to tolerate surgery better, you got to get right onto it.

Nick Jikomes 29:09

What are some in these critical periods of the visual system? What are what's going on in terms of neuroplasticity? What what is? What kinds of plasticity are only allowed during that period? Or how are the cells behaving differently? What's actually shutting off when we start to look under the hood?

Mark Bear 29:28

Yeah, it's really an interesting question is one is really preoccupied. One or two generations of neuroscientists. The idea is to understand why this plasticity we call it diminishes with age, and is there something we can do to boost it in the adult? So, of course, it's a multifaceted problem and sort of the approach that we've taken is try First and foremost to understand. Just to give you an example, what's the mechanism by which connections that are wired to an eye deprived of vision lose strength in the in the cortex? What's the mechanism have that. And I, I, my belief is, is that if when we understand that mechanism, we have a shot at understanding how to reverse it. So that's the approach that we've taken. Everybody's got a different point of view on this, but that's what we've, we've taken and we, I will say that we know a great deal about the mechanisms that cause the loss of synaptic strength. So I should I can tell you a little bit about that if you'd like. Yeah,

Nick Jikomes 30:51

let's let's give people a basic sense for some of the things at least that that can happen here. When this experience dependent, these experiences Bennett changes actually happen? Sure.

Mark Bear 31:02

So the inputs to the cortex that we're talking about these glutamate is a neurotransmitter, so just to review, glutamate as the neurotransmitter at about 80% of the synapses in the brain. And it is, in almost all cases, excitatory, meaning that it causes the, the neurons that it's communicating with to become active. And so there's information that's coming into the cortex from the two eyes is using glutamate as a neurotransmitter. And what happens during deprivation is that temporarily structured activity in the retinas is disrupted. So what do I mean by that? You know, as we look at images, you can imagine shadows crossing the retinas, edges, bars, colors, and there's a spatial temporal correlation in the activity. So the neighboring cells are active at the same time when you're being activated by a stimulus that, for example, includes most of the visual field. And it's sort of that correlated activity that leads to the fine tuning of connections in the brain. And the case of deprivation, what happens is, is that that spatial temporal correlation of activity breaks down. So when we talk about patching an eye, it is not the same. And importantly, it's not the same as shutting the eye off. So it's not the absence of activity, that's the problem. It's the presence of activity that no longer is well correlated. That is the problem. So in the case of an accurate deprivation, just imagine that you have one eye that's giving rise, this beautifully correlated activity as visual stimuli are sweeping across the retina, and the other eye is just static. It's just stuck between radio stations, right? It's just noise. And it is that noise that drives the the connections in the brain down. So that loss of synaptic strength is referred to as long term depression, or shorthand for that is LPD.

Nick Jikomes 33:31

As a so long term depression, the strength of the connection between neurons is decreasing. It's getting weaker, it's not referring to depression. Exactly,

Mark Bear 33:41

yeah, not to be confused with major depressive disorder. But this is a synaptic effect. It's widespread in the brain, especially during development. It serves a useful purpose to winnow out synapses that aren't conveying useful information.

Nick Jikomes 33:58

I see. So the pattern of activity, the temporal structure, how how activity between and across neurons is correlated that can drive neuroplastic changes, such as a weakening of connections, which is what we're talking about here.

Mark Bear 34:11

That's correct. Correct. So. So with this sort of insight, that it's not the absence of activity or the presence of activity, it doesn't correlate with the activation of the target neurons in visual cortex, that we could go in and do experiments and ask, can we recreate that phenomenon in the laboratory? Once we have a preparation where we can study it, we can start to dissect the mechanisms. And we have and we know a great deal about the early molecular events that occur when you've replaced pattern activity with noise. So we have a decent understanding of what's the the pathophysiology of triggers this loss of visual responsiveness And I think the the, as I said, the phenomenon that we can study is called long term depression or Ltd.

