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

[0] Welcome to the Huberman Lab podcast where we discuss science and science -based tools for everyday life.

[1] I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

[2] Today my guest is Dr. Charles Zucker.

[3] Dr. Zucker is a professor of biochemistry and molecular biophysics and of neuroscience at Columbia University School of Medicine.

[4] Dr. Zucker is one of the world's leading experts in perception.

[5] 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.

[6] Dr. Zucker's lab is responsible for a tremendous amount of pioneering and groundbreaking work in the area of perception.

[7] 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.

[8] In recent years, his laboratory is focused mainly on the perception of taste.

[9] 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, savouriness in food.

[10] Dr. Zucker's laboratory is also responsible for doing groundbreaking work on the sense of thirst.

[11] That is, how the nervous system determines whether or not we should ingest more fluid or reject fluids that are offered to us.

[12] A key feature of the work from Dr. Zucker's laboratory is that it bridges the brain and body.

[13] 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.

[14] And that much of the communication between the brain and body leading to our seeking of sugar is below our conscious detection.

[15] Dr. Zucker has received a large number of prestigious awards and appointments as a consequence of his discoveries in neuroscience.

[16] He is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Association for the Advancement of Science.

[17] He is also an investigator with the Howard Hughes Medical Institute.

[18] 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.

[19] And indeed, they have to come back every five years and prove themselves worthy of being reappointed as Howard Hughes investigators.

[20] Dr. Zucker has been a Howard Hughes investigator since 1989.

[21] 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.

[22] 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 tastes in particular, but indeed you will come away with an understanding of how we create internal representations of the entire world around us.

[23] And in doing so, how we come to understand our life experience.

[24] Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

[25] 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.

[26] In keeping with that theme, I'd like to thank the sponsors of today's podcast.

[27] And now for my discussion with Dr. Charles Zucker.

[28] Charles, thank you so much for joining me today.

[29] My pleasure.

[30] I want to ask you about many things related to taste.

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[45] Today's episode is also brought to us by Eight Sleep.

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[47] Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night.

[48] One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment.

[49] And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.

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[57] Again, that's eightsleep .com slash Huberman.

[58] Today's episode is also brought to us by Eight Sleep.

[59] Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.

[60] Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night.

[61] One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment.

[62] And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.

[63] And in order to wake up, feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees.

[64] Eight sleep makes it incredibly easy to control the temperature of your sleeping environment by allowing you to program the temperature of your mattress cover at the beginning, middle, and end of the night.

[65] I've been sleeping on an eight sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better.

[66] Eight Sleep recently launched their newest generation pod cover, the Pod4 Ultra.

[67] The Pod4 Ultra has improved cooling and heating capacity, higher fidelity sleep tracking technology, and it also has snoring detection that remarkably will automatically lift your head a few degrees to improve your airflow and stop your snoring.

[68] If you'd like to try an eight sleep mattress cover, you can go to eight sleep .com slash Huberman to save $350 off their Pod4 Ultra.

[69] Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU and Australia.

[70] Again, that's eight sleep .com slash Huberman.

[71] 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?

[72] 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?

[73] 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.

[74] And it gets transformed into a mind.

[75] And this mind changes the human condition.

[76] It makes, it changes, it transforms, you know, fear into courage, conformity into creativity.

[77] sadness into happiness.

[78] How the hell does that happen?

[79] Now, the challenge that the brain faces is that the world is made of real things.

[80] You know, this here is a glass, and this is a cord, and this is a microphone.

[81] But the brain is only made of neurons that only understand electrical signals.

[82] So how do you transform that reality...

[83] into nothing that electrical signals that now need to represent the world.

[84] And that process is what we can operationally define as perception.

[85] In the senses, let's say olfactory, other taste, vision, we can very straightforwardly separate detection from perception.

[86] 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.

[87] That's detection.

[88] You haven't perceived anything yet.

[89] That is just your cells in your tongue interacting with this chemical.

[90] But now that cell gets activated and sends a signal to the brain.

[91] And now detection gets transformed into perception.

[92] And he's trying to understand how that happens that's been the maniacal drive of my entire career in neuroscience.

[93] How does the brain ultimately transform detection into perception so that it can guide actions and behaviors?

[94] Does that make sense?

[95] Absolutely.

[96] And is a very clear and beautiful description.

[97] A sort of high -level question related to that.

[98] And then I think we can get into some of the intermediate steps.

[99] Yes.

[100] I think many people would like to know whether or not my perception of the color of your shirt is the same as your perception of the color of your shirt.

[101] What an excellent question.

[102] Am I okay to interrupt you as I'm guessing what you're going?

[103] All right.

[104] Interruption is welcome on this podcast.

[105] The audience will always penalize me for interrupting you and will never penalize you for interrupting me. I like the one way penalize.

[106] 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.

[107] 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.

[108] Okay?

[109] And I'll tell you about an experiment.

[110] It's a simple experiment, yet brilliant, that demonstrates why we perceive the world, how we perceive the world different.

[111] 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 green.

[112] Blue, green, and red, if we go, you know, from shore to long wavelength.

[113] And these three are sufficient to accommodate the full visible spectra.

[114] I'm going to take three light projectors.

[115] and I'm going to project with one into a white screen, a red light, and the other one, green light.

[116] I'm going to overlap the two beams, and on the screen, it'll be yellow.

[117] Okay, this is the superposition when you have two beams of red and green.

[118] And then I'm going to take a third projector, and I'm going to put a filter that projects right next with that mixed beam, a spectrally pure yellow.

[119] And I'm going to ask you to come to the red and green projectors and play with the intensity knobs so that you can match that yellow that you're projecting to the spectrally pure next to it.

[120] Is this making sense?

[121] Perfect sense.

[122] And I'm going to write down the numbers in those two volume intensity knobs.

[123] And then I'm going to ask the next person to do the same.

[124] And then I'm going to ask every person around this area of Battery Park in New York to do the same.

[125] And guess what?

[126] We're going to end up with thousands of different number combinations.

[127] Amazing.

[128] So for all of us, it's yellow enough that we can use a common language.

[129] But for every one of us, that yellow is going to be ever so slightly differently.

[130] And so I think that simple psychological experiment beautifully illustrates how we truly perceive the world differently.

[131] I love that example.

[132] And yet in that example, we know the basic elements from which color is created.

[133] If we migrate into a slightly different sense, let me pick a hard one.

[134] Like sound, sound or olfaction.

[135] Yeah, very hard then to do an experiment.

[136] 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.

[137] But I have no way whether the two of us are experiencing the same.

[138] But it's close enough that we can both pretty much say that it has the following, you know, features or other determinants.

[139] But no question that your experience is different than my.

[140] 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.

[141] You got it.

[142] It raises a thought about a statement made by a colleague of ours, Marcus Meister at Caltech.

[143] It'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 outcomes downstream of three basic emotional responses.

[144] Yum. I like it.

[145] Yuck.

[146] I hate it.

[147] Or meh.

[148] whatever.

[149] What do you think about, I'm not looking to establish a debate between you, Marcus, without Marcus here.

[150] I understand.

[151] 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.

[152] 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.

[153] And yet we function.

[154] 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.

[155] So is there a general statement that we can make about the brain, not just as an organ to generate perception, not just as an organ to keep us alive, but also an organ that is trying to batch our behaviors into general categories of outcome.

[156] I think so, but again, I think the role of Marcus too.

[157] And I think he's right that, you know, broadly speaking, you could categorize a lot of behaviors falling into those true categories.

[158] And that's 100 % likely to be the case for animals in the wild.

[159] where, you know, the choices are not necessarily binary, but they're very unique and distinct.

[160] Do I want to eat this?

[161] Do I want to kill that?

[162] Do I want to go there or do I want to go here?

[163] We humans deviated from that long ago and you know, learn to experience life where we do things that we should not be doing.

[164] Some of us more than others.

[165] Exactly.

[166] You know, in my own world of taste, yeah, the likelihood that an animal in the wild will enjoy eating something bitter, it's inconceivable.

[167] Yet we...

[168] you know, love tonic water.

[169] We enjoy, we like living on the edge.

[170] We love enjoying experiences that makes us human.

[171] And that goes beyond that simple set of categories, which is yummy, yucky, ah, who cares?

[172] And so I think it's not a bad palate, but I think it's overly reductionist for certainly what we humans.

[173] I agree.

[174] And since we're here in New York, I can say 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.

[175] 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.

[176] First of all, I'd like to know why you migrated from studying vision to studying taste.

[177] 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.

[178] My goal has always been to understand, as I highlighted before, how the brain does its magic.

[179] You know, what part you might wonder.

[180] Ideally, I like to help contribute to understand all of it.

[181] You know, how do you encode and decode emotions?

[182] How do you encode and decode memories and actions?

[183] How do you make decisions?

[184] How do you transform detection into perception?

[185] And the list goes on and on.

[186] But one of the key things in science, as you know, is ensuring that you always ask the right question so that you have an...

[187] possibility of answering it.

[188] 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.

[189] Make sense?

[190] From a first person perspective, yes.

[191] The hardest question, the most important question is, what question are you going to try and answer?

[192] You got it, yeah.

[193] And so, for example, I would have to understand the neural basis of empathy.

[194] It's a big market for that.

[195] 100%.

[196] But I wouldn't even know, I mean at the molecular level, that's what we do.

[197] How do the circuits in your brain create that sense?

[198] I have no clue how to do it.

[199] I can come up with ways to think about it, but I like to understand what in your brain makes someone a great philanthropist.

[200] What is the neural basis of love?

[201] I wouldn't even know where to begin.

[202] 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.

[203] But in a way that I can ask questions that get me answers.

[204] And among the senses, that, you know, have the capacity of transforming detection into perception, of being stories, of creating emotions, of giving you different actions and perceptions as a function of the internal state.

