WEBVTT

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This is the Convergent Science Network podcast. Leading researchers in the domain

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of neuroscience, brain theory and technology are interviewed by Paul Vesure and Tony Prescott.

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Yeah, all right. This is Paul Vesure with the Convergent Science Network.

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This is our BCBT School 2015. And I'm here with Brian Kolb, who this morning

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was in his lecture dealing with the whole question of epigenetics and how, in some experience,

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can affect our behavior even for a number of generations after us.

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So what is specific about this epigenetic perspective on behavior and changes in behavior?

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Well, I think that historically people had this view of nature and nurture and

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that most of what we developed, we learned, and it was sort of independent of anything else.

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And I think what we now know is that there's an interaction between the activity

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of genes in the brain and experiences.

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So specific experiences turn different genes on and off.

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And when they're doing that, it alters how the brain responds to other experiences.

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So, for example, if you're taking a drug, let's just say it's nicotine,

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the nicotine is changing the expression of genes in the brain.

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The job of genes is to make proteins, so what the proteins are making are different.

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And so the organization of synapses, circuits, is altered by the drug in an indirect way.

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But it turns out that it depends on which genes are already on and off,

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so that the baseline gene profile is going to actually influence how experiences do this.

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But now, in some sense, anything that a cell does, or almost anything,

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will have an impact on gene transcription.

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Yes. So, however, there's a certain subset of gene transcription that are of

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specific relevance to this question of the epigenetics, where,

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as I say, the gene expression and environment are coming together.

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So is there a specialized, if

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you want, system that is supporting these epigenetic changes to behavior?

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That's the general belief. But if you now say, where is that system and what is it, we don't know.

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But that's sort of the assumption that we start off with. Yeah,

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and it may be that it's microRNAs that are changing and non-coding parts of

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the gene that are changing and

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controlling all of this, but we're still pretty naive on how that works.

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Right. So can you give me,

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what's a typical example that you would have in mind that really expresses most

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clearly these epigenetic impacts that we have on the phenotype?

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Well, if you look, I mean, we've looked a lot at stress and various kinds of

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stressors because stress produces such big changes and these changes persist.

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So we know that changes actually can cross at least four generations.

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If you experience stress in uterus or gestational stress, we know that there

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are changes in a whole bunch of things and these changes persist.

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So we're looking at different kinds of stressors and trying to compare them

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and see if we can get some understanding as to which pathways are actually changed by the stressors.

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So basically we're taking a sledgehammer and trying to see, okay,

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if you use a sledgehammer, what do you get?

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Rather than something more subtle like social interaction, which would be much harder.

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I'm sure it's doing things. And our example of play behavior is one example

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where the way in which animals play.

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Is going to alter gene expression and it's going to alter synaptic organization,

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but it's much more subtle.

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But now, if we talk about these kinds of changes, how would you measure those?

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If you now say, okay, there's some environmental, let's say,

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a stressor that is impacting a mother rat, now the offspring will be changed as a phenotype.

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What are you looking for in that phenotype? So there are various things you

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can do. So the first measure, so when the rubber hits the road,

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this is all about behavior.

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And so we're looking for changes in behavior. If we find none,

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it might be that our measurements are too simple, they're not sophisticated

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enough, or it may be that there aren't any changes.

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So at that, first we're looking for changes in behavior. When we see them,

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we know we're on the right track.

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Then the second thing we're interested in is, okay, can we see changes in the circuits in the brain?

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And where are those changes in the circuits? is because you can't look at gene

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expression everywhere.

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It's just not practical. So you're looking for a needle in a haystack.

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So when we look at using brain staining, using a Golgi technique,

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we can look at the changes in the number of synapses on cells.

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Once we see a region that looks like it's showing significant changes,

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we then can zero in there and say, okay, there's where we'll take our tissue

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and do our gene chip arrays or whatever it is we're doing to try and identify the genes.

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Now, the problem is, the ideal thing would be to find one gene.

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Well, that's not going to happen.

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You're going to find cascades of genes. So we often are finding 1,000 or 1,500 genes.

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That's useless. So what you have to do is to see, okay, these are going to be

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related to one another in some way.

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And so we're looking at trying to get some sense of what the pathways are.

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Are they all related to the production of proteins related to.

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Synaptogenesis or neurogenesis or some other thing.

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So that's the process. Behavior, then where in the brain are things changing,

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and then drill down with your genes.

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And we start with looking at global methylation.

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So what methylation is telling you is that if you have a change in methylation,

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up or down, you have more or less genes being expressed.

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The more methylation, the less gene expression. Once you've seen that,

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then you can say, okay, that's just a clue that something's going on,

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but it doesn't tell you much.

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It just tells you something happened, then we can look at the actual genes themselves.

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Because it's expensive, and you don't want to waste time looking at places where

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nothing happened. Right.

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So now, a first example that you emphasized a lot was the role of tactile stimulation

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as an epigenetic factor. So how does that play out exactly?

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So just to give the background, if we take young animals and we use a little

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brush and we tactilely stimulate them for 15 minutes, three times a day for

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10 days, let's say, and then wait until they're adults,

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we can see changes in their behavior.

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So we see enhanced cognitive skills, better memory, better learning.

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I don't know about perceptual skills. We haven't done that. then we can look

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in the brain and say, okay, are there changes in synaptic organization? Yes.

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So where are they? And it turns out with tactile stimulation,

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there's pretty widespread.

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And then we can say, okay, what are the changes in gene expression?

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And can that give us some clues to what the tactile stimulation is actually doing?

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The advantage of that is if we now want to use that tactile stimulation as a

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therapy, let's say for an animal that was stressed, can we reverse the effects

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of the stress and reverse the effects of the gene expression.

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Well, if it turns out that it's totally different systems of genes,

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it's going to be a tougher cell than if there's some relationship between the two.

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But now, you also emphasized the release of FGF2 as a result of tactile stimulation.

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So why do you emphasize that factor so much?

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So we started looking at FGF2 for other reasons.

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Because we knew that in vitro, it stimulates neurogenesis.

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And so we originally thought, well, maybe we'll be able to use FGF2 to stimulate

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neurogenesis, or maybe the tactile stimulation will increase neurogenesis.

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So that's why we started with it. And it turns out it did seem to be released

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with enhanced tactile stimulation, enhanced the release of FGF2.

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And so then we thought, okay, can we see a pathway in the brain related to this?

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Is there an increase in the genes related to this?

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FGF-2 receptors or the production of FGF or whatever. So really,

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it's one of these things that's your favorite molecule by accident.

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But once you've found something, let's stick with it and we'll see what we can

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get from it. Right. Okay.

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So because also other substances are released in response to tactile stimulation.

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Of course. Like endorphins, for instance. Sure. And so are probably cholinergic systems in the skin.

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That are related to pain and whatnot, right? All of those things were released

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too. And so we have looked at acetylcholine levels, and they do change too.

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But we haven't pursued that and haven't seen any evidence in the epigenetics

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that acetylcholine is really going to be a likely candidate for the big one,

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if you like. Right. Okay.

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So now an important, from there, so after tactile stimulation,

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but also identifying a possible pathway

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of then such an epigenetic channel,

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because it means the tactile stimulation is also then already,

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let's say, with the mother, right, the pregnant mother, and then the stimulation

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would then have an effect on the pups.

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So what's the behavioral impact that that would have?

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So, I mean, there's two issues here. One is, how do we know that the tactile

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stimulation hasn't changed the mother's brain, and it therefore changes her

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behavior towards the pups? and that's what's doing it.

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We don't. But we do know that if we look in the brains of the pups,

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we see change in FGF2 receptors, for example.

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And if we look at their behaviors, we're going to see enhanced cognitive behaviors,

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enhanced motor behaviors, and not so much species-typical behaviors, but like play and so on.

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So we know that whatever the FGF2 is doing to the mum and to the fetus is producing

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these behavioral outcomes.

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Okay. So but then, actually you made quite a big jump, right?

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Because then we looked at the growth of vocabulary in humans.

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So how is that, what's the effect that you observed there? So the idea there

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is that experience early in life is going to make a huge difference to the development of language.

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I'll give you a simple example, and that is when you're a month old or a newborn,

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you can discriminate all speech sounds in all languages.

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And a few months later, you're losing that.

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So if you're only exposed to Dutch, for example, you're not going to find Korean

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so easy. You're going to have difficulty discriminating those speech sounds,

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and the longer we go, the less able you are.

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So we're going to have that going on. The other thing we're going on is that

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exposure to words makes a huge difference to the development of cognitive abilities.

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But it's exposure to words isn't just hearing the words, it's actually using

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the words. So some people will call this serve and return.

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So if I say, Paul, what did you do today? I'm expecting a response.

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If, on the other hand, you're listening to radio or television,

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you're not responding. And so you're not using language in the same way.

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So there's a really interesting experiment which children, and I forget the

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age, it was like one and a half or two, were either watching somebody teach

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them Japanese, or a Japanese person was in a screen and there was serve and return.

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So they had to say the sounds.

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And it turns out if they were actually interacting with an individual,

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there was a social aspect.

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The kids learned Japanese words, whereas the ones who were doing it on a television monitor didn't.

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So that serve and return seems to be important. So what is it about that?

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Well, there's a social aspect.

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And if you're actually teaching an infant things, there's normally a lot of contact.

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So you're getting tactile stimulation of them. They're sitting on your lap or

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your arms around them or whatever, right? So all of these factors are going together.

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So then if you say, well, why is it that children who live in higher socioeconomic

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status houses have a larger vocabulary? Is it because their parents are smarter?

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No. No, their parents have a larger vocabulary. So they're exposed by age three

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to about a million more words than the kids in the lower SES families.

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Not a million different words, but a million more words total that they're exposed

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to. A lot of them are different words.

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And largely it's because for one reason or another, the higher SES families,

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there's more serve and return. turn.

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So there's more discussion about things than there is in the low SES families,

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perhaps because the caregivers in the more wealthy families have more time,

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or that there is a caregiver that's hired that's there all the time,

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a nanny or whatever it might be.

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Whereas in the less well-off families, they don't have that.

