Welcome to the Huberman Lab Podcast,
where we discuss science
and science-based tools for everyday life.
I’m Andrew Huberman,
and I’m a professor of neurobiology and ophthalmology
at Stanford School of Medicine.
Today, my guest is Dr. Charles Zucker.
Dr. Zucker is a professor of biochemistry
and molecular biophysics and of neuroscience
at Columbia University School of Medicine.
Dr. Zucker is one of the world’s leading experts
That is how the nervous system converts physical stimuli
in the world into events within the nervous system
that we come to understand as our sense of smell,
our sense of taste, our sense of vision,
our sense of touch, and our sense of hearing.
Dr. Zucker’s lab is responsible
for a tremendous amount of pioneering
and groundbreaking work in the area of perception.
For a long time, his laboratory worked on vision,
defining the very receptors
that allow for the conversion of light
into signals that the rest of the eye
and the brain can understand.
In recent years, his laboratory has focused mainly
on the perception of taste.
And indeed, his laboratory is responsible
for discovering many of the taste receptors
leading to our perception of things like sweetness,
sourness, bitterness, saltiness, and umami,
that is savoriness in food.
Dr. Zucker’s laboratory is also responsible
for doing groundbreaking work on the sense of thirst.
That is how the nervous system determines
whether or not we should ingest more fluid
or reject fluids that are offered to us.
A key feature of the work from Dr. Zucker’s laboratory
is that it bridges the brain and body.
As you’ll soon learn from today’s discussion,
his laboratory has discovered a unique set
of sugar-sensing neurons that exist
not just within the brain, but a separate set of neurons
that sense sweetness and sugar within the body.
And that much of the communication
between the brain and body leading to our seeking of sugar
is below our conscious detection.
Dr. Zucker has received a large number
of prestigious awards and appointments
as a consequence of his discoveries in neuroscience.
He is a member of the National Academy of Sciences,
the National Academy of Medicine,
and the American Association for the Advancement of Science.
He is also an investigator
with the Howard Hughes Medical Institute.
For those of you that are not familiar
with the so-called HHMI, the Howard Hughes Medical Institute,
Howard Hughes Medical Institute investigators
are selected on an extremely competitive basis.
And indeed, they have to come back every five years
and prove themselves worthy of being reappointed
as Howard Hughes investigators.
Dr. Zucker has been a Howard Hughes investigator since 1989.
What all that means for you as a viewer
and or a listener of today’s podcast
is that you are about to learn about the nervous system
and its ability to create perceptions,
in particular, the perception of taste and sugar sensing
from the world’s expert on perception and taste.
I’m certain that by the end of today’s podcast,
you’re not just going to come away
with a deeper understanding of our perceptions
and our perception of tastes in particular,
but indeed, you will come away with an understanding
of how we create internal representations
of the entire world around us.
And in doing so,
how we come to understand our life experience.
Before we begin, I’d like to emphasize that this podcast
is separate from my teaching and research roles at Stanford.
It is, however, part of my desire and effort
to bring zero cost to consumer information about science
and science-related tools to the general public.
In keeping with that theme,
I’d like to thank the sponsors of today’s podcast.
And now for my discussion with Dr. Charles Zucker.
Charles, thank you so much for joining me today.
I want to ask you about many things related to taste.
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And gustatory perception, but maybe to start off,
and because you’ve worked on a number
of different topics in neuroscience, not just taste,
how do you think about perception?
Or rather, I should say, how should the world
and people think about perception,
how it’s different from sensation,
and what leads to our experience of life
in terms of vision, hearing, taste, et cetera?
So, you know, the brain is an extraordinary organ
that weights maybe 2% of your body mass,
yet it consumes anywhere between 25 to 30%
of all of your energy and oxygen.
And it gets transformed into a mind.
And this mind changes the human condition.
It make, it changes, it transforms, you know,
fear into courage, conformity into creativity,
sadness into happiness.
How the hell does that happen?
Now, the challenge that the brain faces
is that the world is made of real things.
You know, this here is a glass, and this is a cord,
and this is a microphone,
but the brain is only made of neurons
that only understand electrical signals.
So how do you transform that reality
into nothing that electrical signals
that now need to represent the world?
And that process is what we can operationally define
In the senses, let’s say olfactory, odor, taste, vision,
you know, we can very straightforwardly separate
detection from perception.
Detection is what happens when you take a sugar molecule,
you put it in your tongue,
and then a set of specific cells
now sense that sugar molecule.
You haven’t perceived anything yet.
That is just your cells in your tongue
interacting with this chemical.
But now that cell gets activated
and sends a signal to the brain,
and now detection gets transformed into perception.
And it’s trying to understand how that happens.
That’s been the maniacal drive
of my entire career in neuroscience.
How does the brain ultimately
transform detection into perception
so that it can guide actions and behaviors?
Does that make sense?
And is a very clear and beautiful description.
A sort of high-level question related to that.
And then I think we can get into
some of the intermediate steps.
I think many people would like to know
whether or not my perception of the color of your shirt
is the same as your perception of the color of your shirt.
What an excellent question.
Am I okay to interrupt you as I’m guessing what you’re going?
All right, very good.
Interruption is welcome on this podcast.
The audience will always penalize me for interrupting you
and will never penalize you for interrupting me.
I like the one-way penalizing.
Now, given what I told you before,
that the brain is trying to represent the world
based in nothing but the transformation
of these signals into electrical languages
that now neurons have to encode and decode.
It follows that your brain is different than my brain.
And therefore it follows that the way
that you’re perceiving the world
must be different than mine,
even when receiving the same sensory cues.
And I’ll tell you about an experiment.
It’s a simple experiment, yet brilliant,
that demonstrates how we perceive the world different.
So in the world of vision, as you well know,
we have three classes of photoreceptor neurons
that sense three basic colors, red, blue, and green.
Blue, green, and red, if we go from short to long wavelength.
And these three are sufficient
to accommodate the full visible spectra.
I’m gonna take three light projectors,
and I’m gonna project one into a white screen,
a red light, and the other one, green light.
I’m gonna overlap the two beams,
and on the screen, there’ll be yellow.
Okay, this is the superposition
when you have two beams of red and green.
And then I’m gonna take a third projector,
and I’m gonna put a filter
that projects right next to that mixed beam,
a spectrally pure yellow.
And I’m gonna ask you to come to the red
and green projectors and play with the intensity knobs
so that you can match that yellow that you’re projecting
to the spectrally pure next to it.
Is this making sense?
And I’m going to write down the numbers
in those two volume intensity knobs.
And then I’m gonna ask the next person to do the same.
And then I’m gonna ask every person
around this area of Battery Park in New York
to do the same.
And guess what?
We’re gonna end up with thousands
of different number combinations.
So for all of us, is yellow enough
that we can use a common language?
But for every one of us,
that yellow is gonna be ever so slightly differently.
And so I think that simple psychological experiment
beautifully illustrates how we truly perceive
the world differently.
I love that example.
And yet in that example,
we know the basic elements from which color is created.
If we migrate into a slightly different sense,
let me pick a hard one,
like sound or olfaction.
Very hard then to do an experiment
that will allow us to get that degree of granularity
and beautiful causality
where we can show that A produces and leads to B.
If I give you the smell of a rose,
you can describe it to me.
If I smell the same rose, I can describe it also.
But I have no way whether the two of us
are experiencing the same.
But it’s close enough that we can both
pretty much say that it has the following features
or other determinants.
But no question that your experience
is different than mine.
The fact that it’s good enough for us to both survive,
that your perception of yellow and my perception of yellow,
at least up until now,
is good enough for us both to survive.
You got it.
It raises a thought about a statement made
by a colleague of ours, Marcus Meister at Caltech.
He’s never been on this podcast,
but in the review that I read by Marcus at one point,
he said that the basic function of perception
is to divide our behavioral responses
into the outcomes downstream
of three basic emotional responses.
Yum, I like it.
Yuck, I hate it.
Or meh, whatever.
What do you think about,
I’m not looking to establish a debate between you, Marcus,
without Marcus here.
But what I like about that is that it seems like,
we know the brain is a very economical organ in some sense,
despite its high metabolic demands.
And this variation in perception
from one individual to the next,
at once seems like a problem
because we’re all literally seeing different things.
And yet we function.
We function well enough for most of us
to avoid death and cliffs and eating poisons and so forth,
and to enjoy some aspects of life, one hopes.
So is there a general statement
that we can make about the brain,
not just as a organ to generate perception,
not just as an organ to keep us alive,
but also an organ that is trying to batch our behaviors
into general categories of outcome?
I think so.
But again, I think the role of Marcus too,
and I think he’s right that broadly speaking,
you could categorize a lot of behaviors
falling into those true categories.
And that’s 100% likely to be the case
for animals in the wild,
where the choices are not necessarily binary,
but they’re very unique and distinct.
Do I wanna eat this?
Do I wanna kill that?
Do I wanna go there or do I wanna go here?
We humans deviated from that world long ago
and learned to experience life
where we do things that we should not be doing.
Some of us more than others.
You know, in my own world of taste,
the likelihood that an animal in the wild
will enjoy eating something bitter,
Yet we, you know, love tonic water.
We enjoy, we like living on the edge.
We love enjoying experiences
that makes us human.
And that goes beyond that simple set of categories,
which is yummy, yucky, ah, who cares?
And so I think it’s not a bad palette,
but I think it’s overly reductionist
for certainly what we humans do.
And since we’re here in New York,
since we’re here in New York,
I can say that the many options,
the extensive variety of food, flora and fauna in New York
explains a lot of the more nuanced behaviors
that we observe.
Let’s talk about taste
because while you’ve done extensive work
in the field of vision,
and it’s a topic that I love,
you could spend all day on,
taste is fascinating.
First of all, I’d like to know why you migrated
from studying vision to studying taste.
And perhaps in that description,
you could highlight to us why we should think about
and how we should think about this sense of taste.
My goal has always been to understand,
as I highlighted before, how the brain does its magic.
You know, what part you might wonder?
Ideally, I’d like to help contribute
to understand all of it.
You know, how do you encode and decode emotions?
How do you encode and decode memories and actions?
How do you make decisions?
