Welcome back, my name is Erich Jarvis. I'm an associate professor at the Duke University Medical Center
and also a Howard Hughes Medical Institute Investigator.
And we are talking about brain pathways for vocal learning behaviour,
which is the ability to imitate sounds, including speech.
And in part 3 of my presentation, we're going to talk about some knowledge we've gained recently
about the genes that are involved in functions of vocal learning circuits
and genes that have specialized behaviours in these circuits.
And the first one I want to talk about is called FoxP2. In humans, when the FoxP2 gene is mutated,
we lose the ability to appropriately produce normal speech.
We go ah, buh, hoooww are yoouu? It's hard to sequence phonemes together.
And so, that was the first gene that was discovered for that ability
and itself is a gene that regulates the synthesis of other genes.
My lab and several other labs have actually looked at the FoxP2 gene in the songbird brain
and here's what it looks like in a zebra finch.
Here again is the forebrain and here is the basal ganglia. FoxP2 is expressed at high levels
in this basal ganglia region called the striatum. The white signal here. It's also in the thalamus.
And at a young age, it's pretty high, including in this area X song nucleus,
and when a juvenile zebra finch gets to become what we call this juvenile sub-song stage of singing,
FoxP2 goes up to higher levels in area X and then when he becomes an adult,
it comes down. And shown down here, you know, is the age of those animals at hatching,
here is your juvenile, here is this juvenile, what we call, the sub song.
And he's not imitating well the song of the adult tutor, this is a male, who is singing to a tutee.
But when he's an adult, that juvenile becomes an adult and gets his orange cheek patch,
and all his nice colored feathers, he sings a well imitated song.
And so, FoxP2 expression is going up during that imitation process, and it goes down.
So, this is interesting. What my colleagues Sebastian Haesler and Constance Scharff did
is to inject an inhibitor of FoxP2 into the area X song nucleus. It's called an RNAi inhibitor,
it binds to the mRNA product of FoxP2 and prevents it from being made into a protein.
And what you see down here is called a Western blot and you have a control knockdown
where it's not the FoxP2 gene, some other gene and FoxP2 is still synthesized.
When you put an RNAi to FoxP2 inside of area X, you prevent the protein synthesis.
Other genes are not affected.
And this is just showing a quantification of it being knocked-down.
So, when they did the control knock-down and gave an animal a tutor, this is what we see.
So, here is the song of the tutor and you can hear it's a sequence of 5 different syllables,
and now here is the song of a tutee that grew up with this tutor.
And if you listen to that, they sound quite similar, it's a good copy.
Now, here's a song of another tutor, again with about 5 different syllables,
and now we're going to play the song of the tutee with a FoxP2 knockdown.
You heard that. Go ahead and play it again.
And what you can hear is that yes, the bird is still singing, but he hasn't quite imitated the song that well.
He's imitated individual syllables, but he produces them out of sequence.
And some of those syllables, like this syllable D here, is not a good match of the syllable D here.
And we're going to show a longer example here, play the tutor song.
(Tweets)
And now play the tutee song with the FoxP2 knock-down.
(Tweets)
Did you hear that? Play it again.
(Tweeting)
So, basically, what it shows is that FoxP2, like in the human brain, is not necessary for actual speaking,
or in this case, singing, but it's necessary to actually imitate the songs appropriately.
And what we think is really happening here
is that FoxP2 might be controlling certain kinds of connections in the brain.
And so we began to ask the question, what are the genes that FoxP2 regulates?
And one of the genes that FoxP2 regulates is what we call an axon guidance molecule
called Slit1. The human version of Slit1, I mean the human version of FoxP2,
regulates this neural connectivity gene differently than the chimpanzee version.
What about in songbirds?
Well, we have looked at the Slit1 gene in songbirds and the receptor which the Slit1 gene binds to,
in one of the song nuclei, in this case the RA nucleus that sends a projection out of forebrain to the brainstem.
And what we find is that in all vocal learning birds, the RA nucleus has down regulation of Slit1
compared to the surrounding brain areas in a songbird, a hummingbird and a parrot.
And what's more interesting about the parrot is that it has two parts to its motor learning nucleus.
One part that makes a projection down to the vocal organs for controlling vocal behaviour,
and another part here, that connects up to other brain areas for vocal behaviour.
It's only the part that makes that specialized connection to the vocal motor neurons
that actually has this specialized gene regulation. And if you look at the brain of a non-vocal learner,
an animal here, such as a ring dove and a quail, you can see
that they don't have these brain areas of low gene regulation for this axon guidance molecule.
So, we think that this connection here might be associated with specialized regulation of this Slit1 gene.
And this is new data that we're working on now, it's unpublished,
but it's something that gives you a teaser of what's to happen next.
And our hypothesis is that if we can control these neural connections
through down-regulating or up-regulating these genes in vocal learning circuits
in the non-vocal learning species, maybe we can control its vocal learning behaviour.
So, I'm going to summarize here to put this in a broader context,
to think about how these brain circuits evolve.
We like to think of the brain as something special, but what I'm suggesting from our hypothesis
is that the way brains evolved is much like the way other organ systems evolve.
For instance, in the evolution of wings, what is thought to have happened is wings evolved
three times independently, if not more, in birds, bats, ancient flying dinosaurs, who are petrols.
And basically, what has happened is that each time, the wings evolved at the sides of the body,
at the center of gravity, so when the bird flies, in this case, the earth's gravitational force
is pulling at the center of the body, so you don't want to evolve one wing on the head,
one wing on the tail, or on the back or the chest.