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Or they may just be interacting with siblings, and of course siblings aren't

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going to have as large a vocabulary, and they may not serve in return in the same way as adults.

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And the effect of this is to get kids on a trajectory of.

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So that they're learning more and more words. And as I mentioned this morning,

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the kids who at age 36 months have a vocabulary that's about three times as

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big as the kids who are less well off.

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That difference just continues to get larger and larger and larger.

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And so by age 11, those kids in the high SES families have a larger vocabulary

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than the moms of the other kids.

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I also mentioned the fact that you could say, well, school is going to reverse

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this. So once they get to school, they're all going to be exposed to the same.

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That's true. But the less fortunate kids are way behind.

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And a study in New Zealand showed that after eight years of school,

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it didn't make any difference.

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The kids who were low are still low. Kids who are high are even better.

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And so we need to do something in school to try and reverse this.

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And part of it may be to increase the amount of serve and return for these lower

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SES kids, more interaction to try and get them using language more aggressively.

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But now you could also argue that you mentioned stress earlier,

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that these sort of lower socioeconomic status families have also higher stress

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and that the real explanation is more at the end of stress than at the end of,

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let's say, exposure to language.

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They're obviously intertwined, so stress is clearly going to be an issue.

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So one of the ways you could study it is retrospectively, in a sense,

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and that is look at stress levels in the two groups and try and tease that out.

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People are trying to do that, and as well as diet and a variety of other things.

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One of the best studies on this is done in Cuba, and it's a social experiment.

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So Castro, it turns out, was really interested in children. So after the revolution,

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he set up, he changed the educational system and they started pouring resources into children.

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And children had to go to, well, the mums first of all, to what were called polyclinics.

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So they had to report monthly to this nurse. And if they didn't show up,

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they went and found them and brought them in. And the polyclinics are associated with schools.

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And so when UNESCO did their first studies on Latin American skills in kids,

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they compared kids in Cuba to kids in Chile, Argentina, Mexico, and so on.

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And what they found was that the kids in Cuba were significantly better in both

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literacy and arithmetic skills.

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So the question is, well, is it just that Latin America isn't all that good,

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and this little bit of extra experience in Cuba worked?

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There's two ways to look at that. One is to say, I'm from Canada,

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and say, well, how do Canadian kids do?

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We're probably better than the Cuban kids. And the answer is, no, we're not.

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We're actually less good than the Cuban kids.

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Well, can you take what they did in Cuba and apply that,

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in less advantaged places. So there was a study in South Carolina working with

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children from disadvantaged black families.

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They used the same system and they ended up with the Cuban scores.

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Similar study done in Mexico, same outcome. So it looks like pouring resources

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in early makes a big difference.

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And there's another UNESCO study, it was an OECD study, looking at literacy skills.

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And they identify five levels of literacy.

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And you're going to have literacy level five because of your education and experiences.

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But the average person doesn't. And in Canada, about 42% of the population is

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considered illiterate, even though they all went to school.

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So they're levels one or two. In the United States, it's even higher.

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And in Britain, it's higher as well. The United States is about 56% is considered illiterate.

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So this is pretty scary.

00:18:31.028 --> 00:18:32.908
Well, let's look at other countries. So if you look at Sweden,

00:18:33.008 --> 00:18:38.648
it's about 30%. So are Swedes innately smarter than Brits or Canadians or Americans?

00:18:38.908 --> 00:18:42.368
I prefer to think not. What's the difference? They pour more resources,

00:18:42.428 --> 00:18:45.788
just like Cuba does, into early childhood development.

00:18:46.088 --> 00:18:50.628
And that seems to have a huge impact on language skills and subsequent literacy,

00:18:50.768 --> 00:18:55.648
which literacy has a huge impact on your health and your income.

00:18:56.508 --> 00:19:01.668
But the consequence of this also that maybe the real impact is actually before

00:19:01.668 --> 00:19:05.528
children go to school. Oh, it is. There's no question that it is.

00:19:05.748 --> 00:19:10.968
It's in those first three years probably. Right. So then what's the benefit

00:19:10.968 --> 00:19:12.128
of going to school? Well.

00:19:13.085 --> 00:19:17.385
Well, you're learning information, obviously. And you and I went to school for

00:19:17.385 --> 00:19:19.065
a long time and we learned a lot of information.

00:19:19.985 --> 00:19:23.505
So why didn't the people who were in levels one and two benefit so much?

00:19:25.185 --> 00:19:29.345
They were behind the eight ball to start with. And it wasn't that they were

00:19:29.345 --> 00:19:31.885
stupid, to use a sort of blunt term.

00:19:32.145 --> 00:19:36.985
They really were set on a trajectory that was disadvantageous.

00:19:37.125 --> 00:19:41.305
So the challenge here, and the Swedes have got it right, is to intervene really early.

00:19:42.405 --> 00:19:47.765
And in those first three years and put the money there rather than trying to

00:19:47.765 --> 00:19:50.505
reverse things when the kids are 10 or 11 when it's too late.

00:19:51.085 --> 00:19:59.245
Right. But then a key factor that you emphasize a lot is notion of stress.

00:19:59.445 --> 00:20:03.485
And also you looked a lot at stress in rats and how does it impact their offspring

00:20:03.485 --> 00:20:11.645
or how it impacts their mates. So you take a rat.

00:20:11.785 --> 00:20:15.865
I understand the main procedure to induce stress is to put them on a raised platform.

00:20:16.505 --> 00:20:21.705
And that's some sort of predator anxiety that they are exposed to.

00:20:21.745 --> 00:20:22.665
That's a source of stress.

00:20:23.625 --> 00:20:26.865
And now you observe a number of interesting effects, right?

00:20:26.925 --> 00:20:31.165
So rats, just on their own, rats that are exposed to that stress,

00:20:31.325 --> 00:20:33.745
what does it do to their brain and their behavior?

00:20:33.745 --> 00:20:38.745
Just if I take an adult rat and I would put it on this platform for a number

00:20:38.745 --> 00:20:43.965
of times okay so we've done that just taking adult rats and we increase their

00:20:43.965 --> 00:20:48.165
anxiety we affect their ability to learn complex motor skills,

00:20:49.105 --> 00:20:56.825
we see big changes in the organization of synapses in prefrontal cortex and

00:20:56.825 --> 00:21:01.185
different effects on different parts of prefrontal cortex and we see changes

00:21:01.185 --> 00:21:02.905
in gene expression expression.

00:21:05.046 --> 00:21:08.886
It's a bit confounded because how do we know that the behaviors that they're

00:21:08.886 --> 00:21:11.906
exhibiting now, the anxiety, isn't producing the changes in gene expression?

00:21:12.106 --> 00:21:12.726
Well, they don't know that.

00:21:13.026 --> 00:21:18.826
There's no way for me to separate those two things, except by correlation and

00:21:18.826 --> 00:21:21.746
say the ones who are the most anxious, do they show bigger changes?

00:21:22.546 --> 00:21:25.446
Yeah, but that's still confounded. Yeah, so it's very difficult.

00:21:25.666 --> 00:21:29.886
But we do know that we can produce similar effects in adults as we can produce

00:21:29.886 --> 00:21:32.266
indirectly in the developing brain.

00:21:32.746 --> 00:21:37.326
So now how do you assess anxiety in those rats? So we can do it in a variety of ways.

00:21:38.066 --> 00:21:43.966
The simplest way is to put animals in a situation where they can hide and be

00:21:43.966 --> 00:21:45.766
safe, or they can go out and explore.

00:21:46.266 --> 00:21:51.826
And the inference here, the implication is that animals who hide are afraid,

00:21:51.926 --> 00:21:54.606
and the ones who go out and explore are not.

00:21:54.686 --> 00:21:57.526
Well, I think you mentioned in a question this morning that,

00:21:57.546 --> 00:21:59.566
well, how do I know that this doesn't make them more active?

00:21:59.966 --> 00:22:03.186
So there's another test you can use. We haven't actually done this yet,

00:22:03.206 --> 00:22:06.766
but we're going to, and that is, it's called a burying test.

00:22:07.846 --> 00:22:11.526
So let's imagine you're in an environment, and there's this little probe that

00:22:11.526 --> 00:22:16.286
comes out, and you go and you touch it, and you get a shock, and you're a rat.

00:22:16.426 --> 00:22:20.326
Not a bad shock, but like a carpet shock, okay? So you get this shock.

00:22:21.686 --> 00:22:26.026
Animals that are anxious will bury that probe.

00:22:26.466 --> 00:22:29.686
They'll cover it up, and the more anxious they are, the more they cover it up.

00:22:29.686 --> 00:22:34.106
Animals that think it's trivial, for whatever reason, because they're on Valium

00:22:34.106 --> 00:22:38.346
or something at the time, go, never mind, just avoid it.

00:22:38.666 --> 00:22:42.766
So that's another measure of anxiety that we're going to cover that up.

00:22:44.006 --> 00:22:48.506
And another way you could do this is to take animals that appear to be anxious,

00:22:48.586 --> 00:22:53.246
for example, in that plus maze, and give them anxiolytics and see whether or

00:22:53.246 --> 00:22:56.586
not that reduces the effect you've seen it does.

00:22:58.006 --> 00:23:05.226
Right. But now, okay, so we have the adult rat, but now if, what you also told

00:23:05.226 --> 00:23:08.686
us, if I take this adult rat and I bring it back to its mate,

00:23:08.866 --> 00:23:12.766
they will actually communicate about their experience. Yeah.

00:23:12.866 --> 00:23:19.606
So rats have a very complex set of songs that I'll use the term loosely, songs that they sing.

00:23:21.246 --> 00:23:27.286
Pardon me. And the rat that's distressed will come back and sing a series of

00:23:27.286 --> 00:23:30.506
different distressed songs. So life is crap songs.

00:23:31.086 --> 00:23:36.606
And the mate will sing back songs that are usually associated with happy things. Life is good.

00:23:36.766 --> 00:23:42.666
And this goes on for hours. And apparently, this is an inference not proven,

00:23:42.766 --> 00:23:47.386
hearing this distressed song for so long is stressful.

