This is the Convergent Science Network podcast. Leading researchers in the domain
of neuroscience, brain theory and technology are interviewed by Paul Vesure and Tony Prescott.
Yeah, all right. This is Paul Vesure with the Convergent Science Network.
This is our BCBT School 2015. And I'm here with Brian Kolb, who this morning
was in his lecture dealing with the whole question of epigenetics and how, in some experience,
can affect our behavior even for a number of generations after us.
So what is specific about this epigenetic perspective on behavior and changes in behavior?
Well, I think that historically people had this view of nature and nurture and
that most of what we developed, we learned, and it was sort of independent of anything else.
And I think what we now know is that there's an interaction between the activity
of genes in the brain and experiences.
So specific experiences turn different genes on and off.
And when they're doing that, it alters how the brain responds to other experiences.
So, for example, if you're taking a drug, let's just say it's nicotine,
the nicotine is changing the expression of genes in the brain.
The job of genes is to make proteins, so what the proteins are making are different.
And so the organization of synapses, circuits, is altered by the drug in an indirect way.
But it turns out that it depends on which genes are already on and off,
so that the baseline gene profile is going to actually influence how experiences do this.
But now, in some sense, anything that a cell does, or almost anything,
will have an impact on gene transcription.
Yes. So, however, there's a certain subset of gene transcription that are of
specific relevance to this question of the epigenetics, where,
as I say, the gene expression and environment are coming together.
So is there a specialized, if
you want, system that is supporting these epigenetic changes to behavior?
That's the general belief. But if you now say, where is that system and what is it, we don't know.
But that's sort of the assumption that we start off with. Yeah,
and it may be that it's microRNAs that are changing and non-coding parts of
the gene that are changing and
controlling all of this, but we're still pretty naive on how that works.
Right. So can you give me,
what's a typical example that you would have in mind that really expresses most
clearly these epigenetic impacts that we have on the phenotype?
Well, if you look, I mean, we've looked a lot at stress and various kinds of
stressors because stress produces such big changes and these changes persist.
So we know that changes actually can cross at least four generations.
If you experience stress in uterus or gestational stress, we know that there
are changes in a whole bunch of things and these changes persist.
So we're looking at different kinds of stressors and trying to compare them
and see if we can get some understanding as to which pathways are actually changed by the stressors.
So basically we're taking a sledgehammer and trying to see, okay,
if you use a sledgehammer, what do you get?
Rather than something more subtle like social interaction, which would be much harder.
I'm sure it's doing things. And our example of play behavior is one example
where the way in which animals play.
Is going to alter gene expression and it's going to alter synaptic organization,
but it's much more subtle.
But now, if we talk about these kinds of changes, how would you measure those?
If you now say, okay, there's some environmental, let's say,
a stressor that is impacting a mother rat, now the offspring will be changed as a phenotype.
What are you looking for in that phenotype? So there are various things you
can do. So the first measure, so when the rubber hits the road,
this is all about behavior.
And so we're looking for changes in behavior. If we find none,
it might be that our measurements are too simple, they're not sophisticated
enough, or it may be that there aren't any changes.
So at that, first we're looking for changes in behavior. When we see them,
we know we're on the right track.
Then the second thing we're interested in is, okay, can we see changes in the circuits in the brain?
And where are those changes in the circuits? is because you can't look at gene
expression everywhere.
It's just not practical. So you're looking for a needle in a haystack.
So when we look at using brain staining, using a Golgi technique,
we can look at the changes in the number of synapses on cells.
Once we see a region that looks like it's showing significant changes,
we then can zero in there and say, okay, there's where we'll take our tissue
and do our gene chip arrays or whatever it is we're doing to try and identify the genes.
Now, the problem is, the ideal thing would be to find one gene.
Well, that's not going to happen.
You're going to find cascades of genes. So we often are finding 1,000 or 1,500 genes.
That's useless. So what you have to do is to see, okay, these are going to be
related to one another in some way.
And so we're looking at trying to get some sense of what the pathways are.
Are they all related to the production of proteins related to.
Synaptogenesis or neurogenesis or some other thing.
So that's the process. Behavior, then where in the brain are things changing,
and then drill down with your genes.
And we start with looking at global methylation.
So what methylation is telling you is that if you have a change in methylation,
up or down, you have more or less genes being expressed.
The more methylation, the less gene expression. Once you've seen that,
then you can say, okay, that's just a clue that something's going on,
but it doesn't tell you much.
It just tells you something happened, then we can look at the actual genes themselves.
Because it's expensive, and you don't want to waste time looking at places where
nothing happened. Right.
So now, a first example that you emphasized a lot was the role of tactile stimulation
as an epigenetic factor. So how does that play out exactly?
So just to give the background, if we take young animals and we use a little
brush and we tactilely stimulate them for 15 minutes, three times a day for
10 days, let's say, and then wait until they're adults,
we can see changes in their behavior.
So we see enhanced cognitive skills, better memory, better learning.
I don't know about perceptual skills. We haven't done that. then we can look
in the brain and say, okay, are there changes in synaptic organization? Yes.
So where are they? And it turns out with tactile stimulation,
there's pretty widespread.
And then we can say, okay, what are the changes in gene expression?
And can that give us some clues to what the tactile stimulation is actually doing?
The advantage of that is if we now want to use that tactile stimulation as a
therapy, let's say for an animal that was stressed, can we reverse the effects
of the stress and reverse the effects of the gene expression.
Well, if it turns out that it's totally different systems of genes,
it's going to be a tougher cell than if there's some relationship between the two.
But now, you also emphasized the release of FGF2 as a result of tactile stimulation.
So why do you emphasize that factor so much?
So we started looking at FGF2 for other reasons.
Because we knew that in vitro, it stimulates neurogenesis.
And so we originally thought, well, maybe we'll be able to use FGF2 to stimulate
neurogenesis, or maybe the tactile stimulation will increase neurogenesis.
So that's why we started with it. And it turns out it did seem to be released
with enhanced tactile stimulation, enhanced the release of FGF2.
And so then we thought, okay, can we see a pathway in the brain related to this?