This is the most energetic way to fly; if there's a mutation in the genome
that accidentally puts a wing-like structure on the head,
then the bird is not going to survive. But each time wings evolve, it also used the upper limbs here,
so the arms, in these different animals. So, there was a pre-existing substrate.
I argue that in the brain, like the evolution of wings, there's a pre-existing substrate.
That is the brain pathways controlled motor sequence behaviour. Alright.
Whereas, in the wings, it's the arms. So, we have a pre-existing substrate
which we call a deep homology and then it becomes either useful for another structure,
like the wings, or even duplicated, as I'm suggesting for vocalizations.
For the evolution of wings here, I mentioned there's a genetic constraint which is the upper limbs,
here, that led to the evolution of these wings. And the epigenetic constraint
is the center of gravity. Is there such an epigenetic constraint for the brain?
And my answer has been possibly yes. And shown here is one such hypothesis.
All vocal learners use their learned vocalizations to try to attract mates.
And do so by generating a complex syntax of vocalizations.
So, that is, they sequence their sounds in a complex way.
And this idea came to me one day when I was sitting out in a park at Duke University,
reading a paper and there was this song sparrow sitting at the top of a tree
singing a song, going "whistle, whistle," and he was doing that for fifteen minutes.
So, I first noticed him and then, you know, I sat down and was reading and so forth,
and I tuned out. And then suddenly, he goes "whistle, whistle," and that then made me look up
and notice him. And so that meant that that bird was trying to get attention.
He wasn't trying to get my attention, per se, but he was trying to get the attention of the opposite sex.
And that's what we mean by mate attraction in this case.
Another theory is that vocal learners have the ability to propagate their sounds in different environments.
So, a pigeon vocalizes best on the ground, some other bird species vocalize best in the trees,
or the savannah, because of the way they can change the pitch of their vocalizations,
or the frequency modulation. Whereas non-vocal learning species
only can produce sounds best in a particular environment. So, this ability of vocal learning
allows vocal learners, like humans, to adapt their vocalizations in an environment
that's forever changing and it's thought that humans evolved in the East African Rift Valley
in an area roughly 200,000 years ago that became tropics, savannah, desert and coastline,
all within a hundred mile radius. And this is one idea, is that a complex, varying environment
could also select for the need to produce vocalizations in different ways.
Now, you may be asking, well, if mate attraction
or rapid adaptation to different sound propagations in different environments
is a way to select for vocal learning and all it takes is a few mutations
to make a new pathway and a new connection,
why isn't it so common? And my hypothesis is that not only are the mates paying attention to you,
and, you know, listening to your songs and not habituating to it when you change it,
but so are the predators. And so my hypothesis is that when you produce all these complex, different sounds,
from the top of a tree and advertise yourself and say
"Hey, look, I can keep switching my sounds and make you pay attention to me,"
hawk is going to swoop down and eat you, basically.
So, if you're going to evolve vocal learning abilities,
my idea is that that ability also gets heavily selected against.
And in support of this hypothesis, a colleague of mine, Kazuo Okanoya has shown that
vocal learning species, bird species, kept in captivity for many generations, like the Bengalese finch,
who have not been selected for songs by humans sing more complex songs
than their wild-type counterparts. And guess what?
The females of those songbird species, the wild females prefer the domesticated songs
than they do their wild counterparts.
And so, there is some selection for more complexity once you remove predators away from the species.
And all vocal learners amongst mammals, most of them at least, tend to be at the top of the food chain.
Humans, elephants, dolphins, whales and parrots are also quite smart at evading predators.
But, this is a theory still, it's a hypothesis that needs to be tested.
So, I'm going to end here to say that we've talked about convergent behaviour
and brain pathways for vocal learning and the associated convergent molecular changes
in axon guidance genes like Slit1 and I didn't talk about other genes, but neural protection genes,
and the genes that regulate the axon guidance ones, like FoxP2.
We've also talked about the brain pathways that are controlling vocal learning
that may have emerged by duplication and divergence from an ancient pathway
that controls motor learning.
A concept of deep homology, in this case for the brain pathways.
This theory helps explain a possible idea, another one, that is thought to be involved in the evolution of speech.
That is, the gestural hypothesis of speech evolution where, if you may have noticed
throughout my entire presentation, if you go back over it, when I talk, I move my limbs.
And it's been found that all people move their limbs, particularly their hands,
when they talk. Not only that, when you talk in different languages, you move your limbs in a different way.
That is, gesturing is learned. And gesturing occurs actually even before you learn how to speak.
Chimpanzees can learn how to gesture, but they can't learn how to vocalize.
They can learn how to do sign language. And so, one idea is that the brain pathways
that control gesturing are somehow linked up with the brain pathways that control vocalizations
and that they're somehow evolutionarily related.
And I think my motor theory of vocal learning origin helps explain that.
And then finally, I propose that this mechanism of brain pathway duplication and divergence
for new behaviour may be a general mechanism for evolution of complex behavioural traits.
All this work is not just done by me, but it takes a team of scientists as you can see here,
in my lab back in 2010, where we have different people doing different aspects of this work.
For example, Rui Wang here, discovered the Slit1 gene is differentially expressed
in the song nuclei, along with a collaborator in the lab, Erina Hara.
Miriam Rivas was studying some of these genes as well
and we have Osceola Whitney and Andreas Pfenning, who were students in the lab
and a post-doc, who were also studying how these pathways regulate genes in the brain.
That is, how vocal learning behaviour regulates these genes.
So, it takes a team effort.
And I hope this presentation will inspire other students
to ask the questions and work as a team with other scientists
who are interested in how the brain controls complex behaviours.