Huberman LabThe Biology of Taste Perception & Sugar Craving | Dr. Charles Zuker
EVERY SPOKEN WORD
150 min read · 30,454 words- 0:00 – 3:05
Dr. Charles Zuker & Taste Perception
- AHAndrew Huberman
(Upbeat music) 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
- 3:05 – 4:35
Momentous Supplements
- AHAndrew Huberman
life experience. I'm pleased to announce that the Huberman Lab Podcast is now partnered with Momentous supplements. We often talk about supplements on the Huberman Lab Podcast, and while supplements aren't necessary for everybody, many people derive tremendous benefit from them, for things like enhancing the quality and speed with which you get into sleep, or for enhancing focus, or for hormone support. The reason we partnered with Momentous supplements is several-fold. First of all, their supplements are of the absolute highest quality. Second of all, they ship internationally, which is important because many of our podcast listeners reside outside the US. Third, many of the supplements that Momentous makes, and most all of the supplements that we partnered with them directly on, are single-ingredient formulations. This is important for a number of reasons. First of all, if you're going to create a supplement protocol that's customized for your needs, you want to be able to figure out which supplement ingredients are most essential and only use those, and supplements that combine lots of ingredients simply won't allow you to do that. So, in trying to put together a supplement protocol for yourself that's the most biologically effective and cost-effective, single-ingredient formulations are going to be the most useful. If you'd like to see the supplements that we partnered with Momentous on, you can go to livemomentous.com/huberman, and there, you'll see many of the supplements that we've talked repeatedly about on the Huberman Lab Podcast episodes. I should mention that the catalog of supplements that are available at livemomentous.com/huberman is constantly being expanded, so you can check back there, livemomentous.com/huberman, to see what's currently available, and from time to time, you'll notice new supplements being added to the inventory. Before
- 4:35 – 8:35
Thesis, ROKA, Helix Sleep
- AHAndrew Huberman
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. Our first sponsor is Thesis. Thesis makes custom nootropics, and for frequent listeners of this podcast, you may remember that I'm not a big fan of the word nootropics because the word nootropics means smart drugs or smart compound. And the reason I don't like that phrase is that the brain has many different circuits that it uses in order to perform things like focus, or task switching, or creativity. So, the idea that there's a single thing that we would call a smart drug is simply not in concert with the biology. Well, Thesis understands this, and as a consequence, has developed custom nootropic formulations that are tailored to your unique needs. So for instance, Thesis will allow you to try different blends over the course of a month and determine which blends of specific ingredients work best for you to focus or for you to gain motivation and energy for workouts or for cognitive work of some sort. I've been using Thesis custom nootropics for well over six months now, and they completely transform the way that I do cognitive work, and indeed, the way that I do physical fitness. If you want to try your own personalized nootropic starter kit, you can go online to takethesis.com/huberman. There, you'll just do a brief three-minute quiz, and Thesis will send you four different formulas to try in your first month. That's takethesis.com/huberman, and use the code "Huberman" at checkout to get 10% off your first box. Today's episode is also brought to us by ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind and with the biology of the visual system in mind.I've spent my lifetime working on the visual system, and I can tell you that your visual system has to contend with a number of very important challenges in order to be able to see the world around you clearly, things like adjusting for background illumination so that when you go from a sunny area to a shady area, you can see what's in front of you still with crystal clarity. ROKA takes all of that into account when designing their eyeglasses and sunglasses. Their eyeglasses and sunglasses also have some unique qualities. For instance, because they were d- initially designed for performance, with things like running and cycling, if you get sweaty, they won't fall off your face. Also, they're extremely lightweight. In fact, most of the time, I don't even remember that I'm wearing them. I wear ROKA eyeglasses at night, so I wear readers, and I wear sunglasses often during the day if it's very bright or if I'm driving. If you'd like to try ROKA eyeglasses and sunglasses, you can go to ROKA, that's roka.com, and enter the code Huberman to save 20% off your first order. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are uniquely tailored to your sleep needs. I've talked repeatedly about the fact that sleep is the foundation of mental health, physical health, and performance. So getting adequate deep sleep is absolutely essential. Now, one of the key things to getting a great night's sleep is to make sure that the surface that you're sleeping on is the right one for you. Helix understands this, and they've created a sleep quiz. That is, you go to their website, and you fill out a brief quiz that asks questions like, do you sleep on your side, your back, your stomach? Do you tend to run hot or cold during the night? Maybe you don't know the answers, in which case you simply say you don't know. By taking that quiz, they will match you to a mattress that is ideal for your sleep needs. I took that quiz, and I matched to the so-called Dusk, D-U-S-K, mattress, and I've been sleeping on that mattress for some time now, and it's the best sleep that I've ever had. So if you're interested in upgrading your mattress to one that's uniquely tailored to your sleep needs, you can go to helixsleep.com/huberman, take their two-minute sleep quiz, and they'll match you to a customized mattress. And you'll get up to $200 off any mattress order and two free pillows. They have a 10-year warranty, and you get to try out that mattress for 100 nights risk-free. They'll even pick it up for you if you don't love it, but I do believe that you will love it, because you'll be sleeping far better than you have before. Again, if you're interested, you can go to helixsleep.com/huberman to get up to $200 off and two free pillows. And now for my discussion with Dr. Charles
- 8:35 – 11:48
Sensory Detection vs. Sensory Perception
- AHAndrew Huberman
Zucker. Charles, thank you so much for joining me today.
- CZCharles Zuker
My pleasure.
- AHAndrew 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? And, 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?
