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

Andrew Huberman:
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 Zuker. Dr. Zuker is a professor of biochemistry and molecular biophysics and of neuroscience at Columbia University School of Medicine. Dr. Zuker 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. Zuker'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. Zuker'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. Zuker'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. Zuker 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. Zuker has been a Howard Hughes investigator since 1989. What all that means for you as a viewer and/or 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 taste 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 Zuker. Charles, thank you so much for joining me today.

Dr. Charles Zuker:
My pleasure.

Andrew Huberman:
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 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?

Dr. Charles Zuker:
So, the brain is an extraordinary organ that weighs 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 changes, it transforms 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. 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, 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?

Andrew Huberman:
Absolutely, and it's a very clear and beautiful description. A sort of high-level question related to that-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... and then I think we can get into some of the intermediate steps.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
What an excellent question. Am I okay to interrupt you as I'm guessing where you're going? All right, very good.

Andrew Huberman:
Interruption is welcome on this podcast. The audience will always penalize me for interrupting you-

Dr. Charles Zuker:
Good

Andrew Huberman:
... and will never penalize you for interrupting me.

Dr. Charles Zuker:
I like the one-way penalizing. Now, given what I told you before, that the brain is trying to represent the world based on 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 differently. 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. Or 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 going to take three light projectors, and I'm going to project one into a wide screen, a red light, and the other one green light. I'm going to overlap the two beams, and on the screen it'll be yellow. Okay, this is the superposition when you have two beams of red and green. And then I'm going to take a third projector, and I'm going to put a filter that projects right next to that mixed beam, a spectrally pure yellow. And I'm going to 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?

Andrew Huberman:
Perfect sense.

Dr. Charles Zuker:
And I'm going to write down the numbers in those two volume intensity knobs. And then I'm going to ask the next person to do the same. And then I'm going to ask every person around this area of Battery Park in New York to do the same. And guess what? We're going to end up with thousands of different number combinations.

Andrew Huberman:
Amazing.

Dr. Charles Zuker:
Yeah. So, for all of us, it's yellow enough that we can use a common language. But for every one of us, that yellow is going to be ever so slightly different. Okay? And so I think that simple psychological experiment beautifully illustrates how we truly perceive the world differently.

Andrew Huberman:
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-

Dr. Charles Zuker:
Sound

Andrew Huberman:
... sound or olfaction.

Dr. Charles Zuker:
Yeah. 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 of knowing 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.

Andrew Huberman:
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-

Dr. Charles Zuker:
You got it

Andrew Huberman:
... 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 a 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.

Dr. Charles Zuker:
Yeah.

Andrew Huberman:
What do you think about-- I'm not looking to establish a debate between you and Marcus without Marcus here.

Dr. Charles Zuker:
I understand.

Andrew Huberman:
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-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... death and cliffs and eating poisons and so forth, and to enjoy some aspects of life, one hopes.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
So is there a general statement that we can make about the brain, not just as an 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?

Dr. Charles Zuker:
I think so. But again, I think the world of Marcus too, and I think he's right that broadly speaking, you could categorize a lot of behaviors falling into these 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 want to eat this? Do I want to kill that? Do I want to go there, or do I want to 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.

Andrew Huberman:
Some of us more than others.

Dr. Charles Zuker:
Exactly. In my own world of taste, the likelihood that an animal in the wild will enjoy eating something bitter, it's inconceivable. Yet we love tonic water. 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, eh, who cares? And so I think it's not a bad palate, but I think it's overly reductionist for certainly what we humans do.

Andrew Huberman:
I agree, and 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 although you've done extensive work in the field of vision, and it's a topic that I love, we 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.

Dr. Charles Zuker:
My goal has always been to understand, as I highlighted before, how the brain does its magic. What part, you might wonder. Ideally, I like to help contribute to understand all of it. 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.

Andrew Huberman:
From a first-person perspective, yes. The hardest question, the most important question is what question are you going to try and answer?

Dr. Charles Zuker:
You got it.

Andrew Huberman:
Right. Sure.

Dr. Charles Zuker:
And so, for example, I would love to understand the neural basis of empathy.

Andrew Huberman:
There's a big market for that.

Dr. Charles Zuker:
100%. But I wouldn't even know, 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 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. 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.

Andrew Huberman:
What are, just by way of example-

Dr. Charles Zuker:
Yeah

Andrew Huberman:
... some foods that are rich in the umami evoking stimulation?

Dr. Charles Zuker:
Seaweed, tomatoes, cheese.

Andrew Huberman:
Okay.

Dr. Charles Zuker:
And it's a 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. 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 hard wire 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.

Andrew Huberman:
Could I interrupt you just briefly-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... and ask a question about that exact point?

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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?

Dr. Charles Zuker:
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 and see them happening in animals because the first thing you do is you stop licking, 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.

Andrew Huberman:
It's incredible.

Dr. Charles Zuker:
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 palate 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 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 palate 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 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. 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?

Andrew Huberman:
Yeah. Almost like the primary colors to create the full array of the color spectrum.