[205] You know, when you're hungry, things taste very differently that when you're sated, How?

[206] Why?

[207] When you taste something, you now remember this amazing meal you had with your first date.

[208] How does that happen?

[209] All right.

[210] So if I want to begin to explore all of these things that the brain does, I have to choose a sensory system that affords some degree of simplicity in the way that the input output relationships are put together, and in a way that still can be used to ask every one of these problems that the brain has to ultimately compute, encode, and decode.

[211] 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.

[212] You know, we knew that we could taste what has been usually defined as the big, the five basic taste qualities.

[213] Sweet, sour, bitter, salty, and umami.

[214] Umami is a Japanese word that means yummy, delicious.

[215] And that's nearly every animal species, the taste of amino acids.

[216] And in humans, it's mostly associated with the taste of MSG, monosodium glutamate, one amino acid in particular.

[217] Just by way of example, some foods that are rich in the umami evoking stimulation.

[218] Seweed, tomatoes, cheese.

[219] And it's a great, great flavor enhancer.

[220] It enriches our sensory experience.

[221] And so the beautiful thing of the system is that the lines of input are limited to five.

[222] you know, sweets, sour, bitter, salty, and umami.

[223] And each of them has a predetermined meaning.

[224] You are born liking sugar and disliking bitter.

[225] You have no choice.

[226] These are hard wire systems.

[227] But of course, you can learn to dislike sugar and to like bitters, but in the while, Let's take humans out of the question.

[228] These are 100 % predetermined.

[229] You're born with that specific valence, value for each taste.

[230] Sweet, umami, and low salt are attractive taste qualities.

[231] They evoke appetitive responses.

[232] I want to consume them.

[233] And bitter and sour...

[234] are innately predetermined to be aversive.

[235] Could I interrupt you just briefly and ask a question about that exact point?

[236] For something to be appetitive and some mother tastes 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?

[237] A hundred percent.

[238] You got it.

[239] The activation of the receptors in the tongue that recognize sweet versus the ones that recognize bitter activate an entire behavioral program.

[240] And that program that we can refer as...

[241] appetitiveness or aversion, it's composed of many different subroutines.

[242] In the case of bitter, it's very easy to actually look, see them happening in animals, because the first thing you do is you stop leaking, then you put unhappy face, then you squint your eyes, and then you start gagging.

[243] And that entire thing happens by the activation of a bitter molecule in a bitter sense in cell in your talk.

[244] It's incredible.

[245] 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, you know, unique.

[246] sensory stimuli.

[247] Now, let me say that this palette of five basic tastes accommodates all the dietary needs of the organism.

[248] Sweet to ensure that we get the right amount of energy.

[249] Umami, to ensure that we get proteins, and that essential nutrient.

[250] Salt, the three appetitive ones, to ensure that we maintain our electrolyte balance.

[251] Bitter to prevent the injection of toxic, nauseous chemicals.

[252] Nearly all bitter -tasting, you know, things out in the wild are bad for you.

[253] And sour, most likely to prevent the injection of spoil, acid, fermented foods.

[254] And that's it.

[255] That is the palate that we deal with.

[256] Now, of course, there's a difference between basic taste and flavor.

[257] Flavor is the whole experience.

[258] 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.

[259] 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.

[260] 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.

[261] So we give the animal sweet or we give them a bitter or we give them sour.

[262] 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?

[263] Yeah, almost like the primary colors to create the full array of the color spectrum.

[264] Exactly.

[265] 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 There is, for example, what about fat?

[266] I love the taste.

[267] I love fat too.

[268] 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.

[269] and then serve it back to me and I thought that's disgusting.

[270] And then I tasted it and it's delightful.

[271] It is.

[272] There's nothing quite like it.

[273] This goes back to this notion before that we like to live on the edge.

[274] Yeah?

[275] And we like to do things that we should not be doing, Andrew.

[276] But on the other hand, look at those muscles.

[277] I don't suggest anyone eat pure fat.

[278] The listeners of this podcast will immediately, I'm sure there'll be a YouTube video soon that I like eating pure fat.

[279] I'm not on a ketogenic diet, et cetera.

[280] But fat is tasty, as evidenced by...

[281] The obesity problem that exists in this country.

[282] We'll talk about that, you know, in a little bit about the, you know, the gut brain axis.

[283] I think it'll be important to cover it because it's the other side of the taste system.

[284] And so missing taste, you know, one is fat.

[285] Although, like you clearly highlighted, a lot of fat taste, in quotation marks, is really the feeling of fat rolling on your tongue.

[286] And so there is a compelling argument that a lot of what we call fat taste is really mechanosensory.

[287] 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.

[288] 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.

[289] For example, and another one, you know, you could argue it's metallic taste.

[290] You know, I know exactly what it tastes like.

[291] You know, if you ask me to explain it, I will have a hard time.

[292] you know, what are the palettes of that color that can allow me to define it?

[293] I wouldn't be easy, but I know precisely what it tastes like.

[294] You know, take a penny put it in your mouth and you know what it tastes like, yeah?

[295] Or blood.

[296] Or blood, that's another very good example.

[297] And is there really, you know, a receptor for metallic taste or it's nothing but this magical combination of the activation of the existing lines.

[298] Think of it as lines of information, yes, separate lines, like the keys of a piano, yeah?

[299] Sweet, sour, beat, a salty umami, you play the key and you activate that one chord.

[300] And that one chord, in the case of a piano, leads to a note, you know, a tune.

[301] And in the case of taste, leads to an action and a behavior.

[302] But you play many of them together and something emerges that it's different than any one of the pieces.

[303] And it's possible that metallic, for example, represents the combination of the activity just in the right ratio of these other lines.

[304] Makes sense.

[305] 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.

[306] 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.

[307] So let's start by debunking that old tail and myth.

[308] Who came up with that?

[309] There are many views, but the most prevalent is that there was an original drawing describing the sensitivity of the tongue to different tastes.

[310] So imagine I can take a Q -tip.

[311] This is a thought experiment, yeah?

[312] And I'm going to dip that Q -tip in salt and in quinine as something bitter and glucose as something sweet.

[313] 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.

[314] And then I'm going to change the concentration of the amount of...

[315] salt or the amount of bitter and ask, can I get some sort of a map of sensitivity to the different tastes?

[316] And the argument that has emerged is that there is a good likelihood that the data was simply mistranslated as it was being drawn.

[317] And of course, that led to an entire industry.

[318] 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 happened.

[319] All right.

[320] Now, there is no tongue map.

[321] all right we have taste bats distributed in various parts of the tongue so there is a map on the distribution of taste baths but each taste bat has around a hundred 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 bads have the representation of all five taste qualities.

[322] Now, there's no question that there is a slight bias for some taste.

[323] Like bitter is particularly enriched at the very back of your tongue.

[324] And there is a teleological basis for that, actually a biological basis for that.

[325] That's the last line of defense before you swallow something bad.

[326] 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.

[327] and get rid of this that otherwise may kill you okay that's good sense 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 oh i was just going to ask are there first of all thank you for dispelling that myth yes 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.

[328] The other one is, are there taste receptors anywhere else in the mouth, for instance, on the lips?

[329] Yeah, the palate, the palate, not the lips.

[330] So it's in the far inch at the very back of the oral cavity, the tongue, and the palate.

[331] And the palate is very rich in sweet receptors.

[332] I'll have to pay attention to this the next time I eat something sweet.

[333] Whether you pull it up, yeah?

[334] Now, The important thing is that, you know, after the receptors for these five detectors, the molecules that sense sweet, sour, beta, salt, umami, these are receptors, proteins found on the surface of taste receptor cells that interact with these chemicals.

[335] 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.

[336] Now having these receptors, and my laboratory identify the receptors for all five basic taste classes, sweet, bitter, salt, umami, and most recently sour.

[337] 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.

[338] 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.

[339] This is not a guess.

[340] This is now a physical map that says the sweet receptors are found here.

[341] The bitter are found here.

[342] 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.

[343] Amazing.

[344] And as it turns out, and I'm sure you'll tell us, important in terms of thinking about how the brain computes and codes and decodes, this thing we call taste.

[345] 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.

[346] and burning my tongue is the way I would describe it.

[347] Horrible and then disrupting my sense of taste for some period of time afterward.

[348] Yes.

[349] When I experienced that phenomenon, that unfortunate phenomenon, have I destroyed taste receptors that regenerate?

[350] Or have I somehow used temperature to distort the function of the circuit so that I no longer taste the way I did before?

[351] Excellent question and the answer is both.

[352] It turns out that your taste receptors only leave for around two weeks.

[353] 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.

[354] Use your imagination.

[355] And so...

[356] you need to make sure that these cells are always coming back in a way that can I re -experience the world in the right way.

[357] And there are other organs that have the same underlying logic, okay?

[358] Your gut, your intestines are the same way.

[359] Amazing.

[360] Again, they're receiving everything that you ingest.

[361] God forbid what's there.

[362] From the spiciest, you know, to the most horrible tasting so the most delicious.

[363] And again, those intestinal cells whose role is to ultimately take all these nutrients and bring them into the body, also renewal in a very, very fast cycle.

[364] Alphactory neurons in your nose is the other example.

[365] So then A, yes, you're burning a lot of your cells and it's over for those.

[366] The good news is that they're going to come back.

[367] But we know that when you burn yourself with T, they come back, you know, within 20 minutes, 30 minutes, an hour.

[368] And these cells are not renewing in that time frame.

[369] They're not listening to your needs.

[370] They have their own internal clock.

[371] Okay.

[372] And so you are really affecting, you're damaging them in a way that they can recover.

[373] And then they come back and you also damage your somatosensory cells.

[374] These are the cells that feel things, not taste things.

[375] And then, you know, you wait half an hour or so and then...

[376] My goodness, thank God, it's back to normal.

