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

Welcome to Huberman Lab Essentials, [music] 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 Zucker. Charles, thank you so much for joining me today. My pleasure. 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? 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 but 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 of the of my entire career in neuroscience. How does the brain ultimately transform detection into perception so that it can guide actions and behaviors? 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 what's 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 the five basic taste qualities, sweet, sour, bitter, salty, and umami. Umami is a Japanese word that means yummy, delicious. And that's the and 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 of sweet, umami, and low salt are attractive taste qualities. They evoke appetitive responses. I want to consume them. And bitter and sour are innately predetermined to be aversive. 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 an unhappy face. Then you squint your eyes and then you start gagging. Okay? And that entire thing happens by the activation of a bitter molecule in a bitter sensing cell in your tongue. It's incredible. It's It's again the magic of the brain. You know how how [clears throat] it it's able to encode and decode these extraordinary actions and behaviors in response of nothing but a simple very, you know, 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 and other essential nutrients. Salt, the three appetitive ones to ensure that we maintain our electrolyte balance. Bitter to prevent the ingestion of toxic noxious chemicals. Nearly all bitter tasting, you know, things out in the wild are bad for you. And sour most likely to prevent the ingestion of spoil acid. Yeah? Fermented foods. And that's it. That is the palate that we deal with. Now, of course, there's a difference between basic taste and flavor. Flavor is the whole experience. Flavor is the combination of multiple tastes coming together together with smell, with texture, with temperature, with the look of it, that gives you what you and I would call the full sensory experience, eh? But but we scientists need to reduce the the problem into its basic elements so we can begin to break it apart before we put it back together. So, when we think about the sense of taste, and we try to figure out how these lines of information go from your tongue to your brain, and how they signal, and how they get integrated, and how they trigger all these different behaviors, we look at them as individual qualities, eh? So, we give the animal sweet, or we give them a bitter, we give them sour. We avoid mixes. Think of it as lines of information, yeah? Separate lines, like the keys of a piano, yeah? Sweet, sour, bitter, salty, umami. You play that key and you activate that 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. If you would describe the sequence of neural events leading to a perceptual event of taste, We have taste buds distributed in various parts of the tongue. So, there is a map on the distribution of taste buds. But each taste bud has around 100 taste receptor cells. And those taste receptor cells can be of five types, yeah? 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 these 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 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 would 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. It's one of the taste ganglia. These are the neurons that innervate your tongue and the oral cavity. Where do they sit approximately? Are there some >> Around there, yeah. Right here around the the lymph nodes, more or less? >> You got it. And there are two main ganglia that innervate the vast majority of all taste buds in the oral cavity. And then from there, that sweet signal goes onto the brain stem. The brain stem is the entry of the body into the brain. And there are different areas of the brain stem, and there are different groups of neurons in the brain stem, and this is a unique area in a unique topographically defined location in the rostral side of the brain stem that receives all of the taste input. A very dense area of the brain. A very rich area of the brain, exactly. And from there, the sweet signal goes to this other area, higher up on the brain stem, and then it goes through a number of stations where that sweet signal goes from sweet neuron to sweet neuron to sweet neuron to eventually get to your cortex. And once it gets to your taste cortex, that's where meaning is imposed into that signal. It's then, this is what the data suggests, that now you can identify this as a sweet stimuli. And how quickly does that all happen? You know, the time scale of the nervous system, it's fast, yeah? And so >> less than a second. Yeah. And then, 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, yeah? And now, in there, you impose meaning to that taste. There's an area of your brain that represents the taste of sweet in taste cortex, and a different area that represents the taste of bitter. In essence, there is a topographic map of these taste qualities inside your brain. How much plasticity do you think there is there, and in particular across the lifespan? Because I think one of the most salient examples of this is that kids don't seem to like certain vegetables, but they all are hardwired to like sweet tastes. And yet, you could also imagine that one of the reasons why they may eventually grow to incorporate vegetables is because of some knowledge that vegetables might be good for you. >> 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 childhood to to early development? >> taste, we just told you that's, you know, predetermined, hardwired. But, predetermined hardwired doesn't mean that's not modulated by learning or experience. It only means that you're 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. And in the case of coffee, of course, it's caffeine activating a whole group of neurotransmitter systems that give you that that that high associated with coffee. So, yes, this taste system is changeable, it's malleable, and it's subjected to learning and experience. Can you imagine a sort of system by which people could leverage that. Where does this this desensitizing happens? That's the term that we use, eh? I think it's 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 side of this modulation. And then the next, I believe, is the integrated, again, loss of signaling that happens by continuous activation of the circuit at each of these different neural stations. From the tongue to the ganglia, from the ganglia to the first station in the brain stem, a second station in the brain stem, to the thalamus, then to the cortex. So, there are multiple steps that this signal is traveling. Now, you might say, "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'm going to give you one example of of how the internal state changes the way the taste system works. Salt is very appetitive at low concentrations. And that's because we need it. It's our electrolyte balance requires salt. Every one of 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. But at high concentrations, let's say ocean water is incredibly aversive. And we all know this because we go into 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, 1 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. I'd love 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. >> 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. That this is a two-way highway where the brain is not only monitoring, but is now modulating back what the body needs to do. And that includes all the way from monitoring the frequency of heartbeats and the way that inspiration and aspirations in the breathing cycle operate to what happens when you ingest sugar and fat. Let me give you a an example. So, Pavlov in his classical experiments in conditioning, you know, associative conditioning, he would take a bell, he 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 is the vagus nerve that is 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." And I should point out, as you well know, every organ, spleen, pancreas, lung, >> 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. I do as well. >> 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, let 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 fibers 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. Okay, let me tell you about the gut-brain axis and our insatiable appetite for sugar. This is work of 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 going to put either sugar or an artificial sweetener. All right? They both are sweet. They have slightly different tastes, but that's simply because artificial sweeteners have some off tastes. But as far as the sweet receptor is concerned, they both activate the same receptor, trigger the same signal. And if you give an animal an option of a bottle containing sugar or a sweetener versus water, this animal will drink 10 to 1 from the bottle containing sweet. That's the taste system. It 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 going to take the mice, and we're going to genetically engineer it to remove the sweet receptors. So, these mice no longer have in their oral cavity any sensors that can detect sweetness. Be that sugar molecule, be it an artificial sweetener, be it anything else that tastes sweet. And if you give these mice an option between sweet versus water, 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 48 hours, something extraordinary happens when I come 48 hours later. That mouse is drinking almost exclusively from the sugar bottle. During those 48 hours, the mouse learned 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, I see, send a signal and that signal is received by the vagal neuron directly. Got it. 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, fatty 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. 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 their reinforcement that that is what I need. And indeed, you know, animals evolved these two systems. One is the taste system that allows you to recognize them and trigger this 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 the circuits in a way that we would have never happened in nature. And then we not only find these things up 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." Well, 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 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. >> Absolutely. Understanding the circuits is giving us important insights and how ultimately, 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. I mean, it's nuts that the overnutrition happens to be such a prevalent problem. Yeah. And I also think the training of people who are thinking about metabolic science and metabolic disease is largely divorced from the training of the neuroscientists and vice versa. No one field is to blame, but I fully agree that the the brain is is the key over or the nervous system, to be more accurate, is the one of the key overlooked features. >> Is the arbiter. Ultimately, is the arbiter of many of these pathways. 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. It was great fun. Thank you for having me. We'll do it again. >> We [music] shall.