Dr. Charles Zuker:
Exactly.

Andrew Huberman:
Before I ask you about the first and second and third stages of taste and flavor perception-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... is there any idea that there may be more than five?

Dr. Charles Zuker:
There is. For example, what about fat?

Andrew Huberman:
I love the taste.

Dr. Charles Zuker:
Oh, you love fat, too.

Andrew Huberman:
And I love the texture of fat, especially if it's slightly burnt. 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.

Dr. Charles Zuker:
It is.

Andrew Huberman:
There's nothing quite like it.

Dr. Charles Zuker:
This goes back to this notion before that we like to live on the edge. And we like to do things that we should not be doing, Andrew. But on the other hand, look at those muscles.

Andrew Huberman:
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.

Dr. Charles Zuker:
It is.

Andrew Huberman:
As evidenced by the obesity problem that exists in this country.

Dr. Charles Zuker:
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 missing taste, 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 is really mechanosensory, is 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.

Andrew Huberman:
I love the idea that there is a perception of fat, regardless of whether or not there's a dedicated receptor for fat.

Dr. Charles Zuker:
You got it.

Andrew Huberman:
Mostly because it's evoking sensations and imagery of the taste of slightly burnt fat.

Dr. Charles Zuker:
For example. And another one you could argue is metallic taste. I know exactly what it tastes like. If you ask me to explain it, I will have a hard time. What are the palettes of that color that can allow me to define it? It wouldn't be easy, but I know precisely what it tastes like. Take a penny, put it in your mouth, and you know what it tastes like, yeah?

Andrew Huberman:
Or blood.

Dr. Charles Zuker:
Or blood. That's another very good example. And is there really 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, separate lines. Like the keys of a piano, yeah? Sweet, sour, bitter, salty, umami. You play the key, and you activate the one chord, and that one chord, in the case of a piano, leads to a note, 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-

Andrew Huberman:
Makes sense

Dr. Charles Zuker:
... of these other lines.

Andrew Huberman:
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-

Dr. Charles Zuker:
Mm-hmm

Andrew Huberman:
... 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-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... or elsewhere in the mouth.

Dr. Charles Zuker:
Yes. So let's start by debunking that old tale and myth.

Andrew Huberman:
Who came up with that?

Dr. Charles Zuker:
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 going to dip that Q-tip in salt and in quinine as something bitter, and glucose as something sweet. And I'm going to 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 going to 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 100 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 is no question that there is a slight bias for some tastes. Like bitter is particularly enrich 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?

Andrew Huberman:
Makes good sense.

Dr. Charles Zuker:
But the notion that all sweet is in the front and salt is on the side, it's not real. And they're... Go ahead.

Andrew Huberman:
Oh, I was just going to ask, first of all, thank you for dispelling that myth.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
The other one is, are there taste receptors anywhere else in the mouth? For instance, on the lips?

Dr. Charles Zuker:
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.

Andrew Huberman:
Hmm. I'll have to pay attention to this the next time I eat something sweet.

Dr. Charles Zuker:
Yeah. When you pull it up. Yeah?

Andrew Huberman:
Mm-hmm.

Dr. Charles Zuker:
Now, the important thing is that after the receptors for these five, the detectors, the molecules that sense 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.

Andrew Huberman:
Amazing. And as it turns out, and I'm sure you'll tell us, important in terms of thinking about how the brain computes, encodes, and decodes this thing we call taste.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
Horrible.

Andrew Huberman:
Horrible, and then disrupting my sense of taste for some period of time afterward.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
When I experience 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?

Dr. Charles Zuker:
Excellent question, and the answer is both. It turns out that your taste receptors only live 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.

Andrew Huberman:
Use your imagination.

Dr. Charles Zuker:
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 are receiving everything that you ingest, God forbid what's there, from the spiciest 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 going to come back. But we know that when you burn your cells with tea, they come back 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. Okay? 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 wait half an hour or so, and then, my goodness, thank God, it's back to normal.

Andrew Huberman:
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.

Dr. Charles Zuker:
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 could say black and white, they are polar opposites. One detects only one thing, the other one detects everything. But they don't evoke different behaviors.

Andrew Huberman:
Right. Even political parties have some overlap.

Dr. Charles Zuker:
Sweet and bitter are the two opposite ends of the sensory spectra. Now, a taste can be defined by two features. Again, I'm a reductionist, so I'm reducing it in a way that I think is 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.

Andrew Huberman:
I can taste it now, even as you describe it.

Dr. Charles Zuker:
But it also has a valence, and that's a negative valence because it evokes aversive behaviors. Are we on?

Andrew Huberman:
Absolutely.

Dr. Charles Zuker:
All right.

Andrew Huberman:
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 lip. They'll actually evoke the-

Dr. Charles Zuker:
The anticipatory response. Absolutely. Yeah. 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.

Andrew Huberman:
Where do they sit, approximately? Are they-

Dr. Charles Zuker:
Around there.

Andrew Huberman:
Yeah. Right here, around the lymph nodes, more or less.