[377] And 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.

[378] But as the next step along the circuit, let's assume I ingest some, let's keep it simple, a sweet taste.

[379] Let's make it even simpler.

[380] but at the same time perhaps more informative.

[381] Let's compare and contrast sweet and bitter as we follow their lines from the tongue to the brain.

[382] So the first thing is that the two evoke diametrically opposed behaviors.

[383] If we have to come up with two sensory experience that represent polar opposites, it will be sweet and bitter.

[384] There are not two colors that represent polar opposites because, you know, you can say black and white, they are polar opposites.

[385] One detects only one thing, the other one detects everything.

[386] But they don't evoke different behaviors.

[387] Even political parties have some over that.

[388] Sweet and bitter are the two opposite ends of the sensory spectra.

[389] Now, a taste...

[390] can be defined by two features.

[391] Again, I'm a reductionist, so I'm reducing it in a way that I think it's easier to follow the signal.

[392] And the two features are its quality and its valence.

[393] 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?

[394] Or in this case, of that stimuli.

[395] And you take sweet.

[396] Sweet has a quality, an identity, and that's what you and I will refer to us the taste of sweet.

[397] We know exactly what it tastes like.

[398] But sweet also has a positive valence.

[399] which makes it incredibly attractive and appetitive.

[400] But it's attractive and appetitive, as I'll tell you in a second, independent of its identity and quality.

[401] In fact, we have been able to engineer animals where we completely remove the valence from the stimuli.

[402] So these animals can taste sweet, can recognize it as sweet, but it's no longer attractive.

[403] It's just one more chemical stimulus.

[404] And that's because the identity and the valence are encoded in two separate parts of the brain.

[405] In the case of bitter, again, it has, on the one hand, its identity, its quality.

[406] And you know exactly what bitter tastes like.

[407] I can taste it now even as you describe it.

[408] But it also has a valence.

[409] And that's a negative valence because it evokes adverse behaviors.

[410] Are we on?

[411] Absolutely.

[412] And it comes to mind.

[413] I remember telling some kids recently that we're going to go get ice cream and it was interesting.

[414] They looked up and they started smacking their lit, like, you know, they'll actually vote.

[415] The anticipatory response.

[416] Absolutely.

[417] When we talk about the gut brain, maybe we'll get there.

[418] 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.

[419] 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 tastes ganglia.

[420] These are the neurons that innervate your tongue and the oral cavity.

[421] Where do they sit approximately?

[422] Around there.

[423] Yeah, right here, around the lymph nodes, more or less.

[424] You got it.

[425] And there are two main ganglia that innervate the vast majority of all taste butts in the oral cavity.

[426] And then from there, that sweet signal goes onto the brain stem.

[427] The brain stem is the entry of the body into the brain.

[428] 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, a topographically defined location in the rostral side of the brain stem that receives all of the taste input.

[429] A very dense area of the brain.

[430] A very rich area of the brain, exactly.

[431] And from there, the sweet signal goes to this other area higher up on the brain stem.

[432] And then he goes through a number of stations where that sweet signal goes from sweet neuron to sweet neuron to sweet neuron to eventually get to your cortex.

[433] And once it gets to your taste cortex, that's where meaning is imposed into that signal.

[434] It's then, and only then, this is what the data suggests, that now you can identify this as a sweet stimuli.

[435] And how quickly does that all happen?

[436] You know, the time scale of the nervous system is fast, yeah?

[437] Within less than a second.

[438] Yeah, absolutely, yeah.

[439] I rarely mistake bitter for sweet.

[440] Yeah.

[441] Maybe with respect to people and my own poor judgment, but not with respect to taste.

[442] Yeah.

[443] And in fact, we can demonstrate this because we can stick electrodes at each of these stations.

[444] conceptually, yeah?

[445] And we can stimulate the tongue and then we can record the signals pretty much time log to stimulus delivery.

[446] You deliver the stimuli and within a fraction of a second, you see now the response in this following stations.

[447] Now it gets to the cortex, and now in there you impose meaning to that taste.

[448] 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.

[449] In essence, there is a topographic map of this taste qualities inside your brain.

[450] Now, we're going to do a thought experiment, all right?

[451] Now, if this group of neurons in your cortex really represents the sense of sweet, and this added different group of neurons in your brain represents the taste, the perception of bitter, then we should be able to do two things.

[452] 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.

[453] And conversely, I should be able to go into your brain, come up with a way to activate those neurons.

[454] Well, I'm giving you absolutely nothing.

[455] And you're going to think that you're getting that full percept.

[456] And that's precisely what we have done.

[457] And that's precisely what you get.

[458] This, of course, is in the brain of mice, eh?

[459] But presumably in humans, it would work similarly.

[460] Absolutely the same.

[461] Zero doubt.

[462] I have no question.

[463] So this attest to two important things.

[464] The first to the predetermined nature of the sense of taste.

[465] Because it means I can go to these parts of your brain in the absence of any stimuli.

[466] and have you throw the full behavioral experience.

[467] In fact, when we activate in your cortex, these bitter neurons, the animal can start gagging.

[468] But it's drinking only water.

[469] but the animal thinks that it's getting a bitter stimuli.

[470] This is amazing.

[471] And so, 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.

[472] It is that, you know, it substantiates this capacity of the brain to segregate to separate in these nodes of action.

[473] the representation of these two diametrically oppose percepts, which is sweet, for example, versus bitter.

[474] The reason I say amazing, and that is also amazing, is the following.

[475] 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.

[476] So that raises the question for me of whether or not those separate sets of neurons are connected to areas of the brain that create this sense of valence or whether or not they're simply connected, excuse me, to sets of neurons that evoke distinct behaviors of moving towards and inhaling more and licking or aversive.

[477] Are we essentially interpreting our behavior and our micro responses?

[478] or are micro responses and our behaviors the consequence of the persa?

[479] Excellent, excellent question.

[480] So first the answer is they go into an area of the brain where valence is imposed.

[481] And that area is known as the amygdala.

[482] And the sweet neurons go to a different area than the bitter neurons.

[483] Now, I want to do a thought experiment because I think your audience might appreciate this.

[484] Let's say I activate this group of neurons and the animal increases leaking.

[485] And I'm activating the sweet neurons.

[486] And so that's expected because now it's, you know, tasting this, this water as if it was sugar.

[487] Now, this is moses, transforming water into wine.

[488] In this case, we're going to, and today is Passover.

[489] So then this is an appropriate, you know, example.

[490] We're transforming it into sweet.

[491] Yeah?

[492] But how do I know, how do I know that activating them is evoking a positive feeling inside, a goodness, a satisfaction or I love it, versus I'm just increasing leaking.

[493] Which is the other option because all we're seeing is that the animal is leaking more and we're trying to infer...

[494] that that means that he's feeling something really good versus, you know what?

[495] That piano line is going back straight into the tongue and all he's doing is forcing it to move faster.

[496] Well, we can actually separate this by doing experiments that allows to fundamentally distinguish them.

[497] And imagine the following experiment.

[498] I'm going to take the animal and I'm going to put them inside a box that has two sides.

[499] And the two sides have features that make him different.

[500] One has yellow little toys, the other one has green toys.

[501] One has little black stripes, the other one has blue stripes.

[502] So the animal can tell the two halves.

[503] I take the mouse, put them inside this arena, this play arena, and it will explore and pots around both sides with equal frequency.

[504] And now what I'm going to do is I'm going to activate these neurons, these sweet neurons, every time the animal is on the side with the yellow stripes.

[505] And if that is creating a positive internal state, what would the animal now want to do?

[506] It will want to stay on the side with the yellow stripes.

[507] There's no leaking here.

[508] The animal is not extending its tongue every time I'm activating this neurons.

[509] This is known as a place preference test.

[510] And it's generally used.

[511] It's just one form of many different tests to demonstrate that the activation of a group of neurons in the brain is imposing...

[512] For example, a positive versus a negative valence.

[513] Whereas if I do the same thing by activating the bitter neurons, the animal will actively want now to stay away from the side where these neurons are being activated.

[514] And that's precisely what you see.

[515] And that's precisely what we see.

[516] 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.

[517] 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 adapt evolutionarily adaptive reasons why this such a phenomenon would exist Do we have any concept of where in this pathway that exists?

[518] We know actually a significant amount at a general level there.

[519] In fact, more than shrimp, oysters are even a more dramatic example.

[520] One bad oyster is all you need to be driven away for the next six months.

[521] I think because the texture alone is something that one learns to overcome.

[522] I actually really enjoy oysters.

[523] I despise muscles, despise shrimp, not the animal, but the taste.

[524] And yet oysters for some reason, I've yet to have a bad experience.

[525] It's like uni, by the way.

[526] You know, texture is hard to get over.

[527] But once you get over, it's delicious.

[528] That's what they tell me. We were both in San Diego at one point, and I'll give a plug to sushi otas, kind of the famous little sushi.

[529] And they have amazing uni, and I've tried it twice, and it's a, I'm 0 for two.

[530] Somehow the texture outweighs any kind of the deliciousness that people report.

[531] It's a very acquired taste.

[532] It's like beer.

[533] You know, if you, I grew up in Chile.

[534] That's where the accent comes from in case anyone wonder.

[535] And you know, by the time I came here to graduate school, I was 19, too old to, you know, overcame my heavy Chilean accent.

[536] So here I am, 50 years, 50 years late, not quite, 40 plus.

[537] And I still sound like I just came off the boat.

[538] So in Chile, you don't drink beer when you're young.

[539] You drink wine.

[540] You know, Chile is a huge wine producer.

[541] So when I came to the U .S., 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, beer drinking and, you know, graduate school, you're working 18 hours a day, every day.

[542] The way they, you know, relax, let's go and have some beers.

[543] And beer is cheaper.

[544] And beer is cheap.