Nick Jikomes 35:08

So, so you know, the system that you study, you've got a good anatomical map of all the connections, you guys have gotten into some of the electrophysiological mechanisms, you understand things like long term depression, and how that relates to the visual experience and the deprivation. When it comes to something like amblyopia, amblyopia? How experimental animal models, how have you guys treated this? And what does that involve in terms of changing neural activity? Yeah,

Mark Bear 35:39

perfect question. So, you know, we deprive an eye of vision, we induce LDD, those synapses get weaker, we have an extremely exquisite understanding of the mechanisms that are involved in that. And the question is, Can we can we bring those synapses back to life, and we can start with may be able to start with what happens clinically. So in clinically, I mentioned that the strategy is to patch the good eye to force vision through the weak guy. And so you, first you have to, you have to restore vision through the the eye that had been affected. So in other words, remove the cataract, or realign the eyes, or correct refractive error. Okay, that's obligatory. And then what you want to do is try to promote the recovery of synaptic strength in the cortex. And the way it's done clinically, is to patch the good on. And indeed, We can do this in the animal models of amblyopia, and it works, you patch the fellow eye, and then you can see the responses come back to the deprived time. Again, restricted to a critical period. But nevertheless, it gives you some hopeful news, which is that the deprivation effect is not permanent, it can be reversed with timely treatment, and then we have the opportunity to understand, Okay, what's the mechanism by which the recovery occurs? And I'd say we know, we probably know less than we think we know. But this is what I this is what we think we know is that connections get stronger. So I said connections get weaker when the input activity is poorly correlated with the activity of the postsynaptic target cell. On the other hand, we know that synapses get stronger when input activity consistently does correlate with evoked activity in the target cell. So, in other words, when the presynaptic input is active, at the same time, or just shortly before the postsynaptic neuron is active, and we know that that's a favorable condition to make synapses stronger. And that's another phenomenon that's been studied for a number of decades now. And it's called long term potentiation LTP. So it's the flip side of LTD is LTP. So what we think is happening is that LTP is occurring at these weakened synapses, and causing them to gain strength. But there's a there's a conundrum here, which is, we know that LTP typically requires very strong, robust correlations between the presynaptic input in the postsynaptic cell. But in the case of I love this example, in the case of patching because when we patch we've, we have the seeing eye is no longer providing input. That is to say the strong eye is no longer providing input. And the seeing eye is too weak to elicit a response. That's the deprived day. So how is it ever possible to satisfy the conditions required for long term potentiation? Right, it seems unlikely that it could work, and yet it does. So the question is, what is it about patching the fellow eyes that enables this long term potentiation to occur and if we understood that, we might be able to come up with some clever ways to exploit that even after the critical period. So my work is strongly influenced by a theory of synaptic modification. The mathematical theory of synaptic modification that was developed by a colleague and friend at Brown University when I was on the faculty there many years ago. His name is Leon Cooper. And Leon is well known, because he won the Nobel Prize in Physics for a Theory of Superconductivity. It was called the BCS theory. And he won the Nobel Prize, I think it was in 1972. And as many Nobel laureates do, their minds start to wander and he became interested in another insoluble problems such as learning and memory in the brain. And he was interested to know if he could develop a learning rule, sort of a set of rules that govern the modification of synapses based on experience. And Leon had the extremely good tastes to not do this, and sort of a vacuum, but to try to do it in a context that where his assumptions can be experimentally validated. So that's one thing to say just dream up solutions and run computer simulations. But it's really quite another to say, Okay, I'm gonna try to apply this theory to observations that can experimental observations, and at that time, the preeminent model to look at experience dependent plasticity in the brain was the visual cortex. So he made his theory, he constructed this theory, very, with the express purpose of having it tested experimentally in the visual cortex. So for me, this was like, I mean, I'm much his junior, but he was very kind to teach me about his theory. And I was trying to reciprocate by teaching him a little bit about the biology of synaptic transmission. And we, we came up with some ideas for what the synaptic mechanisms might be, in fact, I will just say that Leon's theory, which is called the BC M theory, was really the inspiration for the discovery of long term depression. That was that discovery was made in 1992. And it was really motivated by Leon's theory. But so returning to why patching works. So Leon, so that's a great question. And I was puzzling over myself. And he said, How do you guys solve this problem. And what he proposed in his theory was that the threshold level of correlation between pre and post synaptic activity that is required for long term potentiation is not a fixed value. But rather, it can adjust depending on the average activity of the postsynaptic cells. So intuitively, this makes beautiful sense. So just to recap, a little bit, so imagine that there's a degree of correlation and pre and post synaptic activity that elicits LTP. And if you're less than that threshold, you get Ltd, instead of that act of synthesis. So there's a crossover point, and he called that point, the modification threshold. Now, you can imagine an a neural network, where all the synaptic weights were set a little bit too high, so that always the synapses were exceeding the modification threshold, then all the synapses would strengthen, and the whole system would sort of blow up all the would saturate all the synaptic weights.

