Dr. Charles Zuker on Huberman Lab: Why gut drives craving

1. 0:00 – 0:20

   Charles Zuker

   1. AHAndrew Huberman0:00

      Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Charles Zuker.

2. 0:20 – 2:29

   Senses & Perception

   1. AHAndrew Huberman0:20

      Charles, thank you so much for joining me today.

   2. CZDr. Charles Zuker0:23

      My pleasure.

   3. AHAndrew Huberman0:24

      I want to ask you about many things related to taste and gustatory perception, but maybe to start off, and because you've worked on a number of different topics in neuroscience, not just taste, how should the world and people think about perception, how it's different from sensation, and what leads to our experience of life in terms of vision, hearing, taste, et cetera?

   4. CZDr. Charles Zuker0:48

      The world is made of real things. You know, this here is a glass, and this is a cord, and this is a microphone. But the brain is only made of neurons that only understand electrical signals. So how do you transform that reality into nothing that electrical signals that now need to represent the world? And that process is we can, is what we can operationally define as perception. In the senses, let's say olfactory, odor, taste, vision, you know, we can very straightforwardly separate detection from perception. Detection is what happens when you take a sugar molecule, you put it in your tongue, and then a set of specific cells now sense that sugar molecule. That's detection. You haven't perceived anything yet. That is just your cells in your tongue interacting with this chemical. But now that cell gets activated and sends a signal to the brain, and now detection gets transformed into perception. And it's trying to understand how that happens that's been the, the maniacal drive, eh, of my entire career in neuroscience. How does the brain ultimately transform detection into perception so that it can guide actions and behaviors?

3. 2:29 – 5:49

   Taste, 5 Taste Qualities & Dietary Needs

   1. CZDr. Charles Zuker2:29

      So if I want to begin to explore all of these things that the brain does, I felt I have to choose a sensory system that affords some degree of simplicity in the way that the input-output relationships are put together, and in a way that still can be used to ask every one of these problems that the brain has to ultimately compute, encode, and decode. And what was remarkable about the taste system at the time that I began working on this is that nothing was known about the molecular basis of taste. You know, we knew that we could taste what has been usually defined as the ba- the five basic taste qualities, sweet, sour, bitter, salty, and umami. Umami is a Japanese word that means yummy, delicious, and that's the, uh, nearly every animal species, the taste of amino acids. And in humans, it's mostly associated with the taste of MSG, monosodium glutamate, one amino acid in particular. And so the beautiful thing of the system is that the lines of input are limited to five, and each of them has a predetermined meaning. You're born with that specific valence value for each taste. Sweet, umami, and low salt are attractive taste qualities. They evoke appetitive responses. I want to consume them. And bitter and sour are innately predetermined to be aversive. In the case of bitter, it's very easy to actually look at, see them happening in animals, because the first thing you do is you stop licking, then you put a unhappy face, then you squint your eyes, and then you start gagging. Eh? And that entire thing happens by the activation of a bitter molecule in a bitter sensing cell in your tongue.

   2. AHAndrew Huberman4:47

      It's incredible.

   3. CZDr. Charles Zuker4:48

      It's, it's, it's, it's again, the magic of the brain, you know, how, how it, it's able to encode and decode these extraordinary actions and behaviors in response of nothing but a simple, very s- you know, a, a unique sensory stimuli. This palette of five basic tastes accommodates all the dietary needs of the organism. Sweet to ensure that we get the right amount of energy, umami to ensure that we get proteins, another essential nutrient, salt, the three appetitive ones to ensure that we maintain our electrolyte balance, bitter to prevent the ingestion of toxic, nauseous chemicals. Nearly all bitter tasting, you know, things out in the wild are bad for you. And sour, most likely to prevent the ingestion of spoiled acid, eh, fermented foods. And that's it. That is the palette that we deal

4. 5:49 – 7:05

   Taste vs Flavor

   1. CZDr. Charles Zuker5:49

      with. Now, of course, there's a difference between basic taste and flavor. Flavor is the whole experience. Flavor is the combination of multiple tastes coming together.Together with smell, with texture, with temperature, with the look of it, that gives you what you and I would call the full sensory experience. But, but we scientists need to reduce the, the problem into its basic elements so we can begin to break it apart before we put it back together. So when we think about the sense of taste, and we try to figure out how these lines of information go from your tongue to your brain and how they signal and how they get integrated and how they trigger all these different behaviors, we look at them as individual qualities. So we give the animals sweet or we give them a bitter, we give them sour. We avoid mixes. Think of it as lines of information, separate lines, like the keys of a piano. Sweet, sour, bitter, salty, umami. You play the key and you activate a one chord. And that one chord, in the case of a piano, leads to a note, you know, a tune, and in the case of taste, leads to an action and a behavior.