[545] And we were being clearly underpaid, may I add.

[546] Yeah.

[547] I couldn't do it.

[548] It's an acquired taste.

[549] It was too late by then.

[550] And here I am, you know, 60 plus.

[551] And if you take all the beer I've drunk in my entire life, I would say they add to less than an 8 ounce glass of water.

[552] Impressive.

[553] Well, your health is probably better for it.

[554] I'm not sure.

[555] Your physical health, anyway.

[556] So, you know, it goes back to, you know, acquire taste.

[557] This is the connection to uni and to oysters.

[558] Now, going back to the one trial learning, you know, this is the great thing about our brains.

[559] Certain things, we need to repeat a hundred times to learn them.

[560] Hello, operator, can I have the phone number for Sushi Otta, please?

[561] And then she'll give it to you over the phone, at least in the old days.

[562] And then you need to repeat it to yourself over and over and over the next minute so you can dial Sushi Otta.

[563] And five minutes later, it's gone.

[564] That's what we call working memory.

[565] Then there is the short -term memory.

[566] We park our car.

[567] And if we're lucky, by the end of the day, we remember where it is.

[568] And then there is the long -term memory.

[569] We remember the birthdays of every one of our children for the rest of our lives.

[570] Well, there are events that a single event is so traumatic.

[571] Yeah?

[572] That it activates the circuits in a way that it's a one -trial learning.

[573] And the taste system is literally at the top of that food chain.

[574] And there is a phenomenon known as conditioned taste aversion.

[575] You can pair an attractive stimuli with a really bad one.

[576] And you can make an animal begin to vehemently dislike, for example, sugar.

[577] 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.

[578] 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?

[579] And this is the way now you begin to explore how the brain changes the nature, the quality, the meaning of stimuli as a function of its state.

[580] I have a number of questions related to that, all of which relate to this idea of context.

[581] Because you mentioned before that flavor is distinct from taste because flavor involves smell, texture, temperature, and some other features.

[582] Uni, sea urchin being a good example of, I can sense the texture.

[583] It actually, no, I won't describe what it reminds me of for various reasons.

[584] 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 many different tastes on the taste dial, to go back to your analogy earlier, the color dial, do you think that there could be for something as fixed as bitter?

[585] So for instance, I don't think I like bitter tastes, but I like some fermented foods that seem to have a little bit of sour and have a little bit of that briny flavor.

[586] How much plasticity do you think there is there?

[587] And in particular, across the lifespan.

[588] 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.

[589] And yet you could also imagine that one of the reasons why they may eventually grow to incorporate vegetables is because of some knowledge that vegetables might be good for you, better for them.

[590] So is there a change in the receptors, the distribution, the number, the sensitivity, etc., that can explain the transition from wanting to avoid vegetables to being willing to eat vegetables?

[591] simply in childhood to early development.

[592] I'm going to take the question slightly differently, but I think it would illustrate the point.

[593] And I want to just use the difference between the olfactory system and the taste system to make the point.

[594] Taste system, five basic palettes.

[595] So it's our bit of salt and omami.

[596] Each of them has a predetermined identity.

[597] We know exactly what, and valence.

[598] These are attractive, these are aversive.

[599] In the olfactory system, it's claimed that we can smell millions of different others.

[600] Yet, for the most part, none of them have an innate predetermined meaning.

[601] In the olfactory system, meaning is imposed by learning and experience.

[602] Even the smell of smoke?

[603] So I'm gonna give you, I'm gonna make it differently.

[604] There are, a handful of the millions of others that were claimed that you could immediately tell me these are aversive and these are attractive.

[605] Voment.

[606] So vomit, it's not...

[607] 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 adverse reaction.

[608] Really?

[609] Really.

[610] Sulfur would be maybe a universal.

[611] I'm not talking pheromones, okay?

[612] Pheromones are in a different category that trigger innate responses.

[613] But nearly every other...

[614] is afforded meaning by learning and experience.

[615] And that's why you like broccoli.

[616] And I despise broccoli because I remember my mother forcing me to eat broccoli.

[617] Same sensory experience.

[618] All right.

[619] This accommodates two important things.

[620] In the case of taste, you have neurons at every station that are for sweet, for sour, for bitter, for salty and umami.

[621] It's only five classes.

[622] So it's not going to take a lot of your brain.

[623] If we can, in fact, smell a million others, and everyone else of others had to have predetermined meaning, there's not going to be enough brain just to accommodate that one sense.

[624] And so evolution in its infinite wisdom...

[625] evolve a system where you put together a pathway and a cortex, olfactory cortex, where you have the capacity to associate every other in a specific context that now gives it the meaning.

[626] Now, let's go back to the original question then.

[627] other than clearly plastic, mega -plastic, because it's fundamental basis and neural organization.

[628] But tastes, we just told you that's, you know, predetermined hardwire.

[629] But predetermined hardwire doesn't mean that it's not modulated by learning or experience.

[630] It only means that you are born liking sweet and disliking bitter.

[631] And we have many examples of plasticity, beer being one example.

[632] So why do we learn to love beer?

[633] It's in coffee.

[634] It's because it has an associated gain to the system.

[635] And that gain to the system, that positive valence that emerges out of that negative signal is sufficient to create that positive association.

[636] And in the case of beer, of course, is alcohol.

[637] The feeling good that we get after is more than sufficient to say, I want to have more of this.

[638] And in the case of coffee, of course, is caffeine activating a whole group of neurotransmitter systems that give you that high associated with coffee.

[639] So, yes, the taste system is changeable, it's malleable, and is subjected to learning and experience.

[640] But unlike the olfactory system, it's restricted in what you could do with it because it's goal...

[641] is to allow you to get nutrients and survive.

[642] The goal of the olfactory system is very different.

[643] It's being used, not in our case, but in every animal species, to identify friend versus foe, to identify mate, to identify ecological niches they want to be in.

[644] So it plays a very broad role.

[645] that then requires that it be set up, organized, and function in a very different type of context.

[646] Taste is about can we get the nutrients we need to survive?

[647] And can we ensure that we are attracted to the ones we need?

[648] And we are versed to the ones that are going to kill us.

[649] I'm being overly simplistic and reductionist, but I think it illustrates a huge difference between these two kimosensory systems.

[650] I don't think it would be overly simplicity.

[651] I think it illustrates the key and tractable nature of this system and the way you've approached it.

[652] And I think it's important for people to hear that because everybody, as we are mystified with empathy and love, et cetera.

[653] So in fairness to that, I'm going to ask a sort of high level question or abstract question.

[654] This was based on a conversation I had with a former girlfriend where we're talking about chemistry between individuals.

[655] Yes.

[656] Very complicated topic on the one hand.

[657] 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.

[658] at least for some period of time.

[659] I didn't know this was that kind of a podcast.

[660] No, well, the reason I...

[661] But this has to do with taste because she said something, I think in part to maybe irritate me a bit, but we were commenting not about our own experience of each other, but of someone that she was now very excited about.

[662] We're on good terms.

[663] Uh -huh.

[664] And she said, what do you think it is this thing of chemistry?

[665] So maybe she was trying to, you know.

[666] Warn you of what's coming.

[667] Warn me what's coming.

[668] And she said, I have a feeling something about it is in smell.

[669] And something about it is actually in taste.

[670] Literally the taste of somebody's breath.

[671] That's the way she described it.

[672] And I thought that was a very interesting example for a number of reasons, but in particular because it gets to the merging of odor and taste, but also to the idea that, of course, the context of a new relationship, I'm assuming that, and in fact, they're both attractive people, et cetera.

[673] 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.

[674] Because you just didn't like it.

[675] But because it just didn't like it.

[676] But that's because you associated with other others that trigger that...

[677] negative, you know, aversive reaction, by the way.

[678] Absolutely.

[679] There are certain perfumes to me that are aversive.

[680] You got it.

[681] And there are other scents, I can recall sense of skin, of foods, et cetera, that are immensely appetitive.

[682] So I've experienced both sides of this equation myself.

[683] 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.

[684] even mothers describing the smell of their baby's head, right?

[685] A mother in us.

[686] I mean, you know, our own babies, when they're in their necks.

[687] That's the magical place.

[688] The back of their neck.

[689] There you go.

[690] Oh my goodness.

[691] I have a grandchild now, so I know exactly what Rio, that's his name, smells like.

[692] Okay, so more beautiful examples.

[693] It's always more fun to think about the beautiful positive, the appetitive examples.

[694] The smell of the back of your grandson's neck Yes.

[695] I mean, you could get more specific than that, but not a lot more specific.

[696] So what is going on in terms of the combination of odor and taste, given that these two systems are so different?

[697] Yes.

[698] And they come together.

[699] Ultimately, there is a place in the brain where they come together to integrate the two into what we would call, you know, that sensory experience.

[700] And I'll tell you an experiment that you could do that demonstrates this.

[701] I think it's good for the, you know, for your audience here to get a sense of how we approach these problems so that we can get, you know, meaningful scientific answers.

[702] So we know where the olfactory cortex is in the brain.

[703] We know where the taste cortex is in the brain.

[704] They're in two different places.

[705] We can go to each of these two cortices, put color traces.

[706] We put green in one, we put red in the other, and we see where the colors go to.

[707] That's a reflection of where those neurons are projecting to into their next targets.

[708] Once they get the signal, where do they send the signal to?

[709] And then we reason that if odor and tastes come together somewhere in the brain, we should find an area that now it's getting red and green color.

[710] And we found such an area.

[711] And next, we anticipated, we hypothesized that maybe this is the area in the brain of the mouse, corresponding area in the brain of humans, that integrates other and taste.

[712] It's known, the term normally uses, multi -sensory integration.

[713] And if this is true, we could do the following experiment.

[714] We can train a mouse to lick sweet, and if they guess correctly, that that is supposed to be sweet, they should go now to the right port to the right side to get a water reward.