Nick Jikomes 43:43

Yeah, there's no, there's no real refinement, there's no specificity. Everything is just

Mark Bear 43:48

Yeah, and no constraints on it just goes goes to one. Conversely, if you settle your synaptic weights a little bit too low, it would all go to zero, right? Everybody undergrad Ltd. So he said, Well, obviously, this is not a robust solution, right? So the idea they came up with was to let this threshold level slide back and forth, as a function of the average activity that so So now think about this. Let's think about it in the context of patching. So we set up a situation where the seeing eye isn't strong enough to elicit a response and the cortex, and the strong eye isn't seeing. So what's gonna happen in the cortex, the assumption is reasonable assumption is that the activity in the cortex is going to fall. And as a consequence of that, there's going to be an adjustment in the value of this threshold. So it's just going to make it easier to get LTP. It's going to make it less stringent conditions to get LTP. And so he calls this the sliding modification threshold. And it's really a mechanism to maintain homeostasis. asis have synapses in a network of neurons. And so they've done a lot of simulations and so on to show that it's very robust way of storing information and so on. And it's actually been, you know, created in silico, as well, or chips that have BCM modifications on them. But in the context of treating of this patch therapy, that's the way we imagined that it works, which is that you've changed the conditions required to get LTP, so that the weekend put, although it's weak, it's now correlated, because you've restored visual clarity in the eye. And that these weak correlations are now adequate, sufficient to drive those synapses.

Nick Jikomes 45:48

By patching patching the good eye, there's less overall inflammation going to the cortex, the threshold, the brain is then setting for what cat for what it needs to see in order to strengthen a synapse goes down. So now it's easier. And that's what's enabling LTP to come from the amblyopic eye. Perfect.

Mark Bear 46:08

Yep. Exactly. Exactly. And that, oh, go ahead. I was just gonna introduce a term because so this is Leon's theory. And that's the sliding threshold. But but there are other, there are other examples where the prior history of activity can affect the rules of synaptic plasticity. And I was really fortunate to do my sabbatical in New Zealand with a colleague named Cliff Abraham. And we were, we were trying to think of a term that could capture the general concept that plasticity rules at any given moment, depended on what happened before, basically, and we came up with the term meta plasticity and meta plasticity is now widely used expression. And basically, in most cases, it's capturing the essence of the sliding threshold of the BCM theory.

Nick Jikomes 47:09

Yeah, okay, that makes perfect sense. I didn't know about this theory, by the way. So this is interesting. So meta plasticity. It's easy to think about that in terms of something like the critical period, right? There's this critical period, which is, the brain has a heightened capacity to engage in things like long term depression, or potentiation. And when that window closes, that corresponds to a lessened ability for those specific types of neuroplasticity to actually be triggered.

Mark Bear 47:45

The statements you've made are correct, except that the meta plasticity piece of it need not be what's controlling the critical period. So the

the vulnerability to deprivation diminishes with age, and that's, I'm sure a good thing. And that really doesn't have much to do with meta plasticity, we don't think. We think that there are very likely, you know, another set of mechanisms that open and close this window of plasticity in the brain. And I think a very simple way of thinking about this is that everything we're talking about depends on the input activity and the levels of correlation. And the input activity is under the control of inhibitory mechanisms in the brain. Now, I get a lot of mileage out of just thinking about excitatory synapses. And I usually reminded that there's more to the brain than excitation. And in fact, I would say the prevailing theory right now for what brings the critical period close is the maturation of inhibitory mechanisms in the cortex. I think there's almost a consensus on that point. I think what's less clear at this stage is what is it about maturing inhibition that that curtails the plasticity of excitatory synapses? And sort of a, an easy one explanation, which I'm sure is at least partially true, is that the inhibition filters out the patterns of activity, since this since all this plasticity is driven by patterns of activity. If you turn down the volume on those things, you'll have less plasticity. So I think that that's considered the most likely explanation for what's ending the critical period