- CZCharles Zuker
So, you know, 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. Eh, it- it- it- it- it- it make, it- it changes, it transforms, you know, fear into courage, conformity into creativity, sadness into happiness. How- how- how the hell does that happen? Now, the challenge that the brain faces is that the world is made of real things. You know, this here is a glass, and this is a cord, and this is a microphone. But the brain is only made of neurons that only understand electrical signals. So how do you transform that reality into nothing that electrical signals that now need to represent the world? And that process is we can, is what we can operationally define as perception. In the senses, let's say olfactory, odor, taste, vision, you know, we can very straightforwardly separate detection from perception. Detection is what happens when you take a sugar molecule, you put it in your tongue, and then a set of specific cells now sense that sugar molecule. That's detection. You haven't perceived anything yet. That is just your cells in your tongue interacting with this chemical. But now that cell gets activated and sends a signal to the brain, and now detection gets transformed into perception. And it's trying to understand how that happens that's been the- the maniacal drive, eh, 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?
- AHAndrew Huberman
Absolutely, and is a very clear
- 11:48 – 16:20
Individual Variations within Perception, Color
- AHAndrew Huberman
and beautiful description. A sort of high-level question related to that-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... and then I think we can get into some of the, uh, intermediate steps.
- CZCharles Zuker
Yes.
- AHAndrew 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-
- CZCharles Zuker
What an excellent-
- AHAndrew Huberman
... of the color of your shirt.
- CZCharles Zuker
... question. Am I okay to interrupt you as you're, as I'm guessing what you're going? All right, very good.
- AHAndrew Huberman
Interruption is welcome on this podcast.
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
The audience will always penalize me for interrupting you-
- CZCharles Zuker
Good.
- AHAndrew Huberman
... and will never penalize you for interrupting you.
- CZCharles Zuker
I like the one-way penalizing.
- AHAndrew Huberman
(laughs)
- CZCharles Zuker
(laughs) Now, given what I told you before-... that the brain is trying to represent the world based in nothing but the transformation of these signals into electrical, you know, 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 perceiving the same sensory cues. Okay? And I'll tell you about an experiment, it's a simple experiment, yet brilliant, that demonstrates why we perceive the world, how we perceive the world different. So, in the world of vision, as you know... well, well know, we have three classes of photoreceptor neurons that sends three basic colors, red, blue, and green. E- or blue, green, and red, if we go, you know, 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 with one into a white screen, eh, red light, and the other one green light. I'm going to overlap the two beams, and on the screen there'll be yellow. Okay. This the superposition when you have two beams of r- 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 intensity knobs so that you can match that yellow that you're projecting to the spectrally pure next to it. Is this making sense?
- AHAndrew Huberman
Perfect sense.
- CZCharles 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.
- AHAndrew Huberman
Amazing.
- CZCharles 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 differently. Okay? And so I think that simple psychological experiment beautifully illustrates how we truly perceive the world differently.
- AHAndrew 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-
- CZCharles Zuker
Sound.
- AHAndrew Huberman
... sound or olfaction.
- CZCharles 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 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, you know, features, yeah, or other determinants. But no question that your experience is different than
- 16:20 – 20:19
Perceptions & Behaviors
- CZCharles Zuker
mine.
- AHAndrew 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 (laughs) both to survive-
- CZCharles Zuker
Yes. You got it.
- AHAndrew 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, uh, 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.
- CZCharles Zuker
Yeah.
- AHAndrew Huberman
What do you think about... I- I'm not looking to establish a debate between you and Marcus-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... without Marcus here.
- CZCharles Zuker
I, I, I, I understand, yeah.
- AHAndrew Huberman
But what I like about that is that it seems like the... 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-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... death and cliffs and, uh, eating poisons and so forth, and to enjoy some aspects of life, one hopes.
- CZCharles Zuker
Yes.
- AHAndrew Huberman
So, is there a general statement that we can make about the brain, not just as a, uh, organ to generate perception, not just as an organ to keep us alive, but also an organ that is, is trying to batch our behaviors into general categories of, of outcome?
- CZCharles Zuker
I, I think, I think so, but, but... And again, I think the world of, of Marcus too, and I think he's right that, you know, broadly speaking, you could categorize a lot of behaviors falling into those three categories, and that's 100% likely to be the case for animals in the wild, where, you know, the choices are not necessarily binary, but they're very unique and distinct, yeah?... 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, you know, learned to experience life where we do things that we should not be doing.
- AHAndrew Huberman
Some of us more than others.
- CZCharles Zuker
Exactly. You know, in- in- in- in- in my own world of taste, yeah, the likelihood that an animal in the wild will enjoy eating something bitter, it's inconceivable. Yet we, you know, love tonic water. We enjoy, we like living on the edge. We, we, and love enjoying experiences that makes us human, and that goes beyond that simple set of categories which is yummy, yucky, eh, who cares? Yeah. And so I- I think it's not a bad palate, but I think it's- it- it's overly reductionist for certainly what we humans do.
- AHAndrew Huberman
I agree. And, um, since we're here in New York, I can say with the- 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.
- 20:19 – 26:18
The 5 Taste Modalities
- AHAndrew Huberman
Let's talk about taste, because while you've done extensive work in the field of vision, and it's a topic that I love, 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.
- CZCharles Zuker
My goal has always been to understand, as I highlighted before, how the brain does its magic. You know, what part you might wonder. Ideally, I like to help contribute to understand all of it. You know, how- 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. Yeah. 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.
- AHAndrew Huberman
From a first person perspective, yes.
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
The- the hardest question, the most important question is what are you going, what question are you going to try and answer?
- CZCharles Zuker
You got it. Yeah.
- AHAndrew Huberman
Right.
- CZCharles Zuker
And so, and so for example, you know, I will have to understand the neural basis of empathy.