[715] If they go to the left when it was sweet, then they're incorrect and they get no reward.

[716] And they actually get a time out.

[717] Now, the mice are Thursday, so they're very motivated to perform.

[718] And if you repeat this task a hundred times, a hundred trials, Incredibly enough, this animal learned to recognize the sweet and execute the right action.

[719] And by their action, we now are being told what that animal is tasting.

[720] We can make it more interesting and we can give him sweet and bitter and say, if it's sweet go to the right and his bitter, go to the left.

[721] And after you train him this mice with 90 % accuracy, we'll tell you when you randomize now the stimuli, what was sweet and what was bitter.

[722] All right.

[723] We can now do the same experiment, but now mix taste with odor.

[724] And say, if you got odor alone, go to the right or push this lever.

[725] in mice.

[726] If you get taste alone, go to this other part or push this other lever.

[727] And if you get the two together, do this something else.

[728] And if you train the mice, the mice are able now to report back to you when it's sensing, taste alone, odor alone, or the mix.

[729] Make sense?

[730] Makes sense.

[731] Now we can go to the brain of this mice and go to this area that we now uncover, discover as being the site of multi -sensory integration between this and other, and silence it.

[732] Prevent it from being activated experimentally.

[733] And if that area really represented the integration of these two, the animals should still be able to recognize the taste alone.

[734] They still should be able to recognize the other alone, but should be incapable now to recognize the mix.

[735] And exactly as predicted, that's exactly what you get.

[736] All right?

[737] The brain is basically a series of engineered circuits.

[738] Complex.

[739] You got it.

[740] And our task is, you know, to figure out how can we extract, you know, this amazing architecture of these circuits in a way that we can begin to uncover the mysteries, you know, of the brain.

[741] And why certain people's breath tastes so good and other people's not so good.

[742] so i never answered that but i told you how we can figure out where in the brain is happening as we've been having this discussion i thought a few times about similarities to the visual system or differences to the visual system the visual system there are a couple of phenomenon that i wonder if they also exist in the taste system and 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.

[743] We offset this with little micro eye movements, et cetera, but the principle is a fundamental one, this habituation or desensization.

[744] Everyone seems to call it something different, but you get the idea, of course.

[745] In the taste system, I'm certainly familiar with eating something very, very sweet for the first time in a long time, and it tastes very sweet.

[746] But a few more licks, a few more bites, and now it tastes not as sweet.

[747] with olfaction, I'm familiar with the odor in a room I don't like or I like, and then it disappearing.

[748] So similar phenomena.

[749] Where does that occur?

[750] And can you imagine a sort of system by which people could leverage that?

[751] Because I do think that most people are interested in eating not more sugar, but less sugar.

[752] I think we have better ways to approach that.

[753] And we can transition from taste into these other circuits that makes sugar so extraordinarily impossible not to consume.

[754] Impossible.

[755] Exactly.

[756] Come on.

[757] So where does this desensitizing happens?

[758] That's the term that we use, eh?

[759] And it's, I think, happening at multiple stations.

[760] It's happening at the receptor level, i .e., the cells in your tongue that are sensing that sugar.

[761] As you activate this receptor and it's triggering activity after activity after activity, eventually you exhaust the receptor.

[762] Again, I'm using terms which are extraordinarily loose.

[763] For sake of this discussion, the receptor gets to a point where it undergoes a set of changes, chemical changes, where it now signals far less efficiently, or it even gets removed from the surface of the cell.

[764] And now what will happen is that the same amount of sugar will trigger far less of a response.

[765] And that is a huge side of this modulation.

[766] 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.

[767] 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.

[768] So there are multiple steps that this signal is traveling.

[769] Now, you might say, why, if this is a label line, why do you need to have so many stations?

[770] 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.

[771] And each of these nodes provides a new side to give it plasticity and modulation, not necessarily to change the way that something tastes, but to ensure that you consume more or less or differently of what you need.

[772] I'm going to give you one example of how the internal state changes the way the taste system works.

[773] Salt...

[774] is very appetitive at low concentrations, and that's because we need it.

[775] It's our electrolyte balance requires salt.

[776] Every one of their neurons uses salt as the most important of the ions, you know, with potassium to ensure that you can transfer these electrical signals within and between neurons.

[777] But at high concentrations, let's say ocean water, is incredibly aversive.

[778] And we all know this because we're going to the ocean and then when you get it in your mouth, it's not that great.

[779] However, if I salt deprive you, and we can do this in experimental models quite readily, Now this incredibly high concentration of salt, one molar sodium chloride, becomes amazingly appetitive and attractive.

[780] What's going on in here?

[781] Your tongue is telling you, this is horrible, but your brain is telling you, I don't care.

[782] You need it.

[783] And this is what we call the modulation of the taste system by the internal state.

[784] And presumably if one is hungry enough, even uni will taste good.

[785] Just kidding to me. You hit it right on the money.

[786] No, no, this is exactly correct.

[787] Or if you're thirsty and hungry, you suppress hunger so that you don't waste water molecules in digesting food.

[788] Why?

[789] Because if you're thirsty and you have no water, you will die within a week or so.

[790] 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.

[791] Water is a different story.

[792] So you could see that there are multiple layers at which the taste system that guides our drive and our motivation to consume the nutrients we need.

[793] has to be modulated in response to the internal state.

[794] And of course, internal state itself has to be modulated by the external world.

[795] 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.

[796] Because you have to ensure that a You know, each step you give the system that level of flexibility or what we call in neuroscience plasticity.

[797] I think we're headed into the gut, 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.

[798] Yes.

[799] Is there any kind of signal for the absence of taste?

[800] despite having something in the mouth.

[801] And here is why I ask, what I'm thinking about is saliva.

[802] 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.

[803] I must confess, when I eat a lot of these highly processed foods, I don't particularly like them.

[804] I tend to crave healthier foods, but that's probably for contextual reasons about nutrients, et cetera.

[805] But I could imagine an experiment where...

[806] Is there a taste of no taste?

[807] Right.

[808] Is there a taste of no taste?

[809] Because in the visual system, there is.

[810] Right?

[811] You close the eyes and you start getting increases in activity in the visual system as opposed to decreases, which often surprises people.

[812] But there are reasons for that because everything is about signal to noise, signal to background.

[813] And it's a good question.

[814] I can tell you that most of our work is trying to focus on how the taste system works.

[815] Not how it doesn't work.

[816] I know.

[817] I'm just being pleased.

[818] I know you're being playful.

[819] And I knew when inviting you here today, I was setting myself up for.

[820] I actually on a different.

[821] We're trying to learn things.

[822] Yeah, I know.

[823] However.

[824] All right.

[825] Listen, I was weaned in this system of that.

[826] And I'll say it here for the second.

[827] Actually, I recorded a podcast recently with a very prominent podcast, Lex Friedman podcast.

[828] And I made reference to the so -called New York neuroscience mafia.

[829] I won't say whether or not we are sitting in the presence of the New York neuroscience mafia member.

[830] But in any event, I know the sorts of a ribbing that they provide.

[831] For those listening, this is the kind of hazing that happens, benevolent hazing in academia.

[832] I'm the target.

[833] Of course.

[834] It's a sign of love.

[835] Exactly.

[836] He's going to tell me that.

[837] And it's always about the science in the end.

[838] Right.

[839] But it's an interesting question.

[840] Look, I am.

[841] I don't know the answer and I don't even know how I would explore it in a way that it will rigorously teach me. But here, let me tell you why I'm asking, and then I'll offer an experiment.

[842] Yes.

[843] That I'd love to see someone in here.

[844] Excellent.

[845] I'm thinking about saliva.

[846] Yes.

[847] Which it's so hard.

[848] No, no, but that we know that we can figure it out.

[849] But the question is whether or not the...

[850] saliva in a fed state is distinct from the saliva in an unfed state such that it modulates the sensitivity of the receptors.

[851] That experiment has been done, no. It has been done.

[852] And so the answer is no. It's not.

[853] And the way you could do the experiment is because we use artificial saliva.

[854] There's such a thing.

[855] I know there's artificial tears.

[856] No, no, we, I don't mean that you go to Walgreens that you get, I mean, we in my laboratory, we know the composition of saliva, and so you can make such a thing.

[857] And you can take, you know, taste cells in culture or in a tongue where you wash it out of, and then you can apply artificial saliva.

[858] And what happens is that the system is being engineered to desensitize to become agnostic for saliva to become invisible.

[859] And there is no difference on the state of the animal.

[860] Great.

[861] Well, this is the reason to do experiments.

[862] Yeah, absolutely.

[863] So it doesn't defeat any grand hypothesis.

[864] It's just a pure curiosity.

[865] So you know that curiosity killed the cat, yeah?

[866] I do.

[867] But saves the career of the scientist every single time.

[868] That's what drives us.

[869] Absolutely.

[870] Every single time.

[871] It's a story of our lives.

[872] Exactly.

[873] Okay.

[874] So if it's not saliva, and apparently it is not, what about internal state?

[875] And what aspects of the internal milieu are relevant?

[876] Because there's autonomic, there's a sleep and awake, there's stress.

[877] One of the questions that I got from hundreds of people when I solicited questions in advance of this episode was, why do I crave sugar when I'm stressed, for instance?

[878] And that could be contextual.

[879] But what are the basic elements?

[880] Because it makes us feel good.

[881] By the way, we'll get to that.

[882] That says the answer.

[883] Soothe.

[884] It activates...

[885] what I'm going to generically refer to as reward pleasure centers in a way that it dramatically changes our internal state.

[886] This is, you know, why do we eat a gallon ice cream when we're very depressed?

[887] Yeah.

[888] In fact, this is a good segue to go into this an entire different world, yeah, of the body telling your brain.