Is there an increase in the genes related to this?
FGF-2 receptors or the production of FGF or whatever. So really,
it's one of these things that's your favorite molecule by accident.
But once you've found something, let's stick with it and we'll see what we can
get from it. Right. Okay.
So because also other substances are released in response to tactile stimulation.
Of course. Like endorphins, for instance. Sure. And so are probably cholinergic systems in the skin.
That are related to pain and whatnot, right? All of those things were released
too. And so we have looked at acetylcholine levels, and they do change too.
But we haven't pursued that and haven't seen any evidence in the epigenetics
that acetylcholine is really going to be a likely candidate for the big one,
if you like. Right. Okay.
So now an important, from there, so after tactile stimulation,
but also identifying a possible pathway
of then such an epigenetic channel,
because it means the tactile stimulation is also then already,
let's say, with the mother, right, the pregnant mother, and then the stimulation
would then have an effect on the pups.
So what's the behavioral impact that that would have?
So, I mean, there's two issues here. One is, how do we know that the tactile
stimulation hasn't changed the mother's brain, and it therefore changes her
behavior towards the pups? and that's what's doing it.
We don't. But we do know that if we look in the brains of the pups,
we see change in FGF2 receptors, for example.
And if we look at their behaviors, we're going to see enhanced cognitive behaviors,
enhanced motor behaviors, and not so much species-typical behaviors, but like play and so on.
So we know that whatever the FGF2 is doing to the mum and to the fetus is producing
these behavioral outcomes.
Okay. So but then, actually you made quite a big jump, right?
Because then we looked at the growth of vocabulary in humans.
So how is that, what's the effect that you observed there? So the idea there
is that experience early in life is going to make a huge difference to the development of language.
I'll give you a simple example, and that is when you're a month old or a newborn,
you can discriminate all speech sounds in all languages.
And a few months later, you're losing that.
So if you're only exposed to Dutch, for example, you're not going to find Korean
so easy. You're going to have difficulty discriminating those speech sounds,
and the longer we go, the less able you are.
So we're going to have that going on. The other thing we're going on is that
exposure to words makes a huge difference to the development of cognitive abilities.
But it's exposure to words isn't just hearing the words, it's actually using
the words. So some people will call this serve and return.
So if I say, Paul, what did you do today? I'm expecting a response.
If, on the other hand, you're listening to radio or television,
you're not responding. And so you're not using language in the same way.
So there's a really interesting experiment which children, and I forget the
age, it was like one and a half or two, were either watching somebody teach
them Japanese, or a Japanese person was in a screen and there was serve and return.
So they had to say the sounds.
And it turns out if they were actually interacting with an individual,
there was a social aspect.
The kids learned Japanese words, whereas the ones who were doing it on a television monitor didn't.
So that serve and return seems to be important. So what is it about that?
Well, there's a social aspect.
And if you're actually teaching an infant things, there's normally a lot of contact.
So you're getting tactile stimulation of them. They're sitting on your lap or
your arms around them or whatever, right? So all of these factors are going together.
So then if you say, well, why is it that children who live in higher socioeconomic
status houses have a larger vocabulary? Is it because their parents are smarter?
No. No, their parents have a larger vocabulary. So they're exposed by age three
to about a million more words than the kids in the lower SES families.
Not a million different words, but a million more words total that they're exposed
to. A lot of them are different words.
And largely it's because for one reason or another, the higher SES families,
there's more serve and return. turn.
So there's more discussion about things than there is in the low SES families,
perhaps because the caregivers in the more wealthy families have more time,
or that there is a caregiver that's hired that's there all the time,
a nanny or whatever it might be.
Whereas in the less well-off families, they don't have that.
Or they may just be interacting with siblings, and of course siblings aren't
going to have as large a vocabulary, and they may not serve in return in the same way as adults.
And the effect of this is to get kids on a trajectory of.
So that they're learning more and more words. And as I mentioned this morning,
the kids who at age 36 months have a vocabulary that's about three times as
big as the kids who are less well off.
That difference just continues to get larger and larger and larger.
And so by age 11, those kids in the high SES families have a larger vocabulary
than the moms of the other kids.
I also mentioned the fact that you could say, well, school is going to reverse
this. So once they get to school, they're all going to be exposed to the same.
That's true. But the less fortunate kids are way behind.
And a study in New Zealand showed that after eight years of school,
it didn't make any difference.
The kids who were low are still low. Kids who are high are even better.
And so we need to do something in school to try and reverse this.
And part of it may be to increase the amount of serve and return for these lower
SES kids, more interaction to try and get them using language more aggressively.
But now you could also argue that you mentioned stress earlier,
that these sort of lower socioeconomic status families have also higher stress
and that the real explanation is more at the end of stress than at the end of,
let's say, exposure to language.
They're obviously intertwined, so stress is clearly going to be an issue.
So one of the ways you could study it is retrospectively, in a sense,
and that is look at stress levels in the two groups and try and tease that out.
People are trying to do that, and as well as diet and a variety of other things.
One of the best studies on this is done in Cuba, and it's a social experiment.
So Castro, it turns out, was really interested in children. So after the revolution,
he set up, he changed the educational system and they started pouring resources into children.
And children had to go to, well, the mums first of all, to what were called polyclinics.
So they had to report monthly to this nurse. And if they didn't show up,
they went and found them and brought them in. And the polyclinics are associated with schools.
And so when UNESCO did their first studies on Latin American skills in kids,
they compared kids in Cuba to kids in Chile, Argentina, Mexico, and so on.
And what they found was that the kids in Cuba were significantly better in both
literacy and arithmetic skills.
So the question is, well, is it just that Latin America isn't all that good,
and this little bit of extra experience in Cuba worked?
There's two ways to look at that. One is to say, I'm from Canada,
and say, well, how do Canadian kids do?
We're probably better than the Cuban kids. And the answer is, no, we're not.
We're actually less good than the Cuban kids.
Well, can you take what they did in Cuba and apply that,
in less advantaged places. So there was a study in South Carolina working with
children from disadvantaged black families.