How do you transform detection into perception?
And the list goes on and on.
But one of the key things in science, as you know,
is ensuring that you always ask the right question
so that you have a possibility of answering it.
Because if the question cannot be tractable
or reduced to an experimental path
that helps you resolve it,
then we end up doing some really fun science,
but not necessarily answering the important problem
that we want to study.
From a first-person perspective, yes.
The hardest question, the most important question is,
what question are you going to try and answer?
You got it.
And so, for example,
I would love to understand the neural basis of empathy.
It’s a big market for that.
But I wouldn’t even know,
I mean, at the molecular level, that’s what we do.
How do the circuits in your brain create that sense?
I have no clue how to do it.
I can come up with ways to think about it,
but I like to understand what in your brain
makes someone a great philanthropist?
What is the neural basis of love?
I wouldn’t even know where to begin.
So if I want to begin to study these questions
about brain function
that can cover so many aspects of the brain,
I need to choose a problem that affords me that window,
but in a way that I can ask questions that give me answers.
And among the senses that have the capacity
of transforming detection into perception,
of being stored as memories, of creating emotions,
of giving you different actions and perceptions
as a function of the internal state.
When you’re hungry, things taste very differently
than when you’re sated.
When you taste something,
you now remember this amazing meal
you had with your first date.
How does that happen?
So if I want to begin to explore all of these things
that the brain does,
I have to choose a sensory system
that affords some degree of simplicity
in the way that the input-output relationships
are put together.
And in a way that still can be used
to ask every one of these problems
that the brain has to ultimately compute,
encode and decode.
And what was remarkable about the taste system
at the time that I began working on this
is that nothing was known about the molecular basis of taste.
You know, we knew that we could taste
what has been usually defined
as the five basic taste qualities,
sweet, sour, bitter, salty, and umami.
Umami is a Japanese word that means yummy, delicious.
And that’s in nearly every animal species,
the taste of amino acids.
And in humans, it’s mostly associated
with the taste of MSG, monosodium glutamate,
one amino acid in particular.
Just by way of example,
some foods that are rich in the umami-evoking stimulation.
Seaweed, tomatoes, cheese.
And it’s a great, great flavor enhancer.
It enriches our sensory experience.
And so the beautiful thing of the system
is that the lines of input are limited to five.
You know, sweet, sour, bitter, salty, and umami.
And each of them has a predetermined meaning.
You are born liking sugar and disliking bitter.
You have no choice.
These are hardwire systems.
But of course you can learn to dislike sugar
and to like bitters.
But in the wild, let’s take humans out of the equation.
These are 100% predetermined.
You’re born with that specific valence value
for each taste.
Sweet, umami, and low salt are attractive taste qualities.
They evoke appetitive responses.
I want to consume them.
And bitter and sour are innately predetermined
to be aversive.
Could I interrupt you just briefly
and ask a question about that exact point?
For something to be appetitive to,
and some other taste to be aversive,
and for those to be hardwired,
can we assume that the sensation of very bitter,
or of activation of bitter receptors in the mouth
activates a neural circuit that causes closing of the mouth,
retraction of the tongue, and retraction of the body,
and that the taste of something sweet
might actually induce more licking?
100%, you got it.
The activation of the receptors in the tongue
that recognize sweet versus the ones that recognize bitter
activate an entire behavioral program.
And that program that we can refer as appetitiveness
or aversion, it’s composed of many different subroutines.
In the case of bitter, it’s very easy
to actually look at, see them happening in animals,
because the first thing you do is you stop licking,
then you put an unhappy face, then you squint your eyes,
and then you start gagging, right?
And that entire thing happens
by the activation of a bitter molecule
in a bitter-sensing cell in your tongue.
It’s, again, the magic of the brain,
how it’s able to encode and decode
these extraordinary actions and behaviors
in response of nothing but a simple,
very unique sensory stimuli.
Now, let me say that this palette of five basic tastes
accommodates all the dietary needs of the organism.
Sweet to ensure that we get the right amount of energy.
Umami to ensure that we get proteins,
another essential nutrient.
Salt, the three appetitive ones,
to ensure that we maintain our electrolyte balance.
Bitter to prevent the ingestion of toxic, nauseous chemicals.
Nearly all bitter-tasting, you know,
things out in the wild are bad for you.
And sour, most likely to prevent ingestion
of spoiled acid, fermented foods.
And that’s it.
That is the palette that we deal with.
Now, of course, there’s a difference
between basic taste and flavor.
Flavor is the whole experience.
Flavor is the combination of multiple tastes
coming together, together with smell,
with texture, with temperature, with the look of it,
that gives you what you and I would call
the full sensory experience, eh?
But we scientists need to reduce the problem
into its basic elements so we can begin to break it apart
before we put it back together.
So when we think about the sense of taste
and we try to figure out how these lines of information
go from your tongue to your brain and how they signal
and how they get integrated and how they trigger
all these different behaviors,
we look at them as individual qualities, eh?
So we give the animal sweet or we give them a bitter,
we give them sour.
We avoid mixes because the first stage of discovery
is to have that clarity as to what you’re trying
to extract so that you can hopefully,
meaningfully make a difference by being able to figure out
how is it that A goes to B to C and to D.
Does this make sense?
Yeah, almost like the primary colors to create
the full array of the color spectrum.
Before I ask you about the first and second
and third stages of taste and flavor perception,
is there any idea that there may be more than five?
There is, for example.
What about fat?
I love the taste.
I love fat too.
And I love the texture of fat,
especially if it’s slightly burnt like the…
In South America, when I visited Buenos Aires,
I found that at the end of a meal, they would take a steak,
the trimming off the edge of the steak, burn it slightly
and then serve it back to me.
And I thought that’s disgusting.
And then I tasted it and it’s delightful.
There’s nothing quite like it.
This goes back to this notion before
that we like to live on the edge.
And we like to do things that we should not be doing,
But on the other hand, look at those muscles.
The, I don’t suggest anyone eat pure fat.
The listeners of this podcast will immediately,
I’m sure there’ll be a YouTube video soon
that I like eating pure fat.
I’m not on a ketogenic diet, et cetera,
but fat is tasty.
It’s enhanced by the obesity problem
that exists in this country.
Yeah, we’ll talk about that in a little bit
about the gut brain axis.
I think it’ll be important to cover it
because it’s the other side of the taste system.
And so, so missing tastes, you know, one is fat.
Although like you clearly highlighted,
a lot of fat taste in quotation marks
is really the feeling of fat rolling on your tongue.
And so there is a compelling argument
that a lot of what we call fat taste,
it’s really mechanosensory.
It’s somatosensory cells,
cells that are not responding to taste,
but they’re responding to mechanical stimulation
of fat molecules rolling on the tongue
that gives you that perception of fat.
I love the idea that there is a perception of fat
regardless of whether or not
there’s a dedicated receptor for fat,
mostly because it’s evoking sensations
and imagery of the taste of slightly burnt fat.
For example, and another one, you know,
you could argue is metallic taste.
You know, I know exactly what it tastes like.
You know, if you ask me to explain it,
I will have a hard time.
You know, what are the palettes of that color
that can allow me to define it?
I wouldn’t be easy,
but I know precisely what it tastes like.
You know, take a penny, put it in your mouth
and you know what it tastes like, yeah?
Or blood, that’s another very good example.
And is there really, you know,
a receptor for metallic taste
or it’s nothing but this magical combination
of the activation of the existing lines.
Think of it as lines of information, yeah?
Separate lines, like the keys of a piano, yeah?
Sweet, sour, bitter, salty, umami.
You play the key and you activate that one chord.
And that one chord in the case of a piano
leads to a note, you know, a tune.
And in the case of taste,
leads to an action and a behavior.
But you play many of them together
and something emerges that it’s different
than any one of the pieces.
And it’s possible that metallic, for example,
represents the combination of the activity
just in the right ratio of these other lines.
It makes sense.
And it actually provides a perfect,
your example of the piano provides a perfect segue
for what I’d like to touch on next,
which is if you would describe the sequence of neural events
leading to a perceptual event of taste,
and I’m certain that somewhere in there
you will embed an answer to the question
of whether or not we indeed have different taste receptors
distributed in different locations on our tongue
or elsewhere in the mouth.
So let’s start by debunking that old tale and myth.
Who came up with that?
There are many views, but the most prevalent
is that there was an original drawing
describing the sensitivity of the tongue
to different tastes.
So imagine I can take a Q-tip.
This is a thought experiment, yeah?
And I’m gonna dip that Q-tip in salt
and in quinine as something bitter
and glucose as something sweet.
And I’m gonna take that Q-tip,
ask you to stick your tongue out
and start moving it around your tongue
and ask you, what do you feel?
And then I’m going to change the concentration
of the amount of salt or the amount of bitter
and ask, can I get some sort of a map of sensitivity
to the different tastes?
And the argument that has emerged
is that there is a good likelihood
that the data was simply mistranslated
as it was being drawn.
And of course, that led to an entire industry.
This is the way you maximize your wine experience
because now we’re going to form the vessel
that you’re gonna drink from
so that it acts maximally on the receptors
which happen, all right.
Now, there is no tongue map, all right?
We have taste buds distributed
in various parts of the tongue.
So there is a map on the distribution of taste buds
but each taste bud has around a hundred
taste receptor cells.
And those taste receptor cells can be of five types,
sweet, sour, bitter, salty, or umami.
And for the most part,
all taste buds have the representation
of all five taste qualities.
Now, there’s no question that there is a slight bias
for some tastes.
Like bitter is particularly enriched
at the very back of your tongue.
And there is a teleological basis for that,
actually a biological basis for that.
That’s the last line of defense
before you swallow something bad.
And so let’s make sure that the very back of your tongue
has plenty of these bad news receptors
so that if they get activated,
you can trigger a gagging reflex
and get rid of this that otherwise may kill you, okay?
That’s good sense.
But the notion that, you know,
all sweet is in the front and salt is on the side,
it’s not real.
And there, go ahead.
Oh, I was just gonna ask, are there,
first of all, thank you for dispelling that myth.
And we will propagate that information
as far and wide as we can,
because I think that’s the number one myth related to taste.
The other one is, are there taste receptors
anywhere else in the mouth?