Nick Jikomes 50:00

And, you know, when we talk about treating something like amblyopia, or just reversing some impairment of the visual system, you've told us about this critical period, this a window in which you have the opportunity to make those changes. And if you get past that window, if it closes, then it's much harder to correct the problem. So you have to come up with solutions and apply them during this window. But another strategy that you can imagine in principle, is you could somehow induce the brain to become more sensitive, and more plastic again. Is that feasible? Is that something people think about? Yeah,

Mark Bear 50:39

it's great. It is. And so you know, I just put the kibosh on meta plasticity as the basis for the ending of the critical. But, but I will say that we could, perhaps one might exploit meta plasticity to enable recovery of vision in the context of amblyopia, or any other disorder of brain wiring. And it was with that motivation, that a student, a former student of mine, Betsy Quinlan, who is now at University of Wisconsin, did an experiment that I wish I had done. But she did it. And it was a beautiful experiment. And she took animals that were rendered amblyopic. So they've long term monocular, deprivation, the reopen the eye, but there was a permanent visual disability through one eye. So modeling, untreated amblyopia, and a human. And then what she did was, she put the animals in complete darkness. So a completely dark room, meaning zero photons, no light at all. And she left the animals in there for about two weeks or so. And she asked, if I so you can see the logic here, I suppose, which is to say, okay, average activity is definitely different. If the animals are in complete darkness. When the animals are returned to light, we are we able to sort of now see a recovery of vision. And that's exactly what she saw. So that when the animals were brought out of the dark, into the light with both eyes, seeing she got a very nice recovery vision, so which otherwise would not have been possible. Now say that her experiments were done in rats, they're not the, you know, gold standard species, at least for relevance to human vision, but the experiments were replicated and by others, particularly Don Mitchell and Kevin Duffy at Dalhousie University using more traditional species with excellent visual system, and they got exactly the same result. So, so, this was really thrilling that oh my goodness, maybe we can take advantage of metal plasticity to promote recovery. So, there was a there are a few details that that are important. One is that it did require a long duration of dark exposure. So minimum, minimum 10 days in the animal models.

Nick Jikomes 53:35

And when was this happening in development remind us? Are

Mark Bear 53:39

these are adults? Okay, adults. Okay.

Nick Jikomes 53:42

So the idea is, you have a strong deprovision in adulthood after critical periods verde closed. And now,

Mark Bear 53:48

let me clarify. So the the animals were menarche deprived during the critical period, okay, induce amblyopia, that would not spontaneously recover. So. So it's like a child that grows up with a unilateral cataract, and then the cataract is removed as a young adult, but there's no recovery. So that's kind of the analogy. Got

Nick Jikomes 54:08

it, so that something was wrong early in development. And envision is impaired in adulthood.

Mark Bear 54:16

Right. And so what that's the showed originally was you put the animals in the dark for an extended period of time, and when they come back out, now, conditions have changed. So the visual experience through the amblyopic is sufficient to start to drive an increase in responsiveness to that eye. And so, so this is a very exciting development. Now, I was gonna say the caveats here are that the exposure to darkness had to be prolonged. So as I said, at least 10 days of dark exposure, and it couldn't be interrupted even temporarily by light had to literally be A photon free environment, you couldn't get the same effect by just for example, putting patches over the eyes, which leaves the retinas still quite active and able to respond, luminance changes in the environment. So we were intrigued by this result. And in the meantime, we were doing some experiments using a compound, a drug called to Trento, toxin, or TX for short. And T ATX. is isolated from the ovaries of puffer fish. And it's one of the most toxic substances on Earth because it binds tightly to the ion channels that are responsible for nerve impulses. So, you know, there sushi chefs to train for, for years to serve puffer fish sushi, which get when it's perfect, it gives us a slight numbness to the lips and the tongue. But every so often they don't get it right, and they'll lose somebody because of a GTX toxicity. So, but it's been an extremely useful tool. And I will say that it is not unreasonable to expect it's used therapeutically. When you consider botulinum toxin is used therapeutically now as well. So you just have to be careful and use the right dose. And

Nick Jikomes 56:44

you're Are you referring to Botox there?

