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Speaker A: 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 Doctor Charles Zucker. Doctor Zucker is a professor of biochemistry and molecular biophysics and of neuroscience at Columbia University School of Medicine. Doctor Zucker is one of the world's leading experts in perception. That is, how the nervous system converts physical stimuli in the world into events within the nervous system that we come to understand as our sense of smell, our sense of taste, our sense of vision, our sense of touch, and our sense of hearing. Doctor Zucker's lab is responsible for a tremendous amount of pioneering and groundbreaking work in the area of perception. For a long time, his laboratory worked on vision, defining the very receptors that allow for the conversion of light into signals that the rest of the eye and the brain can understand. In recent years, his laboratory has focused mainly on the perception of taste. And indeed, his laboratory is responsible for discovering many of the taste receptors leading to our perception of things like sweetness, sourness, bitterness, saltiness, and umami. That is, savoriness in food. Doctor Zucker's laboratory is also responsible for doing groundbreaking work on the sense of thirst. That is how the nervous system determines whether or not we should ingest more fluid or reject fluids that are offered to us. A key feature of the work from Doctor Zucker's laboratory is that it bridges the brain and body. As you'll soon learn from today's discussion, his laboratory has discovered a unique set of sugar sensing neurons that exist not just within the brain, but a separate set of neurons that sense sweetness and sugar within the body, and that much of the communication between the brain and body leading to our seeking of sugar, is below our conscious detection. Doctor Zucker has received a large number of prestigious awards and appointments as a consequence of his discoveries in neuroscience. He is a member of the National Academy of Sciences, the National Academy of Medicine, and the American association for the Advancement of Science. He is also an investigator with the Howard Hughes Medical Institute. For those of you that are not familiar with the so called HHMI, the Howard Hughes Medical Institute, Howard Hughes Medical Institute investigators are selected on an extremely competitive basis, and indeed, they have to come back every five years and prove themselves worthy of being reappointed as Howard Hughes investigators. Doctor Zucker 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 expertise on perception and taste. I'm certain that by the end of today's podcast, you are 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 Doctor Charles Zucker. Charles, thank you so much for joining me today.

Speaker B: My pleasure.

Speaker A: I want to ask you about many things related to taste. Our first sponsor is athletic Greens. Athletic Greens is an all in one vitamin mineral probiotic drink. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens, and the reason I still take athletic greens once or twice a day is that it helps me cover all of my basic nutritional needs. It makes up for any deficiencies that I might have. In addition, it has probiotics, which are vital for microbiome health. I've done a couple of episodes now on the so called gut microbiome and the ways in which the microbiome interacts with your immune system, with your brain to regulate mood, and essentially with every biological system relevant to health throughout your brain and body. With athletic greens, I get the vitamins I need, the minerals I need, and the probiotics to support my microbiome. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and claim a special offer. They'll give you five free travel packs plus a year's supply of vitamin D three k too there are a ton of data now showing that vitamin D three is essential for various aspects of our brain and body health. Even if we're getting a lot of sunshine, many of us are still deficient in vitamin D three and k two is also important because it regulates things like cardiovascular function, calcium in the body, and so on. Again, go to athleticgreens.com huberman to claim the special offer of the five free travel packs and the year supply of vitamin D three k two today's episode is also brought to us by element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the exact ratios of electrolytes are an element, and those are sodium, magnesium, and potassium, but it has no sugar. I've talked many times before on this podcast about the key role of hydration and electrolytes for nerve cell function, neuron function, as well as the function of all the cells and all the tissues and organ systems of the body. If we have sodium, magnesium, and potassium present in the proper ratios, all of those cells function properly and all our bodily systems can be optimized. If the electrolytes are not present and if hydration is low, we simply can't think as well as we would otherwise. Our mood is off, hormone systems go off. Our ability to get into physical action, to engage in endurance and strength and all sorts of other things is diminished. So with element, you can make sure that you're staying on top of your hydration and that you're getting the proper ratios of electrolytes. If you'd like to try element, you can go to drink element. That's lmnt.com huberman and you'll get a free element sample pack with your purchase. They're all delicious. So again, if you want to try element, you can go to elementlmnt.com hubermanda. Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga Nidra sessions, and NSDR non sleep deep rest protocols. I started using the waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations, and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much. So I gave the waking up app a try, and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions for those of you who don't know yoga Nidra is a process of lying very still, but keeping an active mind. It's very different than most meditations. And there's excellent scientific data to show that yoga Nidra and something similar to it called non sleep, deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's wakingup.com Huberman to access a free 30 day trial 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, etcetera.