For instance, on the lips?
Yeah, the palate, the palate, not the lips.
So it’s in the pharynx at the very back of the oral cavity,
the tongue and the palate.
And the palate is very rich in sweet receptors.
I’ll have to pay attention to this
the next time I eat something sweet.
When you pull it up, yeah?
Now, the important thing is that, you know,
after the receptors for these five, the detectors,
the molecules that sends sweet, sour, bitter, salt, umami,
these are receptors, proteins,
found on the surface of taste receptor cells
that interact with these chemicals.
And once they interact,
then they trigger the cascade of events,
biochemical events inside the cell
that now sends an electrical signal
that says there is sweet here, or there is salt here.
Now, having these receptors,
and my laboratory identify the receptors
for all five basic taste classes,
sweet, bitter, salt, umami, and most recently, sour.
Now, completing the palate,
you can now use these receptors to really map
where are they found in the tongue in a very rigorous way.
This is no longer about using a Q-tip
and trying to figure out what you’re feeling,
but rather what you have in your tongue.
This is not a guess.
This is now a physical map that says
the sweet receptors are found here.
The bitter are found here.
And when you do that, you find that in fact,
every taste bud throughout your oral cavity
has receptors for all of the basic taste classes.
And as it turns out, and I’m sure you’ll tell us,
important in terms of thinking about how the brain
computes and codes and decodes this thing we call taste.
I’m going to inject a quick question
that I’m sure is on many people’s minds
before we get back into the biological circuit,
which is many people, including myself,
are familiar with the experience of drinking a sip of tea
or coffee that is too hot and burning my tongue
is the way I would describe it.
Horrible and then disrupting my sense of taste
for some period of time afterward.
When I experienced that phenomenon,
that unfortunate phenomenon,
have I destroyed taste receptors that regenerate
or have I somehow used temperature
to distort the function of the circuit
so that I no longer taste the way I did before?
And the answer is both.
It turns out that your taste receptors
only leave for around two weeks.
And this, by the way, makes sense
because here you have an organ, the tongue,
that is continuously exposed
to everything you could range from the nicest
to the most horrible possible things.
Use your imagination.
And so you need to make sure
that these cells are always coming back in a way
that I can re-experience the world in the right way.
And there are other organs
that have the same underlying logic, okay?
Your gut, your intestines are the same way.
Again, they’re receiving everything
that you ingest, God forbid what’s there,
from the spiciest, you know,
to the most horrible tasting, to the most delicious.
And again, those intestinal cells whose role
is to ultimately take all these nutrients
and bring them into the body,
also renewal in a very, very fast cycle.
Olfactory neurons in your nose is the other example.
So then A, yes, you’re burning a lot of your cells
and it’s over for those.
The good news is that they’re gonna come back.
But we know that when you burn yourself with tea,
they come back, you know, within 20 minutes,
30 minutes, an hour.
And these cells are not renewing in that timeframe.
They’re not listening to your needs.
They have their own internal clock.
And so you are really affecting,
you’re damaging them in a way that they can recover.
And then they come back and you also damage
your somatosensory cells.
These are the cells that feel things, not taste things.
And then, you know, you wait half an hour or so,
and then, my goodness, thank God, it’s back to normal.
Yeah, and most of the time,
I don’t even notice the transition,
realizing as you told me.
And later I’ll ask you about the relationship
between odor and taste.
But as a next step along this circuit,
let’s assume I ingest some,
let’s keep it simple, a sweet taste.
Let’s make it even simpler,
but at the same time, perhaps more informative.
Let’s compare and contrast sweet and bitter
as we follow their lines from the tongue to the brain.
So the first thing is that the two evoke
diametrically opposed behaviors.
If we have to come up with two sensory experience
that represent polar opposites,
it will be sweet and bitter.
There are no two colors that represent polar opposites
because, you know, you could say black and white,
they are polar opposites,
one that takes only one thing,
the other one that takes everything.
But they don’t evoke different behaviors.
Even political parties have some overlap.
Sweet and bitter are the two opposite ends
of the sensory spectra.
Now, a taste can be defined by two features.
And again, I’m a reductionist,
so I’m reducing it in a way that I think
it’s easier to follow the signal.
And the two features are its quality and its valence.
And valence, with a little V,
that’s what we say in Spanish, with a V,
means the value of that experience, all right?
Or in this case of that stimuli.
And you take sweet, sweet has a quality, an identity,
and that’s what you and I will refer to
as the taste of sweet.
We know exactly what it tastes like.
But sweet also has a positive valence,
which makes it incredibly attractive and appetitive.
But it’s attractive and appetitive,
as I’ll tell you in a second,
independent of its identity and quality.
In fact, we have been able to engineer animals
where we completely remove the valence from the stimuli.
So these animals can taste sweet,
can recognize it as sweet, but it’s no longer attractive.
It’s just one more chemical stimuli.
And that’s because the identity and the valence
are encoded in two separate parts of the brain.
In the case of bitter, again, it has, on the one hand,
its identity, its quality.
And you know exactly what bitter tastes like.
I can taste it now, even as you describe it.
But it also has a valence, and that’s a negative valence,
because it evokes aversive behaviors.
Are we on?
And it comes to mind,
I remember telling some kids recently
that we’re going to go get ice cream,
and it was interesting.
They looked up and they started smacking their lips,
like, you know, they’ll actually evoke-
The anticipatory response, absolutely.
When we talk about the gut brain, maybe we’ll get there.
So then the signals, if we follow now these two lines,
they’re really like two separate keys
at the two ends of this keyboard.
And you press one key and you activate this cord.
So you activate the sweet cells throughout your oral cavity,
and they all converge into a group of sweet neurons
in the next station, which is still outside the brain.
It’s one of the taste ganglia.
These are the neurons that innervate your tongue
and the oral cavity.
Where do they sit approximately?
Around there, yeah.
Right here around the lymph nodes, more or less.
You got it.
And there are two main ganglia
that innervate the vast majority
of all taste buds in the oral cavity.
And then from there,
that sweet signal goes onto the brainstem.
The brainstem is the entry of the body into the brain.
And there are different areas of the brainstem,
and there are different groups of neurons in the brainstem.
And there’s this unique area
in a unique topographically defined location
in the rostral side of the brainstem
that receives all of the taste input.
A very dense area of the brain.
A very rich area of the brain, exactly.
And from there, the sweet signal goes to this other area,
higher up on the brainstem.
And then it goes through a number of stations
where that sweet signal goes from sweet neuron
to sweet neuron to sweet neuron
to eventually get to your cortex.
And once it gets to your taste cortex,
that’s where meaning is imposed into that signal.
It’s then, and only then,
this is what the data suggests,
that now you can identify this as a sweet stimuli.
And how quickly does that all happen?
You know, the timescale of the nervous system, it’s fast.
Within less than a second.
Yeah, absolutely, yeah.
I rarely mistake bitter for sweet.
Maybe with respect to people and my own poor judgment,
but not with respect to taste.
Yeah, and in fact, we can demonstrate this
because we can stick electrodes
at each of these stations conceptually, yeah?
And we can stimulate the tongue
and then we can record the signals pretty much time log
to stimulus delivery.
You deliver the stimuli and within a fraction of a second,
you see now the response in these following stations.
Now it gets to the cortex, yeah?
And now in there, you impose meaning to that taste.
There’s an area of your brain
that represents the taste of sweet in taste cortex
and a different area that represents the taste of bitter.
In essence, there is a topographic map
of these taste qualities inside your brain.
Now we’re gonna do a thought experiment, all right?
Now, if this group of neurons in your cortex
really represents the sense of sweet
and this added different group of neurons in your brain
represents the taste, the perception of bitter,
then we should be able to do two things.
First, I should be able to go into your brain,
somehow silence those neurons,
find a way to prevent them from being activated
and I can give you all the sweet you want
and you’ll never know that you’re tasting sweet.
And conversely, I should be able to go into your brain,
come up with a way to activate those neurons
when I’m giving you absolutely nothing
and you’re gonna think that you’re getting that full percept.
And that’s precisely what we have done
and that’s precisely what you get.
This of course is in the brain of mice, eh?
But presumably in humans, it would work similarly.
Absolutely the same, zeroed out.
I have no questions.
So this attests to two important things.
The first, to the predetermined nature of the sense of taste
because it means I can go to these parts of your brain
in the absence of any stimuli
and have you throw the full behavioral experience.
In fact, when we activate in your cortex,
these bitter neurons, the animal can start gagging.
But it’s drinking only water.
But the animal thinks that it’s getting a bitter stimuli.
This is amazing.
Yeah, and the second, just to finish the line
so that it doesn’t sound like it teaches two things
and then I only give you one lesson,
is that it substantiates this capacity of the brain
to segregate, to separate in these nodes of action
the representation of these two
diametrically opposed percepts, eh?
Which is sweet, for example, versus bitter.
The reason I say amazing, and that is also amazing,
is the following.
You told us earlier, and you’re absolutely correct,
of course, that at the end of the day,
whether or not it’s one group of neurons over here
and another group of neurons over there,
just the way it turns out to be,
electrical activity is the generic common language
of both sets of neurons.
So that raises the question for me
of whether or not those separate sets of neurons
are connected to areas of the brain
that create this sense of valence,
or whether or not they’re simply connected, excuse me,
to sets of neurons that evoke distinct behaviors
of moving towards and inhaling more
and licking or aversive.
Are we essentially interpreting our behavior
and our micro-responses,
or are micro-responses in our behaviors
the consequence of the percept?
Excellent, excellent question.
So first the answer is they go into an area of the brain
where valence is imposed.
And that area is known as the amygdala.
And the sweet neurons go to a different area
than the bitter neurons.
Now, I wanna do a thought experiment
because I think your audience might appreciate this.
Let’s say I activate this group of neurons
and the animal increases licking,
and I’m activating the sweet neurons.
And so that’s expected because now it’s, you know,
tasting this water as if it was sugar.
Now, this is Moses transforming water into wine.
In this case, we’re gonna, and today’s Passover,
so then it’s an appropriate, you know, example.
We’re transforming it into sweet, yeah?
But how do I know?