[889] what you need in important things like sugar and fat okay okay but anyways go ahead you were going to ask something well no i i would like to discuss the most basic elements of internal state in particular the ones that are below our conscious detection and this is a of course as 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 couple posters at a meeting.

[890] And then now I believe you and others there are companies, there have companies, there are active research programs, and beautiful work.

[891] Maybe you could describe some of that work that you and others have been involved in.

[892] A lot of the listeners of this podcast will have heard of the gut brain axis.

[893] And there are a lot of misconceptions about the gut brain axis.

[894] Many people think that this means that we think with our stomach because of the quote -unquote gut feeling aspect.

[895] But I'd love for you to talk about the aspects of gut brain signaling that drive our, or change our perceptions and behaviors that are completely beneath our awareness.

[896] Yes.

[897] Excellent.

[898] So let me begin maybe by...

[899] by stating that, you know, the brain needs to monitor the state of every one of our organs.

[900] It has to do it.

[901] 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.

[902] Now, this monitoring of the brain has been known for a long time, but I think what hadn't been fully appreciated, that this is a two -way highway where the brain is not only monitoring, but is now modulating back what the body needs to do.

[903] And that includes all the way from monitoring the frequency of heartbeats, and the way that inspiration and aspirations in the breeding cycle operate to what happens when you ingest sugar and fat.

[904] Now, let me give you an example again of how the brain can take what we would refer to contextual associations and transform it into incredible changes in physiology and metabolism.

[905] Remember Pavlov?

[906] So Pavlov, in his classical experiments in conditioning, you know, associative conditioning, he would take a bell, it would ring the bell every time he was going to feed the dog.

[907] And eventually the dog learned to associate the ringing of the bell with food coming.

[908] Now, the first incredible finding he made is the fact that the dog now, in the presence of the bell alone, will start to salivate.

[909] And we will call that, you know, neurologically speaking, an anticipatory response.

[910] Okay, I could understand it.

[911] I get it.

[912] 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.

[913] But what's even more remarkable is that those animals are also releasing insulin.

[914] in response to a bell.

[915] Okay.

[916] This illustrates one part of this two -way highway, the highway going down.

[917] Somehow the brain created these associations and their neurons in your brain now that no food is coming and send a signal somehow all the way down to your pancreas, that now it says release insulin because sugar is coming down.

[918] 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 yeah i share i share your delight and fascination there's not a day or a lecture or uh some talks are better than others or talk where i don't sit back and just think it's absolutely how it's amazing it's amazing now Now, over the past, I don't know, dozen years, and with great force over the last five years.

[919] Now, the main highway that is communicating the state of the body with the brain has been uncovered as being, what we now refer to as the gut brain axis.

[920] And the highway is a specific bundle of nerves.

[921] you know, which emerge from the vagal ganglia, the nodus ganglia.

[922] And so it's the vagus nerve that it's innervating the majority of the organs in your body.

[923] 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.

[924] And I should point out, as you well know, every organ, spleen, pancreas, lungs.

[925] They all must be monitored.

[926] In fact, you know, I now...

[927] I have no doubt that diseases that we abnormally associated with metabolism, physiology, and even immunity are likely to emerge as diseases, conditions, states of the brain.

[928] I don't think obesity is a disease of metabolism.

[929] I believe obesity is a disease of brain circuits.

[930] I do as well.

[931] Yeah.

[932] And so 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.

[933] You know, led us to, you know, to view, of course, these issues and problems as being one of metabolism, physiology, and so forth.

[934] They remain to be...

[935] the carriers of the ultimate signal, but the brain ultimately appears to be the conductor of this orchestra of physiology and metabolism.

[936] All right.

[937] Now, let's go to the gut brain and sugar.

[938] May we?

[939] Please.

[940] Please.

[941] No, I mean, the vagus nerve has in popular culture, has been kind of converted into this single meaning of calming pathways, mostly because I actually have to tip my hat to the yogic community was among the first to talk about Vegas on and on and on.

[942] there are calming pathways of, you know, so -called parasympathetic pathways within the Vegas.

[943] But I think that the more we learn about the Vegas, the more it seems like an entire set of neural connections as opposed to one nerve.

[944] I just wanted to just mention that because I think a lot of people have heard about the Vegas.

[945] Turns out experimentally in the laboratory, many neuroscientists will stimulate the Vegas 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 Vegas is one of the ways to wake up the brain, counter to the idea that it's just this way of calming oneself down.

[946] And also, of course, I mean, one has to be cautious there in that.

[947] So the Vegas nerve is made out of many thousands of fibers.

[948] you know, individual fibers that make this gigantic bundle.

[949] And it's likely, as we're speaking, that each of these fibers carries a slightly different meaning.

[950] They're not necessarily one by one, maybe five fibers, ten, fivers, twenty do the, all right.

[951] But they carry meaning that's associated with their specific task.

[952] This group of fibers is telling the brain about the state of your heart.

[953] This group of fiber is telling the brain about the state of your gut.

[954] This is telling your brain about its nutritional state.

[955] This is your pancreas.

[956] This is your lungs.

[957] And they are, again, to make the same simple example, the keys of this piano.

[958] Yes, you're right.

[959] There is a lot of data.

[960] showing that activating the entire vagal bundle has very meaningful effects in a wide range of conditions.

[961] In fact, it's being used to treat untractable depression.

[962] A little stimulator.

[963] Epileptic seizures.

[964] But again, there are thousands of fibers carrying different functions.

[965] So to some degree...

[966] You know, this is like turning the lights on the stadium because you need to illuminate where you lost your keys under your seat.

[967] Yet 10 ,000 bulbs of a thousand watts each have just come on.

[968] Only one of this is pointing to work.

[969] And so I'm lucky enough that one of them happened to point to my side.

[970] So here you activate the bundle, thousands of fibers.

[971] 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 epileptic.

[972] But it should not be misconstrued as arguing that this broad activation has any type of selectivity or specificity.

[973] We're just lucky enough that among all the things that are being done, some of those happen to change the biology of these processes.

[974] 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.

[975] And our goal and along with many other great, you know, scientists, including Steve Liverless that started a lot of, you know, this molecular dissection on this vagal gut -brain communication line at Harvard, is trying to uncover what are each of those lines doing.

[976] What are each of those keys of this piano playing?

[977] What's the latest there?

[978] Just as a brief update.

[979] I know Stephen Lee really's, I think I was there when he got his Howard Hughes and I did not.

[980] So that was fun.

[981] Always great to get beat by excellent people.

[982] First of all, I'm happy you didn't because that way you can focus on this amazing podcast.

[983] Thank you.

[984] That's very gracious of you.

[985] It's always feels...

[986] better, if not good to get beat out by excellent people.

[987] Steven is second to none.

[988] And he is defining, as you said, the molecular constituents of different elements of these many, many fibers.

[989] Is there an update there?

[990] Are they finding multiple parallel pathways?

[991] They are, they are.

[992] Some that control heartbeat, some that control the respiratory cycle, some that might be involved in a gastric movement you know, this notion that you are full and you feel full in part because your gut gets distended, your stomach, for example.

[993] And then there are little sensors that they're reading that and telling the brain you're a fool.

[994] So the textbooks will soon change on the basis of the liberties and other work.

[995] In essence, I think we are learning enough about these lines that could really help put together this holistic view of how the brain truly changing body physiology, metabolism, and immunity.

[996] The part that hasn't been yet developed and that it needs a fair amount of work, but it's an exciting, thrilling, you know, the journey of discovery is how the signal comes back to now change that biology.

[997] You know, the example I gave you before with Pavlov's dog, yeah?

[998] All right, I figure out, you know, how the association created this link between the belt, but then how does the brain tell the pancreas to release in the right amount of insulin?

[999] Okay, so tell me, tell me, let me tell you about the gut brain axis and our insatiable appetite for sugar and fat.

[1000] insatiable for sugar and quenchable for fat.

[1001] And this is a story about the fundamental difference between liking and wanting.

[1002] Liking sugar is the function of the taste system.

[1003] And it's not really liking sugar, it's liking sweet.

[1004] Wanting sugar, our never ending appetite for sugar, is the story of the gut brain access.

[1005] Liking versus wanting.

[1006] And this work is work of my own laboratory, that began long ago when we discovered the sweet receptors.

[1007] And you can now engineer mice that lack these receptors.

[1008] So in essence, these animals will be unable to taste sweet, a life without sweetness.

[1009] How horrible.

[1010] And if you give a normal mouse, a bottle containing sweet, and we're gonna put either sugar or an artificial sweetener.

[1011] All right?

[1012] They both are sweet.

[1013] They have slightly different tastes.

[1014] But that's simply because artificial sweeteners have some off tastes.

[1015] But as far as the sweet receptor is concerned, they both activate the same receptor, trigger the same signal.

[1016] And if you give an animal an option of a bottle containing sugar or a sweetener versus water, this animal will drink 10 to 1 from the bottle containing sweet.

[1017] That's the taste system.

[1018] Animal Go samples, each one leaks a couple of leaks, and then says, uh -uh, that's the one I want because it's a pettitive and because I love it.

[1019] So it prefers sugar to artificial sweetener.

[1020] No, no, no, no. Equally artificial sweet.

[1021] In this experiment, I'm going to put only sweet in one bottle.

[1022] And it could be either sugar or artificial sweetener.

[1023] It doesn't matter which one.

[1024] Okay, we're going to do the next experiment where we separate us two.

[1025] For now, it's sweet versus water.

[1026] Okay.

[1027] And sweet means sweet, not sugar.

[1028] Sweet means anything that tastes sweet.

[1029] All right?

[1030] And sugar is one example.

[1031] And Splenda is another example.

[1032] Aspartame, monk fruit, stevia, doesn't matter.

[1033] Yeah, I mean, there's some that only humans can taste.