5. 7:05 – 8:54

   Taste Buds; Bitter

   1. AHAndrew Huberman7:05

      If you would, describe the sequence of neural events-

   2. CZDr. Charles Zuker7:09

      Mm-hmm.

   3. AHAndrew Huberman7:09

      -leading to a perceptual event of taste.

   4. CZDr. Charles Zuker7:12

      We have taste buds distributed in various parts of the tongue. So there is a map on the distribution of taste buds. But each taste bud has around 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 buds have the representation of all five taste qualities. Now, there's no question that there is a slight bias for some taste. Like bitter is particularly enriched at the very back of your tongue. And there is a teleological basis for that, actually a biological basis for that. That's the last line of defense before you swallow something bad. And so let's make sure that the very back of your tongue has plenty of these bad news receptors, so that if they get activated, you can trigger a gagging reflex and get rid of this that otherwise may kill you. The important thing is that, you know, after the receptors for these five, the, the detectors, the molecules that sense sweet, sour, bitter, salt, umami, these are receptors, proteins found on the surface of taste receptor cells that interact with these chemicals. And once they interact, then they trigger the cascade of events, biochemical events inside the cell that now sends an electrical signal that says, "There is sweet here," or, "There is salt here." Let's

6. 8:54 – 11:56

   Sweet vs Bitter, Sensory Perception from Tongue to Brain

   1. CZDr. Charles Zuker8:54

      compare and contrast sweet and bitter as we follow their lines from the tongue to the brain. So the first thing is that the two evoke diametrically opposed behaviors. If we have to come up with two sensory experience that represent polar opposites, it will be sweet and bitter. So then the signals, if we follow now these two lines, they're really like two separate keys at the two ends of this keyboard. And you press one key and you activate this chord, so you activate the sweet cells throughout your oral cavity, and they all converge into a group of sweet neurons. In the next station, which is still outside the brain, is one of the taste ganglia. These are the neurons that innervate your tongue and the oral cavity.

   2. AHAndrew Huberman9:43

      Where do they sit approximately? Are they sort of-

   3. CZDr. Charles Zuker9:44

      Around there.

   4. AHAndrew Huberman9:45

      Yeah, right here around the-

   5. CZDr. Charles Zuker9:46

      Yeah.

   6. AHAndrew Huberman9:46

      -the lymph nodes, more or less.

   7. CZDr. Charles Zuker9:47

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

   8. AHAndrew Huberman10:26

      A very dense area of the brain.

   9. CZDr. Charles Zuker10:28

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

   10. AHAndrew Huberman11:09

       And how quickly does that all happen?

   11. CZDr. Charles Zuker11:11

       You know, the time scale of the nervous system, it's fast, yeah? And so-

   12. AHAndrew Huberman11:16

       Within less than a second.

   13. CZDr. Charles Zuker11:18

       Yeah. And, and in fact, we can demonstrate this because we can stick electrodes at each of these stations. You deliver the stimuli, and within a fraction of a second, you see now the response in these following stations. Now it gets to the cortex. And now in there, you impose meaning to that taste. There is an area of your brain that represents the taste of sweet in taste cortex, and a different area that represents the taste of bitter. In a sense, there is a topographic map of these taste qualities inside your brain.

7. 11:56 – 13:22

   Taste Plasticity & Changing Food Preferences

   1. AHAndrew Huberman11:56

      How much plasticity do you think there is there, and in particular across the lifespan? Because I think one of the most salient examples of this is that kids don't seem to likeCertain vegetables, but they all are hardwired to like sweet tastes. And yet you could also imagine that one of the reasons why they may eventually grow to incorporate vegetables is because of some knowledge that vegetables might be-

   2. CZDr. Charles Zuker12:19

      Good for you

   3. AHAndrew Huberman12:19

      ... better for them. Is there a change in the receptors that can explain the transition from wanting to avoid vegetables to being willing to eat vegetables simply in-

   4. CZDr. Charles Zuker12:29

      Yes

   5. AHAndrew Huberman12:29

      ... childhood to, to early development?