00:23:47.986 --> 00:23:53.406
And that affects the offspring of what we call the bystander animal.

00:23:55.006 --> 00:23:55.506
Okay, but then…,

00:23:56.629 --> 00:24:01.469
What's the impact on the offspring? How strong is that impact as compared to

00:24:01.469 --> 00:24:05.729
the mother having been exposed to that stress herself directly?

00:24:06.809 --> 00:24:09.089
I think the best answer is the effect is different.

00:24:10.269 --> 00:24:15.009
We see an effect. We see increased anxiety. We see reduction in brain weight.

00:24:15.269 --> 00:24:20.669
We see impaired motor skills. But in each case, it's not as big as the direct

00:24:20.669 --> 00:24:22.209
stress. It's a smaller effect.

00:24:22.789 --> 00:24:29.249
So the next question is, well, can you vary the intensity of stress given directly to the mom?

00:24:29.329 --> 00:24:32.769
And would you see, so for example, we, instead of putting them on that platform

00:24:32.769 --> 00:24:35.129
for 20 minutes, put them on platform for 10 minutes.

00:24:35.569 --> 00:24:39.809
Would you see a different effect? And the answer is yes. So the intensity of

00:24:39.809 --> 00:24:41.269
the stress seems to make a difference.

00:24:41.769 --> 00:24:47.589
And so we're mimicking a low, lower intensity stress, um, using the bystander

00:24:47.589 --> 00:24:48.729
stress. Right, exactly.

00:24:49.009 --> 00:24:56.549
But then the offspring will show also higher anxiety, as we saw earlier in the

00:24:56.549 --> 00:24:57.989
adult rat exposed to the stress?

00:24:58.189 --> 00:25:01.689
Yes. Or would it also show other kinds of behavioral changes?

00:25:02.729 --> 00:25:07.269
We can actually look at behavior at about nine days.

00:25:07.769 --> 00:25:12.449
And there's a variety of behavioral tests you can use to try and look at nervous system development.

00:25:12.609 --> 00:25:17.429
And it looks like rats exposed to that kind of stress are delayed in development by about a day.

00:25:17.949 --> 00:25:23.109
They're slower to develop some of the early behavior. So we can see it right away.

00:25:23.989 --> 00:25:30.909
If we look at adults, we see changes in cognitive skills, motor skills in particular.

00:25:31.309 --> 00:25:35.509
Now, one of the questions we've been asking is, well, if you've had that early

00:25:35.509 --> 00:25:39.869
stress, how do you respond to stressors later? Sure.

00:25:40.606 --> 00:25:44.566
Is there any kind of inoculation effect, an advantage? And the answer is,

00:25:44.586 --> 00:25:45.706
it kind of looks like there is.

00:25:46.206 --> 00:25:50.726
That if you've had that early stress, that a later stressor,

00:25:50.726 --> 00:25:54.366
say as a juvenile, isn't as effective in changing your brain.

00:25:55.406 --> 00:25:59.426
It's like you've been inoculated against stress. So we're pursuing that now

00:25:59.426 --> 00:26:03.126
and varying the age of the second stress and the first stress and trying to

00:26:03.126 --> 00:26:04.606
see, okay, how does that work?

00:26:05.006 --> 00:26:08.746
But that means you might have paid a price for that in terms of your cognitive

00:26:08.746 --> 00:26:15.106
abilities. You may have paid a price for that, but you may have gained an advantage in coping skills.

00:26:15.826 --> 00:26:19.186
Right, exactly. But it's a trade-off. It's not something that comes for free.

00:26:19.606 --> 00:26:23.846
Exactly. And then that might mean that also the offspring,

00:26:24.246 --> 00:26:30.046
now the third generation, might also again be still under the influence of that

00:26:30.046 --> 00:26:37.106
stress that then their grandparent was exposed to.

00:26:37.546 --> 00:26:40.866
So how far down the lineage would this go? Well, my colleague,

00:26:40.966 --> 00:26:42.926
Gerlinda Metz, has been studying this.

00:26:42.986 --> 00:26:45.666
We've done a couple of experiments with her. We've gone to the fourth generation,

00:26:45.786 --> 00:26:46.746
and we can still see effects.

00:26:47.826 --> 00:26:54.186
One of the interesting effects is on the gestational age at birth of,

00:26:54.306 --> 00:26:56.986
say, the grandchildren and great-grandchildren offspring.

00:26:57.246 --> 00:27:01.406
And it turns out that those early stressors are actually changing the length

00:27:01.406 --> 00:27:03.566
of gestation by half a day or so.

00:27:04.546 --> 00:27:09.086
So, to what extent is that the cause of all of this rather than the stress itself?

00:27:10.006 --> 00:27:13.046
Don't know. So, you can see it starts to get complicated.

00:27:14.286 --> 00:27:18.826
The reason that she's doing, I'm not interested so much in the gestational period,

00:27:18.926 --> 00:27:23.426
but the reason she's doing it is because in humans, it looks as though stressful

00:27:23.426 --> 00:27:24.886
experiences will do the same thing.

00:27:24.926 --> 00:27:27.346
They'll change. You get more premature babies.

00:27:28.026 --> 00:27:30.886
And so, what's that doing? Right. Yeah.

00:27:31.006 --> 00:27:35.506
But then, do you see this wash out? So after how many generations would it be

00:27:35.506 --> 00:27:37.906
washed out? Well, it has to wash out.

00:27:38.886 --> 00:27:42.346
Logically, it has to wash out and you're going to have regression to the mean.

00:27:42.666 --> 00:27:47.506
So Michael Meaney at McGill has looked at it in a slightly different way. And,

00:27:48.249 --> 00:27:51.149
What he's done is say, okay, we don't stress anybody.

00:27:51.249 --> 00:27:54.869
We'll just look at the endogenous behavior of mums. And what he identifies is

00:27:54.869 --> 00:27:59.349
mums who do a lot of licking and grooming of their offspring and mums who don't

00:27:59.349 --> 00:28:00.949
do as much. So you have a normal curve.

00:28:01.069 --> 00:28:03.929
Let's look at the two tails. Can you breed for that?

00:28:04.449 --> 00:28:08.389
And it turns out you can't. There's a slow regression to the mean.

00:28:09.589 --> 00:28:12.869
And why would you even care about licking and grooming? Because it's related

00:28:12.869 --> 00:28:17.349
to behavior, just like the tactile stimulation is related to behavior.

00:28:18.889 --> 00:28:24.589
But over time it seems to go away because we thought, well, we could just breed

00:28:24.589 --> 00:28:27.529
for this and no, it doesn't work.

00:28:27.869 --> 00:28:35.649
But now there must be a range of stress to which the animal is sort of genetically, let's say, prepared.

00:28:35.829 --> 00:28:40.189
Yes. That it can tolerate and it will not have these kinds of epigenetic knock-on effects.

00:28:40.509 --> 00:28:42.909
Yes. So how broad is that range?

00:28:43.309 --> 00:28:47.069
That's a good question. I mean, clearly, if you think about the old psychological

00:28:47.069 --> 00:28:50.749
inverted U function for stress, you need some stress or you're not awake,

00:28:50.909 --> 00:28:53.069
right? If you have too much stress, you're dead.

00:28:53.449 --> 00:29:01.709
And so where exactly in that inverted U function is the effect optimal and when is it worse?

00:29:01.949 --> 00:29:05.969
And so that's the kind of experiment that one needs to do to try and figure

00:29:05.969 --> 00:29:06.909
that out. We don't know that.

00:29:07.109 --> 00:29:11.489
Okay. But I'm sure that there's a level of stress that nature is expecting to

00:29:11.489 --> 00:29:12.769
encounter. There has to be.

00:29:13.589 --> 00:29:17.409
And so it's had millions of years to adapt to that and to expect it.

00:29:17.829 --> 00:29:22.729
So when we talk about brain plasticity, we talk about experience expectant.

00:29:22.849 --> 00:29:25.329
The brain is expecting certain kinds of experiences.

00:29:25.729 --> 00:29:30.269
If it doesn't get it or it gets too much of it, it goes, whoa, what's going on?

00:29:30.569 --> 00:29:35.029
And you say, yeah. But now the interpretation in this case is rather nonspecific

00:29:35.029 --> 00:29:39.869
because we say, well, there's some environmental manipulation leading to stress on the animal.

00:29:40.389 --> 00:29:42.789
And the stress then has an epigenetic impact. Thank you.

00:29:43.361 --> 00:29:47.081
But maybe with this manipulation, you could argue, well, maybe the impact is very specific.

00:29:47.601 --> 00:29:53.301
It is basically telling this mother rat directly or indirectly that this is

00:29:53.301 --> 00:29:55.001
an environment filled with predators.

00:29:55.421 --> 00:30:02.761
Yes. And that then the epigenetic effect is actually very specific adaptation, which is weird.

00:30:02.841 --> 00:30:07.741
Let's say, stay hidden more, don't go out a lot, avoid open spaces.

00:30:07.741 --> 00:30:12.281
So what we then interpret as a nonspecific impact of stress is maybe very specific

00:30:12.281 --> 00:30:15.781
adaptation to a world that is filled with predators.

00:30:16.001 --> 00:30:18.921
Absolutely. And if you think about the Barker hypothesis,

00:30:19.241 --> 00:30:27.821
which is a nickname for that kind of idea, if you look at the onset of adolescence

00:30:27.821 --> 00:30:31.981
in animals who were stressed, it's earlier.

00:30:32.821 --> 00:30:36.241
So we see this. So why would that be? Well, if it's a dangerous world,

00:30:36.881 --> 00:30:37.941
you want to have your baby sooner.

00:30:38.421 --> 00:30:43.521
You don't have the luxury of waiting. And whereas the animals that are raised

00:30:43.521 --> 00:30:46.121
by moms who are very attentive, it's later.

00:30:46.981 --> 00:30:49.841
So again, it looks like it's adapting to the environment that's going to be

00:30:49.841 --> 00:30:52.881
there. Which adaptation is correct?

00:30:53.081 --> 00:30:55.561
Well, it depends on what the environment turns out to be. Right, exactly.