How do I know that activating them
is evoking a positive feeling inside,
a goodness, a satisfaction, oh, I love it,
versus I’m just increasing licking?
Which is the other option because all we’re seeing
is that the animal is licking more,
and we’re trying to infer that that means
that he’s feeling something really good
versus you know what?
That piano line is going back straight into the tongue,
and all he’s doing is forcing it to move faster.
Well, we can actually separate this by doing experiments
that allow us to fundamentally distinguish them.
And imagine the following experiment.
I’m gonna take the animal,
and I’m gonna put him inside a box that has two sides.
And the two sides have features that make him different.
One has yellow little toys, the other one has green toys.
One has little, you know, black stripes,
the other one has blue stripes.
So the animal can tell the two halves.
I take the mouse, put him inside this arena,
this play arena, and he will explore
and pots around both sides with equal frequency.
And now what I’m going to do is I’m gonna activate
these neurons, these sweet neurons,
every time the animal is on the side with the yellow stripes.
And if that is creating a positive internal state,
what would the animal now want to do?
It will want to stay on the side with the yellow stripes.
There’s no leaking here.
The animal is not extending its tongue
every time I’m activating these neurons, okay?
This is known as a place preference test.
And it’s generally used as just one form
of many different tests to demonstrate
that the activation of a group of neurons in the brain
is imposing, for example,
a positive versus a negative valence.
Whereas if I do the same thing
by activating the bitter neurons,
the animal will actively want now to stay away
from the side where these neurons are being activated.
And that’s precisely what you see.
And that’s precisely what we see.
Many people, including myself,
are familiar with the experience of going to a restaurant,
eating a variety of foods,
and then, fortunately, it doesn’t happen that often,
but then feeling very sick.
I learned coming up in neuroscience
that this is one strong example of one trial learning,
that from that point on,
it’s not the restaurant or the waitress or the waiter
or the date, but it’s my notion
of it had to have been the shrimp.
That leads me to then want to avoid shrimp in every context,
maybe even shrimp powder.
You got it.
For a very long time.
I can imagine all the evolutionarily adaptive reasons
why this such a phenomenon would exist.
Do we have any concept of where in this pathway that exists?
We know, actually, a significant amount
at a general level.
In fact, more than shrimp,
oysters are even a more dramatic example.
One bad oyster is all you need
to be driven away for the next six months.
I think because the texture alone
is something that one learns to overcome.
I actually really enjoy oysters.
I despise mussels, despise shrimp,
not the animal, but the taste.
And yet oysters, for some reason,
I’ve yet to have a bad experience.
It’s like uni, by the way.
Texture is hard to get over,
but once you get over, it’s delicious.
That’s what they tell me.
We were both in San Diego at one point,
and I’ll give a plug to Sushi Ota
as kind of the famous little sushi.
And they have amazing uni, and I’ve tried it twice,
and I’m O for two.
Somehow the texture outweighs any kind of the deliciousness
that people report.
It’s a very acquired taste.
It’s like beer.
You know, I grew up in Chile.
That’s where the accent comes from, in case anyone wonder.
And you know, by the time I came here to graduate school,
I was 19, too old to, you know,
overcome my heavy Chilean accent.
So here I am, 40 years, 50 years late, not quite, 40 plus.
We appreciate it.
And I still sound like I just came off the boat.
So in Chile, you don’t drink beer when you’re young.
You drink wine.
You know, Chile is a huge wine producer.
So when I came to the US,
all of my, you know, classmates, you know,
were drinking beer.
Because they, you know, they had finished college
where they were all, you know, beer drinking,
and, you know, graduate school,
you’re working 18 hours a day, every day.
The way they, you know, relax, let’s go and have some beers.
And beer is cheaper.
And beer is cheap.
And we were being clearly underpaid, may I add.
I couldn’t do it.
It’s an acquired taste.
It was too late by then.
And here I am, you know, 60 plus.
And if you take all the beer I’ve drunk in my entire life,
I would say they add to less than an eight ounce
glass of water.
Well, your health is probably better for it.
I’m not sure.
Your physical health, anyway.
So, you know, it goes back to, you know, acquired taste.
This is the connection to uni and to oysters.
Now, going back to the one trial learning,
you know, this is the great thing about our brains.
Certain things we need to repeat a hundred times
to learn them.
Hello, operator, can I have the phone number
for Sushi Ota, please?
And then she’ll give it to you over the phone,
at least in the old days.
And then you need to repeat it to yourself
over and over and over the next minute
so you can dial Sushi Ota.
And five minutes later, it’s gone.
That’s what we call working memory.
Then there is the short-term memory.
We park our car and if we’re lucky,
by the end of the day, we remember where it is.
And then there is the long-term memory.
We remember the birthdays of every one of our children
for the rest of our lives.
Well, there are events that a single event is so traumatic,
that it activates the circuits in a way
that it’s a one trial learning.
And the taste system is literally
at the top of that food chain.
And there is a phenomenon known
as conditioned taste aversion.
You can pair an attractive stimuli with a really bad one.
And you can make an animal begin to vehemently dislike,
for example, sugar.
And that’s because you’ve conditioned the animals
to now be averse to this otherwise nice taste
because it’s been associated with malaise.
And when you do that, now you could begin to ask,
what is change in the signal as it travels from the tongue
to the brain in a normal animal versus an animal
where you have now transformed sweet
from being attractive to being aversive?
And this is the way now you begin to explore
how the brain changes the nature, the quality,
the meaning of a stimuli as a function of its state.
I have a number of questions related to that,
all of which relate to this idea of context.
Because you mentioned before
that flavor is distinct from taste
because flavor involves smell, texture, temperature,
and some other features, uni, sea urchin
being a good example of, I can sense the texture.
It actually, yeah, I won’t describe what it reminds me of
for various reasons.
The ability to place context on,
to insert context into a perception
or rather to insert a perception into context is so powerful.
And there’s an element of kind of mystery about it,
but if we start to think about some of the more nuance
that we like to live at the edge, as you say,
how many different tastes on the taste dial,
to go back to your analogy earlier, the color dial,
do you think that there could be
for something as fixed as bitter?
So for instance, I don’t think I like bitter tastes,
but I like some fermented foods
that seem to have a little bit of sour
and have a little bit of that briny flavor.
How much plasticity do you think there is there?
And in particular across the lifespan,
because I think one of the most salient examples of this
is that kids don’t seem to like certain vegetables,
but they all are hardwired to like sweet tastes.
And yet you could also imagine that one of the reasons
why they may eventually grow to incorporate vegetables
is because of some knowledge
that vegetables might be-
Good for you.
Better for them.
So is there a change in the receptors,
the distribution, the number, the sensitivity, et cetera,
that can explain the transition
from wanting to avoid vegetables
to being willing to eat vegetables,
simply in childhood to early development?
I want to take the question slightly differently,
but I think it would illustrate the point.
And I want to just use the difference
between the olfactory system
and the taste system to make the point.
Taste system, five basic palates,
sweet, sour, bitter, salt, and umami,
each of them has a predetermined identity.
We know exactly what, and valence.
These are attractive, these are aversive.
In the olfactory system,
it’s claimed that we can smell millions of different odors.
Yet for the most part,
none of them have an innate predetermined meaning.
In the olfactory system,
meaning is imposed by learning and experience.
Even the smell of smoke?
So I’m going to give you, I’m going to make it differently.
There are a handful of the millions of odors
that were claimed that you could immediately tell me
these are aversive and these are attractive.
So vomit, it’s not correct
because I can assure you that there are cultures
and societies where things
which are far less appealing than vomit
do not evoke an aversive reaction.
Sulfur would be maybe a universal.
I’m not talking pheromones, okay?
Pheromones are in a different category
that trigger innate responses.
But nearly every other is afforded meaning
by learning and experience.
And that’s why you like broccoli.
And I despise broccoli
because I remember my mother forcing me to eat broccoli.
I’m so sorry.
Same sensory experience.
This accommodates two important things.
In the case of taste,
you have neurons at every station that are for sweet,
for sour, for bitter, for salty, and umami.
It’s only five classes.
So it’s not going to take a lot of your brain.
If we can in fact smell a million odors
and every one of those odors
had to have predetermined meaning,
there’s not going to be enough brain
just to accommodate that one sense.
And so evolution in its infinite wisdom,
evolve a system where you put together a pathway
and a cortex, olfactory cortex,
where you have the capacity to associate every other
in a specific context that now gives it the meaning.
Now let’s go back to the original question then.
So other than clearly plastic, mega plastic,
because it’s fundamental basis and neural organization.
But taste, we just told you that’s, you know,
predetermined hard wire.
But predetermined hard wire,
it doesn’t mean that it’s not modulated
by learning or experience.
It only means that you are born liking sweet
and disliking bitter.
And we have many examples of plasticity,
beer being one example.
So why do we learn to love beer?
It’s in coffee.
It’s because it has an associated gain to the system.
And that gain to the system,
that positive valence that emerges
out of that negative signal is sufficient
to create that positive association.
And in the case of beer, of course, it’s alcohol.
The feeling good that we get after
is more than sufficient to say,
I want to have more of this.
And in the case of coffee, of course,
it’s caffeine activating a whole group
of neurotransmitter systems that give you
that high associated with coffee.
So yes, this taste system is changeable.
It’s malleable and is subjected to learning and experience.
But unlike the olfactory system,
it’s restricted in what you could do with it
because its goal is to allow you
to get nutrients and survive.
The goal of the olfactory system is very different.
It’s being used, not in our case,
but in every animal species to identify friend versus foe,
to identify mate,
to identify ecological niches they want to be in.
So it plays a very broad role
that then requires that it be set up, organized,
and function in a very different type of context.
Taste is about, can we get the nutrients we need to survive?
And can we ensure that we are attracted
to the ones we need?
And we are averse to the ones that are going to kill us.
I’m being overly simplistic and reductionist,
but I think it illustrates a huge difference
between these two chemosensory systems.
I don’t think you’re being overly simplistic.
I think it illustrates the key intractable nature
of this system and the way you’ve approached it.
And I think it’s important for people to hear that
because everybody, as we are,
is mystified with empathy and love, et cetera.