- AHAndrew Huberman
There's a big market for that. (laughs)
- CZCharles Zuker
100%. But- but I wouldn't even know, I- I mean, at the molecular level, yeah, 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'd 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 get me answers. And among the senses that, you know, have the capacity of transforming detection into perception, of being stored as memories, of creating emotions, of giving you different- the- the- the- different actions and perceptions as a function of the internal state. You know, 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- so if I want to begin to explore all of these things that the brain does, I feel I have to choose a sensory system that affords some degree of simplicity in the way that the input-output relationships are put together, and in a way that still can be used to ask every one of these problems that the brain has to ultimately compute, encode, and decode. And what was remarkable about the taste system at the time that I began working on this is that nothing was known about the molecular basis of taste. You know, we knew that we could taste what has been usually defined as the ba- the five basic taste qualities, sweet, sour, bitter, salty, and umami. Umami is a Japanese word that means yummy, delicious, and that's, and nearly every animal species, the taste of amino acids.... and in humans is mostly associated with the taste of MSG, monosodium glutamate, one amino acid in particular.
- AHAndrew Huberman
What are, e- g- just by way of example, some foods that are rich in the umami-evoking, uh, stimulation?
- CZCharles Zuker
Seaweed, tomatoes, cheese-
- AHAndrew Huberman
Eh?
- CZCharles Zuker
... and it's a great, great flavor enhancer. It enriches our sensory experience. And so the beautiful thing of the system is that the lines of input are limited to five. You know, sweet, sour, bitter, salty, and umami, and each of them has a predetermined meaning. You are born liking sugar and disliking bitter. You have no choice. These are hardwired systems. But of course, you can learn to dislike sugar and to like bitter, see? But in the wild, let's take humans out of the equation, eh, these are 100% predetermined. You're born with that specific valence, value for each taste, of sweet, umami, and low salt are attractive taste qualities. They evoke appetitive responses, "I want to consume them." And bitter and sour are innately predetermined to be aversive.
- 26:18 – 28:00
Aversive Taste, Bitter Taste
- AHAndrew Huberman
Could I interrupt you just briefly-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... and ask a question about that exact point?
- CZCharles Zuker
Yes.
- AHAndrew 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?
- CZCharles 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 at, 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, right? And that entire thing happens by the activation of a bitter molecule in a bitter-sensing cell in your tongue.
- AHAndrew Huberman
It's incredible.
- CZCharles Zuker
There is r- it's, it's, it's again, the magic of the brain, you know, how, how it, it's able to encode and decode these extraordinary actions and behaviors in response of nothing but a simple very s- you know, a, a unique sensory stimuli. Now, let me say that this
- 28:00 – 30:14
Survival-Based & Evolutionary Reasons for Taste Modalities, Taste vs. Flavor
- CZCharles Zuker
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 and other essential nutrient, salt, the three appetitive ones to ensure that we maintain our electrolyte balance, bitter to prevent the ingestion of toxic, noxious chemicals. Nearly all bitter-tasting, you know, things out in the wild are bad for you. And sour most likely to prevent ingestion of spoil, acid, yeah, 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, eh? But, but we scientists need to reduce the, the problem into its basic elements so we can begin to break it apart before we put it back together. So when we think about the sense of taste and we try to figure out how these lines of information go from your tongue to your brain, and how they signal, and how they get integrated, and how they trigger all these different behaviors, we look at them as individual qualities, eh? So we give the animals 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?
- AHAndrew Huberman
Yeah, almost like the primary colors to create the full array of the color spectrum.
- CZCharles Zuker
You got it. Exactly.
- AHAndrew Huberman
Before I ask you about the
- 30:14 – 34:02
Additional Taste Modalities: Fat & Metallic Perception
- AHAndrew Huberman
n- the first and second and third stages of taste and flavor perception-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... is there any idea that there may be more than five?
- CZCharles Zuker
It, th- there is. For example, eh, what about fat?
- AHAndrew Huberman
I love the taste-
- CZCharles Zuker
I love fat too. (laughs)
- AHAndrew Huberman
... and I love the texture of fat, especially if it's slightly burnt like the, the f- 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.
- CZCharles Zuker
It is.
- AHAndrew Huberman
There's nothing quite like it.
- CZCharles Zuker
Thi- this goes back to this notion before that we like to live on the edge.
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
Yeah. And we like to do things that we should not be doing, Andrew. But on the other hand, look at those muscles. (laughs)
- AHAndrew Huberman
The, uh, the, uh, the, uh...
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
I- I don't suggest anyone eat pure fat.
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
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 in... on a ketogenic diet, et cetera. But, um, but fat is tasty-
- CZCharles Zuker
It is.
- AHAndrew Huberman
... as evidenced by-
- CZCharles Zuker
So-
- AHAndrew Huberman
... the obesity problem that exists in this country.
- CZCharles Zuker
Yeah, we'll, we'll talk about that-
- AHAndrew Huberman
Mm-hmm, yeah.
- CZCharles Zuker
... you know, in a little bit about the, you know, the gut-brain axis. I, I think it'll be important to cover it, because it's the other side of the taste system. And, and so, so missing tastes, you know, one is fat, a- 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, a, a, a, 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.
- AHAndrew Huberman
I love the idea that there is a perception of fat regardless of whether or not there's a dedicated receptor for fat-
- CZCharles Zuker
You got it.
- AHAndrew Huberman
... mostly because it's ma- evoking sensations and imagery of, of the taste of slightly burnt fat.
- CZCharles Zuker
Uh, uh, uh, for, for example. And another one, you know, you could argue is metallic taste. You know, I, I know exactly what it tastes like. You know, if you ask me to explain it, I will have a hard time. You know, what, what are the palettes of that color that can allow me to define it? I, I, I wouldn't be easy, but I know precisely what it tastes like. You know, take a, take a penny, put it in your mouth, and you know what it tastes like, yeah?
- AHAndrew Huberman
Yeah, or blood.
- CZCharles Zuker
Or blood. That's another-
- 34:02 – 39:34
Tongue “Taste Map,” Taste Buds & Taste Receptors
- AHAndrew Huberman
like to touch on next, which is, if you would, describe the sequence of neural events-
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
... leading to a perceptual event of taste, and I'm certain that somewhere in there, uh, 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-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... or elsewhere in the mouth.