   6. CZDr. Charles Zuker12:31

      So, so taste, we just told you that's, you know, predetermined, hardwired. But predetermined and hardwired doesn't mean that it's not modulated by learning or experience. It only means that you are born liking sweet and disliking bitter. And we have many examples of plasticity. Coffee, it has an associated gain to the system, and that gain to the system, that positive valence that emerges out of that negative signal is sufficient to create that positive association. I mean, the case of coffee, of course, is caffeine activating a whole group of neurotransmitter systems that give you that, that, that high associated with coffee. So yes, the taste system is changeable, it's malleable, and is subjected to learning and experience.

8. 13:22 – 16:17

   Taste Modulation; Salt

   1. AHAndrew Huberman13:22

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

   2. CZDr. Charles Zuker13:28

      Where does this, this desensitizing happens? That's the term that we use, eh? I think it happening at multiple stations. It's happening at the receptor level, i.e., the cells in your tongue that are sensing that sugar. As you activate this receptor and it's triggering activity after activity after activity, eventually you exhaust the receptor. Again, I'm using terms which are extraordinarily loose. The receptor gets to a point where it undergoes a set of changes, chemical changes, where it now signals far less efficiently or it even gets removed from the surface of the cell. And that is a huge site of this modulation. And then the next, I believe, is the integrated, again, loss of signaling that happens by continuous activation of the circuit at each of these different neural stations, from the tongue to the ganglia, from the ganglia to the first station in the brainstem, a second station in the brainstem to the thalamus, then to the cortex. So there are multiple steps that this signal is traveling. Now, you might say, "Why, if this is a labeled line, why do you need to have so many stations?" And that's because the taste system is so important to ensure that you get what you need to survive, that it has to be subjected to modulation by the internal state. And each of these nodes provides a new site to give it plasticity and modulation. I, I'm gonna give you one example of, of, of how the internal state changes the way the taste system works. Salt is very appetitive at low concentrations, and that's because we need it. It's our electrolyte balance requires salt. Every one of the neurons uses salt as the most important of the ions, you know, with potassium to ensure that you can transfer these electrical signals within and between neurons. But at high concentrations, let's say ocean water, it's incredibly aversive. And we all know this because we've gone to the ocean, and then when you get it in your mouth, it's not that great. However, if I salt deprive you, now this incredibly high concentration of salt, one molar sodium chloride, becomes amazingly appetitive and attractive. What's going on in here? Your tongue is telling you, "This is horrible," but your brain is telling you, "You need it." And this is what we call the modulation of the taste system by the internal state.

9. 16:17 – 20:50

   Gut-Brain Signaling

   1. AHAndrew Huberman16:17

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

   2. CZDr. Charles Zuker16:26

      Yes. You know, the brain needs to monitor the state of every one of our organs. It has to do it. This is the only way that the brain can ensure that every one of those organs are working together in a way that we have healthy physiology. This is a two-way highway where the brain is not only monitoring, but is now modulating back what the body needs to do. And that includes all the way from monitoring the frequency of heartbeats and the way that inspiration and aspirations in the breathing cycle operate to what happens when you ingest sugar and fat. Let me give you a, an example. So Pavlov, in his classical experiments in conditioning, you know, associative conditioning, he would take a bell and would ring the bell every time he was going to feed the dog. Eventually, the dog learned to associate the ringing of the bell with food coming. The dog now, in the presence of the bell alone, will start to salivate, and we will call that, you know, neurologically speaking, an anticipatory response. Neurons in the brain that form that association now represent food is coming, and they're sending a signal to motor neurons to go into your salivary glands to squeeze them so you release, you know, you know, saliva because you know food is coming. But what's even more remarkable is that those animals are also releasing insulin in response to a bell. Somehow the brain created these associations, and there are neurons in your brain now that know food is coming.And send a signal somehow all the way down to your pancreas that now it says release insulin because sugar is coming down. Now, the main highway that is communicating the state of the body with the brain is a specific bundle of nerves which emerge from the vagal ganglia, the nodose ganglia. And so it's the vagus nerve that it's innervating the majority of the organs in your body. It's monitoring their function, sending a signal to the brain, and now the brain going back down and saying, "This is going all right, do this," or, "This is not going so well, do that."