So in fairness to that,
I’m going to ask a sort of a high-level question
or abstract question.
This was based on a conversation I had
with a former girlfriend,
where we were talking about chemistry between individuals.
Very complicated topic on the one hand,
but on the other hand, quite simple in that certain people,
for whatever reason, evoke a tremendous sense of arousal,
for lack of a better word,
between two people, one would hope.
At least for some period of time.
I didn’t know this was that kind of a podcast.
No, well, the reason I,
but this has to do with taste because she said something,
I think in part to maybe irritate me a bit,
but we were commenting,
not about our own experience of each other,
but of someone that she was now very excited about.
We’re on good terms.
And she said, what do you think it is,
this thing of chemistry?
So maybe she was trying to, you know.
Warn you of what’s coming.
Warn me of what’s coming.
And she said, I have a feeling something about it
is in smell and something about it is actually in taste.
Literally the taste of somebody’s breath.
That’s the way she described it.
And I thought that was a very interesting example
for a number of reasons,
but in particular,
because it gets to the merging of odor and taste,
but also to the idea that of course,
the context of a new relationship,
I’m assuming, and in fact,
they’re both attractive people, et cetera.
There’s a whole context there,
but I’ve had the experience of the odor of somebody’s breath
not because I could identify it as aversive.
Because you just didn’t like it.
But because it just didn’t like it.
But that’s because you associated with other odors
that trigger that negative, you know,
aversive reaction, by the way.
There are certain perfumes to me that are aversive.
You got it.
And there are other scents,
and I can recall scents of skin, of foods, et cetera,
that are immensely appetitive.
So I’ve experienced both sides of this equation myself,
and she was describing this.
And to me, more than tasting wine,
which is the typical example,
where people inhale it and then they drink it,
to me, this seems like something
that more people might be able to relate to,
that certain things and people smell delicious.
Even mothers describing the smell of their baby’s head.
Well, you know, a mother.
I mean, you know.
Men too, yeah, of course.
Our own babies, when they’re in their necks,
that’s the magical place.
The back of their neck.
There you go.
Oh my goodness.
I have a grandchild now,
so I know exactly what Rio, that’s his name, smells like.
Okay, so more beautiful examples.
It’s always more fun to think about the beautiful,
positive, the appetitive examples.
The smell of the back of your grandson’s neck.
I mean, you could get more specific than that,
but not a lot more specific.
So what is going on in terms of the combination
of odor and taste,
given that these two systems are so different?
And they come together.
Ultimately, there is a place in the brain
where they come together to integrate the two
into what we would call, you know, that sensory experience.
And I’ll tell you an experiment that you could do
that demonstrates this.
I think it’s good for your audience here
to get a sense of how we approach these problems
so that we can get, you know,
meaningful scientific answers, eh?
So we know where the olfactory cortex is in the brain.
We know where the taste cortex is in the brain.
They’re in two different places.
We can go to each of these two cortices,
put color traces, we put green in one,
we put red in the other,
and we see where the colors go to.
That’s a reflection of where those neurons
are projecting to into their next targets.
Once they get the signal,
where do they send the signal to?
And then we reason that if odor and taste
come together somewhere in the brain,
we should find an area that now
it’s getting red and green color.
And we found such an area.
And next, we anticipated, we hypothesized,
that maybe this is the area in the brain of the mouse,
corresponding area in the brain of humans,
that integrates odor and taste.
It’s known, the term normally used
is multisensory integration.
And if this is true, we could do the following experiment.
We can train a mouse
to lick sweet,
and if they guess correctly
that that is supposed to be sweet,
they should go now to the right port,
to the right side, to get a water reward.
If they go to the left when it was sweet,
then they’re incorrect and they get no reward.
And they actually get a timeout.
Now the mice are thirsty,
so they’re very motivated to perform.
And if you repeat this task a hundred times,
a hundred trials, incredibly enough,
this animal learned to recognize the sweet
and execute the right action.
And by their action,
we now are being told what that animal is tasting.
We can make it more interesting
and we can give them sweet and bitter
and say if it’s sweet, go to the right,
and if it’s bitter, go to the left.
And after you train them,
these mice with 90% accuracy will tell you
when you randomize now the stimuli,
what was sweet and what was bitter.
We can now do the same experiment,
but now mix taste with odor.
And say, if you got odor alone,
go to the right or push this lever in mice.
If you get taste alone,
go to this other part or push this other lever.
And if you get the two together,
do this something else.
And if you train the mice,
the mice are able now to report back to you
when it’s sensing taste alone, odor alone, or the mix.
We can go to the brain of these mice
and go to this area that we now uncover,
discover as being the site of multi-sensor integration
between taste and odor,
and silence it.
Prevent it from being activated experimentally.
And if that area really represented
the integration of these two,
the animals should still be able
to recognize the taste alone.
They still should be able to recognize the odor alone,
but should be incapable now to recognize the mix.
And exactly as predicted,
that’s exactly what you get.
The brain is basically a series of engineered circuits.
You got it.
And our task is to figure out
how can we extract this amazing architecture
of these circuits in a way
that we can begin to uncover the mysteries of the brain.
And why certain people’s breath tastes so good
and other people’s not so good.
So I never answered that,
but I told you how we can figure out
where in the brain is happening.
As we’ve been having this discussion,
I thought a few times about similarities
to the visual system,
or differences to the visual system.
The visual system,
there are a couple of phenomenon
that I wonder if they also exist in the taste system.
In the visual system,
we know, for instance,
that if you look at something long enough
and activate the given receptors long enough,
that object will actually disappear.
We offset this with little micro eye movements, et cetera.
But the principle is a fundamental one,
this habituation or desensitization.
Everyone seems to call it something different,
but you get the idea, of course.
In the taste system,
I’m certainly familiar with eating something
very, very sweet for the first time in a long time,
and it tastes very sweet.
But a few more licks, a few more bites,
and now it tastes not as sweet.
With olfaction, I’m familiar with the odor in a room
I don’t like or I like, and then it disappearing.
So similar phenomenon.
Where does that occur?
And can you imagine a sort of a system
by which people could leverage that?
Because I do think that most people
are interested in eating not more sugar, but less sugar.
I think we have better ways to approach that,
and we can transition from taste into these other circuits
that makes sugar so extraordinarily impossible
not to consume.
So where does this desensitizing happens?
That’s the term that we use, eh?
And it’s, I think, happening at multiple stations.
It’s happening at the receptor level,
i.e. the cells in your tongue that are sensing that sugar.
As you activate this receptor
and it’s triggering activity after activity after activity,
eventually you exhaust the receptor.
Again, I’m using terms which are extraordinarily loose.
But for sake of this discussion-
For the sake of this discussion,
the receptor gets to a point
where it undergoes a set of changes, chemical changes,
where it now signals far less efficiently,
or it even gets removed from the surface of the cell.
And now what will happen is that the same amount of sugar
will trigger far less of a response.
And that is a huge side of this modulation.
And then the next, I believe,
is the integrated, again, loss of signaling
that happens by continuous activation of the circuit
at each of these different neural stations.
You know, there is from the tongue to the ganglia,
from the ganglia to the first station in the brainstem,
a second station in the brainstem,
to the thalamus, then to the cortex.
So there are multiple steps that this signal is traveling.
Now you might say, why, if this is a label line,
why do you need to have so many stations?
And that’s because the taste system is so important
to ensure that you get what you need to survive,
that it has to be subjected to modulation
by the internal state.
And each of these nodes provides a new site
to give it plasticity and modulation.
Not necessarily to change the way that something tastes,
but to ensure that you consume more or less,
or differently, of what you need.
I’m gonna give you one example
of how the internal state changes
the way the taste system works.
Salt is very appetitive at low concentrations.
And that’s because we need it.
It’s our electrolyte balance requires salt.
Every one of their neurons uses salt
as the most important of the ions,
you know, with potassium to ensure
that you can transfer these electrical signals
within and between neurons.
But at high concentrations, let’s say ocean water,
it’s incredibly aversive.
And we all know this because we’ve gone to the ocean
and then when you get it in your mouth,
it’s not that great.
However, if I salt deprive you,
and we can do this in experimental models quite readily,
now this incredibly high concentration of salt,
one molar sodium chloride,
becomes amazingly appetitive and attractive.
What’s going on in here?
Your tongue is telling you, this is horrible,
but your brain is telling you, I don’t care, you need it.
And this is what we call the modulation
of the taste system by the internal state.
And presumably if one is hungry enough,
even uni will taste good.
Just get to me.
You hit it right on the money.
No, no, this is exactly correct.
Or if you’re thirsty and hungry,
you suppress hunger so that you don’t waste water molecules
in digesting food.
Because if you’re thirsty and you have no water,
you will die within a week or so.
But you can go on a hunger strike
as long as you have water for months,
because you’re gonna eat up all your energy reserves.
Water is a different story.
So you could see that there are multiple layers
at which the taste system that guides our drive
and our motivation to consume the nutrients we need
has to be modulated in response to the internal state.
And of course, internal state itself has to be modulated
by the external world.
And so that I think is a reason why
what could otherwise would have been
an incredibly simple system from the tongue
to the cortex in one just wire, it’s not.
Because you have to ensure that each step
you give the system that level of flexibility
or what we call in neuroscience plasticity.
I think we’re headed into the gut.
But I have a question that has just been on my mind
for a bit now, because I was drinking this water
and it has essentially no taste.
Is there any kind of signal for the absence of taste
despite having something in the mouth?
And here is why I ask, what I’m thinking about is saliva.
And while it’s true that if I eat a lot
of very highly palatable foods,
that does change how I experience more bland foods.
I must confess when I eat a lot of these
highly processed foods, I don’t particularly like them.
I tend to crave healthier foods,
but that’s probably for contextual reasons
about nutrients, et cetera.
But I could imagine an experiment where-
Is there a taste of no taste?
Right, is there a taste of no taste?
Because in the visual system there is, right?
You close the eyes and you start getting increases
in activity in the visual system as opposed to decreases,
which often surprises people.
But there are reasons for that,
because everything is about signal to noise,
signal to background.
And it’s a good question.
I can tell you that most of our work is trying to focus
on how the taste system works, not how it doesn’t work.
