Welcome to Huberman Lab Essentials,

where we revisit past episodes for the

most potent and actionable science-based

tools for mental health, physical

health, and performance.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stanford School of Medicine. And now for

my discussion with Dr. Charles Zooker.

Charles, thank you so much for joining

me today.

>> My pleasure. I want to ask you about

many things related to taste 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 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, etc.

>> The world is made of real things. You

know, this here is a glass

and this is a chord 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 but electrical signals that

now need to represent the world

and that process is we can is what we

can operationally define as perception

in the senses

let's say alactory

other 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 he's trying to understand how that

happens. That's been the

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? So if I

want to begin to explore all of these

things that the brain does,

I felt 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 b

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 is mostly associated with the

taste of MSG monos sodium glutamate one

amino acid in particular and so the

beautiful thing of the system is that

the lines of input are limited to five

and each of them has a predetermined

meaning you're born with that specific

veilance value for each taste of 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. 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 leaking. Then

you put a unhappy face. Then you squint

your eyes and then you start gagging.

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 it's it's again the magic of the

brain. You know how how it it's able to

encode and decode these extraordinary

actions and behaviors in response of

nothing but a simple very you know

unique sensory stimuli. 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 pallet 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. But but we scientists need

to reduce the 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. So we

give the animals sweet or we give them a

bitter, we give them sour. We avoid

mixes.

Think of it as lines of information.

Just separate lines like the keys of a

piano. Yeah.

sweet sour beam. 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 lead to an action and a behavior.

>> If you would describe the sequence of

neural events leading to a perceptual

event of taste.

>> We have taste bats 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 100

taste receptor cells and those taste

receptor cells can be of five

types. Yeah. 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 taste like bitter is

particularly enriched at the very back

of your tongue and there is a teological

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. The

important thing is that you know after

the receptors for these five the the

detectors the molecules that sense sweet

sour be to mommy. 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. 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.

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 chord. 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 is one of the

taste ganglia.

These are the neurons that intervate

your tongue and the oral cavity.

>> Where do they sit approximately? Are

there

>> around there?

>> Yeah, right here around the 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 brain stem. The brain stem is the

entry of the body into the brain. And

there are different areas of the brain

stem and there are different groups of

neurons in the brain stem. And there's a

unique area in a unique topographically

defined

location

in the rostral side of the brain stem

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, this sweet signal goes

to this other area higher up on the

brain stem. 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 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 time scale of the nervous

system it's fast. Yeah. And

>> within less than a second.

>> Yeah. And and in fact we can demonstrate

this because we can stick electrodes at

each of these stations. You deliver the

stimuli and within a fraction of a

second you see now the response in this

following stations. Now it gets to the

cortex 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.

>> 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. Is there a change in

the receptors that can explain the

transition from wanting to avoid

vegetables to being willing to eat

vegetables simply in childhood to to

early development?

>> It tastes we just told you that's you

know predetermined hardwire but

predetermined hardwire doesn't mean it's

not modulated by learning or experience.

It only means that you are born

liking sweet and dislike in bitter. And

we have many examples of plasticity.

Coffee, it has an associated gain to the

system. And that gain to the system,

that positive veilance that emerges out

of that negative signal is sufficient to

create that positive association. And in

the case of coffee, of course, is

caffeine in activating a whole group of

neurotransmitter systems that give you

that that that high associated with

coffee. So yes, this T system is

changeable. It's malleable and is

subjected to learning and experience.

>> Can you imagine a sort of a system by

which people could leverage that where

does this this desensitizing happens

that's the term that we use I think it

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 the receptor gets

to a point where it under goes 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 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 from the tongue to the

ganglia from the ganglia to the first

station in the brain stem a second

station in the brain stem to the

phalamus 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 I'm

going to give you one example of of of

how the internal state changes the way

the taste system works. 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 is

incredibly aversive. And we all know

this because we gone to the ocean and

then when you get it in your mouth, it's

not that great. However, if I salt

deprive you 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 you need it. And

this is what we call the modulation of

the taste system by the internal state.