   3. AHAndrew Huberman18:53

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

   4. CZDr. Charles Zuker18:58

      They all must, they all must be monitored. I have no doubt that diseases that we have normally associated with metabolism, physiology, and even immunity are likely to emerge as diseases, conditions, states of the brain. I don't think obesity is a disease of metabolism. I believe obesity is a disease of brain circuits.

   5. AHAndrew Huberman19:25

      I do as well.

   6. CZDr. Charles Zuker19:26

      Yeah. And so this, this view that we have, you know, been working on for the longest time because, you know, the molecules that we're dealing with are in the body, not in the head. You know, led us to, you know, to view, of course, these issues and problems as being one of metabolism, physiology, and so forth. They remain to be the carriers of the ultimate signal, but the brain ultimately appears to be the conductor of this orchestra of physiology and metabolism. Now, let's go to the gut-brain and sugar. The vagus nerve is made out of many thousands of fibers that make this gigantic bundle, and it's likely, as we're speaking, that each of these fibers, they carry meaning that's associated with their specific task. This group of fibers is telling the brain about the state of your heart. This group of fiber is telling the brain about the state of your gut. This is telling your brain about its nutritional state. They are, again, to make the same simple example, the keys of this piano. 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.

10. 20:50 – 26:34

    Sugar Appetite & Gut-Brain Axis; Artificial Sweeteners, Sugar Cravings

    1. CZDr. Charles Zuker20:50

       Okay, let me tell you about the gut-brain axis and our insatiable appetite for sugar. This is work of, uh, my own laboratory, you know, that began long ago when we discovered the sweet receptors. You can now engineer mice that lack these receptors. So in essence, these animals will be unable to taste sweet. And if you give a normal mouse a bottle containing sweet, and we're gonna put either sugar or an artificial sweetener. All right? They both are sweet. They have slightly different tastes, but that's simply because artificial sweeteners have some off tastes. But as far as the sweet receptor is concerned, they both activate the same receptor, trigger the same signal. And if you give an animal an option of a bottle containing sugar or a sweetener versus water, this animal will drink ten to one from the bottle containing sweet. That's the taste system. Animal goes, samples each one, licks a couple of licks, and then says, "Uh-uh, that's the one I want because it's appetitive and because I love it." Now, we're gonna take the mice and we're gonna genetically engineer it to remove the sweet receptors. So these mice no longer have in their oral cavity any sensors that can detect sweetness, be that sugar molecule, be it an artificial sweetener, be it anything else that tastes sweet. And if you give these mice an option between sweet versus water, it will drink equally well from both because it cannot tell them apart, because it doesn't have the receptors for sweet, so that sweet bottle tastes just like water. But if I keep the mouse in that cage for the next forty-eight hours, something extraordinary happens when I come forty-eight hours later. That mouse is drinking almost exclusively from the sugar bottle. During those forty-eight hours, the mouse learn that there is something in that bottle that makes me feel good, and that is the bottle I want to consume. And that is the fundamental basis of our unquenchable desire and our craving for sugar, and is mediated by the gut-brain axis. So we reason if this is true, and it's the gut-brain axis that's driving sugar preference, then there should be a group of neurons in the brain that are responding to post-ingestive sugar. And lo and behold, we identify a group of neurons in the brain that does this, and these neurons receive their input directly from the gut-brain axis. And so what's happening is that sugar is recognized normally by the tongue, activates an appetitive response. Now you ingest it, and now it activates a selective group of cells in your intestines that now send a signal to the brain via the vagal ganglia that says, "I got what I need." The tongue doesn't know that you got what you need. It only knows that you tasted it. This knows that it got to the point that it's going to be used, which is the gut.And now it sends the signal to now reinforce the consumption of this thing because this is the one that I needed, sugar, source of energy. So these are gut cells that recognize the sugar molecule-

    2. AHAndrew Huberman24:31

       I see

    3. CZDr. Charles Zuker24:31

       ... send a signal, and that signal is received by the vagal neuron directly.

    4. AHAndrew Huberman24:35

       Got it.