[1034] Mice cannot taste because their receptors between humans and mice are different.

[1035] But we have put the human receptor into mice.

[1036] We engineer mice, and we completely humanize this mouse's taste world.

[1037] All right?

[1038] But for the purpose of this conversation, we're only comparing sweet versus water.

[1039] An option, my goodness, they will leak to know from the sweet side, 10 to 1 at least versus the water.

[1040] Make sense?

[1041] All right.

[1042] Now we're going to take the mice and we're going to genetically engineer it to remove the sweet receptors.

[1043] So this mice no longer have in their oral cavity any sensors that can detect sweetness, be that sugar molecule, be it an artificial sweetener, be it anything else that tastes sweet.

[1044] And if you give this mice an option between sweet versus water, sugar versus water, artificial sweetener versus water, He will drink equally well from both because he cannot tell them apart.

[1045] Because it doesn't have the receptors for sweet so that sweet bottle tastes just like water.

[1046] Makes sense?

[1047] Makes sense.

[1048] Very good.

[1049] Now, we're going to do the experiment with sugar.

[1050] From now on, let's focus on sugar.

[1051] So I'm going to give a mouse out.

[1052] Sugar versus water.

[1053] Normal mouse will drink from the sugar, sugar, sugar, sugar, sugar, very little from the water.

[1054] knock out the sweet receptors, eliminate them, mouse can no longer tell them apart, and they will drink from both.

[1055] But if I keep the mouse in that case, for the next 48 hours, something extraordinary happens when I come 48 hours later, and I see what the mouse is leaking or drinking from.

[1056] That mouse is drinking almost exclusively from the sugar bottle.

[1057] How could this be?

[1058] He cannot taste it.

[1059] Doesn't have sweet receptors.

[1060] During those 48 hours, the mouse learned that there is something in that bottle that makes me feel good.

[1061] And that is the bottle I want to consume.

[1062] Now, how does the mouse identify that bottle?

[1063] It does so by using other sensory features.

[1064] the smell of the bottle, the texture of the solution inside.

[1065] Sugar, the high concentrations is kind of goopy.

[1066] The sideness in which the bottle is in the cage.

[1067] It doesn't matter what, but the mouse realized there is something there that makes me feel good, and that's what I want.

[1068] And that is the fundamental basis of our unquenchable desire and our craving for sugar, and is mediated by the gut brain axis.

[1069] The first clue is that it takes a long time to develop, immediately suggesting a post -ingestive effect.

[1070] So we reason, if this is true, and it's the gut brain axis that's driving sugar preference, Then there should be a group of neurons in the brain that are responding to post - ingestive sugar.

[1071] And lo and behold, we identify a group of neurons in the brain that does this.

[1072] And these neurons receive their input directly from the gut brain axis.

[1073] From other neurons.

[1074] You got it.

[1075] And so what's happening is that sugar is recognized normally by the tongue.

[1076] activates an appetitive response.

[1077] Now you ingest it, and now it activates a selective group of cells in your intestines that now send a signal to the brain via the vagal ganglia that says, I got what I need.

[1078] The tongue doesn't know that you got what you need.

[1079] It only knows that you tasted it.

[1080] This knows that it got to the point that it's going to be used, which is the gut.

[1081] And now it sends the signal to now reinforce the consumption of this thing because this is the one that I needed.

[1082] Sugar, source of energy.

[1083] Are these neurons in the gut?

[1084] So these are not neurons in the gut.

[1085] So these are gut cells that recognize the sugar molecule.

[1086] I see.

[1087] Send a signal and that signal is received by the vagal neuron directly.

[1088] Got it.

[1089] And they sends a signal through the gut brain access to the cell bodies of these neurons in the vagal ganglia and from there to the brain stem.

[1090] to now trigger the preference for sugar.

[1091] Two questions.

[1092] One, you mentioned that these cells that detect sugar within the gut are actually within the intestine.

[1093] You didn't say stomach, which surprised me. I always think gut as stomach, but of course, intestines.

[1094] They're intestine because that's where all the absorption happens.

[1095] So you want the signal, you see, you want the brain to know that you had successful ingestion and breakdown of whatever you consume into the building blocks of life.

[1096] And, you know, glucose, amino acids, fat, and so you want to make sure that once they are in the form that intestines can now absorb them is where you get the signal back saying, this is what I want.

[1097] Okay?

[1098] Now, let me just take it one step further.

[1099] And this now sugar molecules activates this unique gut brain circuit that now drives the development of our preference for sugar.

[1100] Now, a key element of this circuit is that the sensors in the gut that recognize the sugar do not recognize artificial sweeteners.

[1101] at all because their nutrient value is uncoupled from the taste generically speaking one can make that but it's because it's a very different type of receptor i see turns out that's not the tongue receptors being used in the gut it's a completely different molecule that only recognizes the glucose molecule not artificial sweeteners this has a profound impact on the effect of ultimately artificial sweeteners incurbing our appetite, our craving, our insatiable desire for sugar.

[1102] Since they don't activate the gut brain axis, they'll never satisfy the craving for sugar, like sugar does.

[1103] And the reason I believe that artificial sweeteners have failed in the market to curve our appetite, our need, our desire for sugar, is because they beautifully work on the tongue, the liking to recognize sweet versus non -sweet, but they felt to activate the key sensors in the gut that now inform the brain you got sugar no need to crave anymore so the uh the issue of wanting yes Can we relate that to a particular set of neurochemicals upstream?

[1104] So the pathway is, so glucose is activating the cells in the gut through the Vegas that's communicated through the, presumably the no -dose ganglion and up into the brainstem.

[1105] Very good.

[1106] And from there, where does it go?

[1107] Yeah, where is it going?

[1108] What is the substrate of wanting?

[1109] I, you know, of course I think molecules like dopamine craving.

[1110] There's a book even called the molecule of more, et cetera, et cetera.

[1111] Dopamine is a very diabolical.

[1112] molecule, as you know, because it evokes both a sense of pleasure -ish, but also a sense of desiring more of craving.

[1113] So if I understand you correctly, artificial sweeteners are, and I agree, are failing as a means to satisfy sugar craving at the level of nutrient sensing.

[1114] And yet, if we trigger this true sugar evoked wanting pathway too much, and we've all experienced this, then we eat sugar and we find ourselves wanting more and more sugar.

[1115] Now, that could also be insulin dysregulation, but can we uncouple those?

[1116] Yeah, I mean, look, we have a mega problem with overconsumption of sugar and fat.

[1117] We're facing a unique time in our evolution, where diseases of malnutrition are due to overnutrition.

[1118] I mean, how nuts is that?

[1119] I mean, historically, diseases of malnutrition have always been linked to undernutrition.

[1120] And so we need to come up with strategies that can meaningfully change the activation of these circuits that control are wanting, certainly in the populations at risk.

[1121] And this gut brain circuit that ultimately, it's the lines of communication that are informing the brain, the presence of intestine out sugar in this example, It's a very important target in the way we think about.

[1122] Is there a way that we can meaningfully modulate these circuits?

[1123] So I make your brain think that you got satisfied with sugar even though I'm not giving you sugar.

[1124] so that immediately raises the question are the receptors for glucose in these gut cells susceptible to other things that are healthier for us that's very good excellent idea and i think an important goal will be to come up with a strategy and identify those very means that allow us to modulate the circuits in a way that Certainly for all of those where this is a big issue, it can really have a dramatic impact in improving human health.

[1125] I could be wrong about this and I'm happy to be wrong.

[1126] I'm often wrong and told I'm wrong.

[1127] that we have cells within our gut that don't just sense sugar, glucose, to be specific, but also cells within our gut that sense amino acids and fatty acids.

[1128] I could imagine a scenario where one could train themselves to feel immense amounts of satiety from the consumption of foods that are rich in essential fatty acids, amino acids, perhaps less caloric or less insulin dysregulating than sugar.

[1129] I'll use myself as an example.

[1130] I've always enjoyed sweets, but in the last few years, for some reason, I've started to lose my appetite for them, probably because I just don't eat them anymore.

[1131] At first, that took some restriction.

[1132] Now I just don't even think about it.

[1133] Yeah, and you're not reinforcing the circuits.

[1134] And so you, in essence, are removing yourself from...

[1135] you tend to be the exception.

[1136] You know, we have a huge, a huge, incredible large number of people that are being continuously exposed to highly processed foods, yeah?

[1137] And hidden, so -called hidden sugars.

[1138] They don't even have to be hidden.

[1139] you know it's right there hiding in plain sight yeah i agree so much is made of hidden sugars that um we often overlook that they are there are also the overt sugars yeah i mean we can have a long discussion on the importance of coming up with strategies you know that could meaningfully change public health when it comes to nutrition But I want to just go back to the notion of, you know, this brain centers that are ultimately the ones that are being activated by these essential nutrients.

[1140] So sugar, fat, and amino acids are building blocks of our diets.

[1141] And this is across all animal species.

[1142] So it's not unreasonable then to assume that dedicated brain circuits would have evolved to ensure their recognition, their ingestion, and the reinforcement that that is what I need.

[1143] And indeed, you know, animals evolve these two systems.

[1144] One is the taste system.

[1145] that allows you to recognize them and trigger this predetermined hard wire immediate responses, yes?

[1146] Oh my goodness, this tastes so good, it's so sweet.

[1147] I personally have a sweet tooth, may I add?

[1148] And, you know, oh my God, this is so delicious, it's fatty or umami recognizing amino acids.

[1149] So that's the liking pathway, yeah?

[1150] But in the wisdom of evolution, That's good, but doesn't quite do it.

[1151] You want to make sure that these things get to the place where they are needed.

[1152] And they are not needed in your tongue.

[1153] They are needed in your intestines where they are going to be absorbed as the nutrients that will support life.

[1154] And the brain wants to know this.

[1155] And he wants to know it in a way that he can now form the association between...