I know, I’m just being playful.
I know you’re being playful.
And I knew when inviting you here today,
I was setting myself up for, actually on a different-
We’re trying to learn things, however-
All right, listen, I was weaned in this system of,
and I’ll say it here for the second time.
Actually, I recorded a podcast recently
with a very prominent podcast, the Lex Friedman podcast,
and I made reference
to the so-called New York Neuroscience Mafia.
I won’t say whether or not we are sitting
in the presence of the New York Neuroscience Mafia member,
but in any event, I know the sorts of ribbing
that they provide.
For those listening, this is the kind of hazing
that happens, benevolent hazing in academia.
I’m the target.
It’s a sign of love.
He’s going to tell me that.
And it’s always about the science in the end.
It’s an interesting question.
Look, I don’t know the answer,
and I don’t even know how I would explore it
in a way that it will rigorously teach me,
Let me tell you why I’m asking,
and then I’ll offer an experiment
that I’d love to see someone in your class do.
I’m thinking about saliva.
No, no, no, but that we know,
that we can figure it out easily.
But the question is whether or not the saliva
in a fed state is distinct from the saliva
in an unfed state, such that it modulates-
The sensitivity of the receptors.
That experiment has been done, no.
It has been done.
And so the answer is no.
And the way you could do the experiment
is because we use artificial saliva.
There’s such a thing?
I know there’s artificial tears, but-
No, no, we, I don’t mean that you go to Walgreens
and you get, I mean, we in my laboratory,
we know the composition of saliva,
and so you can make such a thing.
And you can take, you know, taste cells in culture
or in a tongue where you wash it out of,
and then you can apply artificial saliva.
And what happens is that the system
is being engineered to desensitize,
to become agnostic for saliva to become invisible.
And there is no difference on the state of the animal.
Well, this is the reason to do experiments.
So it doesn’t defeat any grand hypothesis.
It’s just a pure curiosity.
Do you know that curiosity kills the cat, eh?
But saves the career of a scientist.
Every single time.
Of course, that’s what drives us.
Every single time.
It’s the story of our lives.
Okay, so if it’s not saliva, and apparently it is not,
what about internal state?
And what aspects of this, the internal milieu are relevant?
Because there’s autonomic, there’s a sleep and awake,
One of the questions that I got from hundreds of people
when I solicited questions was,
from hundreds of people when I solicited questions
in advance of this episode was,
why do I crave sugar when I’m stressed, for instance?
And that could be contextual, but what are the basic-
Because it makes us feel good, by the way.
We’ll get to that.
That’s the answer.
It activates what I’m going to generically refer to
as reward pleasure centers
in a way that it dramatically changes our internal state.
This is, you know, why do we eat a gallon of ice cream
when we’re very depressed?
In fact, this is a good segue to go
into this entirely different world, yeah,
of the body telling your brain what you need
in important things like sugar and fat, yeah?
Okay, but anyways, go ahead.
You were going to ask something.
Well, no, I would like to discuss the most basic elements
of internal state, in particular,
the ones that are below our conscious detection.
And this is a, of course, is a segue
into this incredible landscape,
which is the gut-brain axis,
which I think 15 years ago was almost a,
maybe it was a couple posters at a meeting,
and then now I believe you and others,
there are companies, there are active research programs,
and beautiful work.
Maybe you could describe some of that work
that you and others have been involved in.
And a lot of the listeners of this podcast
will have heard of the gut-brain axis,
and there are a lot of misconceptions
about the gut-brain axis.
Many people think that this means
that we think with our stomach
because of the quote-unquote gut feeling aspect,
but I’d love for you to talk about the aspects
of gut-brain signaling that drive our,
or change our perceptions and behaviors
that are completely beneath our awareness.
So let me begin maybe by stating that,
you know, the brain needs to monitor
the state of every one of our organs.
It has to do it.
This is the only way that the brain can ensure
that every one of those organs are working together
in a way that we have healthy physiology.
Now, this monitoring of the brain
has been known for a long time,
but I think what hadn’t been fully appreciated
that this is a two-way highway
where the brain is not only monitoring,
but is now modulating back what the body needs to do.
And that includes all the way from monitoring
the frequency of heartbeats
and the way that inspiration and aspirations
in the breathing cycle operate
to what happens when you ingest sugar and fat.
Now, let me give you an example again
of how the brain can take
what we would refer to contextual associations
and transform it into incredible changes
in physiology and metabolism.
So Pavlov in his classical experiments
in conditioning, you know, associative conditioning,
he would take a bell,
it would ring the bell
every time he was going to feed the dog.
And eventually the dog learned to associate
the ringing of the bell with food coming.
Now, the first incredible finding he made
is the fact that the dog now,
in the presence of the bell alone,
will start to salivate.
And we will call that, you know, neurologically speaking,
an anticipatory response.
Okay, I could understand it.
I get it.
You know, neurons in the brain that form that association
now represent food is coming
and they’re sending a signal to motor neurons
to go into your salivary glands to squeeze them
so you release, you know, saliva
because you know food is coming.
But what’s even more remarkable
is that those animals are also releasing insulin
in response to a bell.
This illustrates one part of this two-way highway,
the highway going down.
Somehow the brain created these associations
and there are neurons in your brain now
that know food is coming
and send a signal somehow all the way down to your pancreas
that now it says release insulin
because sugar is coming down.
This goes back to the magic of the brain.
It’s a never ending source of both joy and intrigue.
How the hell do they do this?
I mean, the neurons, eh?
I share your delight and fascination.
There’s not a day or a lecture
or some talks are better than others
or a talk where I don’t sit back
and just think it’s absolutely amazing.
Now over the past, I don’t know, dozen years,
and with great force over the last five years.
Now the main highway that is communicating
the state of the body with the brain,
it has been uncovered as being
what we now refer to as the gut-brain axis.
And the highway is a specific bundle of nerves,
you know, which emerge from the vagal ganglia.
They know those ganglia.
And so it’s the vagus nerve
that it’s innervating the majority
of the organs in your body.
It’s monitoring their function,
sending a signal to the brain,
and now the brain going back down and saying,
this is going all right, do this,
or this is not going so well, do that.
And I should point out, as you well know,
every organ, spleen, pancreas, lungs.
They all must be monitored.
In fact, you know, I now,
I have no doubt that diseases
that we abnormally associated with metabolism, physiology,
and even immunity are likely to emerge
as diseases, conditions, states of the brain.
I don’t think obesity is a disease of metabolism.
I believe obesity is a disease of brain circuits.
I do as well.
And so this view that we have, you know,
been working on for the longest time,
because, you know, the molecules that we’re dealing with
are in the body, not in the head,
you know, led us to view, of course,
these issues and problems as being one
of metabolism, physiology, and so forth.
They remain to be the carriers of the ultimate signal,
but the brain ultimately appears to be the conductor
of this orchestra of physiology and metabolism.
All right, now let’s go to the gut, brain, and sugar.
No, I mean, the vagus nerve has, in popular culture,
has been kind of converted
into this single meaning of calming pathways,
mostly because I actually have to tip my hat
to the yogic community was among the first
to talk about vagus on and on and on.
It, there are calming pathways of, you know,
so-called parasympathetic pathways within the vagus,
but I think that the more we learn about the vagus,
the more it seems like an entire set of neural connections
as opposed to one nerve.
I just wanted to just mention that
because I think a lot of people have heard about the vagus.
It turns out experimentally in the laboratory,
many neuroscientists will stimulate the vagus
to create states of alertness and arousal
when animals or even people, believe it or not,
are close to dying or going into coma.
Stimulation of the vagus is one of the ways
to wake up the brain, counter to the idea
that it’s just this way of calming oneself down.
And also, of course, I mean,
one has to be cautious there in that.
So the vagus nerve is made out of many thousands of fibers,
you know, individual fibers that make this gigantic bundle.
And it’s likely, as we’re speaking,
that each of these fibers carries
a slightly different meaning, okay?
Not necessarily one by one, maybe five fibers,
10 fibers, 20 do the, all right.
But they carry meaning that’s associated
with their specific task.
This group of fibers is telling the brain
about the state of your heart.
This group of fiber is telling the brain
about the state of your gut.
This is telling your brain about its nutritional state.
This, your pancreas.
This, your lungs.
And they are, again, to make the same simple example,
the keys of this piano, okay?
Yes, you’re right, there is a lot of data
showing that activating the entire vagal bundle
has very meaningful effects in a wide range of conditions.
In fact, it’s being used to treat untractable depression.
But again, there are thousands of fibers
carrying different functions.
So to some degree, you know, this is like
turning the lights on the stadium
because you need to illuminate
where you lost your keys under your seat.
Yet 10,000 bulbs of 1,000 watts each have just come on.
Only one of these is pointing to work.
And so I’m lucky enough that one of them
happened to point to my site.
So here you activate the bundle, thousands of fibers.
I’m lucky enough that some of those happen to do something
to make a meaningful difference in depression
or to make a meaningful difference in epileptic.
But it should not be misconstrued
as arguing that this broad activation
has any type of selectivity or specificity.
We’re just lucky enough that among all the things
that are being done,
some of those happen to change the biology
of these processes.
Now, the reason this is relevant
because the magic of this gut-brain axis
is the fact that you have these thousands of fibers
really doing different functions.
And our goal, and along with many other great scientists,
including Steve Liverless,
that started a lot of this molecular dissection
on this vagal gut-brain communication line at Harvard,
is trying to uncover what are each of those lines doing?
What are each of those keys of this piano playing?
What’s the latest there, just as a brief update?
I know Stephen Lee released,
I think I was there when he got his Howard Hughes
and I did not, so that was fun.
Always great to get beat by excellent people.
First of all, I’m happy you didn’t
because that way you can focus on this amazing podcast.
Well, thank you, that’s very gracious of you.
It’s always feels better, if not good,
to get beat out by excellent people.
Stephen is second to none.
And he is defining, as you said,
the molecular constituents of different elements
of these many, many fibers.
Is there an update there?
Are they finding multiple parallel pathways?
They are, they are.
Some that control heartbeat,
some that control the respiratory cycle,
some that might be involved in a gastric movement.