Dr. Charles Zuker:
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 on to 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 this unique area in a unique topographically defined location in the rostral side of the brain stem that receives all of the taste input.

Andrew Huberman:
A very dense area of the brain.

Dr. Charles Zuker:
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 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.

Andrew Huberman:
And how quickly does that all happen?

Dr. Charles Zuker:
The timescale of the nervous system, it's fast, yeah? And so-

Andrew Huberman:
Within less than a second.

Dr. Charles Zuker:
Yeah. Absolutely, yeah.

Andrew Huberman:
I rarely mistake bitter for sweet.

Dr. Charles Zuker:
Yeah.

Andrew Huberman:
Maybe with respect to people and my own poor judgment, but-

Dr. Charles Zuker:
But no, you-

Andrew Huberman:
But not with respect to taste.

Dr. Charles Zuker:
Yeah. And in fact, we can demonstrate this because we can stick electrodes at each of these stations conceptually, and we can stimulate the tongue, and then we can record the signals pretty much time lock 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. And now in there you impose meaning to that taste. There is 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 a sense, there is a topographic map of these taste qualities inside your brain. Now, we're going to do a thought experiment, all right? Now, if this group of neurons in your cortex really represents the sense of sweet, and this other 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, while I'm giving you absolutely nothing, and you're going to 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.

Andrew Huberman:
But presumably in humans it would work similarly.

Dr. Charles Zuker:
Absolutely the same. Zero doubt. 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.

Andrew Huberman:
This is amazing.

Dr. Charles Zuker:
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. Which is sweet, for example, versus bitter.

Andrew Huberman:
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, which is 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 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 microresponses, or are microresponses and our behaviors the consequence of the percept?

Dr. Charles Zuker:
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 want to 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 tasting this water as if it was sugar. Now this is Moses transforming water into wine. In this case, and today is Passover, so then it's an appropriate example. We're transforming it into sweet. But how do I know that activating them is evoking a positive feeling inside, a goodness, a satisfaction, or 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 it's feeling something really good versus, you know what? That piano line is going back straight into the tongue, and all it'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 going to take the animal, and I'm going to 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 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 it will explore and putz around both sides with equal frequency. And now what I'm going to do is I'm going to 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 is no licking here. The animal is not extending its tongue every time I'm activating these neurons. 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.

Andrew Huberman:
And that's precisely what you see.

Dr. Charles Zuker:
And that's precisely what we see.

Andrew Huberman:
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-

Dr. Charles Zuker:
You got it

Andrew Huberman:
... 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?

Dr. Charles Zuker:
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-

Andrew Huberman:
Oh

Dr. Charles Zuker:
... is all you need to be driven away for the next six months.

Andrew Huberman:
I think because the texture alone is something that one learns to overcome. I actually really enjoy oysters.

Dr. Charles Zuker:
Me too.

Andrew Huberman:
I despise mussels, despise shrimp, not the animal, but the taste, and yet oysters for some reason, I'm yet to have a bad experience.

Dr. Charles Zuker:
It's like uni, by the way. Texture is hard to get over, but once you get over, it's delicious.

Andrew Huberman:
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-

Dr. Charles Zuker:
Oh, my goodness

Andrew Huberman:
... little sushi. And they have amazing uni, and I've tried it twice, and I'm oh for two. Somehow the texture outweighs any kind of the deliciousness that people report.

Dr. Charles Zuker:
It's a very acquired taste, yeah? It's like beer. I grew up in Chile. That's where the accent comes from, in case anyone wonder. And by the time I came here to graduate school, I was 19, too old to overcome my heavy Chilean accent. So here I am, 40 years, 50 years later, not quite. 40 plus.

Andrew Huberman:
We appreciate it.

Dr. Charles Zuker:
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. Chile's a huge wine producer. So when I came to the US, all of my classmates were drinking beer because they had finished college where they were all beer drinking and graduate school, you're working 18 hours a day, every day. The way they relax, let's go and have some beers.

Andrew Huberman:
And beer is cheaper.

Dr. Charles Zuker:
And beer is cheap.

Andrew Huberman:
Yeah.

Dr. Charles Zuker:
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, 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.

Andrew Huberman:
Impressive. Well, your health is probably better for it.

Dr. Charles Zuker:
I'm not sure.

Andrew Huberman:
Your physical health, anyway.

Dr. Charles Zuker:
So, it goes back to acquired taste. This is the connection to uni and to oysters. Now, going back to the one-trial learning. This is the great thing about our brains. Certain things we need to repeat 100 times to learn them. "Hello, operator, could 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, over the next minute, so you can dial Sushi Ota. And five minutes later, it's gone. That's what we call working memory Yeah. Then there is the short-term memory. Yeah, 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 can begin to ask what has changed 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.

Andrew Huberman:
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-

Dr. Charles Zuker:
Yeah

Andrew Huberman:
... and some other features. Uni, sea urchin being a good example of I can sense the texture. It actually, no. I won't describe what it reminds me of for various reasons. The ability 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-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... 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-

Dr. Charles Zuker:
Good for you

Andrew Huberman:
... 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-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... to early development?