They used the same system and they ended up with the Cuban scores.
Similar study done in Mexico, same outcome. So it looks like pouring resources
in early makes a big difference.
And there's another UNESCO study, it was an OECD study, looking at literacy skills.
And they identify five levels of literacy.
And you're going to have literacy level five because of your education and experiences.
But the average person doesn't. And in Canada, about 42% of the population is
considered illiterate, even though they all went to school.
So they're levels one or two. In the United States, it's even higher.
And in Britain, it's higher as well. The United States is about 56% is considered illiterate.
So this is pretty scary.
Well, let's look at other countries. So if you look at Sweden,
it's about 30%. So are Swedes innately smarter than Brits or Canadians or Americans?
I prefer to think not. What's the difference? They pour more resources,
just like Cuba does, into early childhood development.
And that seems to have a huge impact on language skills and subsequent literacy,
which literacy has a huge impact on your health and your income.
But the consequence of this also that maybe the real impact is actually before
children go to school. Oh, it is. There's no question that it is.
It's in those first three years probably. Right. So then what's the benefit
of going to school? Well.
Well, you're learning information, obviously. And you and I went to school for
a long time and we learned a lot of information.
So why didn't the people who were in levels one and two benefit so much?
They were behind the eight ball to start with. And it wasn't that they were
stupid, to use a sort of blunt term.
They really were set on a trajectory that was disadvantageous.
So the challenge here, and the Swedes have got it right, is to intervene really early.
And in those first three years and put the money there rather than trying to
reverse things when the kids are 10 or 11 when it's too late.
Right. But then a key factor that you emphasize a lot is notion of stress.
And also you looked a lot at stress in rats and how does it impact their offspring
or how it impacts their mates. So you take a rat.
I understand the main procedure to induce stress is to put them on a raised platform.
And that's some sort of predator anxiety that they are exposed to.
That's a source of stress.
And now you observe a number of interesting effects, right?
So rats, just on their own, rats that are exposed to that stress,
what does it do to their brain and their behavior?
Just if I take an adult rat and I would put it on this platform for a number
of times okay so we've done that just taking adult rats and we increase their
anxiety we affect their ability to learn complex motor skills,
we see big changes in the organization of synapses in prefrontal cortex and
different effects on different parts of prefrontal cortex and we see changes
in gene expression expression.
It's a bit confounded because how do we know that the behaviors that they're
exhibiting now, the anxiety, isn't producing the changes in gene expression?
Well, they don't know that.
There's no way for me to separate those two things, except by correlation and
say the ones who are the most anxious, do they show bigger changes?
Yeah, but that's still confounded. Yeah, so it's very difficult.
But we do know that we can produce similar effects in adults as we can produce
indirectly in the developing brain.
So now how do you assess anxiety in those rats? So we can do it in a variety of ways.
The simplest way is to put animals in a situation where they can hide and be
safe, or they can go out and explore.
And the inference here, the implication is that animals who hide are afraid,
and the ones who go out and explore are not.
Well, I think you mentioned in a question this morning that,
well, how do I know that this doesn't make them more active?
So there's another test you can use. We haven't actually done this yet,
but we're going to, and that is, it's called a burying test.
So let's imagine you're in an environment, and there's this little probe that
comes out, and you go and you touch it, and you get a shock, and you're a rat.
Not a bad shock, but like a carpet shock, okay? So you get this shock.
Animals that are anxious will bury that probe.
They'll cover it up, and the more anxious they are, the more they cover it up.
Animals that think it's trivial, for whatever reason, because they're on Valium
or something at the time, go, never mind, just avoid it.
So that's another measure of anxiety that we're going to cover that up.
And another way you could do this is to take animals that appear to be anxious,
for example, in that plus maze, and give them anxiolytics and see whether or
not that reduces the effect you've seen it does.
Right. But now, okay, so we have the adult rat, but now if, what you also told
us, if I take this adult rat and I bring it back to its mate,
they will actually communicate about their experience. Yeah.
So rats have a very complex set of songs that I'll use the term loosely, songs that they sing.
Pardon me. And the rat that's distressed will come back and sing a series of
different distressed songs. So life is crap songs.
And the mate will sing back songs that are usually associated with happy things. Life is good.
And this goes on for hours. And apparently, this is an inference not proven,
hearing this distressed song for so long is stressful.
And that affects the offspring of what we call the bystander animal.
Okay, but then…,
What's the impact on the offspring? How strong is that impact as compared to
the mother having been exposed to that stress herself directly?
I think the best answer is the effect is different.
We see an effect. We see increased anxiety. We see reduction in brain weight.
We see impaired motor skills. But in each case, it's not as big as the direct
stress. It's a smaller effect.
So the next question is, well, can you vary the intensity of stress given directly to the mom?
And would you see, so for example, we, instead of putting them on that platform
for 20 minutes, put them on platform for 10 minutes.
Would you see a different effect? And the answer is yes. So the intensity of
the stress seems to make a difference.
And so we're mimicking a low, lower intensity stress, um, using the bystander
stress. Right, exactly.
But then the offspring will show also higher anxiety, as we saw earlier in the
adult rat exposed to the stress?
Yes. Or would it also show other kinds of behavioral changes?
We can actually look at behavior at about nine days.
And there's a variety of behavioral tests you can use to try and look at nervous system development.
And it looks like rats exposed to that kind of stress are delayed in development by about a day.
They're slower to develop some of the early behavior. So we can see it right away.
If we look at adults, we see changes in cognitive skills, motor skills in particular.
Now, one of the questions we've been asking is, well, if you've had that early
stress, how do you respond to stressors later? Sure.
Is there any kind of inoculation effect, an advantage? And the answer is,
it kind of looks like there is.
That if you've had that early stress, that a later stressor,
say as a juvenile, isn't as effective in changing your brain.
It's like you've been inoculated against stress. So we're pursuing that now
and varying the age of the second stress and the first stress and trying to
see, okay, how does that work?
But that means you might have paid a price for that in terms of your cognitive
abilities. You may have paid a price for that, but you may have gained an advantage in coping skills.