Speaker B: So, you know, the brain is an extraordinary organ that weights maybe 2% of your body mass, yet it consumes anywhere between 25% to 30% of all of your energy and oxygen, and it gets transformed into a mind. And this mind changes the human condition. It 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 chord, and this is a microphone. But the brain is only made of neurons that only understand electrical signals. So how do you transform that reality into nothing? 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, other, 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 he'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?

Speaker A: Absolutely. And is a very clear and beautiful description, a sort of high level question related to that. And then I think we can get into some of the intermediate steps. 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.

Speaker B: Excellent question. Okay, to interrupt you as you're, as I'm guessing what you're going.

Speaker A: All right, very interruption is welcome on this podcast. The audience will always penalize me for interrupting you and never penalize you for interrupting.

Speaker B: I like the one way penalize. Now, given what I told you before, that the brain is trying to represent the world based in nothing but the transformation of these signals into electrical languages that now neurons have to encode and decode, it follows that your brain is different than my brain, and therefore, it follows that the way that you're perceiving the world must be different than mine, even when receiving the same sensory cues. Okay, and I'll tell you about an experiment. It's a simple experiment, yet brilliant, that demonstrates how we perceive the world different. So, in the world of vision, as you know, well know, we have three classes of photoreceptor neurons that sense three basic colors, red, blue, and greenhouse 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 one into a white screen, a red light, and the other one, green light. I'm going to overlap the two beams, and on the screen, there's be yellow. Okay, this is super position 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 are projecting to the spectrally pure next to it. Is this making sense?

Speaker A: Perfect sense.

Speaker B: 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.

Speaker A: Amazing.

Speaker B: So, for all of us, is 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. And so I think that simple psychological experiment beautifully illustrates how we truly perceive the world differently.

Speaker A: I love that example. And yet, in that example, we know the basic elements from which color is created if we migrate into a slightly different sense. Let me pick a hard one, like sound. Sound or olfaction.

Speaker B: 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 features or other determinants. But no question that your experience is different than mine.

Speaker A: 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.

Speaker B: You got it.

Speaker A: Raises a thought about a statement made by a colleague of ours, Marcus Meister, at Caltech. He's never been on this podcast, but in the review that I read by Marcus, at one point, he said that the basic function of perception is to divide our behavioral responses into the out comes downstream of three basic emotional responses. Yum, I like it. Yuck, I hate it. Or meh, whatever. What do you think about? I'm not looking to establish a debate between you, Marcus, without Marcus here.

Speaker B: I understand that.

Speaker A: But what I like about that is that it seems like we know the brain is a very economical organ in some sense, despite its high metabolic demands. And this variation in perception from one individual to the next at once seems like a problem, because we're all literally seeing different things, and yet we function. We function well enough for most of us to avoid death and cliffs and eating poisons and so forth, and to enjoy some aspects of life, one hopes. So. Is there a general statement that we can make about the brain, not just as a organ to generate perception, not just as an organ to keep us alive, but also an organ that is trying to batch our behaviors into general categories of.

Speaker B: I think so. But again, I think the role of Marcus, too, and I think he's right, that, broadly speaking, you could categorize a lot of behaviors falling into those true categories, and that's 100% likely to be the case for animals in the wild, where, you know, 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.

Speaker A: Be doing, some of us more than others.

Speaker B: 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. Ah, 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.

Speaker A: 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 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.

Speaker B: 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 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. 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.

Speaker A: From a first person perspective. Yes. The hardest question, the most important question is, what question are you going to try and answer?

Speaker B: You got it. And so, for example, I would love to understand the neural basis of empathy.

Speaker A: There's a big market for that, 100%.

Speaker B: But I wouldn't even know. I mean, at the molecular level, that's what we do. How do these 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 store as memories, of creating emotions, of giving you 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 if I want to begin to explore all of these things that the brain does, I felt I have to choose a sensory system that affords some degree of simplicity in the way that the input output relationships are put together, and in a way that still can be used to ask every one of these problems that the brain has to ultimately compute, encode, and decode. And what was remarkable about the taste system at the time that I began working on this is that nothing was known about the molecular basis of taste. You know, we knew that we could taste what has been usually defined as the five basic taste. Sweet, sour, bitter, salty, and umami. Umami is a japanese word that means yummy, delicious, and that's nearly every animal species. The taste of amino acids. And in humans, it's mostly associated with the taste of MsG, monosodium glutamate, one.