Dr. Charles Zuker:
So I want to take the question slightly differently, but I think it will 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 valance. 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.

Andrew Huberman:
Even the smell of smoke?

Dr. Charles Zuker:
So 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.

Andrew Huberman:
Vomit.

Dr. Charles Zuker:
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.

Andrew Huberman:
Really?

Dr. Charles Zuker:
Really. Sulfur would be maybe a universal. I'm not talking pheromones, okay?

Andrew Huberman:
Sure.

Dr. Charles Zuker:
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.

Andrew Huberman:
I'm so sorry.

Dr. Charles Zuker:
Same sensory experience. Yeah. All right. This accommodates two important things. Yeah. 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 odor 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 predetermined hardwire. But predetermined hardwire 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, coffee? It's because it has an associated gain to the system, and that gain to the system, that positive valance 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.

Andrew Huberman:
I don't think you're being overly simplistic. I think it illustrates the key and tractable 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 mystified with empathy and love, et cetera. So in a 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.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
I didn't know this was that kind of a podcast.

Andrew Huberman:
No. Well, the reason I-

Dr. Charles Zuker:
I'm going.

Andrew Huberman:
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.

Dr. Charles Zuker:
Uh-huh.

Andrew Huberman:
And she said: "What do you think it is, this thing of chemistry?" So maybe she was trying to, you know-

Dr. Charles Zuker:
Warn you-

Andrew Huberman:
Right

Dr. Charles Zuker:
... of what's coming.

Andrew Huberman:
Warn me 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 it 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-

Dr. Charles Zuker:
Because you just didn't like it

Andrew Huberman:
... but because it just didn't like it.

Dr. Charles Zuker:
But that's because you associate it with other odors-

Andrew Huberman:
Mm-hmm

Dr. Charles Zuker:
... that-

Andrew Huberman:
Mm-hmm

Dr. Charles Zuker:
... trigger that negative aversive reaction, by the way.

Andrew Huberman:
Absolutely. There are certain perfumes to me that are aversive.

Dr. Charles Zuker:
You got it.

Andrew Huberman:
And there are other scents in-

Dr. Charles Zuker:
Mm-hmm

Andrew Huberman:
... 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.

Dr. Charles Zuker:
Of course, a mother.

Andrew Huberman:
Of course.

Dr. Charles Zuker:
Us.

Andrew Huberman:
Men, too. Yeah, of course.

Dr. Charles Zuker:
Our own babies-

Andrew Huberman:
Of course

Dr. Charles Zuker:
... when they're in their necks, that's the magical place.

Andrew Huberman:
Their neck.

Dr. Charles Zuker:
The back of their neck.

Andrew Huberman:
There you go.

Dr. Charles Zuker:
Oh my goodness. I have a grandchild now, so I know exactly what Rio, that's his name, smells like.

Andrew Huberman:
Okay. So more beautiful examples. It's always more fun to think-

Dr. Charles Zuker:
Yeah

Andrew Huberman:
... about the beautiful, positive, the appetitive-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... examples.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
The smell of the back of your grandson's neck.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
You could get more specific than that, but not a lot more specific.

Dr. Charles Zuker:
Exactly.

Andrew Huberman:
So what is going on in terms of the combination of odor and taste, given that these two systems are so different?

Dr. Charles Zuker:
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 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 meaningful scientific answers. 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 multi-sensory 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 time out. Now the mice are thirsty, so they're very motivated to perform, and if you repeat this task 100 times, 100 trials, incredibly enough, this animal learn 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 him 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 him, 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?

Andrew Huberman:
Makes sense.

Dr. Charles Zuker:
Now 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-sensory 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 animal 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?

Andrew Huberman:
The brain is basically a series of engineered circuits. Complex.

Dr. Charles Zuker:
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.

Andrew Huberman:
And why certain people's breath tastes so good and other people's-

Dr. Charles Zuker:
Exactly.

Andrew Huberman:
... not so good.

Dr. Charles Zuker:
So I never answered that, but I told you how we can figure out where in the brain it's happening. Okay?

Andrew Huberman:
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 phenomena. 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

Dr. Charles Zuker:
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.

Andrew Huberman:
Impossible.

Dr. Charles Zuker:
Exactly.

Andrew Huberman:
Oh, my.

Dr. Charles Zuker:
So where does this desensitizing happens? That's the term that we use. 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.

Andrew Huberman:
But for sake of this discussion, that's fine.

Dr. Charles Zuker:
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. There is 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 thalamus, then to the cortex. So there are multiple steps that this signal is traveling. Now you might say, "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 going to 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. Our electrolyte balance requires salt. Every one of the neurons uses salt as the most important of the ions, 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'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.

Andrew Huberman:
And presumably, if one is hungry enough, even uni will taste good. Just to me.

Dr. Charles Zuker:
You hit it right on the money. 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 going to 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, eh? 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 at each step you give the system that level of flexibility or what we call in neuroscience, plasticity.

Andrew Huberman:
I think we're headed into the gut.

Dr. Charles Zuker:
All right.