Right, exactly. But it's a trade-off. It's not something that comes for free.
Exactly. And then that might mean that also the offspring,
now the third generation, might also again be still under the influence of that
stress that then their grandparent was exposed to.
So how far down the lineage would this go? Well, my colleague,
Gerlinda Metz, has been studying this.
We've done a couple of experiments with her. We've gone to the fourth generation,
and we can still see effects.
One of the interesting effects is on the gestational age at birth of,
say, the grandchildren and great-grandchildren offspring.
And it turns out that those early stressors are actually changing the length
of gestation by half a day or so.
So, to what extent is that the cause of all of this rather than the stress itself?
Don't know. So, you can see it starts to get complicated.
The reason that she's doing, I'm not interested so much in the gestational period,
but the reason she's doing it is because in humans, it looks as though stressful
experiences will do the same thing.
They'll change. You get more premature babies.
And so, what's that doing? Right. Yeah.
But then, do you see this wash out? So after how many generations would it be
washed out? Well, it has to wash out.
Logically, it has to wash out and you're going to have regression to the mean.
So Michael Meaney at McGill has looked at it in a slightly different way. And,
What he's done is say, okay, we don't stress anybody.
We'll just look at the endogenous behavior of mums. And what he identifies is
mums who do a lot of licking and grooming of their offspring and mums who don't
do as much. So you have a normal curve.
Let's look at the two tails. Can you breed for that?
And it turns out you can't. There's a slow regression to the mean.
And why would you even care about licking and grooming? Because it's related
to behavior, just like the tactile stimulation is related to behavior.
But over time it seems to go away because we thought, well, we could just breed
for this and no, it doesn't work.
But now there must be a range of stress to which the animal is sort of genetically, let's say, prepared.
Yes. That it can tolerate and it will not have these kinds of epigenetic knock-on effects.
Yes. So how broad is that range?
That's a good question. I mean, clearly, if you think about the old psychological
inverted U function for stress, you need some stress or you're not awake,
right? If you have too much stress, you're dead.
And so where exactly in that inverted U function is the effect optimal and when is it worse?
And so that's the kind of experiment that one needs to do to try and figure
that out. We don't know that.
Okay. But I'm sure that there's a level of stress that nature is expecting to
encounter. There has to be.
And so it's had millions of years to adapt to that and to expect it.
So when we talk about brain plasticity, we talk about experience expectant.
The brain is expecting certain kinds of experiences.
If it doesn't get it or it gets too much of it, it goes, whoa, what's going on?
And you say, yeah. But now the interpretation in this case is rather nonspecific
because we say, well, there's some environmental manipulation leading to stress on the animal.
And the stress then has an epigenetic impact. Thank you.
But maybe with this manipulation, you could argue, well, maybe the impact is very specific.
It is basically telling this mother rat directly or indirectly that this is
an environment filled with predators.
Yes. And that then the epigenetic effect is actually very specific adaptation, which is weird.
Let's say, stay hidden more, don't go out a lot, avoid open spaces.
So what we then interpret as a nonspecific impact of stress is maybe very specific
adaptation to a world that is filled with predators.
Absolutely. And if you think about the Barker hypothesis,
which is a nickname for that kind of idea, if you look at the onset of adolescence
in animals who were stressed, it's earlier.
So we see this. So why would that be? Well, if it's a dangerous world,
you want to have your baby sooner.
You don't have the luxury of waiting. And whereas the animals that are raised
by moms who are very attentive, it's later.
So again, it looks like it's adapting to the environment that's going to be
there. Which adaptation is correct?
Well, it depends on what the environment turns out to be. Right, exactly.
But then there might also be the other extreme. If you have animals that have
zero stress, like it's the WALL-E world.
I don't know if you remember that animation movie of the humans all living in
outer space, being fed high sugar or high glucose drinks all day long.
So would you also see epigenetic change when you have a world that is really
zero stress or like understressed?
I would think you would because using the experience expectant model,
the brain is expecting stress.
And in the absence of it, it's going to change. There's going to be some sort of change.
Now, to do this experimentally would be a bit of a challenge.
But in principle, as a mind experiment, a thought experiment,
that should be the case. Right.
So now, we have a bit of an insight now in the stress case and then also these
effects it has epigenetically.
But another manipulation that you have looked at is drugs, different kinds of
drugs of abuse. use, do you think the impact of drugs of abuse is,
let's say, similar to the impact that stress has, or is it?
So when we did our adult stress study, we compared the effects directly to getting
either nicotine or amphetamine repeatedly.
So we've only used stimulants for this experiment to ask this very question.
The magnitude of the gene expression changes are similar.
It's different pathways that are changed. changed? So the answer is,
yeah, I think we're on the right track here. And we do know that.
Being exposed to stress early sensitizes the brain to make it more sensitive
to drugs, stimulants anyway.
We don't know about other drugs. We do know that every psychoactive drug we've
looked at, every class of psychoactive drugs we've looked at,
so stimulants, depressants, anxiolytics, antipsychotics,
antidepressants, all leave a footprint in the brain that looks to be permanent if you're a rat.
And I can use an anecdote and say that my father-in-law quit smoking 40 years
ago, but he says even now, he'll wake up in the morning and say, I'd like a cigarette.
So that's a long-term effect.
Is he still an addict? Well, he would be if he started taking it.
I'm sure he'd start smoking it, and he thinks so too.
A lot of people who are smokers will say it happened. I took a cigarette and I'm back.
I've got to stop all over again. It's not easy.
But now the changes to the brain, like say if you would look at also get the spine count on neurons,
and for instance, the prefrontal cortex, which is one area that you looked at
with great attention, would those changes be comparable in the epigenetic case
as those of stress, or would the knock-on effect be different?
Like if we take a mother rat exposed to different kinds of drugs,
what is the impact on her offspring?
Is it comparable to the stress case? Or are the changes very different?
The changes are probably different. So here's, I can do it from the anatomy
and then make an inference from that.
If we look at the effects of stimulants on medial prefrontal cortex,
we get an increase in spine density.