Mark Bear 56:47

Yeah, I'm referring to Botox. So, in any case, we were doing experiments with TTS anyway. And we thought that these results, and we decided we would try to reproduce what she had seen with an injection of TT x into both eyes. So the difference between GTX and darkness is that T TX literally abolishes all the nerve impulse activity in the ganglion cells. Whereas exposure to darkness leaves many of those cells active. So many cells are active in the dark. So it's, it is qualitatively different. Certainly a more extreme manipulation. What we discovered was that in bilateral injections of TTS into the eyes, both sides single injection would inactivate the retinas for about 24 to 36 hours, and then they would come back. But when they came back, we saw a really dramatic recovery of vision, and the amblyopic guy. And what was nice about this study was that we also saw it behaviorally as well. So we had animals that were showing the behaviorally the visual impairment to the amblyopic eye, and visually guided behavior came back extremely quickly, after this treatment,

Nick Jikomes 58:16

as always, is the injection happening during that critical period?

Mark Bear 58:21

No, this is adults, these are animals that have been, again rendered amblyopic. They're they're adults. There is no treatment, there is no hope. They'll forever be blind in one eye, and then

Nick Jikomes 58:35

completely shut off activity in the eyes. And when the drug washes away, when it wears off. You actually can cure the amblyopia.

Mark Bear 58:43

Yeah. And so the way the sort of metaphor that I think works is to imagine rebooting your your phone, you know, when when things start to ask act wonky, and we all know what to do, we shut our phones off, and we were rebooting them or, or their computers, same thing. And essentially, what we're doing with this bilateral TTS treatment is we're rebooting the visual system. We're saying, okay, you've got yourself in a bad space. You know, you're in a bad place. We're going to reboot, and we're going to shut everything off for a day, and then we're going to restore activity. And hopefully, I will come back and it does. So in this effect,

Nick Jikomes 59:27

is this is this only been done in rodents has been done in primates. It's been done in cats and mice. That's in life. Is anyone going to trial on humans? Yeah,

Mark Bear 59:41

let me actually let me take it one step farther. So just what set that aside for a second. I'm going to take you on a bit of a of a circuitous journey now, but I'm going to get back to this. So So here's the journey. So I've told you that APL, there are many millions of people in the world that are adults with amblyopia. They live with it, you know, it does limit things that they can do and has societal costs. But they're amblyopic. They see with one good eye. However, occasionally, there is through a disease or an injury, there is the loss of the good eye of the fellow lie. So now they're stuck there in a terrible situation where the if they made us using is no longer functioning. So we would expect from first principles, that that's it, you're, you're, you're going to be blind. But what is observed more commonly than not, not in every case, but more commonly than not? Is, and the surprise clinicians is a gradual recovery of vision through the amblyopic guy, sometimes a full recovery. So sister recap, so we have adult amblyopia. No treatment would work, no traditional treatment would work. But if the fellow eye is removed, destroyed through disease or injury, then over time, there's a recovery of vision through the other way. So

Nick Jikomes 1:01:35

the bad eye gets better by itself. The good eye goes missing.

Mark Bear 1:01:39

Exactly. And so that's kind of a head scratcher. Now, the way people would think about this, was it say, Oh, wow, okay, so the good eye is a sort of exerting a constant suppressive effect on the responses to the other eye. That's called interocular suppression. And that only when you remove that interocular suppression, do you see any anything coming back on the other eye? And if that were the end of the story, then you would say well, okay, but nobody's going to lose their good ice to relieve interocular suppression to help recover the amblyopic. But the alternate hypothesis is, is that it's not the perpetual loss of interocular suppression, but rather, it's the temporary loss of interocular suppression or meta plasticity. That is creating conditions that allow vision through the amblyopic guide to driver recovery. And so we can test that hypothesis in animals. And we have, and so I told you about bilateral GTX. But the more recent experiments that we've done, and I really should acknowledge minify Fong who was a postdoc in my lab, who was driving a lot of this research and Kevin Duffy, who was at Dalhousie, what we the experiment was, we rendered animals amblyopic, amblyopic. Adults, they could only see through one I see well through. And then to test our hypothesis, we put t TX into the fellow eye, but only briefly, so we activated the fellow line, but only briefly,

Nick Jikomes 1:03:31

so temporarily inactivate the good eye. And now the bad eye is the only one you can get visual information through. So so it's an analogous situation to what you saw in humans where they lose the good eye and they're left only.