[1156] That that I just tasted is what God where it needs to be, and it makes me feel good.

[1157] And so now, next time that I have to choose, what should I eat?

[1158] That association now guides me to, that's the one I want.

[1159] I want that fruit, not that fruit.

[1160] I want those leaves, not those leaves.

[1161] Because these are the ones that activate the right circuits that ensure that the right nutrients got to the right place and told the brain, this is what I want and need.

[1162] are we on we're on one thing that intrigues me and puzzles me yes is that this effect took a couple of days at least in mice yes and the sensation uh sorry the perception of taste is immediate is immediate and yet this is a slow system and so in a beautiful way but in a kind of mysterious way the brain is able to couple the taste of a sweet drink with the experience of nutrient extraction in the gut under a context where the mouse and the human is presumably ingesting other things, smelling other mice, smelling other people.

[1163] That's incredible.

[1164] Yeah, but you have to think of it not as humans.

[1165] Remember, we inherited the circuits of our ancestors and they, through evolutionary, from their ancestors.

[1166] And we haven't had that many...

[1167] you know, years to have fundamentally changed in many of these hard wire circuits.

[1168] So forget as humans, let's look at animals in the wild, okay?

[1169] Which is easier now to comprehend the logic.

[1170] You know, why should this take a long time of continual reinforcement, given that I can taste it in a second?

[1171] You want to make sure that this source of sugar, for example, in the wild, is the best.

[1172] It's the riches.

[1173] It's the one where I get the most energy for the least amount of extraction, the least amount of work.

[1174] I want to identify rich sources of sugar.

[1175] And if the system simply responds immediately to the first sugar that gets to your gut, you're going to form the association with those sources of food, which are not the ones that you should be eaten from.

[1176] Don't fall in love with the first person you encounter.

[1177] Oh my goodness, exactly.

[1178] And so evolutionarily, by having the taste system giving you the immediate recognition, but then by forcing this gut brain access to reinforce it only when sustained, you know, repeated exposure has informed the brain.

[1179] This is the one you don't want to form the association before.

[1180] And so, you know, when we remove it from the context of, you know, we just go to, you know, the supermarket.

[1181] We're not hunting there in the wild where I need to form.

[1182] And so what's happening is that highly processed foods are hijacking, you know, co -opting the circuits in a way that it would have never happened in nature.

[1183] And then we not only find these things appetitive and palatable, but in addition, we are continuously reinforcing you know, the wanting in a way that, oh my God, this is so great.

[1184] What do I feel like eating?

[1185] Let me have more of this.

[1186] You've just forever changed the way that I think about supermarkets and restaurants.

[1187] They're understanding this fast signaling and this slower signaling and the utility of having both.

[1188] makes me realize that supermarkets and restaurants are about the most unnatural thing for our system ever.

[1189] Almost the equivalent of living in small villages with very few suitable mates versus online dating, for instance.

[1190] Look, I'm not going to make a judgment call there because they do serve an important purpose.

[1191] I like restaurants too.

[1192] Yeah, and so do supermarkets, thank God.

[1193] I think they're not the culprits.

[1194] I think the culprits, of course, you know, are reliance on foods that are not necessarily healthy.

[1195] Now, going back to the supermarket, don't fall in love with the forest, they need to work.

[1196] You know, you take...

[1197] a tangerine.

[1198] And you take an extract of tangerine that you used to cook that spike, let's say, with sugar.

[1199] And you equalize in both where they both provide the same amount of calories.

[1200] If you eat them both, they're going to have a very different effect.

[1201] in your gut brain axis and your system.

[1202] Once you make the extract and you process it and you add it processed sugar, you know, to use it now to cook, to add, to make it really sweet tangerine thing.

[1203] Now you're providing now fully ready to use broken down source of sugar.

[1204] In the tangerine, that sugar is mixed in the complexity of a whole set of other chemical components fiber long chains of sugar molecules that need a huge amount of work by your stomach your gut system to break it down so you're using a huge amount of energy to extract energy and the balance It's very different that when I take this process, highly extracted, tangerine, by the way, I used tangerines because I had a tangerine just before I came here.

[1205] Delicious.

[1206] They are delicious.

[1207] And so, and so this goes back to the issue of supermarkets.

[1208] And so to some degree, you know, A, given a choice, you don't want to eat highly processed foods because everything has already been broken down for you.

[1209] And so your system has no work.

[1210] And so you are co -opting, hijacking the circuits in a way that they're being activated at a time scale that normally wouldn't happen.

[1211] This is why I often feel that, and I think a lot of data are now starting to support the idea that while indeed the laws of thermodynamics apply, calories ingested versus calories burned is a very real thing, right?

[1212] That the...

[1213] appetite for certain foods and the wanting and the liking are phenomena of the nervous system, brain and gut, as you've beautifully described, and that that changes over time depending on how we are receiving these nutrients.

[1214] Absolutely.

[1215] Look, we have a lot of work to do.

[1216] I'm talking a society.

[1217] I'm not talking about you and I. We also have a lot of work to do.

[1218] Now, I think understanding the circuits is giving us important insights and how ultimately, hopefully, we can improve human health and make a meaningful difference.

[1219] Now, it's very easy to try to, you know, Connect the dots, A to B, B to C, C to D. And I think there's a lot more complexity to it, but I do think that the lessons that are emerging out of understanding how the circuits operate can ultimately inform how we deal with our diets.

[1220] in a way that we avoid what we're facing now, you know, as a society.

[1221] I mean, it's nuts that the overnutrition happens to be such a prevalent problem.

[1222] And I also think the training of people who are thinking about metabolic science and metabolic disease is largely divorced from the training of the neuroscientist and vice versa.

[1223] No one field is to blame.

[1224] But I fully agree that the brain is the key or the nervous system to be more accurate is one of the key overlooked features.

[1225] It's the arbitrary.

[1226] Ultimately, it's the arbiter of many of these pathways.

[1227] As a final question, and one which is simply to entertain my curiosity and the curiosity of the listeners, what is your absolute favorite food?

[1228] Oh my goodness.

[1229] Taste, I should say.

[1230] Yes.

[1231] Taste to distinguish between taste and the nutritive value or lack of.

[1232] Yes.

[1233] Look, we, unlike every animal species, eat for the enjoyment of it.

[1234] It doesn't happen in the wild.

[1235] Most animals eat when they need to eat.

[1236] It doesn't mean they don't enjoy it, but it's a completely different story.

[1237] Yeah.

[1238] I have too many favorite foods because I enjoy the sensory experience.

[1239] Rather than the food itself, to me, is the whole thing.

[1240] It's from the present.

[1241] Look, they've been these experiments done in psychophysics, eh?

[1242] I'm going to take a salad made out of 11 components.

[1243] And I'm going to mix them all up in a pot -pourri of greens and other things here.

[1244] And in the other one, I'm going to present it in a beautiful arrangement, and I'm going to put it behind a glass cabinet, and I'm going to sell them.

[1245] And I'm going to sell one for $2 and one for $8.

[1246] Precisely the same ingredients, exactly the same amount of each.

[1247] Ultimately, you're going to mix them.

[1248] They're all going to be the same.

[1249] And people will pay the $8 because, you know what?

[1250] It evokes a different person.

[1251] It gives you the feel that, oh my goodness, I'm going to enjoy that salad.

[1252] So going back to what is my favorite food?

[1253] To me, eating is really a sensory journey.

[1254] I don't mean the everyday let me have some chicken wings because I'm hungry.

[1255] But every piece, I think, has an important evoking sensory role.

[1256] And so, you know, in terms of categories of food, you know, I grew up in Chile, yes, of meat is always been, but I eat it so seldom now.

[1257] Is that right?

[1258] Yeah, because, you know, I know that it's not necessarily the oldest thing, red meat I'm talking about, eh?

[1259] And so I, you know, I grew up eating it every day.

[1260] I'm talking seven days a week, Chile and Argentina, you know, that's the mainstay of our diet, yeah?

[1261] Now maybe I have red meat.

[1262] I know.

[1263] Once every four weeks.

[1264] And you enjoy it.

[1265] Oh, I love it.

[1266] Part of it is because I haven't had it in four weeks.

[1267] But, you know, I love sushi.

[1268] But I love the art of sushi.

[1269] You know, the whole thing, you know, the way it's presented, it changes the way you taste it.

[1270] I love ethnic food in particular.

[1271] You're in the right place.

[1272] You got it.

[1273] That was the main reason I wanted to come to New York.

[1274] No, I'm just kidding.

[1275] There's also that Columbia University.

[1276] I came here because I wanted to be with, you know, people that are thinking about the brain the same way that I like to think, which, you know, can we solve this big problem?

[1277] This big question.

[1278] And certainly you're making amazing strides in that direction.

[1279] And I love your answer because it really brings together the many features of the circuitries and the phenomena we've been talking about today, which is that while it begins with sensation and perception, ultimately it's the context and that context is highly individual to person, place, and time and many, many other things.

[1280] On behalf of myself, and certainly on behalf of all the listeners, I want to thank you, first of all, for the incredible work that you've been doing now for decades in vision, in taste, and in this bigger issue of how we perceive and experience life.

[1281] It's truly pioneering and incredible work.

[1282] And I feel quite lucky to have been on the sidelines seeing this over the years and hearing the talks and reading the countless beautiful papers, but also for your time today to come down here and talk to us about what drives you and the discoveries you've made.

[1283] Thank you ever so much.

[1284] It was great fun.

[1285] Thank you for having me. We'll do it again.

[1286] And I wish all.

[1287] Thank you for joining me today for my discussion about perception and in particular the perception of taste with Dr. Charles Zucker.

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[1308] Once again, thank you for joining me today, my discussion with Dr. Charles Zucker about the biology of perception and the biology of the perception of taste in particular.

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