Speaker A: Amino acid in particular, just by way of example. Some foods that are rich in the umami, evoking stimulation.

Speaker B: Seaweed, tomatoes, cheese, and it's a great, great flavor enhancer. It enriches our sensory experience. And so the beautiful thing of the system is that the lines of input are limited to five, you know, sweet, sour, bitter, salt, umami. And each of them has a predetermined meaning. You are born liking sugar and dislike. In bitter, you have no choice. These are hardwired 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 question. 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.

Speaker A: Could I interrupt you just briefly and ask a question about that exact point? For something to be appetitive to and some other taste to be aversive, and for those to be hardwired. Can we assume that the sensation of very bitter or 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.

Speaker B: 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 see them happening in animals, because the first thing you do is you stop licking, then you put 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.

Speaker A: It's incredible.

Speaker B: It's again, the magic of the brain. You know, how it's able to encode and decode these extraordinary actions and behaviors in response of nothing but a simple, very unique sensory stimuli. Now, let me say that this palette of five basic tastes accommodates all the dietary needs of the organism. Sweet, to ensure that we get the right amount of energy. Umami, to ensure that we get proteins, another essential nutrient. Salt. The three appetitive ones, to ensure that we maintain our electrolyte balance. Bitter, to prevent the ingestion of toxic, nauseous chemicals. Nearly all bitter. Taste. You know, things out in the wild are bad for you. And sour most likely to prevent ingestion of spoiled, acid fermented foods. And that's it. That is the 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 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?

Speaker A: Yeah, almost like the primary colors to create the full array of the color spectrum.

Speaker B: Exactly.

Speaker A: Before I ask you about the first and second and third stages of taste and flavor perception, is there any idea that there may be more than five?

Speaker B: There is. For example, what about fat?

Speaker A: I love the texture.

Speaker B: I love fat, too.

Speaker A: And I love the texture of fat, especially if it's slightly burnt, like the. In South America, when I visited Buenos Aires, I found that at the end of a meal, they would take a steak, the trimming off the edge of the steak, burn it slightly, and then serve it back to me. And I thought, that's disgusting. And then I tasted it, and it's delightful.

Speaker B: It is.

Speaker A: There's nothing quite like it.

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

Speaker A: I don't suggest anyone eat pure fat. The listeners of this podcast will immediately. 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, as evidenced by the obesity problem that exists.

Speaker B: 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 tastes. 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.

Speaker A: I love the idea that there is a perception of fat regardless of whether or not there's a dedicated receptor for fat, mostly because it's evoking sensations and imagery of the taste of slightly burnt fat, for example.

Speaker B: And another one, you know, you could argue it's metallic taste. You know, I know exactly what it tastes like. You know, if you ask me to explain it, I will have a hard time. You know, what, what are the palettes of that color that can allow me to define it? I wouldn't be easy, but I know precisely what it tastes like. You know, take a, take a penny put it in your mouth and you know what it tastes like. Yeah.

Speaker A: Or blood.

Speaker B: 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, just separate lines. Like the keys of a piano. Yeah. Sweet, sour, bitter, salty, mommy. You play the key and you activate that one chord. And that one chord, in the case of a piano, leads to a note, a tune of. And in the case of taste, leads to an action and a behavior. But you play many of them together and something emerges that it's different than any one of the pieces. And it's possible that metallic, for example, represents the combination of the activity just in the right ratio of these other.

Speaker A: Lines makes sense, and it actually provides a perfect. Your example of the piano provides a perfect segue for what I'd like to touch on next, which is if you would describe the sequence of neural events leading to a perceptual event of taste. And I'm certain that somewhere in there you will embed an answer to the question of whether or not we indeed have different taste receptors distributed in different locations on our tongue or elsewhere in the mouth.

Speaker B: Yes. So let's start by debunking that old tale and myth.

Speaker A: Who came up with that?