- CZCharles Zuker
Yes. So, so let's, let's start by, by, by debunking that, that old tale and myth.
- AHAndrew Huberman
Who came up with that?
- CZCharles Zuker
It, there are many views, but the, 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, something bitter, and glucose, 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, 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's no question that there is a slight bias for some tastes. Like bitter is particularly enriched at the very back of your tongue.... and there is a teleological basis for that, actually a biological basis for that. That's the last line of defense before you swallow something bad. And so let's make sure that the very back of your tongue has plenty of these bad news receptors so that if they get activated, you can trigger a gagging reflex and get rid of this that otherwise may kill you. Okay?
- AHAndrew Huberman
Makes good sense.
- CZCharles Zuker
But, but the notion that, you know, all sweet is in the front and salt is on the side, it- it's not real. And there... Go ahead.
- AHAndrew Huberman
Oh, I was just going to ask, are there... First of all, thank you for dispelling that myth.
- CZCharles Zuker
Mm-hmm. Yes.
- AHAndrew 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.
- CZCharles Zuker
(laughs) Yes.
- AHAndrew Huberman
The other one is, um, are there taste receptors anywhere else in the mouth? Uh, for instance, on the lips?
- CZCharles Zuker
Yeah. The palate. The palate, not the lips. So i- it sits 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.
- AHAndrew Huberman
Hmm. I'll have to pay attention to this the next time I eat something sweet.
- CZCharles Zuker
Yeah. When it, when it- when you pull it up. Yeah?
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
Now, um, the, the, the important thing is that, you know, after the receptors for these five... The, the detectors, the molecules that sends sweet, sour, bitter, salty, 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, salty, 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 pad throughout your oral cavity has receptors for all of the basic taste classes.
- 39:34 – 42:54
Burning Your Tongue & Perception
- CZCharles Zuker
- AHAndrew Huberman
Amazing, and impo- as it turns out, and I'm sure you'll tell us, important in terms of thinking about how the brain computes and codes-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... and decodes this thing we call taste.
- CZCharles Zuker
Yes.
- AHAndrew 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.
- CZCharles Zuker
Horrible.
- AHAndrew Huberman
Horrible. And then disrupting my sense of taste for some period of time afterward.
- CZCharles Zuker
Yes.
- AHAndrew Huberman
When I experienced that phenomenon, that unfortunate phenomenon, have I destroyed taste receptors that regenerate, or have I somehow used temperature to distort the function of the circuit so that I no longer taste the way I did before?
- CZCharles 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, it- that is continuously exposed to everything you could range from the nicest to the most horrible possible things.
- AHAndrew Huberman
Use your imagination. (laughs)
- CZCharles Zuker
(laughs) A- a- and so it- you need to make sure that these cells are always coming back in a way that it can re-experience the world in the right way. And this, there are other organs that have the same underlying logic, okay? Your gut, your intestines are the same way. Amazing. Again, they're receiving everything that you ingest, God forbid what's there, from the spiciest, you know, to the most horrible tastings 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 renew in a very, very fast cycle. Okay? Uh, 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 yourself with tea, they come back, you know, within 20 minutes, 30 minutes, an hour. A- and these cells are not renewing in that, in that timeframe. They're not listening to your needs. They have their own internal clock. Okay? A- and so you are really a- affecting, you're damaging them in a way that they can recover. And then they come back and you also damage your somatosensory cells. These are the cells that feel things, not taste things. Okay? And then, you know, you wait half an hour or so, and then my goodness, thank God, it's back to normal.
- AHAndrew Huberman
And most of the time, I don't even notice the transition, realizing, as you told me, and I'll- later I'll ask you about the relationship between odor and taste.
- 42:54 – 51:55
The “Meaning” of Taste Stimuli, Sweet vs. Bitter, Valence
- AHAndrew Huberman
But, um...... as a next step along the circuit, let's assume I ingest some, l- let's, let's keep it simple, a, a sweet taste.
- CZCharles Zuker
L- let's make it even, eh, 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. (smacks lips) So, the first thing is that the two evoke diametrically opposed behaviors. I- if we have to come up with two sensory experience that represent polar opposites, it will be sweet and bitter. There are not two colors that represent polar opposites because, you know, you could say black and white, they are polar opposites, one detects only one thing, the other one detects everything. I- but they don't evoke different behaviors.
- AHAndrew Huberman
Right.
- CZCharles Zuker
They-
- AHAndrew Huberman
Even political parties have some overlap.
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
(laughs)
- CZCharles Zuker
Sweet and bitter are the two opposite ends of the sensory spectrum. Now, a taste can be defined by two features. A- a- um, again, I'm a reductionist, so I'm reducing it in a way that I, 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, yeah? 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 would 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.
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
In the case of bitter, again, it has, on the one hand, its identity, its quality, and you know exactly what bitter tastes like.
- AHAndrew Huberman
I can taste it now, even as you describe it.
- CZCharles Zuker
But it also has a valence, and that's a negative valence, because it evokes aversive behaviors. Are we on?
- AHAndrew Huberman
Absolutely.
- CZCharles Zuker
All right.
- AHAndrew Huberman
And what comes to mind, I remember telling some kids recently they were going to go get ice cream, and it was interesting. They looked up, and they started smacking their lip, like, you know, they'll actually evoke the-
- CZCharles Zuker
The anticipatory response, absolutely. Yeah, when we talk about the gut-brain, maybe we'll get there. If, 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. Uh-
- AHAndrew Huberman
Where do they sit approximately? Are there sort of-
- CZCharles Zuker
Around there, yeah.
- AHAndrew Huberman
Yeah, right here, around there?
- CZCharles Zuker
Yeah.
- AHAndrew Huberman
The lymph nodes, more or less?