You know, this notion that you are full
and you feel full in part
because your gut gets distended,
your stomach, for example.
And then there are little sensors that are reading that
and telling the brain, you’re full.
So the textbooks will soon change
on the basis of the Lieberle’s and other work.
In essence, I think we are learning enough
about these lines
that could really help put together this holistic view
of how the brain, it’s truly changing body physiology,
metabolism and immunity.
The part that hasn’t been yet developed
and that it needs a fair amount of work,
but it’s an exciting, thrilling journey of discovery
is how the signal comes back to now change that biology.
You know, the example I gave you before
with Pavlov’s dog, yeah?
All right, I figure out, you know,
how the association created this link between the bell,
but then how does the brain tell the pancreas
to release in the right amount of insulin?
Okay, so tell me, let me tell you
about the gut-brain axis
and our insatiable appetite for sugar and fat.
Insatiable for sugar and quenchable for fat.
And this is a story about the fundamental difference
between liking and wanting.
Liking sugar is the function of the taste system.
And it’s not really liking sugar, it’s liking sweet.
Wanting sugar, our never ending appetite for sugar
is the story of the gut-brain axis.
Liking versus wanting.
And this work is work of my own laboratory,
you know, that began long ago
when we discovered the sweet receptors.
And you can now engineer mice that lack these receptors.
So in essence, these animals will be unable to taste sweet.
A life without sweetness, how horrible, okay?
And if you give a normal mouse a bottle containing sweet,
and we’re gonna put either sugar
or an artificial sweetener, all right?
They both are sweet.
They have slightly different tastes,
but that’s simply because artificial sweeteners
have some off tastes.
But as far as the sweet receptor is concerned,
they both activate the same receptor,
trigger the same signal.
And if you give an animal an option
of a bottle containing sugar or a sweetener versus water,
this animal will drink 10 to one
from the bottle containing sweet.
That’s the taste system.
Animal goes, samples each one, licks a couple of licks,
and then says, uh-uh, that’s the one I want
because it’s appetitive and because I love it.
So it prefers sugar to artificial sweetener.
No, no, no, no, no.
Equally artificial sweetener.
In this experiment, I’m gonna put only sweet in one bottle,
and it could be either sugar or artificial sweetener.
It doesn’t matter which one.
Okay, we’re gonna do the next experiment
where we separate those two.
For now, it’s sweet versus water.
And sweet means sweet, not sugar.
Sweet means anything that tastes sweet, all right?
And sugar is one example, and Splenda is another example.
Aspartame, monk fruit.
You got it.
It doesn’t matter.
Yeah, I mean, there’s some that only humans can taste.
Mice cannot taste because their receptors
between humans and mice are different.
But we have put the human receptor into mice.
We engineer mice, and we completely humanize
this mouse’s taste world, all right?
But for the purpose of this conversation,
we’re only comparing sweet versus water.
An option, my goodness, they will leak to know
from the sweet side, 10 to one at least versus the water.
Now, we’re gonna take the mice,
and we’re gonna genetically engineer it
to remove the sweet receptors.
So these mice no longer have in their oral cavity
any sensors that can detect sweetness,
be it a sugar molecule, be it an artificial sweetener,
be it anything else that tastes sweet.
And if you give these mice an option
between sweet versus water, sugar versus water,
artificial sweetener versus water,
it will drink equally well from both
because it cannot tell them apart
because it doesn’t have the receptors for sweet
so that sweet bottle tastes just like water.
Now, we’re gonna do the experiment with sugar.
From now on, let’s focus on sugar.
So I’m gonna give a mouse now sugar versus water.
Normal mouse would drink from the sugar,
sugar, sugar, sugar, very little from the water.
Knock out the sweet receptors, eliminate them.
Mouse can no longer tell them apart,
and it will drink from both.
But if I keep the mouse in that cage
for the next 48 hours,
something extraordinary happens when I come 48 hours later
and I see what the mouse is licking or drinking from.
That mouse is drinking almost exclusively
from the sugar bottle.
How could this be?
He cannot taste it.
Doesn’t have sweet receptors.
During those 48 hours,
the mouse learn that there is something in that bottle
that makes me feel good.
And that is the bottle I want to consume.
Now, how does the mouse identify that bottle?
It does so by using other sensory features.
The smell of the bottle,
the texture of the solution inside.
Sugar at high concentrations is kind of goopy.
The sideness in which the bottle is in the cage,
it doesn’t matter what,
but the mouse realized there is something there
that makes me feel good, and that’s what I want.
And that is the fundamental basis
of our unquenchable desire and our craving for sugar
and is mediated by the gut-brain axis.
The first clue is that it takes a long time to develop.
Immediately suggesting a post-ingestive effect.
So we reason if this is true,
and it’s the gut-brain axis
that’s driving sugar preference,
then there should be a group of neurons in the brain
that are responding to post-ingestive sugar.
And lo and behold,
we identify a group of neurons in the brain that does this,
and these neurons receive their input
directly from the gut-brain axis.
From other neurons.
You got it.
And so what’s happening is that sugar
is recognized normally by the tongue,
activates an appetitive response.
Now you ingest it,
and now it activates a selective group of cells
in your intestines that now send a signal
to the brain via the vagal ganglia
that says, I got what I need.
The tongue doesn’t know that you got what you need.
It only knows that you tasted it.
This knows that you got to the point
that it’s going to be used, which is the gut.
And now it sends the signal to now reinforce
the consumption of this thing,
because this is the one that I needed.
Sugar, source of energy.
Are these neurons in the gut?
So these are not neurons in the gut.
So these are gut cells that recognize the sugar molecule,
send a signal, and that signal is received
by the vagal neuron directly.
And this sends a signal through the gut-brain axis
to the cell bodies of these neurons in the vagal ganglia.
And from there to the brain stem
to now trigger the preference for sugar.
One, you mentioned that these cells
that detect sugar within the gut
are actually within the intestine.
You didn’t say stomach, which surprised me.
I always think gut as stomach, but of course, intestines.
Their intestine, because that’s where
all the absorption happens.
So you want the signal.
You see, you want the brain to know
that you had successful ingestion and breakdown
of whatever you consume into the building blocks of life.
And you know, glucose, amino acids, fat.
And so you want to make sure that once they are in the form
that the intestines can now absorb them
is where you get the signal back saying,
this is what I want.
Now, let me just take it one step further.
And this now sugar molecules activates
this unique gut brain circuit
that now drives the development of our preference for sugar.
Now, a key element of this circuit
is that the sensors in the gut that recognize the sugar
do not recognize artificial sweeteners at all,
because their nutrient value is uncoupled from the taste.
Generically speaking, one can make that,
but it’s because it’s a very different type of receptor.
Turns out that it’s not the tongue receptors
being used in the gut.
It’s a completely different molecule
that only recognizes the glucose molecule,
not artificial sweeteners.
This has a profound impact on the effect of ultimately
artificial sweeteners in curbing our appetite,
our craving, our insatiable desire for sugar.
Since they don’t activate the gut brain axis,
they’ll never satisfy the craving for sugar like sugar does.
And the reason I believe that artificial sweeteners
are failing the market to curb our appetite
or need our desire for sugar
is because they beautifully work on the tongue,
the liking to recognize sweet versus non-sweet,
but they fail to activate the key sensors in the gut
that now inform the brain,
you got sugar, no need to crave anymore.
So the issue of wanting,
can we relate that to a particular set of neurochemicals
upstream of, so the pathway is,
so glucose is activating the cells in the gut
through the vagus that’s communicated
through presumably the no-dose ganglion
and up into the brainstem.
And from there, where does it go?
Yeah, where is it going?
What is the substrate of wanting?
I, you know, of course I think molecules like dopamine,
craving, there’s a book even called
The Molecule of More, et cetera, et cetera.
Dopamine is a very diabolical molecule, as you know,
because it evokes both a sense of pleasure-ish,
but also a sense of desiring more, of craving.
So if I understand you correctly,
artificial sweeteners are, and I agree,
are failing as a means to satisfy sugar craving
at the level of nutrient sensing.
And yet if we trigger this true sugar evoked
wanting pathway too much, and we’ve all experienced this,
then we eat sugar and we find ourselves
wanting more and more sugar.
Now that could also be insulin dysregulation,
but can we uncouple those?
Yeah, I mean, look,
if we have a mega problem with overconsumption of sugar,
and fat, we’re facing a unique time in our evolution
where diseases of malnutrition are due to overnutrition.
I mean, how nuts is that, eh?
I mean, historically, diseases of malnutrition
have always been linked to undernutrition, okay?
And so we need to come up with strategies
that can meaningfully change
the activation of these circuits that control our wanting,
certainly in the populations at risk.
And this gut-brain circuit that ultimately,
you know, it’s the lines of communication
that are informing the brain,
the presence of intestinal sugar in this example,
it’s a very important target in the way we think about,
is there a way that we can meaningfully modulate
So I make your brain think that you got satisfied
with sugar, even though I’m not giving you sugar.
So that immediately raises the question,
are the receptors for glucose in these gut cells
susceptible to other things that are healthier for us?
That’s very good, excellent idea.
And I think an important goal will be to come up
with a strategy and identify those very means
that allow us to modulate the circuits in a way
that certainly for all of those where this is a big issue,
it can really have a dramatic impact
in improving human health.
I could be wrong about this, and I’m happy to be wrong.
I’m often wrong and told I’m wrong,
that we have cells within our gut
that don’t just sense sugar, glucose, to be specific,
but also cells within our gut that sense amino acids
and fatty acids.
I could imagine a scenario where one could train themselves
to feel immense amounts of satiety
from the consumption of foods that are rich
in essential fatty acids, amino acids,
perhaps less caloric or less insulin dysregulating
I’ll use myself as an example.
I’ve always enjoyed sweets, but in the last few years,
for some reason, I’ve started to lose my appetite for them,
probably because I just don’t eat them anymore.
At first, that took some restriction.
Now, I just don’t even think about it.
Yeah, and you’re not reinforcing the circuits.
And so you’re in essence are removing yourself,
but you tend to be the exception.
You know, we have a huge,
a huge, incredibly large number of people
that are being continuously exposed
to highly processed foods.
And hidden, so-called hidden sugars.