Mark Bear 1:03:44

Exactly except the only difference being that we were going to let them we're going to let the good eye come back. Yeah. So you're losing vision for that eye and putting it back

Nick Jikomes 1:03:54

for so you lose patience for that I because of TTS and that's 24 to 36 hours. deprovision Yeah,

Mark Bear 1:04:00

depends on how many injections we do. But you know, minimal 24 hours, sometimes we do it multiple injections. But what we've seen is that the responses come barreling back through the embryo of MCI, and we see this effect, and mice and cats and monkeys. So now we're getting really excited about this, because we think that there is a translational potential to this approach. So you know,

Nick Jikomes 1:04:32

the implication here is that if you injected a human being with amblyopia, you can put t dx into their good eye, that this could cure them.

Mark Bear 1:04:41

Yes, that's the hope. And is

Nick Jikomes 1:04:44

anyone going to literally try doing that in a clinical trial?

Mark Bear 1:04:48

I think that it's you know, safety comes first and all these things and that we've done a lot of experiments that we are able to do that To ensure that there's no lasting toxicity of this treatment, that retinas that are treated are pristine, the visual responses through an activated I come back fully. So we've done a lot of what we can do. But I think that, you know, we're sort of on a go slow program, we want to, we really want to understand the efficacy of the treatment, and try to learn as much as we can from animal experiments, but at some point, there'll be a strong case to be made for trying it in humans. And injecting an AI with, you know, anything is comes with certain risks, but it's also a fairly routine procedure these days. So I think the community or ophthalmologists are probably divided on whether the the, the benefit would outweigh the risk. But most of most clinicians that treat people with specially deprivation, EMLYON are very enthusiastic.

Nick Jikomes 1:06:10

So potential so the, the idea here is that by injecting TT x a very powerful toxin that shuts off all neuronal activity by injecting that into the good eye, you're inducing meta plasticity, and that is enabling the bad eye to become good again, in quite a short amount of time. So are there any other strategies that might work in a similar fashion? What I have in mind here is, you know, I talked to Gould Dolan on the podcast, and according to results from her lab, they can actually use drugs like psychedelics to, according to them reopen critical periods of plasticity? And could something like that be another potential avenue that could be used to do this type of thing? Yes.

Mark Bear 1:06:59

It is possible, at least in principle, right? I mean, every every approach you take is going to come with, you know, upsides and downsides. And I mean, I'm a big fan of gold's work, I can say that we also have done some experiments, ourselves, where we use the, the drug, ketamine, and found that dosing animals with ketamine could restore plus juvenile light plasticity in the adult visual cortex. So it's conceptually similar to what Google is doing. And, you know, the GTX treatment, the upside is, it's very local to the visual system. It's a circumscribed treatment, it's not no no systemic effects, whereas psychedelics or other treatment are systemic. And so you just have to, I guess, the big thing is, is that we're, we're, we're sort of plowing fertile ground now. So we think we have learned that using the knowledge of synaptic plasticity can be can suggest ways to promote adaptive plasticity in the adult brain. And I think they're going to be a lot of different angles of attack on this, but I'm, I'm very excited about the, you know, that we're going to have a breakthrough sometime in the not too distant future on doing this, and I would also say that the whole the concept, the metal plasticity concept, is a very useful way to think about any type of neuro therapeutic approach to, you know, loss of function diseases. Whether it's been recovering from a stroke, for example, or other neurodegenerative diseases is like, Can we can we boosts synaptic plasticity in a way to recover function? And so I think it's a very useful concept worth thinking about and framework to think about neurotherapeutics.

Nick Jikomes 1:09:18

Yeah, I suppose I mean, to the extent that reopening critical periods and using meta plasticity works, in principle, it has, I think, kind of what you were getting at there is it has this potential to be an across the board solution to lots of different types of problems in the brain.