- CZCharles Zuker
You got it. And, and, and there are two main ganglia that innervate the vast majority of all taste buds in the oral cavity. And then from there, that sweet signal goes onto the brain stem. The brain stem is the entry of the body into the brain, and there are different areas of the brain stem, and there are different groups of neurons in the brain stem, and there's this unique area, in a unique, eh, eh, eh, topographically defined, eh, location in the rostral side of the brain stem that receives all of the taste input.
- AHAndrew Huberman
A very dense area of the brain.
- CZCharles 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.
- AHAndrew Huberman
And how quickly does that all happen?
- CZCharles Zuker
Um, you know, the time scale of the nervous system, it's fast, yeah? And so-
- AHAndrew Huberman
Within, within less than a second?
- CZCharles Zuker
Yeah. Absolutely, yeah.
- AHAndrew Huberman
I rarely mistake bitter for sweet.
- CZCharles Zuker
Yeah.
- 51:55 – 56:16
Positive vs. Negative Neuronal Activation & Behavior
- AHAndrew 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 created... connected, excuse me, to sets of neurons that evoke distinct behaviors of moving towards and inhaling more, and licking, or aversive. Are we essentially interpreting our behavior and our micro-responses, or our micro-responses and our behaviors the consequence of the percep-
- CZCharles Zuker
Excellent, excellent question. So, 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, you know, tasting this, this, this water as if it was sugar. Now this is Moses transforming water into wine. In this case, we're going to... And today is Passover, so then it's an appropriate, you know, example. Uh, we're transforming it into, in- in- into sweet, yeah? But, but how do I know, how do I know that activating them is evoking a positive feeling inside, a goodness, a satisfaction of "I love it," versus just increasing licking? Which is the other option, because all we're seeing is that the animal is licking more, and we're trying to infer that that means that he's feeling something really good versus, you know what? That piano line is going back straight into the tongue, and all 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 'em different. One has yellow little toys. The other one has green toys. One has little, you know, black stripes. The other one has blue stripes. So the animal can tell the two halves. I take the mouse, put him inside this arena, this play arena, and he will explore and put around both sides with equal frequency. And now what I'm going to do is I'm going to activate these neurons, the 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 this side with the yellow stripes. There's no licking here. The animal is not extending its tongue every time I'm activating these neurons. Okay? This is known as a place preference test, and it's generally used... it's 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 they 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.
- AHAndrew Huberman
And that's precisely what you see.
- CZCharles Zuker
And that's precisely what we see.
- 56:16 – 1:01:44
Acquired Tastes, Conditioned Taste Aversion
- AHAndrew 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-
- CZCharles Zuker
Absolutely.
- AHAndrew Huberman
... 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-
- CZCharles Zuker
You got it.
- AHAndrew Huberman
... for a very long time. I can imagine all the adapt, evolutionarily adaptive reasons why such a phenomenon would exist. Do we have any concept of where in this pathway that exists?
- CZCharles Zuker
We do. We, we, we, we know actually a significant amount at, at, at, at a general level, yeah? I- in fact more than shrimp, oysters are an even more dramatic example, yeah? One bad oyster-
- AHAndrew Huberman
Oh.
- CZCharles Zuker
... is all you need to be driven away for the next six months, eh? (laughs)
- AHAndrew Huberman
I think because the texture alone is something that one learns to overcome.
- CZCharles Zuker
(laughs)
- AHAndrew Huberman
I actually really enjoy oi- oysters.
- CZCharles Zuker
Me too. (laughs)
- AHAndrew Huberman
I despise mussels, despise shrimp, not the animal but the taste, and, and yet oysters for some reason I, I'm yet to have a bad experience.
- CZCharles Zuker
It's like, it's like uni by the way, you know, texture is hard to get over, but once you get over, it's delicious.
- AHAndrew Huberman
That's what they tell me. We were both in San Diego at one point and I, I'll give a plug to Sushi Ota is kind of the famous little sush-
- CZCharles Zuker
(laughs) Oh my goodness.
- AHAndrew Huberman
... and they have amazing uni and I've, I've tried it twice, and I, it's a, I'm 0 for 2. It, it somehow the texture outweighs any kind of the deliciousness that people report.
- CZCharles Zuker
It's, it's, it's a very acquired taste, yeah? It's like beer, you know, if you take... I grew up in Chile. That's where the accent comes from, in case anyone wonder. And you know, by the... by the time I came here to graduate school I was 19, too old to, you know, overcome my heavy Chilean accent, so here I am 40 years, 50 years later, not quite, 40 plus-
- AHAndrew Huberman
We appreciate it, we appreciate it.
- CZCharles Zuker
... and I still sound like I just came off the boat. (laughs) So in Chile you don't drink beer when you're young, you drink wine, you know, Chile's a huge wine producer. So when I came to the US all of my, you know, classmates, you know, were drinking beer, because they, you know, they had finished college where they were all, you know, "If you're drinking and, you know, graduate school, you're working 18 hours a day every day, the way they, you know, relax, let's go and have some beers."
- AHAndrew Huberman
And beer is cheaper.
- CZCharles Zuker
And beer is cheap, and we were being clearly underpaid, may I add. Eh... I couldn't do it. It's an acquired taste. It was too late by then, and here I am, you know, 60 plus, and if you take all the beer I've drunk in my entire life, I would say they add to less than an eight ounce glass of water.
- AHAndrew Huberman
Impressive. Well, your health is probably better for it.
- CZCharles Zuker
(laughs) I'm not sure. (laughs)
- AHAndrew Huberman
(laughs) Your physical health, anyway.
- CZCharles Zuker
So, so no, it, it goes back to, you know, a- acquired taste. This is the connection to uni and to oysters. Now going back to, to the one-trial learning, you know, 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, yeah, 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.