00:30:56.581 --> 00:31:00.101
But then there might also be the other extreme. If you have animals that have

00:31:00.101 --> 00:31:04.481
zero stress, like it's the WALL-E world.

00:31:04.621 --> 00:31:07.641
I don't know if you remember that animation movie of the humans all living in

00:31:07.641 --> 00:31:13.781
outer space, being fed high sugar or high glucose drinks all day long.

00:31:15.321 --> 00:31:19.841
So would you also see epigenetic change when you have a world that is really

00:31:19.841 --> 00:31:22.581
zero stress or like understressed?

00:31:22.781 --> 00:31:26.041
I would think you would because using the experience expectant model,

00:31:26.301 --> 00:31:28.041
the brain is expecting stress.

00:31:28.681 --> 00:31:33.541
And in the absence of it, it's going to change. There's going to be some sort of change.

00:31:34.021 --> 00:31:36.681
Now, to do this experimentally would be a bit of a challenge.

00:31:38.341 --> 00:31:42.581
But in principle, as a mind experiment, a thought experiment,

00:31:42.801 --> 00:31:44.141
that should be the case. Right.

00:31:44.481 --> 00:31:48.941
So now, we have a bit of an insight now in the stress case and then also these

00:31:48.941 --> 00:31:50.621
effects it has epigenetically.

00:31:51.181 --> 00:31:55.841
But another manipulation that you have looked at is drugs, different kinds of

00:31:55.841 --> 00:31:59.761
drugs of abuse. use, do you think the impact of drugs of abuse is,

00:31:59.781 --> 00:32:03.821
let's say, similar to the impact that stress has, or is it?

00:32:04.181 --> 00:32:12.621
So when we did our adult stress study, we compared the effects directly to getting

00:32:12.621 --> 00:32:14.561
either nicotine or amphetamine repeatedly.

00:32:14.881 --> 00:32:18.761
So we've only used stimulants for this experiment to ask this very question.

00:32:19.621 --> 00:32:23.301
The magnitude of the gene expression changes are similar.

00:32:23.401 --> 00:32:27.081
It's different pathways that are changed. changed? So the answer is,

00:32:27.101 --> 00:32:31.361
yeah, I think we're on the right track here. And we do know that.

00:32:32.955 --> 00:32:38.075
Being exposed to stress early sensitizes the brain to make it more sensitive

00:32:38.075 --> 00:32:40.395
to drugs, stimulants anyway.

00:32:40.575 --> 00:32:44.855
We don't know about other drugs. We do know that every psychoactive drug we've

00:32:44.855 --> 00:32:47.155
looked at, every class of psychoactive drugs we've looked at,

00:32:47.195 --> 00:32:50.855
so stimulants, depressants, anxiolytics, antipsychotics,

00:32:51.475 --> 00:32:57.095
antidepressants, all leave a footprint in the brain that looks to be permanent if you're a rat.

00:32:57.095 --> 00:33:03.275
And I can use an anecdote and say that my father-in-law quit smoking 40 years

00:33:03.275 --> 00:33:08.315
ago, but he says even now, he'll wake up in the morning and say, I'd like a cigarette.

00:33:09.055 --> 00:33:12.115
So that's a long-term effect.

00:33:12.315 --> 00:33:15.895
Is he still an addict? Well, he would be if he started taking it.

00:33:15.915 --> 00:33:17.695
I'm sure he'd start smoking it, and he thinks so too.

00:33:18.335 --> 00:33:22.815
A lot of people who are smokers will say it happened. I took a cigarette and I'm back.

00:33:23.155 --> 00:33:26.495
I've got to stop all over again. It's not easy.

00:33:27.075 --> 00:33:33.115
But now the changes to the brain, like say if you would look at also get the spine count on neurons,

00:33:33.375 --> 00:33:37.075
and for instance, the prefrontal cortex, which is one area that you looked at

00:33:37.075 --> 00:33:43.415
with great attention, would those changes be comparable in the epigenetic case

00:33:43.415 --> 00:33:48.035
as those of stress, or would the knock-on effect be different?

00:33:48.975 --> 00:33:52.615
Like if we take a mother rat exposed to different kinds of drugs,

00:33:53.495 --> 00:33:54.775
what is the impact on her offspring?

00:33:55.075 --> 00:33:59.075
Is it comparable to the stress case? Or are the changes very different?

00:34:00.155 --> 00:34:03.835
The changes are probably different. So here's, I can do it from the anatomy

00:34:03.835 --> 00:34:05.675
and then make an inference from that.

00:34:05.795 --> 00:34:12.955
If we look at the effects of stimulants on medial prefrontal cortex,

00:34:12.955 --> 00:34:15.115
we get an increase in spine density.

00:34:15.275 --> 00:34:18.475
If we look at orbital frontal cortex, we get a decrease in spine density.

00:34:18.915 --> 00:34:20.975
What happens if we look at stress? We get the reverse.

00:34:21.515 --> 00:34:26.455
So what we see from stress is we see a decrease in spine density in medial frontal

00:34:26.455 --> 00:34:29.015
cortex and an increase in orbital frontal cortex.

00:34:29.255 --> 00:34:32.695
You might say, well, how do you account for that? Well, let's use a different

00:34:32.695 --> 00:34:35.035
class of drugs. Let's use opiates.

00:34:35.715 --> 00:34:37.595
If we look at opiates, it looks like stress.

00:34:38.455 --> 00:34:40.195
So it's going to depend on the drug.

00:34:41.660 --> 00:34:47.920
Type that you're using. So, opiates look like stress, stimulants look like the reverse of stress.

00:34:48.480 --> 00:34:52.600
In both cases, it's being changed, but clearly the mechanisms are not the same.

00:34:52.700 --> 00:34:58.360
We haven't done epigenetics with the opiates, so I don't know if it's more similar or not. Right.

00:34:58.720 --> 00:35:03.340
But now, what you were mentioning is that if you look at these stressors as

00:35:03.340 --> 00:35:07.060
non-stressed stressed or drugs, non-drug animals,

00:35:07.360 --> 00:35:13.400
that actually the morphology of the dendrite and the spines on the dendrite

00:35:13.400 --> 00:35:17.900
is rather different in the sense that in, let's say, the healthy control case,

00:35:18.100 --> 00:35:22.800
you have a certain spacing of these spines that might be absent under either

00:35:22.800 --> 00:35:24.700
the stress or drug condition. Right.

00:35:25.240 --> 00:35:30.940
So how relevant is that for understanding then of these developmental and epigenetic

00:35:30.940 --> 00:35:36.560
processes? Well, I think that one of the things it tells us is that subsequent

00:35:36.560 --> 00:35:38.840
experiences are acting on a different brain.

00:35:39.140 --> 00:35:43.460
So let's suppose your mom was a smoker.

00:35:43.920 --> 00:35:47.400
Forget about the effects of carbon monoxide. Let's just pretend the effect is nicotine.

00:35:48.200 --> 00:35:50.440
Your brain has changed. We've shown that.

00:35:51.340 --> 00:35:55.440
And you respond to experiences in a different way later in life.

00:35:55.860 --> 00:36:00.260
Same is true of stress. So your brain is changed. You respond to experiences

00:36:00.260 --> 00:36:03.560
such as drugs differently later in life.

00:36:03.720 --> 00:36:09.040
So we see these, what I'm going to call, metaplastic effects that sort of compound.

00:36:09.080 --> 00:36:13.840
And if you think about it, I mean, human's life is not you get a drug and then we kill you.

00:36:14.140 --> 00:36:17.540
It's one experience after another experience after another experience.

00:36:17.540 --> 00:36:25.540
And so this collage, if you like, of experiences are all meshing together to

00:36:25.540 --> 00:36:26.480
give you the final outcome.

00:36:26.600 --> 00:36:30.820
So this makes it, in humans, pretty darn hard to control.

00:36:31.180 --> 00:36:34.780
So you're going to expect huge individual differences, and of course we see that. Mm-hmm.

00:36:36.295 --> 00:36:38.875
And do you then look at development? Because in some sense, there's,

00:36:38.875 --> 00:36:45.615
if you want, a normal brain with sort of a developmental structure to the morphology of the cell,

00:36:45.675 --> 00:36:52.095
which is then a scaffold in which these future experiences are placed. Right.

00:36:52.655 --> 00:36:55.975
So what would a scaffold look like for the healthy brain?

00:36:56.595 --> 00:37:01.835
And just the cell morphology of a prefrontal or medial prefrontal cortex.

00:37:01.835 --> 00:37:06.855
You mentioned one thing, which is, for instance, the spacing between the spines,

00:37:06.875 --> 00:37:10.315
which I found interesting because you were suggesting with that that you would

00:37:10.315 --> 00:37:11.155
have, let's say, an optimal.

00:37:12.715 --> 00:37:18.515
Initialization of the dendrite, sort of an optimal spacing, so that future experience

00:37:18.515 --> 00:37:21.575
could be more easily linked into those structures.

00:37:21.895 --> 00:37:27.415
Yeah. So we've done experiments in which we've given animals tactile stimulation,

00:37:27.515 --> 00:37:31.055
or we've placed them in complex environments early.

00:37:31.835 --> 00:37:36.875
And compared that to the effects of tactile stimulation or complex environments

00:37:36.875 --> 00:37:39.335
as adults. The effect is the opposite.

00:37:39.595 --> 00:37:45.395
So in the young brain, we have larger spacing between those spines,

00:37:46.215 --> 00:37:48.195
although the dendrites are the same length.

00:37:48.295 --> 00:37:52.395
So there's fewer connections, and it looks as though you can add connections

00:37:52.395 --> 00:37:55.255
much faster in this case.

00:37:56.035 --> 00:38:01.015
In adults, you see an increase in spine density in both situations.

00:38:02.155 --> 00:38:06.815
And it's clearly somehow changing the brain in a different way.

00:38:06.915 --> 00:38:11.795
What we haven't done is to try and.

00:38:13.429 --> 00:38:16.709
Get behavioral tests that are sensitive enough to see is there a difference.