Andrew Huberman:
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.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
Mm-hmm.

Andrew Huberman:
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-

Dr. Charles Zuker:
Is there a taste of no taste?

Andrew Huberman:
Right. Is there a taste of no taste? Because in the visual system there is.

Dr. Charles Zuker:
Mm-hmm.

Andrew Huberman:
Right? You close the eyes, and you start getting increases in activity-

Dr. Charles Zuker:
Mm-hmm

Andrew Huberman:
... in the visual system-

Dr. Charles Zuker:
Mm-hmm

Andrew Huberman:
... 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-

Dr. Charles Zuker:
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.

Andrew Huberman:
Well, but-

Dr. Charles Zuker:
I know. I'm just being playful.

Andrew Huberman:
Yeah, I know you're being playful. And I knew when inviting you here today, I was setting myself up for... I actually, on a different-

Dr. Charles Zuker:
We're trying to learn things.

Andrew Huberman:
Yeah, I know.

Dr. Charles Zuker:
However-

Andrew Huberman:
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 Fridman 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 a 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.

Dr. Charles Zuker:
Of course.

Andrew Huberman:
It's a sign of love.

Dr. Charles Zuker:
Exactly.

Andrew Huberman:
He's going to tell me that.

Dr. Charles Zuker:
And it's always about the science in the end.

Andrew Huberman:
Right. But-

Dr. Charles Zuker:
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-

Andrew Huberman:
Here, let me tell you why I'm asking.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
And then I'll offer an experiment-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... that I'd love to see someone in your lab do.

Dr. Charles Zuker:
Excellent.

Andrew Huberman:
I'm thinking about saliva.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
Which it's-

Dr. Charles Zuker:
No. But that we know. That we can figure it out easily.

Andrew Huberman:
Right. 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-

Dr. Charles Zuker:
It's not

Andrew Huberman:
... the sensitivity of the receptors.

Dr. Charles Zuker:
That experiment has been done. No.

Andrew Huberman:
It has been done.

Dr. Charles Zuker:
Yeah.

Andrew Huberman:
And so the answer is no.

Dr. Charles Zuker:
It's no. Yeah, and the way you could do the experiment is because we use artificial saliva.

Andrew Huberman:
There's such a thing? I know there's artificial tears, but...

Dr. Charles Zuker:
No, we, I don't mean that you go to Walgreens and you get... I mean, we in my laboratory.

Andrew Huberman:
Mm-hmm.

Dr. Charles Zuker:
We know the composition of saliva, and so you can make such a thing.

Andrew Huberman:
Mm-hmm.

Dr. Charles Zuker:
And you can take 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. Yeah? And there is no difference on the state of the animal.

Andrew Huberman:
Great. Well, this is the reason to do experiments.

Dr. Charles Zuker:
Yeah, absolutely.

Andrew Huberman:
So it doesn't defeat any grand hypothesis.

Dr. Charles Zuker:
Yeah, no.

Andrew Huberman:
It's just a pure curiosity. So-

Dr. Charles Zuker:
You know that curiosity killed the cat, yeah?

Andrew Huberman:
I do.

Dr. Charles Zuker:
Go on.

Andrew Huberman:
But saves the career of a scientist.

Dr. Charles Zuker:
Yeah. Of course.

Andrew Huberman:
Every single time.

Dr. Charles Zuker:
That's what drives us. Absolutely.

Andrew Huberman:
Every single time.

Dr. Charles Zuker:
It's the story of our lives.

Andrew Huberman:
Exactly. Okay.

Dr. Charles Zuker:
Very good.

Andrew Huberman:
So if it's not saliva, and apparently it is not, what about internal state? And what aspects of the internal milieu are relevant? Because there's autonomic, there's asleep and awake.

Dr. Charles Zuker:
Absolutely.

Andrew Huberman:
There's stress.

Dr. Charles Zuker:
Totally.

Andrew Huberman:
One of the questions that I got 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 elements?

Dr. Charles Zuker:
Because it makes us feel good. By the way, we'll get to that.

Andrew Huberman:
It's soothing.

Dr. Charles Zuker:
That's the answer.

Andrew Huberman:
Soothing.

Dr. Charles Zuker:
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 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.

Andrew Huberman:
Well, no, I would like to discuss the most basic elements of internal state.

Dr. Charles Zuker:
Mm-hmm.

Andrew Huberman:
In particular, the ones that are below our conscious detection. And this is, of course, as I segue into this incredible landscape, which is the gut-brain axis. Which I think 15 years ago was almost a, maybe it was a-

Dr. Charles Zuker:
Unheard of

Andrew Huberman:
... couple posters at a meeting, and then now I believe you and others, there are companies. There have companies, there are active research programs, and beautiful work.

Dr. Charles Zuker:
Mm-hmm.

Andrew Huberman:
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"-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... aspect. But I'd love for you to talk about the aspects of gut-brain signaling that drive or change our perceptions and behaviors that are completely beneath our awareness.