- AHAndrew Huberman
I have
- 1:01:44 – 1:09:14
Olfaction (Smell) vs. Taste, Changing Tastes over One’s Lifetime
- AHAndrew Huberman
a number of questions related to that, um, all of which relate to this idea of context, um, because you mentioned before that flavor is distinct from taste because flavor-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... involves smell, texture, temperature-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... and some other features. Uni, sea urchin, being a good-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... example of (laughs) I can, I can sense the texture. It actually, it's... Nah, I won't describe what it, what it reminds me of for various reasons. The ability to place context on, into... To insert context into a perception or rather to insert a perception into context is, 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, as you say, how, how many different tastes on the t- taste dial, to go back to your analogy earlier, the color dial, do you think that there could be for something as, um, fixed as bitter? So for instance, I, I don't think I like bitter taste, but, um, I like some fermented foods that seem to have a little bit of sour and have a little bit of br- that briny flavor.
- CZCharles Zuker
Yes.
- AHAndrew Huberman
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-
- CZCharles Zuker
Good for you.
- AHAndrew 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-
- CZCharles Zuker
Yes.
- AHAndrew Huberman
... to, to early development?
- CZCharles Zuker
So, so, uh, y- I'm going to take the question slightly differently, but I think it will illustrate the point. And, and, and I want to just illust- i- i- use the difference between the olfactory system and the taste system to make the point. Taste system, five basic palates, sweet, sour, bitter, salty, umami. Each of them has a predetermined identity, we know exactly what, and valence. These are attractive, these are aversive. In the olfactory system, it's claimed that we can smell millions of different odors. Yet for the most part, none of them have an innate predetermined meaning. In the olfactory system, meaning is imposed by learning and experience.
- AHAndrew Huberman
Even the smell of smoke?
- CZCharles Zuker
So I'm going to give you... I'm going to make it differently. There are a handful of the millions of odors that were claimed that, that you could immediately tell me these are aversive and these are attractive.
- AHAndrew Huberman
Vomit.
- CZCharles 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.
- AHAndrew Huberman
Really?
- CZCharles Zuker
Really. Sulfur would be maybe a universal. I'm not talking pheromones, okay?
- AHAndrew Huberman
Sure.
- CZCharles Zuker
Pheromones are in a different category that trigger innate responses. But nearly every odor is afforded meaning by learning and experience.
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
And that's why you like broccoli-
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
... and I despise broccoli, because I remember my mother forcing me to eat broccoli.
- AHAndrew Huberman
I'm so sorry.
- CZCharles Zuker
Same sensory experience. Yeah. All right. This, 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 (laughs) e- e- evolve a system where you put together a pathway and a cortex, olfactory cortex, yeah, 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 odor, then clearly plastic, mega plastic, because it's, it's fundamental basis and neural organization, but taste, we just told you that's, you know, predetermined hardwire. But predetermined hardwire doesn't mean that'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, why do we learn to love beer? Is in... Coffee. Is because it has an associated gain to the system. And that gain to the system, that positive valence that emerges out of that negative signal is sufficient to create that positive association. And in the case of beer, of course, it's alcohol.... the feeling good that we get after is more than sufficient to say, "I want to have more of this." I mean, in the case of coffee, of course, it's caffeine activating a whole group of neurotransmitter systems that give you that, that, that high associated with coffee. So, yes, the taste system is changeable, it's malleable, and it's subjected to learning and experience. But unlike the olfactory system, it's restricted, yeah, 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, you know, 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're averse to the ones that are going to kill us? I'm being overly simplistic and reductionist, but I think it illustrates it, the huge difference between these two chemosensory systems.
- AHAndrew Huberman
I, I don't think you're being overly simplistic. I think it, it illustrates the, the key intractable nature of this system and the way you've approached it, and I think it's important for people to hear that, because everybody, as we are, is mystified with empathy and love, et cetera. So in fairness to that, I'm going to ask a sort of a high-level question or abstract question.
- 1:09:14 – 1:17:26
Integration of Odor & Taste, Influence on Behavior & Emotion
- AHAndrew Huberman
- CZCharles Zuker
Yes.
- AHAndrew Huberman
This was based on a conversation I had with a former girlfriend, where we were talking about chemistry between individuals.
- CZCharles Zuker
Yes.
- AHAndrew 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 (laughs) , at least for some period of time-
- CZCharles Zuker
I, I didn't know this was that kind of a podcast (laughs) .
- AHAndrew Huberman
No, well, what... The reason I...
- CZCharles Zuker
So go on (laughs) .
- AHAndrew Huberman
But this has to do with taste, because she said something, I think in part to, uh, maybe irritate me a bit, but, 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.
- CZCharles Zuker
Uh-huh.
- AHAndrew Huberman
And s- she said, "What do you think it is, this thing of chemistry?" So maybe she was trying to, you know...
- CZCharles Zuker
Warn you...
- AHAndrew Huberman
Me too, right.
- CZCharles Zuker
... of what's coming.
- AHAndrew 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 i-... Was a very interesting example, (laughs) 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, uh, 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.
- CZCharles Zuker
Because you just didn't like it.
- AHAndrew Huberman
But because I just didn't like it.
- CZCharles Zuker
But, but, but that's because you associate it with other odors...
- AHAndrew Huberman
Mm-hmm.
- CZCharles Zuker
... that trigger that negative, you know, aversive reaction, by the way.
- AHAndrew Huberman
Absolutely. There are certain perfumes-
- CZCharles Zuker
So, so you, you-
- AHAndrew Huberman
... to me that are aversive.
- CZCharles Zuker
You got it.
- AHAndrew Huberman
And there, there are other scents, and per-
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
Uh, I can recall scents of, of skin, of foods, et cetera, that are im- immensely appetitive. So I ca-... 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.
- CZCharles Zuker
Of course, when you're, uh, a mother.
- AHAndrew Huberman
Of course.
- CZCharles Zuker
Us.
- 1:17:26 – 1:24:05
Sensitization to Taste, Internal State Modulation, Salt
- AHAndrew Huberman
we've been having this discussion, I thought a few times about similarities to the visual system, or differences to the visual system. In 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.