00:38:17.089 --> 00:38:20.909
And one of the problems is that the behavioral tests we use are designed to

00:38:20.909 --> 00:38:22.449
identify animals with brain injuries.

00:38:22.909 --> 00:38:26.489
They're not designed to do the experiments we're doing, so they're a bit naive

00:38:26.489 --> 00:38:30.729
in terms of what we're measuring. That's an unfortunate problem at this point.

00:38:31.189 --> 00:38:35.669
And the same with the epigenetics. We haven't actually compared the two in the

00:38:35.669 --> 00:38:40.869
way we have with the dendritic organization because the dendritic organization

00:38:40.869 --> 00:38:42.729
is cheaper to do and simpler to do.

00:38:43.429 --> 00:38:46.669
Than the epigenetics. Right. But now you also mentioned on the one hand we have

00:38:46.669 --> 00:38:49.569
the spines, the generation of spines, now it's the pruning of spines.

00:38:49.769 --> 00:38:54.069
Yeah. And also this pruning process might be affected because this is also a

00:38:54.069 --> 00:38:56.429
regulated process. Yes. It's not a random process.

00:38:56.709 --> 00:39:00.749
No. Right? So do you, if we don't talk about some sort of epigenetic chain where

00:39:00.749 --> 00:39:04.469
gene transcription has to translate into,

00:39:05.149 --> 00:39:09.589
let's say, changes to the circuit, do you see one of the principles or one of

00:39:09.589 --> 00:39:13.109
the mechanisms which can use is the pruning process and the other one is the,

00:39:13.429 --> 00:39:17.069
The generation of spines has two separate processes?

00:39:17.189 --> 00:39:19.749
Yeah, they're two separate processes. And the other thing we have to consider

00:39:19.749 --> 00:39:26.729
is which part of, if you think of the cortical layers, which layers change?

00:39:26.949 --> 00:39:30.789
Do layers in each, the cells in each layer change the same? And my initial assumption

00:39:30.789 --> 00:39:34.469
was, well, of course, because the column is a functional unit.

00:39:35.069 --> 00:39:37.569
Well, let's actually measure that. Well, it turns out it's not true.

00:39:37.829 --> 00:39:41.989
So layers two and three and five, for example, can change in the same way or

00:39:41.989 --> 00:39:43.969
opposite ways. What does that mean? I have no idea.

00:39:44.589 --> 00:39:49.409
It's just a fact that they're not, you can't predict from one layer to another layer.

00:39:49.489 --> 00:39:54.269
So it starts to get really complicated in there. So you're adding and subtracting spines.

00:39:55.249 --> 00:39:57.609
Are you measuring the same cells?

00:39:58.909 --> 00:40:02.429
Or are they different cells that are showing these changes? I don't know.

00:40:04.429 --> 00:40:09.789
Because the techniques we have don't allow us to identify the particular type

00:40:09.789 --> 00:40:12.829
of pyramidal cell it is, what its characteristics are.

00:40:13.289 --> 00:40:17.409
And measure those changes in spines. It's technically possible to do it.

00:40:17.409 --> 00:40:18.309
Now, we just haven't done it.

00:40:18.649 --> 00:40:23.749
But using molecular tricks, you can do it. And people will be doing that.

00:40:23.989 --> 00:40:30.089
Right. Yeah. But now, what we see here is indeed a brain that is hyperplastic

00:40:30.089 --> 00:40:31.789
at different timescales. Yes.

00:40:32.209 --> 00:40:36.409
And very sensitively tuned to changes in experience.

00:40:39.149 --> 00:40:43.029
But now, in some sense, the experimental paradigms were used to probe that brain.

00:40:43.289 --> 00:40:47.009
Are by necessity simple, because otherwise we're going to control them.

00:40:47.129 --> 00:40:51.289
Yes, that's right. So to what extent are we actually getting the full picture here?

00:40:51.629 --> 00:40:54.889
So we're not. So there's another way you could do it in principle,

00:40:55.049 --> 00:41:00.449
and that is to use resting state fMRI and look at the connectome, if you like,

00:41:00.749 --> 00:41:06.869
in humans, and see whether or not you can extract things doing that. I mean, that's….

00:41:08.091 --> 00:41:11.191
Obviously very expensive, but I think that's the route that people are going

00:41:11.191 --> 00:41:16.071
to go to say, okay, can we actually do this in a more sophisticated way once

00:41:16.071 --> 00:41:19.871
we have the computing power to do it and see if we see differences?

00:41:20.051 --> 00:41:21.511
And my guess is we will. Right.

00:41:21.911 --> 00:41:27.051
But now the other link to the substrate is then again this FGF2,

00:41:27.211 --> 00:41:33.091
which is sort of a growth modulator of the brain.

00:41:33.091 --> 00:41:40.571
And what you showed, however, is FGF2, it doesn't have a nonspecific effect.

00:41:40.731 --> 00:41:44.051
It seems rather specific in its targeting of the brain.

00:41:44.671 --> 00:41:48.591
So can you say something about that mechanism of the action of FGF2?

00:41:48.751 --> 00:41:50.771
Well, it's related to where the receptors are densest.

00:41:51.251 --> 00:41:56.191
So if you look in visual cortex, for example, they're very sparse compared to

00:41:56.191 --> 00:41:58.131
prefrontal cortex or hippocampus.

00:41:58.651 --> 00:42:04.611
So the next question is, why the difference? And are there differences at different ages? Yes.

00:42:04.831 --> 00:42:12.151
The peak in the RAD anyway, FGF receptor expression is day 10, postnatal day 10.

00:42:12.271 --> 00:42:16.511
That turns out to be the age at which we get all kinds of wonderful effects

00:42:16.511 --> 00:42:20.071
that we don't see, say, at day five, which is only five days earlier,

00:42:20.231 --> 00:42:21.731
but it makes a huge difference.

00:42:22.951 --> 00:42:30.091
So the FGF is specific in terms of where it's found and in terms of age as to

00:42:30.091 --> 00:42:31.431
when it's most highly expressed.

00:42:31.751 --> 00:42:35.911
Now why i don't know it's

00:42:35.911 --> 00:42:38.931
obviously important for some reason um we

00:42:38.931 --> 00:42:41.931
don't know what's controlling but that means there's a critical period also

00:42:41.931 --> 00:42:48.651
then for fgf2 and its impact yeah and under normal conditions how do you interpret

00:42:48.651 --> 00:42:53.931
that impact is that impact there to to assist in fact to control a last growth

00:42:53.931 --> 00:42:59.051
push of let's say specific brain areas part of the neocore of the cortex maybe

00:42:59.051 --> 00:43:01.491
maybe, or what's the role of that?

00:43:01.631 --> 00:43:06.691
Yeah. So the question you want to ask is what's happening around day seven to 12.

00:43:07.891 --> 00:43:11.371
So 10 plus or minus two or three.

00:43:11.951 --> 00:43:15.731
What's happening there that's different. And what's happening there that's different

00:43:15.731 --> 00:43:20.571
is you're starting to, migration is complete for the most part,

00:43:20.651 --> 00:43:26.451
and you're starting to get great cell differentiation in the beginning of synaptogenesis.

00:43:26.891 --> 00:43:31.731
And so it's a little bit, I'll use a metaphor that might not be great,

00:43:31.811 --> 00:43:35.451
but if you think about pruning a rosebush in the spring or when it's a young

00:43:35.451 --> 00:43:37.811
rose, if you do it at the right time, you get proliferation.

00:43:38.331 --> 00:43:41.691
If you do it at the wrong time, you might kill the rose.

00:43:42.171 --> 00:43:46.071
And so, and I don't know why that is, but presumably it's related to something

00:43:46.071 --> 00:43:50.671
like this, so that at the right time, it's primed to change.

00:43:50.671 --> 00:43:57.271
Let me give you another example, and that is, if you kill the generation of neurons in utero—.

00:43:58.567 --> 00:44:01.727
At the right time, the brain can make up for that.

00:44:01.807 --> 00:44:06.307
Using x-rays, for example, the brain can make up for that and just overproduce

00:44:06.307 --> 00:44:07.387
as though nothing happened.

00:44:08.027 --> 00:44:12.147
That doesn't happen at other times in life. It's just at certain times the brain

00:44:12.147 --> 00:44:15.207
can do it. Is it just a party trick and it's just an accident? Maybe.

00:44:15.847 --> 00:44:17.967
In the case of the x-rays, it probably is.

00:44:18.687 --> 00:44:22.427
In the case of the FGF, it probably isn't.

00:44:23.387 --> 00:44:27.447
Yeah, because associated with that, you also showed that at least certain areas

00:44:27.447 --> 00:44:32.307
of the cortex you can lesion early in development, and it looks like they will

00:44:32.307 --> 00:44:34.047
essentially regenerate. That's correct.

00:44:34.427 --> 00:44:36.427
But that seems to be very region-specific.

00:44:37.207 --> 00:44:42.107
It's very region-specific. It's specific to regions that have a lot of endogenous

00:44:42.107 --> 00:44:44.187
FGF2, which is interesting.

00:44:45.647 --> 00:44:50.687
Yeah, so if you do it in other regions that are really just millimeters away, it doesn't happen.

00:44:50.767 --> 00:44:56.347
But if you introduce the FGF2 subcutaneously then at the right age, then it works.

00:44:56.627 --> 00:44:58.707
So which regions are those? Midline.

00:44:59.127 --> 00:45:05.867
So olfactory bulb, medial prefrontal cortex, and singular cortex.

00:45:06.547 --> 00:45:11.087
Why are those ones the ones that show the effect?

00:45:11.227 --> 00:45:16.047
I think it's because the nursery of cells in the brain, the sub-ventricular

00:45:16.047 --> 00:45:17.447
zone, is right under them.

00:45:18.207 --> 00:45:21.607
And so the cells can be produced there and migrate quite easily.

00:45:22.287 --> 00:45:26.887
They don't seem to migrate as well. So, for example, into more lateral cortical

00:45:26.887 --> 00:45:30.367
areas, there's a lot of stuff in the way, the signals that tell them to come

00:45:30.367 --> 00:45:31.707
may not get to them, and so on.