Dr. Charles Zuker:
Yes. Excellent. So let me begin maybe by stating that 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 associative conditioning, he would take a bell, he 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, neurologically speaking, an anticipatory response. Okay, I could understand it. I get it. 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 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?

Andrew Huberman:
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.

Dr. Charles Zuker:
How? Yeah, all right.

Andrew Huberman:
It's amazing.

Dr. Charles Zuker:
Now, over the past 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 has been uncovered as being what we now refer to as the gut-brain axis, and the highway is a specific bundle of nerves which emerge from the vagal ganglia, the nodose 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."

Andrew Huberman:
And I should point out, as you well know, every organ, spleen, pancreas, lungs-

Dr. Charles Zuker:
They all must be monitored. In fact, I now, I have no doubt that diseases that we have normally 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.

Andrew Huberman:
I do as well.

Dr. Charles Zuker:
Yeah. And so this view that we have been working on for the longest time because the molecules that we're dealing with are in the body, not in the head, 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?

Andrew Huberman:
Please. Please. The vagus nerve, 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. There are calming pathways of 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.

Dr. Charles Zuker:
You got it.

Andrew Huberman:
I just wanted to just mention that because I think a lot of people have heard about the vagus. 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.

Dr. Charles Zuker:
Well, and also, of course, one has to be cautious there in that. So the vagus nerve is made out of many thousands of fibers, 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. 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. 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.

Andrew Huberman:
Little stimulator.

Dr. Charles Zuker:
Epileptic seizures. But again, there are thousands of fibers carrying different functions. So to some degree, 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 where, and so I'm lucky enough that one of them happened to point to my site. So here you activate the bundle of 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 epileptics. 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 Liberles 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?

Andrew Huberman:
What's the latest there, just as a brief update? I know Steven Liberles 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.

Dr. Charles Zuker:
First of all, I'm happy you didn't because that way you can focus on this amazing podcast.

Andrew Huberman:
Well, thank you. That's very gracious of you. It always feels better, if not good, to get beat out by excellent people. Steven is second to none, and he is defining, as you said, the molecular constituents of different elements of these many fibers. Is there an update there? Are they finding multiple parallel pathways?

Dr. Charles Zuker:
They are. Some that control heartbeat, some that control the respiratory cycle, some that might be involved in gastric movement. This notion that you're 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.

Andrew Huberman:
Fantastic.

Dr. Charles Zuker:
Yeah.

Andrew Huberman:
So the textbooks will soon change on the basis of the Liberlese and other work.

Dr. Charles Zuker:
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. The example I gave you before with Pavlov's dog. All right? I figure out 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. Let me tell you about the gut-brain axis and our insatiable appetite for sugar and fat. Insatiable for sugar, unquenchable 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 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 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 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."

Andrew Huberman:
So it prefers sugar to artificial sweetener?

Dr. Charles Zuker:
No.

Andrew Huberman:
No?

Dr. Charles Zuker:
No.

Andrew Huberman:
Equally artificial s-

Dr. Charles Zuker:
In this experiment-

Andrew Huberman:
Mm-hmm

Dr. Charles Zuker:
... I'm going to put only sweet in one bottle, and it could be either sugar or artificial sweetener. It doesn't matter which one. Okay? We're going to do the next experiment where we separate those two. For now, it's sweet versus water.

Andrew Huberman:
Okay.

Dr. Charles Zuker:
And sweet means sweet, not sugar. Sweet means anything that tastes sweet. All right? And sugar is one example, and Splenda is another example.

Andrew Huberman:
Aspartame, monk fruit-

Dr. Charles Zuker:
You got it. All right

Andrew Huberman:
... stevia.

Dr. Charles Zuker:
Yeah. You give-

Andrew Huberman:
Doesn't matter.

Dr. Charles Zuker:
Yeah. There's some that only humans can taste, mice cannot taste.

Andrew Huberman:
Interesting.

Dr. Charles Zuker:
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 lick to no end from the sweet side, 10 to one at least versus the water. Make sense? All right. 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 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?

Andrew Huberman:
Makes sense.

Dr. Charles Zuker:
Very good. Now, we're going to do the experiment with sugar. From now on, let's focus on sugar. So I'm going to give a mouse now sugar versus water. Normal mouse will 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 they 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? It 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. Okay? The sidness in which the bottle is in the cage. It doesn't matter what, but the mouse realize 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.

Andrew Huberman:
From other neurons.

Dr. Charles Zuker:
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 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.

Andrew Huberman:
And are these neurons in the gut? Are they-

Dr. Charles Zuker:
So these are not neurons in the gut. So these are gut cells that recognize the sugar molecule-

Andrew Huberman:
I see

Dr. Charles Zuker:
... send a signal, and that signal is received by the vagal neuron directly.

Andrew Huberman:
Got it.

Dr. Charles Zuker:
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 brainstem to now trigger the preference for sugar.

Andrew Huberman:
Two questions.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
One, you mentioned that these cells that detect sugar within the gut are actually within the intestine. You didn't say-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... stomach.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
Which surprised me. I always think gut as stomach, but of course-

Dr. Charles Zuker:
I know. No

Andrew Huberman:
... intestines.

