Essentials: The Biology of Taste Perception & Sugar Craving | Dr. Charles Zuker

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 ophthalmology at Stanford School of Medicine.

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 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 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 sends that sugar molecule.

That's detection.

You haven't perceived anything yet.

That is, yes, 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?

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 everyone of these problems that the brain has to ultimately compute and code and decode.

And what's 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.

I knew that we could taste what has been usually defined as the basic taste qualities.

Sweet sour, bitter, salty, and umami.

Umami is a Japanese word that means yummy, delicious, and that's 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.

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 valence value for each taste of sweet, umami, and low salt are attractive taste qualities.

They evoke a petitive responses, I want to consume them.

And bitter and sour are innately predetermined to be aversive.

And the case of bitter is 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 guiding.

And that entire thing happens by the activation of a bitter molecule in a bitter sense in selling your talk.

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.

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 spoil, 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 false sensory experience.

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 can integrate it and how they trigger all these different behaviors, we look at them as individual qualities.

So we give the animal sweet, or we give them a bitter, we give them sour, we avoid mixes.

Think of it as lines of information, just separate lines, by the kiss of a piano, yeah? Sweet sour, bitter, salty, mama, you play the key and you activate a 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.

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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 bats.

But each taste bat has around a hundred taste receptor cells, and those taste receptor cells can be of five types, sweet sour, bittersalted, or umami.

And for the most part, all taste bats 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 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.

The important thing is that, you know, after the receptors for these five detectors, the molecules that sense sweet sour, bittersalted, 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 sense 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.

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 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 is one of the taste ganglia.

These are the neurons that innervate your tongue and the oral cavity. Where did they sit approximately?

They're around there. Yeah, right here around there. The lymph nodes more or less.

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 on to the brain stem. The brain stem is the entry of the body into the brain.

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 rich area of the brain exactly. And from there the sweet signal goes to this other area higher up on the brain stem.

And then he 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 timescale of the nervous system it's fast.

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 here. 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 this instance there is a topographic map of this taste quality this 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 taste.

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 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 early development.

Taste we just told you that you know predetermined hardwired but predetermined hardwired doesn't mean that it's not modulated by learning or experience.

It only means that you are born like in 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 valence that emerges out of that negative signal is sufficient to create that positive association.

And in the case of coffee of course is 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.

Can you imagine a sort of system by which people could leverage that?

Where does this sensitizing happens? That's the term that we use it.

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 using terms which are extraordinarily loose.

And 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 that is a huge side of this modulation.

And 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 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 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 provide a new side to give it plasticity and modulation.

I'm going to give you one example of of how the internal state changes the way the taste system works sold is very repetitive at low concentrations and that's because we need it.

It's our electrolyte balance requires sold every one of the neurons uses sold 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're going to the ocean and then when you get in your mouth it's not that great.

However, if I sold the prior view now this incredibly high concentration of salt one molar sodium chloride becomes amazingly repetitive 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.

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I'd love 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 breeding cycle operate to what happens when you ingest sugar and fat.

Let me give you an example so Pablo in his classical experiments in condition in 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 neurological 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 in our 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 their 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 now the main highway that is communicating the state of the body with the brain is.

It's a specific bundle of nerves which emerge from the vagal ganglia the nodos ganglia and so is the vagus nerve that it's innovating 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 will know every organ.

Spleen, pancreas.

They all must be monitor.

I have no doubt that the thesis that we have normally associated with metabolism physiology and even immunity are likely to emerge as the thesis conditions state 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 this is 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 has been 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 got brain and sugar the biggest nerve is made out of many thousands of fibers and 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.

It's 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.

This is relevant because the magic of this got brain access is the fact that you have these thousands of fibers really doing different functions.

Okay let me tell you about the got brain access and our insatiable appetite for sugar this is work of my own laboratory.

So that began long ago when we discovered the sweet receptors you can now engineer mice that lack these receptors.

So in essence this 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.

Alright they both are sweet they have slightly different tastes but that simply because artificial sweeteners have some of 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 1 from the bottle containing sweet.

That's the taste system animal goes samples each one leaks a couple of leaks and then say that's the one I want because it's a petitive 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 this mice no longer have in their oral cavity any sensors that can detect sweetness be that sugar molecule be the 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 you cannot tell them apart because 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 extra ordinary happens when I come 48 hours later that mouse is drinking almost exclusively from the sugar bottle.

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.

And that is the fundamental basis of our unquenchable desire and our craving for sugar and is mediated by the God brain access.

So we reason if this is true and is the God brain access that's driving sugar preference then there should be a group of neurons in the brain that are responding to post ingestive sugar.

Hello and behold we identify a group of neurons in the brain that does this and this neurons receive their input directly from the God brain access.

And so what's happening is that sugar is recognized normally by the tone activates an repetitive response now you ingested and now he activates a selective group of cells in your intestines that now send a signal to the brain via the vehicle ganglia that says I got what I need.

The tongue does not know that you get what you need it only knows that you tasted it this knows that you got to the point that is going to be used which is the God.

And now he 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 God cells that recognize the sugar molecule send the signal and that signal is received by the vagal neuron directly got it and the sense of signal to the God brain access 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 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.

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Now let me just take it one step further this now sugar molecules activates is unique got 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 to not recognize artificial sweeteners is a completely different molecule that only recognizes the glucose molecule not artificial sweeteners.

This as 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 got brain access they'll never satisfy the craving for sugar like sugar this we have a mega problem with over consumption of sugar and fat.

We're facing a unique time in our evolution where the species of malnutrition are due to over nutrition historically the species of malnutrition have always been linked to under nutrition but I want to just go back to the notion of you know this brain centers that are ultimately the ones that are being activated by this 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 hard wire immediate responses yes.

You know oh my god this is so delicious is fatty or umami recognizing amino acids so that's the liking pathway yet 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 opt in the circuits in a way.

That they would have never happened in nature and then we not only find these things up a bit even palatable but in addition we are continuously reinforcing you know the one thing in a way that oh my god this is so great what do I feel like eating let me have more of this.

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 got as you beautifully described and that that changes over time depending on how we are receiving these nutrients.

Absolutely 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 you know connect the dots A to B B to C easy 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 not that over nutrition happens to be such a prevalent problem.

And I also think the training of people who are thinking about metabolic science and metabolic diseases largely divorced from the training of the neuroscientist 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 that one of the key overlooked features.

It's the RV tour ultimately is the RV tour 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 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 do it again. We shall.

Thank you.