>> 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. 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. 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. Let me

give you an example. So Pablo in his

classical experiments in conditioning,

you know, associative conditioning, he

would take a bell, it will ring the bell

every time he was going to feed the dog.

Eventually the dog learn to associate

the ringing of the bell with food

coming. 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. 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 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. Somehow the brain created

these associations and there are neurons

in your brain now that no 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. Now the main highway that is

communicating the state of the body with

the brain is a specific bundle of nerves

which emerge from the veagal ganglia the

nos 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 to well do

that

>> and I should point out as you well know

every organ spleen pancreas

>> they all must they all must be monitored

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.

>> Yeah. And so this 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, you know, 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. Now let's go to the gut

brain and sugar. The vagus nerve is made

out of many thousands of fibers that

make this gigantic bundle. And it's

likely as we're speaking that each of

these fibers, 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. They are again to make the same

simple example the keys of this piano.

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. Okay, let me tell

you about the gut brain axis and our

insatiable appetite for sugar. This is

work of my own laboratory know that

began long ago when we discovered the

sweet receptors. You can now engineer

mice that lack these receptors. So in

essence, these animals will be unable to

taste sweet. And if you give a normal

mouse a bottle containing sweet and

we're going to 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 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. it animal goes samples

each one leaks a couple of leaks and

then said uhuh that's the one I want

because it's aitive and because I love

it. Now we're going to take the mice and

we're going to 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 that sugar molecule, be an artificial

sweetener, be anything else that tastes

sweet. And if you give this mice an

option between sweet versus water, it

will drink equally well from both

because he cannot tell them apart

because it doesn't have the receptors

for sweet. So that sweet bottle tastes

just like water. But if I keep the mouse

in that cage for the next 48 hours,

something extraordinary happens. When I

come 48 hours later, that mouse is

drinking almost exclusively

from the sugar bottle. During those 48

hours, the mouse learned that there is

something in that bottle that makes me

feel good. And that is the bottle I want

to consume. And that is the fundamental

basis of our unquenchable desire and our

craving for sugar and is mediated by the

gutbrain access. So we reason if this is

true and it's the gutb brain axis that's

driving sugar preference then there

should be a group of neurons in the

brain that are responding to

postingestive 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 and so

what's happening is that sugar is

recognized ized 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 veagal 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 it 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. So these are gut cells

that recognize the sugar molecule. I

see.

>> Send a signal and that signal is

received by the veagal neuron directly.

Got it? And this sends a signal through

the gutb brain axis to the cell bodies

of these neurons in the veagal ganglia

and from there to the brain stem to now

trigger the preference for sugar. 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 intestines can

now absorb them is where you get the

signal back saying this what I want.

Okay, now let me just take it one step

further. This now sugar molecules

activates this unique gut brain circuit

that now drives the development of our

preference for sugar. A key element of

this circuit is that the sensors in the

gut that recognize the sugar do not

recognize artificial sweeteners. 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

curving our appetite,

our craving, our insatiable desire for

sugar since they don't activate the gut

brain access. They'll never satisfy the

craving for sugar like sugar does. We

have a mega problem with overconumption

of sugar and fat. You know, we're facing

a unique time in our evolution where

diseases of malnutrition

are due to over nutrition. Historically,

diseases of malnutritions have always

been linked to under nutrition. But I

want to just go back to the notion of,

you know, 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. You know, oh my god,

this is so delicious. It's fatty or

umami recognizing amino acids. So that's

the liking pathway. But in the wisdom of

evolution, that's good, but doesn't

quite do it. You want to make sure that

these things get to the place where

they're needed. 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. Highly processed foods are

hijacking, you know, co-opting these

circuits in a way that they would have

never happened in nature. And then we

not only find these things appetitive

and palatable but in addition we are

continuously reinforcing you know 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. Well, this is why

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? The

appetite for certain foods and the 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. Understanding these 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, you know,

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 these

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 the over nutrition 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

neuroscientist and vice versa. No one

field is to blame. But I fully agree

that the the brain is is the key over or

the nervous system to be more accurate

is the one of the key overlooked

features

>> is the arbiter ultimately is the arbiter

of many of these pathways. 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 uh 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.

>> I wish all