Dr. Charles Zuker:
They're intestine because that's where all the absorption happens.

Andrew Huberman:
Got it.

Dr. Charles Zuker:
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.

Andrew Huberman:
Mm-hmm.

Dr. Charles Zuker:
And 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 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.

Andrew Huberman:
Because their nutrient value is uncoupled from the taste.

Dr. Charles Zuker:
Generically speaking, one can make that bet. It's because it's a very different type of receptor.

Andrew Huberman:
I see.

Dr. Charles Zuker:
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 have failed in the market to curb our appetite, our 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."

Andrew Huberman:
So the issue of wanting-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... can we relate that to a particular set of neurochemicals upstream of... So the pathway is glucose is activating these cells in the gut, through the vagus, that's communicated through presumably the nodose ganglion and up into the brainstem.

Dr. Charles Zuker:
Very good.

Andrew Huberman:
And-

Dr. Charles Zuker:
And from there, where does it go?

Andrew Huberman:
Yeah. Where does it go, and what is the substrate of wanting? Of course, I think molecules like dopamine, craving. There's a book even called "The Molecule of More," 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?

Dr. Charles Zuker:
Yeah. 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. How nuts is that? Historically, diseases of malnutritions have always been linked to undernutrition. 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, 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.

Andrew Huberman:
So that immediately raises the question, are the receptors for glucose in these gut cells susceptible to other things that are healthier for us?

Dr. Charles Zuker:
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.

Andrew Huberman:
I could be wrong about this-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... and I'm happy to be wrong.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
I'm often wrong.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
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.

Dr. Charles Zuker:
Yeah, and you're not reinforcing those circuits. And so you, in essence, are removing yourself. But you tend to be the exception. We have a huge, incredibly large number of people that are being continuously exposed to highly processed foods, yeah?

Andrew Huberman:
And so-called hidden sugars.

Dr. Charles Zuker:
They don't even have to be hidden. It's right there.

Andrew Huberman:
Hiding in plain sight. Yeah, I agree. So much is made of hidden sugars that we often overlook that there are also the overt sugars.

Dr. Charles Zuker:
Yeah. 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 want to 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, animals evolve these two systems. One is the taste system that allows you to recognize them and trigger these predetermined, hardwired, immediate responses. Yes? "Oh my goodness, this tastes so good. It's so sweet." I personally have a sweet tooth, may I add. And, "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, and they're not needed in your tongue. They are needed in your intestines where they are going to be absorbed as the nutrients that will support life. And the brain wants to know this, and it wants to know it in a way that it can now form the association between that that I just tasted ... is what gut 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?

Andrew Huberman:
We're on.

Dr. Charles Zuker:
All right.

Andrew Huberman:
One thing that intrigues me and puzzles me-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... is that this effect took a couple of days, at least in mice.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
And the sensation, sorry, the perception of taste-

Dr. Charles Zuker:
Yes, is immediate

Andrew Huberman:
... is immediate, and yet this is a slow system. And so in a beautiful way, but in a kind of mysterious way-

Dr. Charles Zuker:
Why?

Andrew Huberman:
... the brain is able to couple the taste of a sweet drink-

Dr. Charles Zuker:
Yes

Andrew Huberman:
... 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-

Dr. Charles Zuker:
Totally

Andrew Huberman:
... smelling other people. That's incredible.

Dr. Charles Zuker:
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 change in many of these hardwire circuits. So forget us 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 continued reinforcement given that I can taste it in a second? You want to 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 want to identify rich sources of sugar, and if the system simply responds immediately to the first sugar that gets to your gut, you're going to form the association with those sources of food, which are not the ones that you should be eating from.

Andrew Huberman:
Don't fall in love with the first person you encounter.

Dr. Charles Zuker:
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 want to form the association before. And so, when we remove it from the context of we now 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 these 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."

Andrew Huberman:
You've just forever changed the way that I think about supermarkets and restaurants. 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.

Dr. Charles Zuker:
Look, I'm not going to make a judgment call there because they do serve an important purpose.

Andrew Huberman:
I like restaurants, too.

Dr. Charles Zuker:
Yeah. And so do supermarkets, thank God. I think they're not the culprits. I think the culprits, of course, are our reliance on foods that are not necessarily healthy. Now, going back to the supermarket, the don't fall in love with the first, they need to work. You take a tangerine, and you take an extract of tangerine that you used to cook that's spiked, 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 going to 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, processed sugar, to use it now to cook, to add, to make a 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 than when I take this processed, highly extracted tangerine. By the way, I used tangerines because I had a tangerine just before I came here.

Andrew Huberman:
Delicious. They are delicious.

Dr. Charles Zuker:
And so this goes back to the issue of supermarkets. And so to some degree, A, given a choice, you don't want to eat 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 these circuits in a way that they're being activated at a timescale that normally wouldn't happen.

Andrew Huberman:
Well, 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.

Dr. Charles Zuker:
Absolutely. Look, we have a lot of work to do. I'm talking as a society. I'm not talking about you and I.