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
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 feel, 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 a 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, (laughs) but less sugar.
- CZCharles Zuker
I think we have better ways to a- approach that. And we can transition from taste into these other circuits that makes sugar so extraordinarily impossible not to consume.
- AHAndrew Huberman
Impossible?
- CZCharles Zuker
(laughs) Exactly.
- AHAndrew Huberman
Oh, my.
- CZCharles Zuker
Uh, so where does this, this desensitizing happens? That's the term that we use, eh? And it's, I think, h- 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.
- AHAndrew Huberman
... yeah, for the sake of this discussion, it's fine.
- CZCharles Zuker
For the sake of this, the discussion-
- AHAndrew Huberman
Yeah.
- CZCharles Zuker
... the receptor gets to a point where it undergoes a set of changes, chemical changes, where it now signals far less efficiently, or it even gets removed from the surface of the cell. And now what will happen is that the same amount of sugar will trigger far less of a response. And that is a huge side of this modulation. And then the next, I believe, is the integrated, again, loss of signaling that happens by continuous activation of the circuit at each of these different neural stations. You know, there is from the tongue to the ganglia, from the ganglia to the first station in the brainstem, a second station in the brainstem, to the thalamus, then to the cortex. So there are multiple steps that this signal is traveling. Now you might say, "Why, if this is a label line, why do you need to have so many stations?" And that's because the taste system is so important to ensure that you get what you need to survive, that it has to be subjected to modulation by the internal state. And each of these nodes provides a new site to give it plasticity and modulation. Not necessarily to change the way that something tastes, but to ensure that you consume more, or less of, diff- or differently of what you need. Uh, I'm going to give you one example of, of how the internal state changes the way the taste system works. Salt is very appetitive at low concentrations, and that's because we need it. It's, our electrolyte balance requires salt. Every one of the neurons uses salt as the most important of the ions, you know, with potassium to ensure that you can transfer these electrical signals within and between neurons. But at high concentrations, let's say ocean water, it's incredibly aversive. And we all know this, because we've gone to the ocean, and then when you get it in your mouth, it's not that great. However, if I salt-deprive you, and we can do this in, in experimental models quite readily, eh, 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.
- AHAndrew Huberman
And presumably, if one is hungry enough, even uni will taste good. Just to me.
- CZCharles Zuker
You, you hit it right on the money. No, no, this is exactly correct. Or if you're thirsty and hungry, you suppress hunger, so that you don't waste water molecules in digesting food. Why? Because if you're thirsty and you have no water, you will die within a week or so. But you can go on a hunger strike as long as you have water for months, because you're going to eat up all your energy reserves. Water is a different story. So, you could see, or, or, or, that, that there are multiple layers at which the taste system that guides, you know, 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, that, you know, each step, you give the system that level of flexibility, or what we call in neuroscience, plasticity.
- 1:24:05 – 1:28:10
Taste & Saliva: The Absence of Taste
- AHAndrew Huberman
I think we're headed into the gut.
- CZCharles Zuker
All right.
- AHAndrew 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.
- CZCharles Zuker
Yes.
- AHAndrew Huberman
Is there any kind of signal for the absence of taste, despite having something in the mouth? And here is why I ask.
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
What I'm thinking about is saliva.
- CZCharles Zuker
Mm-hmm.
- AHAndrew 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...
- CZCharles Zuker
Is there a taste of no taste?
- AHAndrew Huberman
Right, is there a taste of no taste? Because in the visual system, there is.
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
Right? You close the eyes and you start getting increases in activity-
- CZCharles Zuker
Mm-hmm. Mm-hmm.
- AHAndrew Huberman
... in the visual system, as opposed to decreases, which often surprises people. But there are reasons for that, because everything is about signal to noise, signal to background, and, and-
- CZCharles 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. (laughs)
- AHAndrew Huberman
Well, but-
- CZCharles Zuker
You know? Yes, because-
- AHAndrew Huberman
No, he's, I know you're being playful, and I knew when inviting you here today, I was setting myself up for it. Actually, on a, on a, on a different...
- CZCharles Zuker
We're trying to learn things.
- AHAndrew Huberman
Yeah, I know.
- CZCharles Zuker
However...
- AHAndrew Huberman
All right, listen, I, I was weaned in this system of the... And I'll say it here for the second... Actually, I recorded a podcast recently with, a very prominent podcast, 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, um, I know the sorts of, uh, ribbing that they provide. For those listening, this is the kind of hazing that happens, benevolent hazing in academia. I'm, I'm the target.
- CZCharles Zuker
It's, it's, of course, it's, it's the, it's-
- AHAndrew Huberman
It's a sign of love.
- CZCharles Zuker
E-e-exactly.
- AHAndrew Huberman
He's going to tell me that.
- CZCharles Zuker
And it's always about the science in the end.
- AHAndrew Huberman
Right. But, but here's-
- CZCharles Zuker
Um, it's an interesting question. Look, I, um, I don't know the answer, and, and I don't even know how I would explore it in a way that it will rigorously teach me, eh, but, um...
- 1:28:10 – 1:36:23
Sugar & Reward Pleasure Centers; Gut-Brain Axis, Anticipatory Response
- AHAndrew Huberman
what aspects of this in- the internal milieu are relevant, because there's autonomic, there's a sleep and awake, there's stress.
- CZCharles Zuker
Absolutely. Totally.
- AHAndrew Huberman
One of the questions that I, I got, uh, 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?
- CZCharles Zuker
Because it makes us feel good. By the way, we'll get to that.
- AHAndrew Huberman
Soothing.
- CZCharles Zuker
That's, that's the answer.
- AHAndrew Huberman
Soothing.
- CZCharles Zuker
It activates, eh, what I'm going to generically refer to as reward pleasure centers in a way that it dramatically, eh, changes our internal state. This is, you know, why do we eat a gallon of ice cream when we're very depressed? Yeah. In, in fact, this is a good segue to go into the, into, into this entirely different world, yeah, eh, of, of the body telling your brain what you need in, in, in, in important things like sugar and fat, yeah? Okay, but anyways, go ahead. You were going to ask something?
