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. 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. Thank you.