If we look at orbital frontal cortex, we get a decrease in spine density.
What happens if we look at stress? We get the reverse.
So what we see from stress is we see a decrease in spine density in medial frontal
cortex and an increase in orbital frontal cortex.
You might say, well, how do you account for that? Well, let's use a different
class of drugs. Let's use opiates.
If we look at opiates, it looks like stress.
So it's going to depend on the drug.
Type that you're using. So, opiates look like stress, stimulants look like the reverse of stress.
In both cases, it's being changed, but clearly the mechanisms are not the same.
We haven't done epigenetics with the opiates, so I don't know if it's more similar or not. Right.
But now, what you were mentioning is that if you look at these stressors as
non-stressed stressed or drugs, non-drug animals,
that actually the morphology of the dendrite and the spines on the dendrite
is rather different in the sense that in, let's say, the healthy control case,
you have a certain spacing of these spines that might be absent under either
the stress or drug condition. Right.
So how relevant is that for understanding then of these developmental and epigenetic
processes? Well, I think that one of the things it tells us is that subsequent
experiences are acting on a different brain.
So let's suppose your mom was a smoker.
Forget about the effects of carbon monoxide. Let's just pretend the effect is nicotine.
Your brain has changed. We've shown that.
And you respond to experiences in a different way later in life.
Same is true of stress. So your brain is changed. You respond to experiences
such as drugs differently later in life.
So we see these, what I'm going to call, metaplastic effects that sort of compound.
And if you think about it, I mean, human's life is not you get a drug and then we kill you.
It's one experience after another experience after another experience.
And so this collage, if you like, of experiences are all meshing together to
give you the final outcome.
So this makes it, in humans, pretty darn hard to control.
So you're going to expect huge individual differences, and of course we see that. Mm-hmm.
And do you then look at development? Because in some sense, there's,
if you want, a normal brain with sort of a developmental structure to the morphology of the cell,
which is then a scaffold in which these future experiences are placed. Right.
So what would a scaffold look like for the healthy brain?
And just the cell morphology of a prefrontal or medial prefrontal cortex.
You mentioned one thing, which is, for instance, the spacing between the spines,
which I found interesting because you were suggesting with that that you would
have, let's say, an optimal.
Initialization of the dendrite, sort of an optimal spacing, so that future experience
could be more easily linked into those structures.
Yeah. So we've done experiments in which we've given animals tactile stimulation,
or we've placed them in complex environments early.
And compared that to the effects of tactile stimulation or complex environments
as adults. The effect is the opposite.
So in the young brain, we have larger spacing between those spines,
although the dendrites are the same length.
So there's fewer connections, and it looks as though you can add connections
much faster in this case.
In adults, you see an increase in spine density in both situations.
And it's clearly somehow changing the brain in a different way.
What we haven't done is to try and.
Get behavioral tests that are sensitive enough to see is there a difference.
And one of the problems is that the behavioral tests we use are designed to
identify animals with brain injuries.
They're not designed to do the experiments we're doing, so they're a bit naive
in terms of what we're measuring. That's an unfortunate problem at this point.
And the same with the epigenetics. We haven't actually compared the two in the
way we have with the dendritic organization because the dendritic organization
is cheaper to do and simpler to do.
Than the epigenetics. Right. But now you also mentioned on the one hand we have
the spines, the generation of spines, now it's the pruning of spines.
Yeah. And also this pruning process might be affected because this is also a
regulated process. Yes. It's not a random process.
No. Right? So do you, if we don't talk about some sort of epigenetic chain where
gene transcription has to translate into,
let's say, changes to the circuit, do you see one of the principles or one of
the mechanisms which can use is the pruning process and the other one is the,
The generation of spines has two separate processes?
Yeah, they're two separate processes. And the other thing we have to consider
is which part of, if you think of the cortical layers, which layers change?
Do layers in each, the cells in each layer change the same? And my initial assumption
was, well, of course, because the column is a functional unit.
Well, let's actually measure that. Well, it turns out it's not true.
So layers two and three and five, for example, can change in the same way or
opposite ways. What does that mean? I have no idea.
It's just a fact that they're not, you can't predict from one layer to another layer.
So it starts to get really complicated in there. So you're adding and subtracting spines.
Are you measuring the same cells?
Or are they different cells that are showing these changes? I don't know.
Because the techniques we have don't allow us to identify the particular type
of pyramidal cell it is, what its characteristics are.
And measure those changes in spines. It's technically possible to do it.
Now, we just haven't done it.
But using molecular tricks, you can do it. And people will be doing that.
Right. Yeah. But now, what we see here is indeed a brain that is hyperplastic
at different timescales. Yes.
And very sensitively tuned to changes in experience.
But now, in some sense, the experimental paradigms were used to probe that brain.
Are by necessity simple, because otherwise we're going to control them.
Yes, that's right. So to what extent are we actually getting the full picture here?
So we're not. So there's another way you could do it in principle,
and that is to use resting state fMRI and look at the connectome, if you like,
in humans, and see whether or not you can extract things doing that. I mean, that's….
Obviously very expensive, but I think that's the route that people are going
to go to say, okay, can we actually do this in a more sophisticated way once
we have the computing power to do it and see if we see differences?
And my guess is we will. Right.
But now the other link to the substrate is then again this FGF2,
which is sort of a growth modulator of the brain.
And what you showed, however, is FGF2, it doesn't have a nonspecific effect.
It seems rather specific in its targeting of the brain.
So can you say something about that mechanism of the action of FGF2?
Well, it's related to where the receptors are densest.
So if you look in visual cortex, for example, they're very sparse compared to
prefrontal cortex or hippocampus.
So the next question is, why the difference? And are there differences at different ages? Yes.
The peak in the RAD anyway, FGF receptor expression is day 10, postnatal day 10.
That turns out to be the age at which we get all kinds of wonderful effects
that we don't see, say, at day five, which is only five days earlier,
but it makes a huge difference.
So the FGF is specific in terms of where it's found and in terms of age as to
when it's most highly expressed.
