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

in perception.

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.

My pleasure.

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

as perception.

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.

That’s detection.

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?

Absolutely.

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.

Yes.

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.

Okay?

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?

Perfect 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.

Amazing.

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.

I understand.

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.

Exactly.

You know, in my own world of taste,

the likelihood that an animal in the wild

will enjoy eating something bitter,

it’s inconceivable.

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.

I agree.

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.

Make sense?

All right.

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.

100%.

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.

How? Why?

When you taste something,

you now remember this amazing meal

you had with your first date.

How does that happen?

All right.

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 incredible.

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.

Exactly.

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.

It is.

There’s nothing quite like it.

This goes back to this notion before

that we like to live on the edge.

Yeah.

And we like to do things that we should not be doing,

Andrew.

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 is.

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.

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.

Yes.

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.

Yes.

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.

Amazing.

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.

Yes.

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?

Excellent question.

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.

Yeah, amazing.

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.

Okay?

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.

Okay?

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?

Absolutely.

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.

And so-

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 do.

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.

Impressive.

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.

Vomit.

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.

Really?

Really.

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.

All right.

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

being aversive,

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.

Absolutely.

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.

Of course.

I mean, you know.

Men too, yeah, of course.

Our own babies, when they’re in their necks,

that’s the magical place.

Their neck.

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.

Yes.

I mean, you could get more specific than that,

but not a lot more specific.

Exactly.

So what is going on in terms of the combination

of odor and taste,

given that these two systems are so different?

Yes.

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.

All right.

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.

Make sense?

Makes sense.

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.

All right?

The brain is basically a series of engineered circuits.

Complex.

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.

Impossible.

Exactly.

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.

Why?

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.

Yes.

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.

Well, but-

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.

Of course.

It’s a sign of love.

Exactly.

He’s going to tell me that.

And it’s always about the science in the end.

Right.

But-

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,

but-

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.

Yes.

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-

It’s not.

The sensitivity of the receptors.

That experiment has been done, no.

It has been done.

And so the answer is no.

It’s not.

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.

Great.

Well, this is the reason to do experiments.

Yeah, absolutely.

So it doesn’t defeat any grand hypothesis.

It’s just a pure curiosity.

So-

Do you know that curiosity kills the cat, eh?

I do.

But saves the career of a scientist.

Every single time.

Of course, that’s what drives us.

Absolutely.

Every single time.

It’s the story of our lives.

Exactly.

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,

there’s stress.

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.

Soothing.

That’s the answer.

Soothing.

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?

Yeah.

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.

Yes, excellent.

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.

Remember Pavlov?

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.

Okay.

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.

All right.

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?

Okay.

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.

How?

You’re right.

It’s 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.

May we?

Please, please.

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.

Those stimulator.

Epileptic seizures.

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.

Okay.

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.

Make sense?

All right.

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.

Make sense?

Makes sense.

Very good.

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.

Got it.

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.

Two questions.

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.

Okay?

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.

I see.

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.

Very good.

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

these circuits?

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

than sugar.

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?

We’re 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.

That’s incredible.

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.

Delicious.

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.

Absolutely.

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.

Yes.

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.

Wish all.

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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