Closing the critical period might actually be neuroprotective.
If we remove the brakes on the plasticity,
then yes, there is a moment for rewiring,
but too much of a good thing could lead to disruption
or degeneration.
I'm John Foxe, director of the Del Monte Institute
for Neuroscience at the University of Rochester.
And I'd like to welcome you to another episode of Neuroscience
Perspectives.
I'm really excited to introduce to you today
my guest, Dr. Takao Hensch.
Dr. Hench is a professor of neurology
at Harvard Medical School at Boston Children's Hospital
and professor of molecular and cellular biology
at Harvard Center for Brain Science.
He leads the National Institute of Mental Health, NIMH,
Silvio Conti Center on Mental Health Research at Harvard
and the International Research Center for Neurointelligence.
He has received a plethora of honors,
including the NIH Director's Pioneer Award
and the Mort Sackler MD Prize for Distinguished Achievement
in Developmental Psychobiology.
His research examines how early life experience shapes
brain function, critical periods of brain development,
and whether plasticity can be opened or targeted
to treat neurodevelopmental and neurodegenerative diseases.
So thank you for joining us.
And I'm just absolutely delighted to have you here, Takawa,
to have a chat here in Neuroscience Perspectives.
Welcome to Rochester.
Thank you for having me.
I know you had a late flight in,
so we really appreciate you getting here and joining us.
Let's get started with your research.
What we're gonna definitely want to do is come back
and understand your journey into science.
But let's talk a little bit about critical periods.
I think actually, you know,
probably everybody on the planet who's read
a basic science book knows about critical periods.
And probably baked into their thinking is, you know,
there's a very small window of time during neurodevelopment
when these periods open up and they close.
And if you haven't learned what you need to learn
in those periods of time, the game is up.
Disabuse us of that notion.
Right, well, throughout human history,
we've appreciated the importance of early childhood
and infancy and shaping our identities.
And this taps into some fundamental biology.
From mouse to human, we see that brain functions
are shaped early in life and that many of them
are kind of locked in.
The degree to which that's true in terms of reversibility
is something that's being actively researched now.
And it's the advent of modern neurobiological techniques
that allow us to understand what opens these windows,
determines their duration,
and ultimately might close them or not.
And by following those paths, we can try to understand
whether they really are closed for good.
Right, and so is the timing of these windows
of opportunity to learn specific functions,
it's stereotyped across individuals,
is it driven by the environment?
What's turning on and off these windows?
Well, it's the classic gene environment interaction question.
And in fact, we know that there are many cellular components
that contribute to the timing mechanism now.
And those are in fact sensitive to environment.
So the answer is of course both are involved.
And in certain extreme cases, mental illness,
you might see this play out in a very dramatic way
as a shift in timing.
Right, and are these developmental windows,
these critical periods, they're in utero as well as
after the birth, is that?
That's right, so some systems like the auditory system
is coming online before birth.
And there's a first important notion
that critical periods are staggered
and not happening synchronously across brain modalities.
So different functions coming online over time,
and maybe the sense is rolling out
in a pseudo sequential form or?
That's right, so there's a rough sense of hierarchy
that primary sensory areas, the first filters
to the outside world seem to be shaped earlier
than higher cognitive functions.
But this is a very rough approximation.
The important notion is that there's not one critical period.
There are multiple critical periods.
Right, right, and then your research really looks at
the molecular biology and the physiology,
neurophysiology of that.
And are there insights that, if you were to say,
like what are my top three things that I know
about this plasticity?
What is plasticity and what are those things
that really give rise to the ability to learn?
Right, well plasticity of course is the ability
to adapt to change, and our brain is a plastic machine.
That's its job.
But we know that this degree of plasticity
changes dynamically across the lifespan.
And so critical periods or sensitive periods arise
because early life experiences are particularly potent
in shaping the brain.
And the experimental work is trying to understand
why that is.
You know, a reasonable question would be,
if this plasticity is so great for learning,
why on earth do we shut it down at all?
Why wouldn't we stay that way throughout the duration
of a lifetime?
Right, that is a great question.
And I think it's always tempting to think more is better.
But as we learn how these windows come about,
and there's some surprises that we've come across
along the way, we understand better why it's important
to dial down and stabilize circuitry.