Now why i don't know it's
obviously important for some reason um we
don't know what's controlling but that means there's a critical period also
then for fgf2 and its impact yeah and under normal conditions how do you interpret
that impact is that impact there to to assist in fact to control a last growth
push of let's say specific brain areas part of the neocore of the cortex maybe
maybe, or what's the role of that?
Yeah. So the question you want to ask is what's happening around day seven to 12.
So 10 plus or minus two or three.
What's happening there that's different. And what's happening there that's different
is you're starting to, migration is complete for the most part,
and you're starting to get great cell differentiation in the beginning of synaptogenesis.
And so it's a little bit, I'll use a metaphor that might not be great,
but if you think about pruning a rosebush in the spring or when it's a young
rose, if you do it at the right time, you get proliferation.
If you do it at the wrong time, you might kill the rose.
And so, and I don't know why that is, but presumably it's related to something
like this, so that at the right time, it's primed to change.
Let me give you another example, and that is, if you kill the generation of neurons in utero—.
At the right time, the brain can make up for that.
Using x-rays, for example, the brain can make up for that and just overproduce
as though nothing happened.
That doesn't happen at other times in life. It's just at certain times the brain
can do it. Is it just a party trick and it's just an accident? Maybe.
In the case of the x-rays, it probably is.
In the case of the FGF, it probably isn't.
Yeah, because associated with that, you also showed that at least certain areas
of the cortex you can lesion early in development, and it looks like they will
essentially regenerate. That's correct.
But that seems to be very region-specific.
It's very region-specific. It's specific to regions that have a lot of endogenous
FGF2, which is interesting.
Yeah, so if you do it in other regions that are really just millimeters away, it doesn't happen.
But if you introduce the FGF2 subcutaneously then at the right age, then it works.
So which regions are those? Midline.
So olfactory bulb, medial prefrontal cortex, and singular cortex.
Why are those ones the ones that show the effect?
I think it's because the nursery of cells in the brain, the sub-ventricular
zone, is right under them.
And so the cells can be produced there and migrate quite easily.
They don't seem to migrate as well. So, for example, into more lateral cortical
areas, there's a lot of stuff in the way, the signals that tell them to come
may not get to them, and so on.
We don't know why that is. All we know for sure is that it's true.
And if we introduce FGF2, we can get cells to go places they wouldn't have normally
gone. on, how do you compare those cells to the endogenous ones?
Well, at least in regions like the motor cortex, which are close by, it's pretty similar.
If you're more lateral, we haven't really quantified it. I'm guessing it's going to be less similar.
It's all related to mechanics of the progenitor cells getting there.
But the FGF2, you earlier also told us that it would enhance,
if you want, brain growth, right? Yes.
In a nonspecific way and also induced by the tactile stimulation. Yes.
But now in this recovery study, let's say, we lesion, we recover under the drive of FGF2.
It seems very specific.
So this seems contradictory in some sense. It does. Because on the one hand,
it's like this factor that leads to non-specific, let's say,
complexification and growth of the brain.
But under conditions of a lesion, it becomes very specific. So one explanation
for that is the brain is different.
So the brain is producing all sorts of things in response to the injury,
which makes it a different brain.
And so when you add a spice to a dish that you're cooking, it depends on what
you're starting with in terms of the effect of that spice, right?
So if you see the FGF as a spice in a sense, a normal brain is different.
Different, the makeup of that brain is different than in the injured brain,
which is producing all kinds of stuff that's trying to heal itself or make it
worse, whatever. But there's both going on.
But that would mean that there's another system yet again that is regulating
that uptake of the FGF2. Yeah, and it may be its glial cells.
So in response to the injury, you're
going to see the production of both astrocytes as well as microglia.
And we know that the astrocytes at least are producing all kinds of chemicals
and they produce FGF2 it turns out.
So what do the microglia do? Are they producing things that are having an effect
too? We don't know the answer to that.
So the brains really are different. So we shouldn't be so surprised that the
effect of any compound is not going to be the same.
The lesion brain is different. But would that mean in your, as with the tactile
stimulation, I generate FGF2, do I in parallel then drive a mechanism that controls its uptake?
Or do you think it's more unspecific than that?
But like maybe what you have to do with tactile stimulation,
I must drive up my FGF2 and I must start to engage my glia cells to make sure
they sort of create the conditions in which uptake can take place effectively.
Yeah, that could very well be.
But how do you think about it? Do you have the simple interpretation or do you
think it's really more complex than that?
Well, in the injured brain, it's clearly more complex. In the experience expected
case, it may be that simple, that the brain is expecting experiences,
and when it gets those experiences, these things happen.
The FGF2 goes up. Think about the visual system. The visual system is expecting visual input.
It doesn't require very much to tune your ocular dominance columns,
the stuff that Colin Blakemore did all those years ago.
I don't recall the total number of minutes, but minutes of visual experience
is sufficient to satisfy the brain and prevent the effect of ocular closure.
Right. So this is largely done on rats, and there are some links to human behavior, largely.
Do you think that these lessons that you've now extracted from the rat brain
and rat behavior about epigenetics generalize directly to the human case?
Is the human case maybe even more susceptible to these epigenetic factors or less?
I would say the human brain is more plastic. There are more neurons.
They're more densely packed than
any other species and certainly much more densely packed than rodents.
So yes I think that it's going to generalize but I think the effects will actually
be larger for that reason it also has more white matter so the grey matter white
matter ratio is totally different in humans than it is in,
rodents in particular and so what does that mean well when we're studying treatments
for stroke I'm sure that it makes a big difference because you can have huge
effects of white matter injury in humans not so much in rats rats.
So we have to keep our eye on these differences that are fairly gross.
Of course, humans have regions that rats don't have. I mean,
no rat talks, at least none that I've met.
And so they don't have Broca's or Wernicke's area.
So what effect are these experiences having on these language-related areas?
We're the only animals that produce music in the sense that we mean it, if not birdsong.
So what does that mean? We know that music has a huge impact on the brain.
So for example, if we looked at...
Cognition in older people, say over 65, there's going to be a decline.
And those people who are also musicians or who, not professional,
but who learned to play instruments early, there's a benefit.