- AHAndrew Huberman
Well, no, I, I would like to discuss the most basic elements of internal state.
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
In particular, the ones that are below our conscious detection. And this is a, uh, of course is a segue into this incredible landscape, which is the gut-brain axis, which I think 15 years ago was almost a, maybe it was a-
- CZCharles Zuker
Unheard of.
- AHAndrew Huberman
... couple posters at a meeting, and then now, I believe you, you and others, there are companies, there are active research programs, there's, um, and beautiful work.
- CZCharles Zuker
Mm-hmm.
- AHAndrew Huberman
Uh, maybe you could describe some of that work that you and others have been involved in. And a lot of the listeners of this podcast will have heard of the gut-brain axis, and there are a lot of misconceptions about the gut-brain axis. Many people think that this means that we think with our stomach because of the, quote-unquote, "gut feeling" aspect.
- CZCharles Zuker
Yes.
- AHAndrew Huberman
But I'd love for you to talk about the aspects of gut-brain signaling that drive our per- or change our perceptions and behaviors that are completely beneath our awareness.
- CZCharles Zuker
Yes, excellent. So, let me begin maybe by, by stating that, you know, the brain needs to monitor the state of every one of our organs, 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 it's 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 a, an example again, of, of, eh, of how the brain can take what we would refer to contextual associations and transform it into incredible changes in physiology and metabolism.... you know, remember Pavlov? So Pavlov, in his classical experiments in conditioning, you know, associative conditioning, he would take a bell and 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 i- is the fact that the dog now, in the presence of the bell alone, will start to salivate, and we will call that, you know, neurologically speaking, an anticipatory response. Okay, I could understand it. I get it. You know, neurons in the brain that form that association now represent food is coming, and they're sending a signal to motor neurons to go into your salivary glands, to squeeze them, so you release, you know, you know saliva because you know food is coming. But what's even more remarkable is that those animals are also releasing insulin in response to a bell. Okay, this illustrates one part of this two-way highway, the highway going down. Somehow the brain created these associations, and there are neurons in your brain now that know food is coming and send a signal somehow all the way down to your pancreas that now it says, "Release insulin because sugar is coming down." All right, this goes back to the magic of the brain. You know, it's a never-ending source of both joy and intrigue. How the hell do they do this? Okay. I mean, the neurons, eh?
- AHAndrew Huberman
No, I share-
- CZCharles Zuker
(laughs) ... I share your delight and fascination. I mean-
- AHAndrew Huberman
There's not a day or a lecture or, uh, some talks are better than others, or a talk where I don't sit back and just think it's absolutely amazing.
- CZCharles Zuker
How-
- AHAndrew Huberman
It's amazing.
- CZCharles Zuker
All right.
- AHAndrew Huberman
It's amazing.
- CZCharles Zuker
Now, now, over the past, I don't know, dozen years i- and with great force over the last five years, now, the main highway that is communicating the state of the body with the brain i- has been uncovered as being what we now refer to as the gut-brain axis, and the highway is a specific bundle of nerves, you know, which emerge from the vagal ganglia, the nodal ganglia. And so it's the vagus nerve that it's enervating 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."
- AHAndrew Huberman
And e- and I should point out, a- as you well know, every organ, spleen, pancreas, lungs-
- CZCharles Zuker
They all must, they all must be monitored. Other w- in fact, you know, 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.
- AHAndrew Huberman
I do as well.
- CZCharles Zuker
Yeah? And, and, and so, and so this, this, this view that we have, you know, been working on for the longest time because, you know, the molecules that we're dealing with are in the body, not in the head, you know, led us to, you know, to view, of course, these issues and problems as being one of metabolism, physiology, and so forth. They remain to be the carriers of the ultimate signal, but the brain ultimately appears to be the conductor of this orchestra of physiology and metabolism. All right, now let's go to the gut, brain, and sugar. May we?
- 1:36:23 – 1:43:09
Vagus Nerve
- AHAndrew Huberman
has, uh, in popular culture has been, um, kind of converted into this w- single meaning of calming pathways, mostly because I, I actually have to tip my hat to the yoga community was among the first to talk about vagus on and on and on. It, there are calming pathways of, you know, so-called parasympathetic pathways within the vagus, but I think that the more we learn about the vagus, the more it seems like an entire, um, set of neural connections as opposed to one nerve.
- CZCharles Zuker
Do you got it-
- AHAndrew 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 i- way of calming oneself down.
- CZCharles Zuker
Well, and also o- o- of course, I mean, y- one has to be conscious there in that. So the, the, the, the vagus nerve is made out of many thousands of fibers, you know, individual fibers that make this gigantic bundle. And it's likely, as we're speaking, that each of these fibers carries a slightly different meaning. They're not necessarily one by one, maybe five fibers, 10 fibers, 20 do th- 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. Yeah. Yes, you're right, there is a, a lot of data, eh, 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.
- AHAndrew Huberman
Little stimulator.
- CZCharles Zuker
Epileptic seizures. But, again, there are thousands of fibers carrying different functions. So to some degree, you know, this is like turning the lights on the stadium because you need to illuminate where you lost your keys under your seat, yet 10,000 bulbs of 1,000 watts each have just come on. Only one of these is pointing to where... And so I'm lucky enough that one of them happened to point to my side. So here, you activate the bundle, thousands of fibers, I'm lucky enough that some of those happen to do something to make a meaningful difference in depression, or to make a meaningful difference in 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 have been 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 of the great, you know, scientists, eh, including Steve Liberles that started a lot of, you know, this molecular dissection on this vagal gut-brain communication line at Harvard. He's trying to uncover what are each of those lines doing, what are each of those keys of this piano playing.
Episode duration: 2:17:37
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