They don’t even have to be hidden.
You know, it’s right there.
Hiding in plain sight.
Yeah, I agree.
So much is made of hidden sugars
that we often overlook that they are,
there are also the overt sugars.
Yeah, I mean, we can have a long discussion
on the importance of coming up with strategies,
that could meaningfully change public health
when it comes to nutrition.
But I wanna just go back to the notion of,
these brain centers that are ultimately
the ones that are being activated
by these essential nutrients.
So sugar, fat, and amino acids are building blocks
of our diets.
And this is across all animal species.
So it’s not unreasonable then to assume
that dedicated brain circuits would have evolved
to ensure their recognition,
their ingestion, and the reinforcement
that that is what I need.
And indeed, you know, animals evolve these two systems.
One is the taste system that allows you to recognize them
and trigger this predetermined hardwire
immediate responses, yes?
Oh my goodness, this tastes so good.
It’s so sweet.
I personally have a sweet tooth, may I add.
And you know, oh my God, this is so delicious.
It’s fatty or umami recognizing amino acids.
So that’s the liking pathway, yeah?
But in the wisdom of evolution,
that’s good, but doesn’t quite do it.
You wanna make sure that these things get to the place
where they’re needed.
And they’re not needed in your tongue.
They are needed in your intestines
where they’re going to be absorbed
as the nutrients that will support life.
And the brain wants to know this.
And he wants to know it in a way
that he can now form the association
between that that I just tasted
is what got where it needs to be,
and it makes me feel good.
And so now, next time that I have to choose
what should I eat, that association
now guides me to that’s the one I want.
I want that fruit, not that fruit.
I want those leaves, not those leaves,
because these are the ones that activate the right circuits
that ensure that the right nutrients
got to the right place and told the brain,
this is what I want and need.
Are we on?
One thing that intrigues me and puzzles me
is that this effect took a couple of days,
at least in mice.
And the sensation, sorry, the perception of taste
is immediate, and yet this is a slow system.
And so in a beautiful way,
but in a kind of mysterious way,
the brain is able to couple the taste of a sweet drink
with the experience of nutrient extraction in the gut
under a context where the mouse and the human
is presumably ingesting other things,
smelling other mice, smelling other people.
Yeah, but you have to think of it
not as humans.
Remember, we inherited the circuits of our ancestors
and they, through evolutionary, from their ancestors.
And we haven’t had that many years
to have fundamentally changed
in many of these hard wire circuits.
So forget as humans, let’s look at animals in the wild, okay?
Which is easier now to comprehend the logic.
Why should this take a long time of continual reinforcement
given that I can taste it in a second?
You wanna make sure that this source of sugar,
for example, in the wild is the best, is the richest,
is the one where I get the most energy
for the least amount of extraction,
the least amount of work.
I wanna identify rich sources of sugar.
And if the system simply responds immediately
to the first sugar that gets to your gut,
you’re gonna form the association
with those sources of food,
which are not the ones that you should be eating from.
Don’t fall in love with the first person you encounter.
Oh my goodness, exactly.
And so evolutionarily, by having the taste system
giving you the immediate recognition,
but then by forcing this gut-brain axis
to reinforce it only when sustained in a repeated exposure
has informed the brain, this is the one
you don’t wanna form the association before.
And so, when we remove it from the context of,
we just go to the supermarket,
we’re not hunting there in the wild where I need to form.
And so what’s happening is that highly processed foods
are hijacking, co-opting the circuits in a way
that it would have never happened in nature.
And then we not only find these things appetitive
and palatable, but in addition,
we are continuously reinforcing the wanting
in a way that, oh my God, this is so great.
What do I feel like eating?
Let me have more of this.
You’ve just forever changed the way
that I think about supermarkets and restaurants.
Their understanding this fast signaling
and this slower signaling and the utility of having both
makes me realize that supermarkets and restaurants
are about the most unnatural thing for our system ever.
Almost the equivalent of living in small villages
with very few suitable mates
versus online dating, for instance.
Look, I’m not gonna make a judgment call there
because they do serve an important purpose.
I like restaurants too.
Yeah, and so do supermarkets, thank God.
I think they’re not the culprits.
I think the culprits, of course,
are reliance on foods that are not necessarily healthy.
Now, going back to the supermarket,
don’t fall in love with the first, they need to work.
You know, you take a tangerine
and you take an extract of tangerine
that you use to cook that spike, let’s say with sugar,
and you equalize in both
where they both provide the same amount of calories.
If you eat them both,
they’re gonna have a very different effect
in your gut-brain axis and your system.
Once you make the extract and you process it
and you add it, process sugar, you know,
to use it now to cook, to add,
to make it really sweet tangerine thing.
Now, you’re providing now a fully ready-to-use
broken down source of sugar.
In the tangerine, that sugar is mixed in the complexity
of a whole set of other chemical components,
fiber, long chains of sugar molecules
that need a huge amount of work by your stomach,
your gut system, to break it down.
So you’re using a huge amount of energy
to extract energy.
And the balance, it’s very different
that when I take this process, highly extracted tangerine,
by the way, I use tangerines
because I had a tangerine just before I came here.
They are delicious.
And so this goes back to the issue of supermarkets.
And so to some degree, you know, A, given a choice,
you don’t want to eat processed, highly processed foods
because everything’s already been broken down for you.
And so your system has no work.
And so you are co-opting, hijacking the circuits
in a way that they’re being activated at a timescale
that normally wouldn’t happen.
This is why I often feel that,
and I think a lot of data are now starting
to support the idea that while indeed
the laws of thermodynamics apply,
calories ingested versus calories burned
is a very real thing, right?
That the appetite for certain foods
and the wanting and the liking
are phenomena of the nervous system,
brain and gut, as you’ve beautifully described,
and that that changes over time
depending on how we are receiving these nutrients.
Look, we have a lot of work to do.
I’m talking as a society.
I’m not talking about you and I.
We also have a lot of work to do.
Now, I think understanding the circuits
is giving us important insights
and how ultimately, hopefully,
we can improve human health
and make a meaningful difference.
Now, it’s very easy to try to connect the dots,
A to B, B to C, C to D.
And I think there’s a lot more complexity to it,
but I do think that the lessons that are emerging
out of understanding how the circuits operate
can ultimately inform how we deal with our diets
in a way that we avoid what we’re facing now,
you know, as a society.
I mean, it’s nuts that overnutrition
happens to be such a prevalent problem.
Yeah, and I also think the training of people
who are thinking about metabolic science
and metabolic disease is largely divorced
from the training of the neuroscientists and vice versa.
No one field is to blame,
but I fully agree that the brain is the key
or the nervous system, to be more accurate,
is one of the key overlooked features.
Is the arbiter, ultimately is the arbiter
of many of these pathways.
As a final question and one which is simply
to entertain my curiosity
and the curiosity of the listeners,
what is your absolute favorite food?
Oh my goodness.
Taste, I should say.
Taste, to distinguish between taste
and the nutritive value or lack thereof.
Yes, look, we, unlike every other animal species,
eat for the enjoyment of it.
It doesn’t happen in the wild.
Most animals eat when they need to eat.
Doesn’t mean they don’t enjoy it,
but it’s a completely different story, yeah?
I have too many favorite foods
because I enjoy the sensory experience, yeah?
Rather than the food itself, to me, it’s the whole thing.
It’s from the present.
Look, there’ve been these experiments done
in psychophysics, yeah?
I’m gonna take a salad made out of 11 components
and I’m gonna mix them all up in a potpourri of greens
and other things here.
And in the other one,
I’m gonna present it in a beautiful arrangement
and I’m gonna put it behind a glass cabinet
and I’m gonna sell them.
And I’m gonna sell one for $2 and one for $8.
Precisely the same ingredient,
exactly the same amount of each.
Ultimately, you’re gonna mix them,
they’re all gonna be the same.
And people will pay the $8 because, you know what?
It evokes a different person, okay?
It gives you the feel that, oh my goodness,
I’m gonna enjoy that salad.
So going back to what is my favorite food.
To me, eating is really a sensory journey.
I don’t mean the every day, let me have some, you know,
chicken wings because I’m hungry.
But every piece, I think,
has an important evoking sensory role.
And so, you know, in terms of food,
and so, you know, in terms of categories of food,
you know, I grew up in Chile,
yes, so meat is always been,
but I eat it so seldom now.
Is that right?
Yeah, because, you know,
I know that’s not necessarily the healthiest thing,
red meat I’m talking about, yeah?
And so I, you know, I grew up eating it every day.
I’m talking seven days a week, Chile and Argentina,
you know, that’s the mainstay of our diet, yeah?
Now maybe I have red meat, I know,
once every four weeks.
And you enjoy it.
Oh, I love it.
Part of it is because I haven’t had it in four weeks.
But, you know, I love sushi,
but I love the art of sushi.
You know, the whole thing, you know,
the way it’s presented, it changes the way you taste it.
I love ethnic food, in particular.
You’re in the right place.
You got it.
That was the main reason I wanted to come to New York.
No, I’m just kidding.
There’s also that Columbia University that’s-
I came here because I wanted to be with, you know,
people that are thinking about the brain
the same way that I like to think,
which, you know, can we solve this big problem,
this big question?
And certainly you’re making amazing strides
in that direction.
And I love your answer because it really brings together
the many features of the circuitries
and the phenomena we’ve been talking about today,
which is that while it begins with sensation and perception,
ultimately it’s the context,
and that context is highly individual to person,
place, and time, and many, many other things.
On behalf of myself,
and certainly on behalf of all the listeners,
I want to thank you.
First of all, for the incredible work
that you’ve been doing now for decades in vision, in taste,
and in this bigger issue of how we perceive
and experience life.
It’s truly pioneering and incredible work.
And I feel quite lucky to have been on the sidelines
seeing this over the years and hearing the talks
and reading the countless beautiful papers,
but also for your time today to come down here
and talk to us about what drives you
and the discoveries you’ve made.
Thank you ever so much.
It was great fun.
Thank you for having me.
We’ll do it again.
Thank you for joining me today
for my discussion about perception,
and in particular, the perception of taste
with Dr. Charles Zucker.
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and the biology of the perception of taste in particular.
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