And in fact, we spend most of our life
in this more stable processing mode.
I guess there are two insights I could elaborate on.
Just computationally speaking, it wouldn't make sense
to rewire with every possible experience.
And in fact, that might be a condition akin
to certain mental illnesses where mechanisms
of closing critical periods are not fully active.
And then from-
Could you give us, sorry to interrupt,
but could you give us an example of that?
I mean, that's a fascinating notion
that it's plasticity run awry
that might give rise to a mental illness.
Right, so at the cellular level,
plasticity is ultimately about rewiring connections.
And one example of that is the pruning of dendritic spines
on the predominant excitatory neurons
in the cortex, for example.
And in mental illnesses like schizophrenia,
a hallmark signature is excessive pruning.
And so this could be because critical periods
have not fully closed and excessive remodeling
has been ongoing.
And in fact, that's how we got interested
in the mental illness angle of critical periods.
As we started to unearth the different mechanisms
that are involved in closure,
they were being linked separately in GWAS studies
to schizophrenia, for example.
So in the big genome-wide association studies,
the genes responsible for this plasticity
are popping up as candidates in this terrible disease.
That's right.
That's very interesting, right,
which would also give some explanation,
which I think fascinates people to,
like, why does schizophrenia emerge
in the late teens and the early 20s,
rather than, you know, it's got that peculiar time course
to it, and of course, this would provide
an explanation for that.
Right, as well as the fact that these windows happen
at different times in different brain regions.
And so the kind of executive functions
that are compromised in schizophrenia
related to prefrontal brain function
are naturally where these windows are closing last.
Right, right.
It gives me two questions.
So, you know, I think people, again,
will be aware now that we now know
that some of this development of brain architecture,
particularly in the prefrontal lobes,
continues right into the 20s.
So some of these critical periods are really late in life,
you know, not an infancy business.
Is that the case?
That's right.
And in fact, in the human, in some brain,
higher-order brain areas, they may never really close.
And that's the second insight I was alluding to.
At a cellular level, the genes that are related
to critical period closure seem to be, surprisingly,
break-like factors that inhibit physically
or functionally the plastic process,
which would mean that critical period closure
is an active process, not the traditional thinking
that plasticity fades away with age.
That's the phenomenology.
But it's actually not because of the loss of plasticity
so much as the active prevention of plasticity.
And it suggests that if you look at brain regions
that have evolved in humans that are not present in mice,
for example, and tend to stay plastic longer,
sure enough, we find fewer of these break-like factors there,
consistent with the idea that human intelligence
has benefited from adding areas
that don't close this plastic window.
Good, that's absolutely fascinating.
So now, of course, that brings us to,
can you get in there and turn on and off these switches
that be an obvious benefit?
I suppose, if you think about things like stroke
or that where people lose a function
and they don't have the plasticity to remap,
to bring brain circuits on to compensate,
is there, there's opportunity there, right?
And that's a big piece of what you do.
Yes, so the kind of science fiction-like notion
of reopening or rejuvenating plasticity in the adult brain
has a very powerful therapeutic implication
for recovery from brain injury, stroke, and adulthood.
Of course, as you've mentioned,
we have to do this in a very measured, careful way
because evolution has turned on these breaks for a reason,
and we can talk more about that.
But the goal with our work at Children's Hospital
and other clinically relevant venues is exactly this.
Can we leverage critical period biology
to recover brain function?
And what, would an aspect of that be
spatially specific targeting and turning on and off circuits?
I mean, there's the obvious thing
to do something systemic and you open up the whole brain
and this may be not where you wanna go.
Right, so now that we know that critical periods
happen sequentially in a well-orchestrated manner
thanks to triggers and breaks
that open and close these windows,
you could imagine how damaging it would be
to reopen the whole brain at once.
But there are probably some fail-safe mechanisms
there as well, and so it's not that we are making
the brain plastic so much as opening a gate
that's permissive for training to change
in a modality-specific way.
Amazing, absolutely astounding.
Takao, you were talking about this business of
the closing of critical periods
and at a relatively high level.
Can we talk a little bit at a more granular level
about some of the molecular biology
and some insights that you might have there?
Yeah, sure.