Speaker B: 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, 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 bats distributed in various parts of the tongue. So there is a map on the distribution of taste bats, 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, taste like bitter is particularly enriched at the very back of your tongue. And there is a teleological basis for that, actually a biological basis for that. That's the last line of defense before you swallow something bad. And so let's make sure that the very back of your tongue has plenty of these bad news receptors, so that if they get activated, you can trigger a gagging reflex and get rid of this. That otherwise may kill you.

Speaker A: Makes good sense.

Speaker B: But the notion that all sweet is in the front and salt is on the side, it's not real. Go ahead.

Speaker A: Oh, I was just gonna ask, are there, first of all, thank you for dispelling that myth. And we will propagate that information as far and wide as we can because I think that's the number one myth related to taste. The other one is, are there taste receptors anywhere else in the mouth, for instance, on the lips?

Speaker B: The palate, not the lips. So it's in the pharynge at the very back of the oral cavity, the tongue and the palate. And the palate is very rich in sweet receptors.

Speaker A: I'll have to pay attention to this the next time I eat something sweet.

Speaker B: When you pull it up, yeah. Now, the important thing is that after the receptors for the detectors, the molecules that sense sweet, sour, beta salt to mummy. 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 bad throughout your oral cavity has receptors for all of the basic taste classes.

Speaker A: 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. I'm going to inject a quick question that I'm sure is on many people's minds before we get back into the biological circuit, which is many people, including myself, are familiar with the experience of drinking a sip of tea or coffee that is too hot and burning my tongue is, the way I would describe it, horrible. And then disrupting my sense of taste for some period of time afterward.

Speaker B: Yes.

Speaker A: 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?

Speaker B: Excellent question. And the answer is both. It turns out that your taste receptors only leave for around two weeks. And this, by the way, makes sense, because here you have an organ, the tongue, that is continuously exposed to everything. You could range from the nicest to the most horrible possible things.

Speaker A: Use your imagination.

Speaker B: And so you need to make sure that these cells are always coming back in a way that 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. Amazing. Again, they are receiving everything that you ingest. God forbid, what's there, from the spiciest 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. 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 within 20 minutes, 30 minutes, an hour. And these cells are not renewing in that timeframe. They're not listening to your needs. They have their own internal clock. And so you are really affecting. You're damaging them in a way that they can recover. And then they come back and you also damage your somatosensory cells. These are the cells that feel things, not taste things. And then, you know, you wait half an hour or so, and then I, my goodness, thank God it's back to normal.

Speaker A: Most of the time, I don't even notice the transition, realizing, as you tell 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.

Speaker B: 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 experiences that represent polar opposites, it will be sweet and bitter. There are no two colors that represent polar opposites, because, you know, you could say black and white, they are polar opposite. One that takes only one thing, the other one that takes everything. But they don't evoke different behaviors.

Speaker A: Even political parties have some over that.

Speaker B: Swede 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 it's easier to follow the signal. And the two features are its quality and its valence, and valence with a little v, that's what we say in Spanish. With a v means the value of that experience. All right? Or in this case, of that stimuli. And you take sweet. Sweet has a quality, an identity, and that's what you and I will refer to as the taste of sweet. We know exactly what it tastes like, but sweet also has a positive valence, which makes it incredibly attractive and appetitive, but is 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.

Speaker A: I can taste it now even as.

Speaker B: You describe it, but it also has a valence, and that's a negative valence because it evokes behaviors. Are we on?

Speaker A: Absolutely. All right. And it comes to mind, I remember telling some kids recently that we're gonna go get ice cream, and it was interesting. They looked up, and they started smacking their lip, like, you know, they'll actually.

Speaker B: Anticipatory response. Absolutely. When we talk about the gut brain, maybe we'll get there. So then the signals, if we follow now these two lines, they're really like two separate keys at the two ends of this keyboard. And you press one key, and you activate this cord. So you activate the sweet cells throughout your oral cavity and they all converge into a group of sweet neurons. In the next station, which is still outside the brain, is one of the taste ganglia. These are the neurons that innervate your tongue and the oral cavity.

Speaker A: Where do they sit? Approximately around there? Yeah, right here.

Speaker B: Around there.

Speaker A: The lymph nodes, more or less.

Speaker B: You got it. And there are two main ganglia that innervate the vast majority of all taste buds in the oral cavity. And then from there, that sweet signal goes onto the brain stem. The brain stem is the entry of the body into the brain. And there are different areas of the brain stem and there are different groups of neurons in the brain stem. And there's a unique area in a unique, topographically defined location in the rostral side of the brainstem that receives all of the taste input.