00:45:32.767 --> 00:45:35.887
We don't know why that is. All we know for sure is that it's true.

00:45:37.047 --> 00:45:43.707
And if we introduce FGF2, we can get cells to go places they wouldn't have normally

00:45:43.707 --> 00:45:50.207
gone. on, how do you compare those cells to the endogenous ones?

00:45:50.787 --> 00:45:56.347
Well, at least in regions like the motor cortex, which are close by, it's pretty similar.

00:45:57.787 --> 00:46:03.387
If you're more lateral, we haven't really quantified it. I'm guessing it's going to be less similar.

00:46:03.827 --> 00:46:07.567
It's all related to mechanics of the progenitor cells getting there.

00:46:07.567 --> 00:46:14.247
But the FGF2, you earlier also told us that it would enhance,

00:46:14.307 --> 00:46:16.067
if you want, brain growth, right? Yes.

00:46:16.427 --> 00:46:21.387
In a nonspecific way and also induced by the tactile stimulation. Yes.

00:46:21.547 --> 00:46:29.447
But now in this recovery study, let's say, we lesion, we recover under the drive of FGF2.

00:46:29.747 --> 00:46:31.067
It seems very specific.

00:46:31.767 --> 00:46:36.047
So this seems contradictory in some sense. It does. Because on the one hand,

00:46:36.047 --> 00:46:41.307
it's like this factor that leads to non-specific, let's say,

00:46:41.447 --> 00:46:43.347
complexification and growth of the brain.

00:46:44.740 --> 00:46:48.780
But under conditions of a lesion, it becomes very specific. So one explanation

00:46:48.780 --> 00:46:50.380
for that is the brain is different.

00:46:51.000 --> 00:46:54.860
So the brain is producing all sorts of things in response to the injury,

00:46:54.920 --> 00:46:56.020
which makes it a different brain.

00:46:56.220 --> 00:47:02.760
And so when you add a spice to a dish that you're cooking, it depends on what

00:47:02.760 --> 00:47:05.220
you're starting with in terms of the effect of that spice, right?

00:47:05.400 --> 00:47:12.700
So if you see the FGF as a spice in a sense, a normal brain is different.

00:47:12.700 --> 00:47:15.880
Different, the makeup of that brain is different than in the injured brain,

00:47:15.960 --> 00:47:22.280
which is producing all kinds of stuff that's trying to heal itself or make it

00:47:22.280 --> 00:47:24.140
worse, whatever. But there's both going on.

00:47:24.540 --> 00:47:28.800
But that would mean that there's another system yet again that is regulating

00:47:28.800 --> 00:47:32.420
that uptake of the FGF2. Yeah, and it may be its glial cells.

00:47:32.720 --> 00:47:34.860
So in response to the injury, you're

00:47:34.860 --> 00:47:38.300
going to see the production of both astrocytes as well as microglia.

00:47:38.300 --> 00:47:44.560
And we know that the astrocytes at least are producing all kinds of chemicals

00:47:44.560 --> 00:47:47.740
and they produce FGF2 it turns out.

00:47:49.240 --> 00:47:54.440
So what do the microglia do? Are they producing things that are having an effect

00:47:54.440 --> 00:47:55.740
too? We don't know the answer to that.

00:47:55.940 --> 00:47:59.420
So the brains really are different. So we shouldn't be so surprised that the

00:47:59.420 --> 00:48:02.500
effect of any compound is not going to be the same.

00:48:02.800 --> 00:48:08.280
The lesion brain is different. But would that mean in your, as with the tactile

00:48:08.280 --> 00:48:17.300
stimulation, I generate FGF2, do I in parallel then drive a mechanism that controls its uptake?

00:48:17.880 --> 00:48:21.200
Or do you think it's more unspecific than that?

00:48:22.460 --> 00:48:25.280
But like maybe what you have to do with tactile stimulation,

00:48:25.380 --> 00:48:30.840
I must drive up my FGF2 and I must start to engage my glia cells to make sure

00:48:30.840 --> 00:48:35.060
they sort of create the conditions in which uptake can take place effectively.

00:48:35.380 --> 00:48:36.280
Yeah, that could very well be.

00:48:36.780 --> 00:48:42.060
But how do you think about it? Do you have the simple interpretation or do you

00:48:42.060 --> 00:48:43.560
think it's really more complex than that?

00:48:44.360 --> 00:48:49.180
Well, in the injured brain, it's clearly more complex. In the experience expected

00:48:49.180 --> 00:48:54.720
case, it may be that simple, that the brain is expecting experiences,

00:48:55.180 --> 00:48:59.700
and when it gets those experiences, these things happen.

00:48:59.840 --> 00:49:04.460
The FGF2 goes up. Think about the visual system. The visual system is expecting visual input.

00:49:04.640 --> 00:49:08.280
It doesn't require very much to tune your ocular dominance columns,

00:49:08.500 --> 00:49:11.920
the stuff that Colin Blakemore did all those years ago.

00:49:11.920 --> 00:49:17.900
I don't recall the total number of minutes, but minutes of visual experience

00:49:17.900 --> 00:49:25.200
is sufficient to satisfy the brain and prevent the effect of ocular closure.

00:49:25.560 --> 00:49:36.920
Right. So this is largely done on rats, and there are some links to human behavior, largely.

00:49:39.825 --> 00:49:43.185
Do you think that these lessons that you've now extracted from the rat brain

00:49:43.185 --> 00:49:48.845
and rat behavior about epigenetics generalize directly to the human case?

00:49:49.005 --> 00:49:52.945
Is the human case maybe even more susceptible to these epigenetic factors or less?

00:49:54.045 --> 00:49:58.505
I would say the human brain is more plastic. There are more neurons.

00:49:59.045 --> 00:50:01.325
They're more densely packed than

00:50:01.325 --> 00:50:04.445
any other species and certainly much more densely packed than rodents.

00:50:05.505 --> 00:50:10.365
So yes I think that it's going to generalize but I think the effects will actually

00:50:10.365 --> 00:50:15.525
be larger for that reason it also has more white matter so the grey matter white

00:50:15.525 --> 00:50:19.285
matter ratio is totally different in humans than it is in,

00:50:19.965 --> 00:50:24.805
rodents in particular and so what does that mean well when we're studying treatments

00:50:24.805 --> 00:50:30.205
for stroke I'm sure that it makes a big difference because you can have huge

00:50:30.205 --> 00:50:33.825
effects of white matter injury in humans not so much in rats rats.

00:50:34.625 --> 00:50:40.905
So we have to keep our eye on these differences that are fairly gross.

00:50:41.125 --> 00:50:44.105
Of course, humans have regions that rats don't have. I mean,

00:50:44.125 --> 00:50:46.905
no rat talks, at least none that I've met.

00:50:47.045 --> 00:50:49.325
And so they don't have Broca's or Wernicke's area.

00:50:49.485 --> 00:50:53.185
So what effect are these experiences having on these language-related areas?

00:50:54.565 --> 00:50:59.125
We're the only animals that produce music in the sense that we mean it, if not birdsong.

00:50:59.765 --> 00:51:03.605
So what does that mean? We know that music has a huge impact on the brain.

00:51:04.085 --> 00:51:05.785
So for example, if we looked at...

00:51:07.939 --> 00:51:14.539
Cognition in older people, say over 65, there's going to be a decline.

00:51:15.119 --> 00:51:18.899
And those people who are also musicians or who, not professional,

00:51:18.939 --> 00:51:22.159
but who learned to play instruments early, there's a benefit.

00:51:22.359 --> 00:51:26.519
So memory's better, attention's better, and so on. And the older you get,

00:51:26.579 --> 00:51:27.559
the bigger that effect is.

00:51:27.999 --> 00:51:32.159
So there's a reduction in, say, dementia in people who have music. What's it doing?

00:51:33.279 --> 00:51:37.719
It's not changing, as far as we know, non-human brains, but it's having a big impact on ours.

00:51:37.939 --> 00:51:43.159
Right. But also you mentioned that in some sense, there might also be,

00:51:43.239 --> 00:51:48.559
let's say, unwanted side effects of some of the medications we use actually in a standard fashion.

00:51:48.679 --> 00:51:54.899
You mentioned the Prozac example that initially might look like a great idea

00:51:54.899 --> 00:51:58.679
to drive also brain development or brain adaptation,

00:51:59.019 --> 00:52:04.579
but maybe from an epigenetic perspective, it might be the wrong thing to do. Yeah.

00:52:05.399 --> 00:52:09.919
So the story there is that we expected that fluoxetine, Prozac,

00:52:09.959 --> 00:52:15.819
would actually stimulate brain growth and we'd get bigger brains. And we didn't.

00:52:16.759 --> 00:52:21.519
We got smaller brains and brains that are less plastic. We didn't expect that.

00:52:21.559 --> 00:52:23.179
And the doses are the same doses.

00:52:23.979 --> 00:52:29.559
The amount in the blood is the same that women would be getting or the babies would be getting.

00:52:29.559 --> 00:52:37.179
Um so yeah that turned out to be you can call it a side effect an unfortunate consequence,

00:52:37.799 --> 00:52:42.459
um of the treatment of anxiety or or depression so right now it is prescribed

00:52:42.459 --> 00:52:51.359
to pregnant women as well it is and there is a suggestion that that it should

00:52:51.359 --> 00:52:56.339
not be prescribed for things like like anxiety, try some other drugs.

00:52:57.039 --> 00:53:02.479
But one of the drugs that's used more in Europe than in North America is valproic acid or valproate.

00:53:02.739 --> 00:53:07.959
It's used for epilepsy as well as anxiety and so on. And that turns out to have a link to autism.

00:53:08.499 --> 00:53:12.759
So the best model for developing autism in rats is to use valproate.

00:53:14.339 --> 00:53:18.299
That's a very unfortunate side effect. In England in particular,

00:53:18.379 --> 00:53:22.819
there have been studies done showing a huge increase in all kinds of neurodevelopmental

00:53:22.819 --> 00:53:27.599
problems and women who were given prescriptions for valproic acid for one of many reasons.