I think there have been two very surprising discoveries
in the study of critical periods.
One is that they are very sensitive
to the development of inhibitory neurons
and that the timing of these windows can be movable
depending on when these inhibitory,
particular class of inhibitory cell matures.
It's surprising because plasticity is often studied
at excitatory connections onto excitatory neurons
which are far more abundant,
but the inhibitory cells seem to drive the bus
and they are of a particular type.
They are fast spiking cells.
They use a lot of energy and so are vulnerable
to oxidative stress which they generate.
And in fact, some of the closure mechanisms
are related to dampening this oxidative stress.
And so closing the critical period
might actually be neuroprotective
and that if we remove the brakes on the plasticity,
then yes, there is a moment for rewiring,
but too much of a good thing could lead
to disruption or degeneration.
And a change in this excitatory inhibitory balance
which is a big piece of our important theory
in neurodegenerative disorder.
And that's how we got into autism in fact.
So discovering that inhibition was pivotal
and that this balance is what we should be looking at,
not just LTP of excitatory connections
has really made headway into autism research.
Yes.
I first came to know about your work
because you were working on mouse models of autism.
I wanted to get a little bit controversial
because I think there are a lot of folks out there
say how on earth is it possible to model a disease
as complex as autism?
Where the symptoms we think about are social communications
and repetitive behaviors and stuff,
the sort of defining symptom clusters.
How can you possibly be studying that in the mouse?
Do you want to give us a little tutorial on that?
Oh, certainly, yes.
We would never be so bold as to claim a mouse has autism.
But they are a very powerful living test tube
of what happens to a complex circuit
when a gene implicated in autism is disrupted.
And so that's how we treat the model system.
Said this with modern machine learning approaches
and more sophisticated analysis of behavior
and being able to think more like a mouse,
we might be able to extract a complex phenotype
even in these animals.
So I think these two thought processes
are running in parallel.
But we've learned quite a bit about how local circuits
and synapses develop, taking the approach
that genes linked to human autism can be probed in mice.
Fantastic.
Okay, that's crystal clear.
Very well put, I must say.
If we can, can we dial the clock back?
And we had a little chat before
and I got to hear a little bit about your trajectory.
You weren't born on these shores.
Can we go back to the beginning,
the genesis of Takawa Hench
and what got you to where you're at at Harvard,
one of the great institutions on the planet
studying autism and mouse models?
Where were you born?
Sure.
How did that impact your development?
Right, well, as you can guess from my name,
I'm half Japanese, half German,
and my father met my mother in Tokyo.
And he was an engineer, computer scientist back in the day.
And he was sent to Japan by IBM
to design the first Chinese character keyboards.
And as you can imagine,
there are thousands of Chinese characters
to encode all of that in keyboards was quite a challenge.
And he came up with a coding scheme,
double-byte character set to encode the characters,
even though he didn't speak a word of Japanese,
taking a very German engineering approach.
And that's still used today
in encoding these characters on keyboards.
Oh, extraordinary.
And during that time, he met my mother.
It was around the time of the first Tokyo Olympic Games.
And I was raised in a multilingual environment.
They took it upon themselves
to speak only their native language with me.
And then we moved to New York.
My father was moved to IBM.
Let me jump in.
So your father was learning Japanese at this point?
Yes, yes, of course.
Given the job he was asked to do.
And my mother was studying German actually, as it turned out.
And so they happened to meet in that way.
And then his job took him to New York
and the whole family moved to the United States
when I was three.
So my-
But at three years of age,
your bilingual Japanese,
or at least a proto bilingual Japanese German speaker,
you haven't heard a word of English at this point.
Not a word of English, that's right.
And then English came in.
But fortunately for me, everything was compartmentalized.
So English was friends and outside the house.
And I grew up in that way.
I also attended a Japanese school in New York
in parallel to the American school.
And so I was able to keep the languages separate
in that way.
And that's what drew my interest to the brain.
And that goes to extraordinary plasticity.
I mean, I think this is one of the things, of course,
about being in America and painting in broad strokes,
but a great number of people in America grow up
in a monolingual environment.
And just the idea that you can pack three entire languages
simultaneously into a child's brain.
I mean, the plasticity must be extraordinary.
Yes, it was surprising to me actually that,
in school we learn a second language.