Mark Bear 1:09:33

Yeah. I think if you you know, yes. Bottom line, yes. You know, once you know it can be tendonitis for example. I mean, tinnitus is probably a disorder of synaptic transmission, around excitability. Can we use our increasingly sophisticated understanding of synapses to come up with a way to quench tinnitus? That's just one example of many, that I think you know that it's a way of attacking you, but it's maybe a fresh perspective on tackling problems. Have

Nick Jikomes 1:10:09

there been? I get? Well, let me just ask you this. So two part question here. One, can you give us some sense of time for how long before people living with amblyopia might, there might be actual clinical work that's done that they can take advantage of, and to you know, in the meantime, you know, since there's quite a number of people out there, you mentioned, this is pretty common with amblyopia, they are impaired by it, they're probably very motivated to fix it, is there anything they can do? That might, you know, give them some amount of recovery by, you know, playing around with their own visual system and, you know, forcing, forcing the bad guy to work harder or something like that?

Mark Bear 1:10:58

You know, I'm not an authority on this. So I'm, I hesitated a little bit. But we do know that there are effective alternative approaches to patching and the work in children that have to do with what's called a dichoptic display. So in other words, instead of eliminating vision and the good eye and foresee visit to the other eyes, sort of you try to take advantage of the good AI to help bootstrap the other AI. So they're called dichoptic therapies. And there's a variety of different approaches. And, and what's really encouraging is that they can yield outcomes and kids that are that rival the the effective patching, even though patching would be considered the sort of medical standard of care right now, these psychotics procedures are coming online. And they have a lot of advantages, one of which is that kids don't mind playing a video game or watching a movie through a dichoptic display. Whereas they do not like to have an eyepatch, nor to the parents. So that's children, I think it's still rather unexplored territory, didn't know how well these things would work in adults. We also know that there are, we're talking about plasticity in the brain being gated by inhibition, for example. And there have been studies done where they've tried manipulations of modulatory, neurotransmitters that are familiar to that normally regulate levels of inhibition in the cortex. For example, acetylcholine is an example it's it's a neurotransmitter that is released during wakefulness in the cortex and less during sleep. And it's been shown to promote synaptic plasticity. And so there are certain studies that have been done to try to boost the levels of acetylcholine in the brain. And you can imagine clever ways of okay, combining that plus some smart visual training exercises, you know, the plasticity, the plasticity is in there. We use it. You know, it's how we learn and remember. And it's a question of, of finding a way to tap into it. So all hope is not lost, I would simply put it that way. And that's one thing we've really shown in the animal studies is that we can get we can do it. Reducing into practice is challenging, but we can do it. Interesting.

Nick Jikomes 1:13:51

Is there anything that you want to reiterate for people are any final thoughts you want to leave them with? regarding any of the stuff that we went over today?

Mark Bear 1:14:02

I'm no, I guess I would, I would only say my evangelical comment is think about meta plasticity in therapeutic contexts. You know, I'm an expert on visual system plasticity. But there are many other disorders that I think an appreciation for meta plasticity, could suggest new new strategies.

Nick Jikomes 1:14:27

Or you guys in your lab doing any work with things you know, you mentioned, you've done some work with ketamine. Are you doing work with any of the drugs that are supposedly reopening or stimulating meta plasticity in the context of what you study in the visual system? No,

Mark Bear 1:14:44

we're not. But that's not to say we won't. We're not now we're very excited about the, you know, the, the experiments that we feel what needed to be done are to now understand Why this fellow ITT X treatment works. And so we have, you know, some very low level but very important questions. How does it work? What is it a lot? Is it the temporary loss of interaction or suppression, for example, and we need to know the answer to that. And I think as we know, the one thing that basic science teaches is, once you understand the mechanisms, it may open up entirely new avenues approaches that can be used therapeutically. So, that's what we're really focused on right now.

Nick Jikomes 1:15:35

All right, well, Dr. Mark Bair, thank you for your time. This was fascinating. And yeah, it's just like a wonderful example of connecting the dots all the way from basic science questions all the way to very 10 tangible solutions to clinical problems that are not years and years away, but might be pretty close to coming to fruition.

Mark Bear 1:15:57

Thank you very much for your interest.

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