So memory's better, attention's better, and so on. And the older you get,
the bigger that effect is.
So there's a reduction in, say, dementia in people who have music. What's it doing?
It's not changing, as far as we know, non-human brains, but it's having a big impact on ours.
Right. But also you mentioned that in some sense, there might also be,
let's say, unwanted side effects of some of the medications we use actually in a standard fashion.
You mentioned the Prozac example that initially might look like a great idea
to drive also brain development or brain adaptation,
but maybe from an epigenetic perspective, it might be the wrong thing to do. Yeah.
So the story there is that we expected that fluoxetine, Prozac,
would actually stimulate brain growth and we'd get bigger brains. And we didn't.
We got smaller brains and brains that are less plastic. We didn't expect that.
And the doses are the same doses.
The amount in the blood is the same that women would be getting or the babies would be getting.
Um so yeah that turned out to be you can call it a side effect an unfortunate consequence,
um of the treatment of anxiety or or depression so right now it is prescribed
to pregnant women as well it is and there is a suggestion that that it should
not be prescribed for things like like anxiety, try some other drugs.
But one of the drugs that's used more in Europe than in North America is valproic acid or valproate.
It's used for epilepsy as well as anxiety and so on. And that turns out to have a link to autism.
So the best model for developing autism in rats is to use valproate.
That's a very unfortunate side effect. In England in particular,
there have been studies done showing a huge increase in all kinds of neurodevelopmental
problems and women who were given prescriptions for valproic acid for one of many reasons.
So there's an important lesson there. Absolutely. But now, so you worked with rats for decades.
I've worked with people too. And you talk to people as well.
But in some sense, how well do we understand rat behavior and the rat experience of the world?
So Ian Wishaw and I have a book called The Behavior of a Laboratory Rat.
It's edited. it. And so I think we understand a lot about the behavior of rats
compared to the behavior of mice or cats for that matter, which aren't used
much for behavioral studies anymore.
So we know a lot about the behavior of rats.
The problem is the sophistication in measuring the behavior isn't always there.
There's two ways to do it. One is to use what I'm going to call an end point measure.
So if we're looking at something like skilled reaching, how many pellets did
you actually successfully reach for?
But we can also ask the question differently and say, are the kinematics of
the movements the same or are they different?
So we can see in animals that have adult strokes, we can give them treatments
and their end point measure appears to be normal, but the way they're doing it is quite different.
And so I think, yes, we know a lot about the rat behavior.
But the sophistication of the average researcher in terms of how you measure
it still needs to be improved. And I'm guilty too.
But then where do you see the future? Do you think that these attempts to,
for instance, start to use virtual reality with these kinds of animals is a
step forward, or do you think that's not helping?
By creating, in that sense, also more dynamic and more complex environments?
So do you think you can use virtual reality in rodents? Well,
it's already happening, right?
People do it. People have rats run on little balls that float in the air, styrofoam balls.
And with that, you then drive a virtual reality display of an environment.
So they run through the environment. People are measuring place cell responses
or grid cell responses using these setups. We know that it works in people.
So if you have stroke patients and have motor problems, by using virtual realities,
you can get quite dramatic improvements.
We don't know why they're improving, but we know that that's happening for sure.
People haven't really done those kinds of experiments in rats looking at the
effects of, say, stroke.
And can you use virtual environments to enhance it? Don't know.
Yeah, we've been treating over 500 patients with that approach here.
Yeah. With really good outcomes. Yeah. So on humans it works great. Yeah.
So you've been in this field now for a long time. You also started life as a
so-called rat runner, or you came from another direction into that?
My master's degree was in ethology, so it was in animal behavior,
but I was looking at rodents.
When I was doing my PhD, I worked with a variety of animals,
including cats and hamsters, gerbils, and rats.
And then pretty much, I then spent time at the Montreal Neurological Institute
studying people with brain injuries and trying to take the lessons I learned
in terms of studying behavior in lab animals to people.
Could you actually score their behavior and see similar effects?
And the answer was, yeah, you can.
I didn't have the opportunity that I had at the Montreal Neurological Institute
because there were so many patients. when I left and went back to Alberta.
So it was pretty much back to rats again.
But I think my experience at the MNI in terms of generating new behavioral tests
that were based on my studies, mostly of cats, more so than rats, was successful.
So it encourages me that, yes, there's going to be a good transfer.
Right. So now, given all this experience you have in the study of rat or animal
behavior or human behavior and the brain.
If you would like to follow in that tradition, what's Brian's law that we should adhere to?
One of them, I think, is what does this mean for people?
So I think that it's really important that people who are studying rats know
something about the human brain.
They know something about the effects of experiences on the human behavior.
Because if you're doing it in a vacuum and you're just studying rats,
it's useless. You really need to have this broader perspective.
And this was one of the reasons that Wishaw and I wrote our textbook,
Fundamentals of Human Neuropsychology, which had more animals in it in the early
days than in the seventh edition.
But it really is trying to take the principles and understand how the human brain is working.
I think you have to keep that in the back of your mind all the time because
if you don't, you end up studying epiphenomena and you're losing touch with
what's important. Right.
So, then five years from now, we're going to go visit your lab and we're going
to check whether a prediction that you're going to share with me now is actually confirmed or not.
So, what's the key prediction that you would like to commit yourself to today
that is the most important one to make progress in your field in this timeframe of five years?
Well, at least in, not in my field, but in my lab, would be understanding metaplasticity.
That is the interaction of experiences, how they combine together to give you
this phenotype down the road. Which ones are more important?
Does the order make a difference? And so on. So that would be sort of the final push.
That's the one. The other one is adolescence, because our emphasis has been
in adults and in developing animals.
But where are some of the biggest changes, especially in prefrontal cortex? Adolescence.
We've begun to look at the effects of treatments in adolescence, and they're different.
And so let's just take, this isn't our work, this is more general.
If you look at the effects of marijuana consumption, if I can use that term,
or nicotine consumption on adolescents,
the incidence of psychotic episodes in the 20s is way higher than it would be
in you if you started taking either of those drugs now post-30 or so. So why is that?