And so I took French.
So just for good measure, you decided to do number four.
And the French class really opened my eyes
that most other kids were not growing up
in a trilingual environment.
And-
I'm really struggling with it.
Yeah, learning French was somehow easier
because I guess I was used to the idea
of multiple representations for the same objects.
And so that's when I started to develop this fascination
with how early life experience can change brain function.
Right, right, right.
Amazing.
Any other languages that we need to know about?
Well, my wife is Italian.
Goodness me.
Working on that.
You're working on that too.
And finding it easy or?
Yes, it's more confusing because of the French.
Yeah.
And so it's a latecomer.
And of course, different words pop in at that point.
Yeah, yeah, yeah.
I'm actually in the process of trying to learn
a little bit of Spanish.
But growing up in Ireland where we have Irish and English,
the fact that that facility is there as well,
I think it makes it a little bit easier
to catch on to a new language.
Right.
And so that is actually a form of,
this business of being multilingual, polyglot,
has really shaped your thinking in a lot of ways.
Very much so.
It shaped my journey into neuroscience
and also how I traversed the trajectory
where I sought out training.
Right, right.
Tell us about that.
So you moved to Long Island, right?
And then you moved to Westchester County,
to Tarrytown, I believe.
Yes.
And that's where you did your schooling,
high school and all that.
And then college from there?
Yes, I went to Harvard and I was very gung-ho
on the first wave, I'm dating myself now,
of AI really, where expert systems,
as they were called in the day,
were achieving great things.
So not neuroscience in the beginning,
you were thinking, was this because
of your dad's engineering background?
Probably, most likely.
Yes, the summer before college,
I worked at IBM Watson Laboratories
in a natural language processing lab.
Which is right there, right?
That's right.
In the northwest, right?
Yeah, in Yorktown Heights, that's right.
And so with that enthusiasm,
I arrived at Harvard thinking computer science
will solve everything.
And then of course, realizing that we know
precious little about the brain.
At the time, it was shortly after Hubel and Wiesel
had won the Nobel Prize for understanding
the fundamental organization of the visual cortex
and critical periods.
And so I switched more into neurobiology at that point.
As an undergraduate?
As an undergraduate.
I see, yeah.
Yeah, and...
And you were really in a hotbed of scientific discovery
in the neurosciences at that point at Harvard.
Yeah, so much going on.
And I kind of worked my way up the noraxis.
I did my undergraduate thesis with Alan Hobson,
the late Alan Hobson in sleep research.
And from there, took a fellowship to Masao Ito's lab
at the University of Tokyo.
He's of course the godfather of the cerebellum
and plasticity in the cerebellar cortex.
And then had a full bright year with Wolf Singer
and the Max Planck in Frankfurt.
And ended up with Michael Stryker at UCSF
to really get to work on critical period mechanisms.
Wow, you've really collected the institutions
and some extraordinarily prominent mentors.
I've been very fortunate, yes.
Amazing, amazing.
And going back to Tokyo, was that a specific choice
based on being of Japanese origin and that?
Oh yes, after college and having grown up in the States,
I really wanted to follow my roots
and spend some time in Japan and Germany.
Outstanding, outstanding.
We wouldn't be complete here without getting back
to your original motivation,
which was around computer science and AI.
And this has come full circle now, right?
With the interface, I mean,
we're in the AI revolution at the moment.
Tell us a little bit about your thoughts
about the role of AI in the neurosciences
as we speak, as we're sitting here.
Yes, isn't this fascinating?
So it really has come full circle,
but now we have several decades
of neurobiological understanding behind it as well.
The current excitement about AI is loosely modeled
on brain structure in terms of deep neural networks.
And with the brute force power of computing
that's available, amazing things are happening
and everyone is familiar with GPTs and so forth.
But I think the question still remains,
why is it seemingly effortless for a child
with very little exposure to learn how to speak one
or multiple languages or learn a variety of skills
in ways that are not yet possible with current AI?
And so the motivation behind our work now
is to understand principles of brain development,
which might bring the AI a little closer
to the way humans acquire their knowledge
or intelligent behaviors.
But at the same time, honoring the fact
that the world has changed and that humans will need
to coexist with the AI and rely on it in ways
that were not possible even a year and a half ago.