00:53:29.221 --> 00:53:36.301
So there's an important lesson there. Absolutely. But now, so you worked with rats for decades.

00:53:38.421 --> 00:53:42.821
I've worked with people too. And you talk to people as well.

00:53:43.121 --> 00:53:50.221
But in some sense, how well do we understand rat behavior and the rat experience of the world?

00:53:50.601 --> 00:53:54.081
So Ian Wishaw and I have a book called The Behavior of a Laboratory Rat.

00:53:54.881 --> 00:53:59.981
It's edited. it. And so I think we understand a lot about the behavior of rats

00:53:59.981 --> 00:54:05.961
compared to the behavior of mice or cats for that matter, which aren't used

00:54:05.961 --> 00:54:07.301
much for behavioral studies anymore.

00:54:07.481 --> 00:54:10.261
So we know a lot about the behavior of rats.

00:54:10.341 --> 00:54:17.921
The problem is the sophistication in measuring the behavior isn't always there.

00:54:18.501 --> 00:54:22.521
There's two ways to do it. One is to use what I'm going to call an end point measure.

00:54:22.981 --> 00:54:27.441
So if we're looking at something like skilled reaching, how many pellets did

00:54:27.441 --> 00:54:29.621
you actually successfully reach for?

00:54:30.381 --> 00:54:34.121
But we can also ask the question differently and say, are the kinematics of

00:54:34.121 --> 00:54:35.601
the movements the same or are they different?

00:54:36.361 --> 00:54:40.721
So we can see in animals that have adult strokes, we can give them treatments

00:54:40.721 --> 00:54:46.301
and their end point measure appears to be normal, but the way they're doing it is quite different.

00:54:46.741 --> 00:54:50.521
And so I think, yes, we know a lot about the rat behavior.

00:54:51.301 --> 00:54:55.421
But the sophistication of the average researcher in terms of how you measure

00:54:55.421 --> 00:54:59.861
it still needs to be improved. And I'm guilty too.

00:55:00.861 --> 00:55:05.401
But then where do you see the future? Do you think that these attempts to,

00:55:05.441 --> 00:55:08.901
for instance, start to use virtual reality with these kinds of animals is a

00:55:08.901 --> 00:55:11.001
step forward, or do you think that's not helping?

00:55:12.541 --> 00:55:15.981
By creating, in that sense, also more dynamic and more complex environments?

00:55:16.901 --> 00:55:20.181
So do you think you can use virtual reality in rodents? Well,

00:55:20.201 --> 00:55:21.021
it's already happening, right?

00:55:21.301 --> 00:55:27.681
People do it. People have rats run on little balls that float in the air, styrofoam balls.

00:55:27.941 --> 00:55:31.581
And with that, you then drive a virtual reality display of an environment.

00:55:31.681 --> 00:55:35.281
So they run through the environment. People are measuring place cell responses

00:55:35.281 --> 00:55:39.421
or grid cell responses using these setups. We know that it works in people.

00:55:39.861 --> 00:55:46.801
So if you have stroke patients and have motor problems, by using virtual realities,

00:55:46.961 --> 00:55:49.481
you can get quite dramatic improvements.

00:55:51.205 --> 00:55:54.865
We don't know why they're improving, but we know that that's happening for sure.

00:55:55.465 --> 00:56:00.005
People haven't really done those kinds of experiments in rats looking at the

00:56:00.005 --> 00:56:01.005
effects of, say, stroke.

00:56:01.065 --> 00:56:04.905
And can you use virtual environments to enhance it? Don't know.

00:56:05.385 --> 00:56:08.645
Yeah, we've been treating over 500 patients with that approach here.

00:56:08.725 --> 00:56:12.945
Yeah. With really good outcomes. Yeah. So on humans it works great. Yeah.

00:56:15.185 --> 00:56:20.185
So you've been in this field now for a long time. You also started life as a

00:56:20.185 --> 00:56:23.945
so-called rat runner, or you came from another direction into that?

00:56:24.845 --> 00:56:30.005
My master's degree was in ethology, so it was in animal behavior,

00:56:30.245 --> 00:56:33.185
but I was looking at rodents.

00:56:33.925 --> 00:56:38.525
When I was doing my PhD, I worked with a variety of animals,

00:56:38.545 --> 00:56:43.105
including cats and hamsters, gerbils, and rats.

00:56:43.105 --> 00:56:48.345
And then pretty much, I then spent time at the Montreal Neurological Institute

00:56:48.345 --> 00:56:53.345
studying people with brain injuries and trying to take the lessons I learned

00:56:53.345 --> 00:56:56.505
in terms of studying behavior in lab animals to people.

00:56:56.625 --> 00:57:00.465
Could you actually score their behavior and see similar effects?

00:57:00.685 --> 00:57:01.885
And the answer was, yeah, you can.

00:57:03.985 --> 00:57:08.745
I didn't have the opportunity that I had at the Montreal Neurological Institute

00:57:08.745 --> 00:57:12.605
because there were so many patients. when I left and went back to Alberta.

00:57:12.845 --> 00:57:14.865
So it was pretty much back to rats again.

00:57:15.905 --> 00:57:22.245
But I think my experience at the MNI in terms of generating new behavioral tests

00:57:22.245 --> 00:57:28.285
that were based on my studies, mostly of cats, more so than rats, was successful.

00:57:28.465 --> 00:57:32.905
So it encourages me that, yes, there's going to be a good transfer.

00:57:33.505 --> 00:57:39.245
Right. So now, given all this experience you have in the study of rat or animal

00:57:39.245 --> 00:57:41.685
behavior or human behavior and the brain.

00:57:43.065 --> 00:57:47.685
If you would like to follow in that tradition, what's Brian's law that we should adhere to?

00:57:50.865 --> 00:57:54.185
One of them, I think, is what does this mean for people?

00:57:54.585 --> 00:57:59.545
So I think that it's really important that people who are studying rats know

00:57:59.545 --> 00:58:00.725
something about the human brain.

00:58:01.185 --> 00:58:05.085
They know something about the effects of experiences on the human behavior.

00:58:05.345 --> 00:58:08.025
Because if you're doing it in a vacuum and you're just studying rats,

00:58:08.205 --> 00:58:12.425
it's useless. You really need to have this broader perspective.

00:58:13.005 --> 00:58:16.565
And this was one of the reasons that Wishaw and I wrote our textbook,

00:58:16.725 --> 00:58:21.245
Fundamentals of Human Neuropsychology, which had more animals in it in the early

00:58:21.245 --> 00:58:23.005
days than in the seventh edition.

00:58:23.145 --> 00:58:27.465
But it really is trying to take the principles and understand how the human brain is working.

00:58:27.665 --> 00:58:30.485
I think you have to keep that in the back of your mind all the time because

00:58:30.485 --> 00:58:35.965
if you don't, you end up studying epiphenomena and you're losing touch with

00:58:35.965 --> 00:58:37.705
what's important. Right.

00:58:38.710 --> 00:58:43.970
So, then five years from now, we're going to go visit your lab and we're going

00:58:43.970 --> 00:58:51.250
to check whether a prediction that you're going to share with me now is actually confirmed or not.

00:58:51.330 --> 00:58:54.790
So, what's the key prediction that you would like to commit yourself to today

00:58:54.790 --> 00:59:00.130
that is the most important one to make progress in your field in this timeframe of five years?

00:59:00.130 --> 00:59:06.790
Well, at least in, not in my field, but in my lab, would be understanding metaplasticity.

00:59:06.810 --> 00:59:12.030
That is the interaction of experiences, how they combine together to give you

00:59:12.030 --> 00:59:15.170
this phenotype down the road. Which ones are more important?

00:59:16.730 --> 00:59:22.590
Does the order make a difference? And so on. So that would be sort of the final push.

00:59:22.650 --> 00:59:27.170
That's the one. The other one is adolescence, because our emphasis has been

00:59:27.170 --> 00:59:30.070
in adults and in developing animals.

00:59:30.270 --> 00:59:35.130
But where are some of the biggest changes, especially in prefrontal cortex? Adolescence.

00:59:35.770 --> 00:59:40.110
We've begun to look at the effects of treatments in adolescence, and they're different.

00:59:40.490 --> 00:59:43.670
And so let's just take, this isn't our work, this is more general.

00:59:43.870 --> 00:59:49.790
If you look at the effects of marijuana consumption, if I can use that term,

00:59:49.890 --> 00:59:53.250
or nicotine consumption on adolescents,

00:59:53.670 --> 00:59:59.590
the incidence of psychotic episodes in the 20s is way higher than it would be

00:59:59.590 --> 01:00:05.870
in you if you started taking either of those drugs now post-30 or so. So why is that?

01:00:06.851 --> 01:00:09.811
There's got to be some sort of change, epigenetic and otherwise,

01:00:09.971 --> 01:00:12.291
in response to the adolescent experience.

01:00:12.611 --> 01:00:16.911
Well, the adolescent brain is changing so rapidly, and I gave you the example

01:00:16.911 --> 01:00:22.531
this morning of in the peri-adolescent period as the prefrontal cortex starts

01:00:22.531 --> 01:00:26.011
to prune, you're losing 100,000 synapses a second.

01:00:26.411 --> 01:00:30.751
That's a huge change in the brain. So any experiences that you're going to encounter

01:00:30.751 --> 01:00:33.471
while this is going on are going to have a huge impact.

01:00:33.851 --> 01:00:37.691
It's like a second sensitive period. We've got the early ones say zero to three,

01:00:37.771 --> 01:00:44.791
then this other one say age 10 to 16 years, that's really going to determine

01:00:44.791 --> 01:00:47.451
who you're going to be. So we don't know anything about this.

01:00:47.731 --> 01:00:51.371
So that's the two things. So one is the metaplasticity and the other one is

01:00:51.371 --> 01:00:54.291
the adolescent brain. We need to understand it. Very good.

01:00:54.631 --> 01:00:56.731
Well, Brian Kolb, thank you very much for this conversation.

01:00:57.051 --> 01:00:58.771
You're welcome, Paul. Thanks for having me. Sure.