Speaker A: A very dense area of the brain?

Speaker B: A very rich area of the brain. Exactly. And from there, this sweet signal goes to this other area higher up on the brain stem. And then it goes through a number of stations where that sweet signal goes from sweet neuron to sweet neuron to sweet neuron to eventually get to your cortex. And once it gets to your taste cortex, that's where meaning is imposed into that signal. It's then and only then. This is what the data suggests, that now you can identify this as a sweet stimuli.

Speaker A: And how quickly does that all happen?

Speaker B: You know, the timescale of the nervous system? It's fast. Yeah.

Speaker A: Within less than a second.

Speaker B: Yeah, absolutely. Yeah.

Speaker A: I rarely mistake bitter for sweet. Yeah, maybe with respect to people and my own poor judgment, but no, you, not with respect to taste.

Speaker B: Yeah, it's. 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 essence, 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. Well, 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.

Speaker A: Of maisie, but presumably in humans, it would work similarly.

Speaker B: Absolutely the same. Zero doubt. I have no question. 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 bit of stimuli.

Speaker A: This is amazing.

Speaker B: 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.

Speaker A: The reason I say amazing, and that is also amazing, is the following you told us earlier, and you're absolutely correct, of course, that at the end of the day, whether or not it's one group of neurons over here and another group of neurons over there, just the way it turns out to be electrical activity, is the generic common language of both sets of neurons. So that raises the question for me, of whether or not those separate sets of neurons are connected to areas of the brain that create this sense of valence, or whether or not they're simply 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 are micro responses in our behaviors the consequence of the percept?

Speaker B: Excellent, excellent question. So, first, the answer is they go into an area of the brain where valence is imposed, and that area is known as the amygdala. And the sweet neurons go to a different area than the beta 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, leaking, and I'm activating the sweet neurons. And so that's expected, because now it's, you know, tasting this water as it was sugar. Now this is Moses transforming water into wine. In this case, we're gonna. And today's Passover. So then it's an appropriate, you know, example. We're transforming it into sweet. Yeah, but how do I know. How do I know that activating them is evoking a positive feeling inside, a goodness, a satisfaction, I love it. Versus I'm just increasingly leaking, which is the other option, because all we're seeing is that the animal is leaking 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 them inside a box that has two sides, and the two sides have features that make him different. One has yellow little toys, the other one has green toys. One has little, you know, black stripes. The other one has blue stripes. So the animal can tell the two halves, I take the mouse, put them inside this arena, this play arena, and it 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 the side with the yellow stripes. There's no leak in 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. 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.

Speaker A: And that's precisely what you see, and.

Speaker B: That'S precisely what we see.

Speaker A: Many people, including myself, are familiar with the experience of going to a restaurant, eating a variety of foods, and then, fortunately, doesn't happen that often, but then feeling very sick. I learned coming up in neuroscience that this is one strong example of one trial learning that from that point on, it's not the restaurant or the waitress or the waiter or the date, but it's my notion of it had to have been the shrimp. That leads me to then want to avoid shrimp in every context, maybe even shrimp powder. You got it for a very long time. I can imagine all the evolutionarily adaptive reasons why this such a phenomenon would exist. Do we have any concept of where in this path exist?

Speaker B: We do. We know, actually a significant amount. At a general level, in fact, more than shrimp. Oysters are even a more dramatic example. One bad oyster is all you need to be driven away for the next.

Speaker A: Six months, I think, because the texture alone is something that one learns to overcome. I actually really enjoy oysters. I despise mussels, despise shrimp. Not the animal, but the taste. And yet oysters, for some reason, I'm yet to have a bad experience.

Speaker B: It's like uni, by the way. You know, texture is hard to get over, but once you get over, it's delicious.

Speaker A: That's what they tell me. We were both in San Diego at one point, and I'll give a plug to sushi. Ota is kind of the famous, and they have amazing uni, and I've tried it twice, and I'm zero for two. Somehow the texture outweighs any kind of the deliciousness that people report.

Speaker B: A very acquired taste. It's like beer. I grew up in Chile. That's where the accent comes from, in case anyone wondered. And, you know, by the time I came here to graduate school, I was 19, too old to, you know, overcome my heavy chilean accent. So here I am, 40 years, 50 years late. Not quite 40 plus.