There's got to be some sort of change, epigenetic and otherwise,
in response to the adolescent experience.
Well, the adolescent brain is changing so rapidly, and I gave you the example
this morning of in the peri-adolescent period as the prefrontal cortex starts
to prune, you're losing 100,000 synapses a second.
That's a huge change in the brain. So any experiences that you're going to encounter
while this is going on are going to have a huge impact.
It's like a second sensitive period. We've got the early ones say zero to three,
then this other one say age 10 to 16 years, that's really going to determine
who you're going to be. So we don't know anything about this.
So that's the two things. So one is the metaplasticity and the other one is
the adolescent brain. We need to understand it. Very good.
Well, Brian Kolb, thank you very much for this conversation.
You're welcome, Paul. Thanks for having me. Sure.
Well, wasn't that fun? That was just, actually it was fun because you're forcing me to do it.
Think about things in a different way because
you're coming at it from a more human perspective
if you like um and we tend to well i'm guessing you do too in your own research
you sort of you have your favorite hypothesis and you're doing this and then
occasionally something happens over there and you say it's trivial and you just
keep chugging along and so that's why i'm giving a lot
of public talks um because of
freezer mustard i mentioned this morning and the importance of educating the
public on early experiences and whatnot
some of the questions i get from the public are sort of whoa so in canada we
have a a very bad history of dealing with our indigenous people um and one of
them in canada the americans had a different solution and that was to kill them all.
In Canada, we said, no, let's just take away their past and put them in what
we called residential schools.
And we'll make them white. But it didn't work. Right. It made it worse.
So you end up with these horrible schools run by the Catholic Church in which
these kids were maltreated.
And now we don't have them anymore. The last ones were closed in the early 60s.
But the effects of those schools are still there. Still there, yeah, right.
And I gave a talk in northern Alberta. And there were a lot of natives there.
And I gave a sort of simple spiel. And this one elder said, let me get this right.
Are you giving me an explanation for why residential schools has such a profound
impact on us? And I said, yes.
Why hasn't anybody told us this before? I said, I'm here. I'm telling you.
You're not to blame. We now understand one mechanism as to how these residential
schools could lead to all sorts of drug abuse. So let's correct it.
Let's correct it. Let's get by it. All right. And figure out ways in which we
can reverse the effects.
Yeah, but that… Because these are cross-generational effects.
Of course. Yeah. And it might be still a long shot, right, to have an influence
on that. Of course. Of the generations.
Of course, yeah. No, but it's also from my perspective, what we do here,
that we definitely have a strong focus towards the society in everything we do.
Especially to stay on track, to stay focused, to stay relevant.
Because otherwise it's very easy to just get sucked into your rabbit hole.
Oh, for sure. And, you know, you get lost forever.
And like Alice in Wonderland, you're just sort of wandering around.
Exactly. It's all beautiful, right? It's all beautiful.
Exactly. So we're in the clinic very prominently. A lot of stroke work we do.
Also farming out to other pathologies. Now Parkinson's disease we're looking
at and palsy. I think cerebral palsy is an important target.
Look at education because I think the educational system is completely broken.
We have to… Is this specific to Spain or… No. Oh, it's all European projects that we're doing.
The CSN podcast was produced by the Convergent Science Network of Biometrics and Biohybrid Systems.
Do whatever you want. A project funded by the European Sevens Research Framework Program. Huh?
Yeah, yeah, yeah, yeah, I will. Don't worry.
So, I was wondering about this distinction between learning and epigenetics, right?
This has been quite a debate. And in some sense, we can impose also the question,
okay, are we back in a more Lamarckian view on evolution?
Because now we're looking at experience-dependent impact across generations,
right? So what's your position on that?
Well, I think in part you've hit it on the head.
We are getting a little Lamarckian, and Lamarck didn't have any way of measuring.
What he thought he was getting was something different than it turns out it
is. but he had some truth to it but we do know that.
Behavior itself produces profound effects on the brain.
So this is, most non-psychologists would be surprised at this,
I think, that behavior changes the brain.
They're going to think the brain changes behavior. Well, that's true as well.
So you've got this interaction. So the experiment that I was mentioning is that
if we train animals on a whole bunch of behavioral tests, cognitive motor and
so on, and just look in the brain, do we see change? We see changes all over the place.
Okay. What if we give them something like nicotine or amphetamine?
We see changes all over the place, but they're not as big.
If we give them those drugs and then later put them on the behavior,
do all the behavioral tests, we see a much bigger effect. So this is a metaplastic effect.
So I think we've underestimated how big the effect of actually learning,
if you like, is on the brain.
It's really producing profound, profound effects. And this takes us back to
the children and their vocabulary early on.
They're learning all of this stuff, and it's producing these profound, long-lasting changes.
So when we sent this paper in, showing and trying to make the point that the
behavioral training was as big or bigger in its effect than the drugs,
the reviewers said, well, this is trivial.
I mean, behavior isn't all that important in understanding changes in the brain.
And he didn't get it at all, so we obviously didn't describe it effectively.
Effectively but um for psychologists it's it's obvious you're going to say well
of course it's going to change the brain but now the but the point and it's
also that we would have a situation where let's say the mother has a certain
exposure this carries over to the offspring.
But you could also argue well it's not necessarily lamarckian because in in
the genome there are let's say different phenotypic programs and they are just
triggered in an experience-dependent way.
Right. Is this how you think about it? Yes. That's how I think about it. Right.
So if we then can be configured along these different epigenetic programs,
how big would that repertoire be? Is it only like stress, no stress?
Or do you think this is a much more high-dimensional space?
Oh, it's more than one-dimensional for sure.
Okay. Because the stress itself is producing changes in behavior.
It's producing changes in cognition and so on. I'll call that a behavior as
well, but people tend not to think of it that way. Right.
And so, yeah, we're getting a multidimensional change.
Yeah. Okay, fantastic. Thank you. This is the one I still wanted to have.
Okay. All right, we're done.
Thank you. Okay. Nobody? Nobody?
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Music.