01:01:02.311 --> 01:01:05.751
Well, wasn't that fun? That was just, actually it was fun because you're forcing me to do it.

01:01:05.751 --> 01:01:08.971
Think about things in a different way because

01:01:08.971 --> 01:01:12.011
you're coming at it from a more human perspective

01:01:12.011 --> 01:01:17.951
if you like um and we tend to well i'm guessing you do too in your own research

01:01:17.951 --> 01:01:22.851
you sort of you have your favorite hypothesis and you're doing this and then

01:01:22.851 --> 01:01:27.471
occasionally something happens over there and you say it's trivial and you just

01:01:27.471 --> 01:01:31.971
keep chugging along and so that's why i'm giving a lot

01:01:31.991 --> 01:01:34.931
of public talks um because of

01:01:34.931 --> 01:01:38.451
freezer mustard i mentioned this morning and the importance of educating the

01:01:38.451 --> 01:01:41.251
public on early experiences and whatnot

01:01:41.251 --> 01:01:46.611
some of the questions i get from the public are sort of whoa so in canada we

01:01:46.611 --> 01:01:54.571
have a a very bad history of dealing with our indigenous people um and one of

01:01:54.571 --> 01:01:58.751
them in canada the americans had a different solution and that was to kill them all.

01:01:59.231 --> 01:02:03.691
In Canada, we said, no, let's just take away their past and put them in what

01:02:03.691 --> 01:02:04.911
we called residential schools.

01:02:06.167 --> 01:02:11.207
And we'll make them white. But it didn't work. Right. It made it worse.

01:02:11.467 --> 01:02:16.187
So you end up with these horrible schools run by the Catholic Church in which

01:02:16.187 --> 01:02:17.627
these kids were maltreated.

01:02:17.927 --> 01:02:22.487
And now we don't have them anymore. The last ones were closed in the early 60s.

01:02:22.487 --> 01:02:26.087
But the effects of those schools are still there. Still there, yeah, right.

01:02:26.207 --> 01:02:31.527
And I gave a talk in northern Alberta. And there were a lot of natives there.

01:02:31.667 --> 01:02:36.307
And I gave a sort of simple spiel. And this one elder said, let me get this right.

01:02:36.707 --> 01:02:41.467
Are you giving me an explanation for why residential schools has such a profound

01:02:41.467 --> 01:02:43.407
impact on us? And I said, yes.

01:02:44.107 --> 01:02:47.607
Why hasn't anybody told us this before? I said, I'm here. I'm telling you.

01:02:48.227 --> 01:02:55.607
You're not to blame. We now understand one mechanism as to how these residential

01:02:55.607 --> 01:02:58.767
schools could lead to all sorts of drug abuse. So let's correct it.

01:02:59.687 --> 01:03:03.287
Let's correct it. Let's get by it. All right. And figure out ways in which we

01:03:03.287 --> 01:03:04.907
can reverse the effects.

01:03:05.387 --> 01:03:08.287
Yeah, but that… Because these are cross-generational effects.

01:03:08.587 --> 01:03:12.287
Of course. Yeah. And it might be still a long shot, right, to have an influence

01:03:12.287 --> 01:03:13.647
on that. Of course. Of the generations.

01:03:13.967 --> 01:03:17.347
Of course, yeah. No, but it's also from my perspective, what we do here,

01:03:17.447 --> 01:03:22.447
that we definitely have a strong focus towards the society in everything we do.

01:03:23.387 --> 01:03:26.647
Especially to stay on track, to stay focused, to stay relevant.

01:03:26.747 --> 01:03:29.687
Because otherwise it's very easy to just get sucked into your rabbit hole.

01:03:29.947 --> 01:03:32.427
Oh, for sure. And, you know, you get lost forever.

01:03:32.707 --> 01:03:35.447
And like Alice in Wonderland, you're just sort of wandering around.

01:03:35.687 --> 01:03:37.507
Exactly. It's all beautiful, right? It's all beautiful.

01:03:37.747 --> 01:03:42.167
Exactly. So we're in the clinic very prominently. A lot of stroke work we do.

01:03:43.227 --> 01:03:47.747
Also farming out to other pathologies. Now Parkinson's disease we're looking

01:03:47.747 --> 01:03:50.207
at and palsy. I think cerebral palsy is an important target.

01:03:50.687 --> 01:03:54.367
Look at education because I think the educational system is completely broken.

01:03:54.567 --> 01:04:00.487
We have to… Is this specific to Spain or… No. Oh, it's all European projects that we're doing.

01:04:02.707 --> 01:04:09.627
The CSN podcast was produced by the Convergent Science Network of Biometrics and Biohybrid Systems.

01:04:09.907 --> 01:04:15.427
Do whatever you want. A project funded by the European Sevens Research Framework Program. Huh?

01:04:15.967 --> 01:04:18.127
Yeah, yeah, yeah, yeah, I will. Don't worry.

01:04:19.667 --> 01:04:24.807
So, I was wondering about this distinction between learning and epigenetics, right?

01:04:24.927 --> 01:04:28.887
This has been quite a debate. And in some sense, we can impose also the question,

01:04:29.027 --> 01:04:32.807
okay, are we back in a more Lamarckian view on evolution?

01:04:33.947 --> 01:04:38.887
Because now we're looking at experience-dependent impact across generations,

01:04:39.247 --> 01:04:41.787
right? So what's your position on that?

01:04:42.047 --> 01:04:44.467
Well, I think in part you've hit it on the head.

01:04:44.767 --> 01:04:49.887
We are getting a little Lamarckian, and Lamarck didn't have any way of measuring.

01:04:50.107 --> 01:04:53.767
What he thought he was getting was something different than it turns out it

01:04:53.767 --> 01:04:58.947
is. but he had some truth to it but we do know that.

01:04:59.983 --> 01:05:02.743
Behavior itself produces profound effects on the brain.

01:05:03.143 --> 01:05:09.363
So this is, most non-psychologists would be surprised at this,

01:05:09.483 --> 01:05:11.443
I think, that behavior changes the brain.

01:05:11.523 --> 01:05:14.563
They're going to think the brain changes behavior. Well, that's true as well.

01:05:14.983 --> 01:05:19.443
So you've got this interaction. So the experiment that I was mentioning is that

01:05:19.443 --> 01:05:24.523
if we train animals on a whole bunch of behavioral tests, cognitive motor and

01:05:24.523 --> 01:05:28.163
so on, and just look in the brain, do we see change? We see changes all over the place.

01:05:28.303 --> 01:05:32.943
Okay. What if we give them something like nicotine or amphetamine?

01:05:33.483 --> 01:05:36.463
We see changes all over the place, but they're not as big.

01:05:37.343 --> 01:05:41.123
If we give them those drugs and then later put them on the behavior,

01:05:41.143 --> 01:05:44.963
do all the behavioral tests, we see a much bigger effect. So this is a metaplastic effect.

01:05:45.543 --> 01:05:51.063
So I think we've underestimated how big the effect of actually learning,

01:05:51.163 --> 01:05:53.343
if you like, is on the brain.

01:05:53.403 --> 01:05:56.863
It's really producing profound, profound effects. And this takes us back to

01:05:56.863 --> 01:05:59.363
the children and their vocabulary early on.

01:05:59.423 --> 01:06:04.363
They're learning all of this stuff, and it's producing these profound, long-lasting changes.

01:06:04.703 --> 01:06:09.103
So when we sent this paper in, showing and trying to make the point that the

01:06:09.103 --> 01:06:13.043
behavioral training was as big or bigger in its effect than the drugs,

01:06:13.363 --> 01:06:15.183
the reviewers said, well, this is trivial.

01:06:15.403 --> 01:06:19.963
I mean, behavior isn't all that important in understanding changes in the brain.

01:06:20.043 --> 01:06:23.583
And he didn't get it at all, so we obviously didn't describe it effectively.

01:06:23.583 --> 01:06:28.203
Effectively but um for psychologists it's it's obvious you're going to say well

01:06:28.203 --> 01:06:32.823
of course it's going to change the brain but now the but the point and it's

01:06:32.823 --> 01:06:36.923
also that we would have a situation where let's say the mother has a certain

01:06:36.923 --> 01:06:40.423
exposure this carries over to the offspring.

01:06:41.403 --> 01:06:46.563
But you could also argue well it's not necessarily lamarckian because in in

01:06:46.563 --> 01:06:51.523
the genome there are let's say different phenotypic programs and they are just

01:06:51.523 --> 01:06:53.563
triggered in an experience-dependent way.

01:06:54.780 --> 01:06:58.460
Right. Is this how you think about it? Yes. That's how I think about it. Right.

01:07:00.440 --> 01:07:05.380
So if we then can be configured along these different epigenetic programs,

01:07:06.040 --> 01:07:10.080
how big would that repertoire be? Is it only like stress, no stress?

01:07:10.300 --> 01:07:13.160
Or do you think this is a much more high-dimensional space?

01:07:13.540 --> 01:07:15.440
Oh, it's more than one-dimensional for sure.

01:07:16.260 --> 01:07:19.940
Okay. Because the stress itself is producing changes in behavior.

01:07:20.960 --> 01:07:26.120
It's producing changes in cognition and so on. I'll call that a behavior as

01:07:26.120 --> 01:07:28.960
well, but people tend not to think of it that way. Right.

01:07:29.740 --> 01:07:33.220
And so, yeah, we're getting a multidimensional change.

01:07:34.880 --> 01:07:38.420
Yeah. Okay, fantastic. Thank you. This is the one I still wanted to have.

01:07:38.600 --> 01:07:40.700
Okay. All right, we're done.

01:07:41.780 --> 01:07:44.440
Thank you. Okay. Nobody? Nobody?

01:07:47.520 --> 01:07:52.920
The CSN Podcast was produced by the Convergent Science Network of Biometrics

01:07:52.920 --> 01:07:59.300
and Biohybrid Systems, a project funded by the European 7th Research Framework Program.

01:08:00.880 --> 01:08:06.180
For more interviews, recorded lectures, or upcoming conferences in the field

01:08:06.180 --> 01:08:12.420
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01:08:13.360 --> 01:08:27.676
Music.