    5. CZDr. Charles Zuker24:36

       And this sends a signal through the gut-brain axis to the cell bodies of these neurons in the vagal ganglia, and from there to the brainstem to now trigger the preference for sugar. You see, you want the brain to know that you had successful ingestion and breakdown of whatever you consume into the building blocks of life. And, you know, glucose, amino acids, fat. And so you want to make sure that once they are in the form that intestines can now absorb them is where you get the signal back saying, "This is what I want." Okay? Now, let me just take it one step further. This now sugar molecules activates this unique gut-brain circuit that now drives the development of our preference for sugar. A key element of this circuit is that the sensors in the gut that recognize the sugar do not recognize artificial sweeteners. It's a completely different molecule that only recognizes the glucose molecule, not artificial sweeteners. This has a profound impact on the effect of ultimately artificial sweeteners in curbing our appetite, our craving, our insatiable desire for sugar. Since they don't activate the gut-brain axis, they'll never satisfy the craving for sugar like sugar does. We have a mega problem with overconsumption of sugar and fat. You know, we're facing a unique time in our evolution where diseases of malnutrition are due to overnutrition. Historically, diseases of malnutritions have always been linked to undernutrition.

11. 26:34 – 30:07

    Taste & Essential Nutrients; Highly Processed Foods; Brain & Food Choices

    1. CZDr. Charles Zuker26:34

       But I want to just go back to the notion of, you know, these brain centers that are ultimately the ones that are being activated by these essential nutrients. So sugar, fat, and amino acids are building blocks of our diets, and this is across all animal species. So it's not unreasonable then to assume that dedicated brain circuits would have evolved to ensure their recognition, their ingestion, and the reinforcement that that is what I need. And indeed, you know, animals evolve these two systems. One is the taste system that allows you to recognize them and trigger these predetermined hardwired immediate responses, yes? You know, "Oh my God, this is so delicious. It's fatty," or umami recognizing amino acids. So that's the liking pathway, yeah? But in the wisdom of evolution, that's good, but doesn't quite do it. You want to make sure that these things get to the place where they're needed. They're needed in your intestines where they're going to be absorbed as the nutrients that will support life. And the brain wants to know this. Highly processed foods are hijacking, you know, co-opting these circuits in a way that it would have never happened in nature, and then we not only find these things ap- 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. What do I feel like eating? Let me have more of this."

    2. AHAndrew Huberman28:19

       This is why I think a lot of data are now starting to support the idea that while indeed the laws of thermodynamics apply, calories ingested versus calories burned is a very real thing, right? The appetite for certain foods [gentle music] and the, 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.

    3. CZDr. Charles Zuker28:48

       Absolutely. Understanding the circuits is giving us important insights on how ultimately and hopefully we can improve human health and make a meaningful difference. Now, it's very easy to try to, you know, connect the dots, A to B, B to C, C to D, and I think there's a lot more complexity to it, but I do think that the lessons that are emerging out of understanding how these circuits operate can ultimately inform how we deal with our diets in a way that we avoid what we're facing now, you know, as a society, yeah? I mean, it's nuts that, that overnutrition happens to be such a prevalent problem.

    4. AHAndrew Huberman29:41

       Yeah. And I also think the training of people who are thinking about metabolic science and metabolic disease is largely divorced from the training of the neuroscientist, and vice versa. No one field is to blame.

    5. CZDr. Charles Zuker29:52

       Yeah.

    6. AHAndrew Huberman29:52

       But I fully agree that the, the brain is, is the key over... or the nervous system, to be, uh, more accurate-

    7. CZDr. Charles Zuker29:58

       More accurate

    8. AHAndrew Huberman29:59

       ... is the one of the key overlooked features.

    9. CZDr. Charles Zuker30:02

       It's the arbiter. Ultimately, it's the arbiter of many of these pathways.

12. 30:07 – 30:52

    Acknowledgements

    1. AHAndrew Huberman30:08

       On behalf of myself, uh, and certainly on behalf of all the listeners, I want to thank you, first of all, for the incredible work that you've been doing now for decades in vision, in taste, and in this bigger issue of how we perceive and experience life. It's, uh, truly pioneering and incredible work, and I feel quite lucky to have been on the sidelines seeing this over the years and hearing the talks and reading the countless beautiful papers, but also for your time today to come down here and talk to us about what drives you and the discoveries you've made. Thank you ever so much.

    2. CZDr. Charles Zuker30:42

       It was great fun. Thank you for having me. [upbeat music]

    3. AHAndrew Huberman30:45

       We'll do it again.

    4. CZDr. Charles Zuker30:45

       I'd like... We should.

Episode duration: 30:52