So the alignment problem of human
and artificial intelligence and having AIs
that understand the motivations of humans
when they're interacting with them is extremely important.
Right, right.
And on that front, I mean, do you think that AI,
you know, watching AIs develop human-like skills
is a pathway to understanding disease, for example?
Is that a?
Yes, I think so.
So from a conceptual point of view,
intelligent behavior can exist in a vacuum or a void
like AI might in the virtual space.
But at the same time, it's a good reminder
that the brain exists in a body
and it's bringing our kind of reductionist approach back out
to consider the brain as a homeostatic organ
within an individual whose job is to move
and adapt to environments and things that AI
doesn't necessarily need to worry about.
And so our brain has evolved to deal
with a particular set of constraints,
namely existing within a body, which AI doesn't.
And this might be one major difference in the way
these two forms of intelligence are being developed.
Right.
But we have the ability to embody an AI, right,
in robotics and so on.
That's right.
So that's part of the work we do with some of our colleagues
in Japan, developmental robotics, as it's called,
to have actual physical robots that are then
programmed with models of the developing brain
to test our understanding of how brain development works,
but also as tools for interacting
with autistic children, for example, who often
might prefer to interact with a robot rather than another human.
Embodied human.
Yeah.
It's absolutely fascinating.
When people worry about the sort of apocalyptic things,
do you have any worries about that, AI jumping the shark?
Of course, it is a concern.
And ethics and the proper use of AI and how it's advanced
needs to really catch up quickly now to make sure
that guidelines are in place.
That's for sure.
So it's in our own control.
Right.
You've had an extraordinary career.
I mean, you really, really have.
And looking back on the things that happened
and the people that you met, has it given you
a sense for the path to success?
And if you were to take that and turn it
into advice for a youngster today,
you have some pearls of wisdom.
We always ask this question.
Yes.
Well, the world is changing dramatically.
So I feel like I'm a bit dated already.
Serendipity has been a big part of this.
I started my lab out of graduate school from UCSF,
went back to Japan.
It was not something that I had imagined doing.
But they were launching a new institute, the Riken Brain
Science Institute.
And the goal was to create something more Western,
not the traditional hierarchical system
of Japanese university.
And I thought, well, who am I?
I'm just starting out.
And I had a lot of interesting ideas, I thought,
for the research, but was just untested.
But I felt that I could bring the kind
of Western infrastructure or ecosystem to a new institution.
And in that way, felt like I could contribute right away
in addition to eventually science.
That was a very, very lucky break.
I was, of course, anxious about doing that,
but excited at the same time.
It was an institution that had no tenure.
It was on a five-year review cycle.
And the challenge was there, also moving
far from the familiar.
But chances come around very rarely.
And so I think my advice would be,
if a young person had an opportunity,
they shouldn't be afraid.
And they should seize the day.
You know, you said something very interesting there
about the business of bringing sort of a Western model,
I assume, like an American model to science.
Is there something about that that
makes it intrinsically better at getting the work done,
do you think?
Better in the sense that young people are brimming with ideas.
And in a hierarchical system like the traditional Japanese
university system.
And much of Europe.
Gaining the independence to follow your own ideas
takes years of patience and moving up the hierarchy.
The US system empowers assistant professors
to be independent with all the risk that comes along
with that, of course.
But also the independence to follow your dream.
So stripping away the politics a little bit.
And maybe is there a more business model to it,
do you think?
Is that part of it?
A business model to the American way
is very successful for advancing science.
The freshest, brightest minds are given the opportunity
right away.
What's more difficult is the long vision.
So I've noticed in Europe and certainly in Japan,
grants are designed around long term vision.
And if you're studying something like Alzheimer's disease,
which takes years to manifest, it's
very hard to imagine doing a holistic study with short three
five year grant cycles.
Very good.
Yeah, absolutely.
So short, sharp kind of bolus of money for a youngster
to get some ideas going.
But the bigger the wicked problems
are a little less tangible with that model.
Well, that's really, really interesting.
And thank you for those exceptional insights.
Takau, it's an absolute pleasure to have you here.
And thanks for joining us on Neuroscience Perspectives.
Thank you for having me.
Thank you.