Andrew Huberman:
We also have a lot of work to do.

Dr. Charles Zuker:
Now. I think understanding these circuits is giving us important insights on 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 these circuits operate can ultimately inform how we deal with our diets in a way that we avoid what we're facing now as a society. It's nuts that overnutrition happens to be such a prevalent problem.

Andrew Huberman:
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.

Dr. Charles Zuker:
Yeah.

Andrew Huberman:
But I fully agree that the brain is the key, or the nervous system, to be more accurate-

Dr. Charles Zuker:
More accurate

Andrew Huberman:
... is one of the key overlooked features.

Dr. Charles Zuker:
It's the arbiter. Ultimately, it's the arbiter of many of these pathways.

Andrew Huberman:
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?

Dr. Charles Zuker:
Oh my goodness.

Andrew Huberman:
Taste, I should say.

Dr. Charles Zuker:
Yes.

Andrew Huberman:
Taste. To distinguish between taste and the nutritive value or lack thereof.

Dr. Charles Zuker:
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. Rather than the food itself, to me it's the whole thing. Look, there've been these experiments done in psychophysics. I'm going to take a salad made out of 11 components, and I'm going to mix them all up in a potpourri of greens and other things here. And then the other one, I'm going to present it in a beautiful arrangement, and then I'm going to put it behind a glass cabinet and I'm going to sell them. And I'm going to sell one for $2 and one for $8. Precisely the same ingredient, exactly the same amount of each. Ultimately, you're going to mix them, they're all going to be the same, and people will pay the $8 because, you know what? It evokes a different person. It gives you the feel that, oh my goodness, I'm going to enjoy that salad. So going back to what is my favorite food. To me, eating is really a sensory journey. I don't mean every day, let me have some chicken wings because I'm hungry. But every piece, I think, has an important evoking sensory role. And so in terms of categories of food, I grew up in Chile, so meat has always been... But I eat it so seldom now.

Andrew Huberman:
Is that right?

Dr. Charles Zuker:
Yeah, because I know that it's not necessarily the healthiest thing. Red meat I'm talking about, yeah? And so I grew up eating it every day. I'm talking seven days a week. Chili in Argentina, that's the mainstay of our diet, eh? Now maybe I have red meat, I know, once every four weeks.

Andrew Huberman:
And you enjoy it.

Dr. Charles Zuker:
Oh, I love it. Part of it is because I haven't had it in four weeks, eh? But I love sushi, but I love the art of sushi, eh? The whole thing, the way it's presented, it changes the way you taste it. I love ethnic food, in particular.

Andrew Huberman:
You're in the right place.

Dr. Charles Zuker:
You got it. That was the main reason I wanted to come to New York. No, I'm just kidding.

Andrew Huberman:
There's also that Columbia University that's-

Dr. Charles Zuker:
I came here because I wanted to be with people that are thinking about the brain the same way that I like to think, which, can we solve this big problem, this big question?

Andrew Huberman:
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.

Dr. Charles Zuker:
It was great fun. Thank you for having me.

Andrew Huberman:
We'll do it again.

Dr. Charles Zuker:
I like. We shall.

Andrew Huberman:
Thank you for joining me today for my discussion about perception, and in particular, the perception of taste with Dr. Charles Zuker. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please subscribe to the podcast on Spotify and Apple. And on Spotify and Apple, you can leave us up to a five-star review. If you have feedback for us in terms of comments related to topics we've covered or questions or topics or guests that you'd like us to cover on future episodes of the Huberman Lab Podcast, please put those in the comments section on YouTube. We do read all the comments. On today's episode of the Huberman Lab Podcast, we didn't talk about supplements, but on many previous episodes of the Huberman Lab Podcast, we talk about supplements that are useful for sleep, for focus, for hormone support, and other aspects of mental health, physical health, and performance. If you're interested in some of those supplements, you can go to livemomentous.com/huberman to see the catalog of supplements that we've helped them formulate and that map directly onto specific protocols described on the Huberman Lab Podcast. Again, that's livemomentous.com/huberman. If you're not already following us on social media, we are hubermanlab on Twitter and hubermanlab on Instagram. And at both Twitter and Instagram, I cover science and science-related tools, some of which overlap with the content of the Huberman Lab Podcast, but much of which is distinct from the information contained in the Huberman Lab Podcast. We also have a newsletter in which we spell out protocols and some summaries from previous podcast episodes. If you'd like to check those out, you can go to hubermanlab.com, go to the menu, and you'll find the Neural Network Newsletter. You can sign up for that newsletter simply by providing an email. It's completely zero cost. We have a very strict privacy policy. We do not share your email with anybody. Again, that's hubermanlab.com. Go to the menu and look for the Neural Network Newsletter. And if you'd like examples of previous newsletters, you'll also find those at hubermanlab.com. Once again, thank you for joining me today in my discussion with Dr. Charles Zuker about the biology of perception and the biology of the perception of taste in particular. I hope you found that discussion to be as enriching as I did. And last but certainly not least, thank you for your interest in science.