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

I'm Andrew Hubertman, 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 chord, and this is a microphone. But the brain is only made of neurons that only understand electrical signals. So how do you transform that reality into nothing that electrical signals that now need to represent the world? And that process is what we can operationally define as perception. In the senses, let's say, all factory, other 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, yes, yourselves, in your tongue, interacting with this chemical. But now that so 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 being the, the maniacal drive of my entire career in neuroscience.

“How does the brain ultimately transform detection into perception so that it can guide actions and behaviors?”

So if I want to begin to explore all of these things that the brain does, I feel I have to choose a sensory system that affords some degree of simplicity in the way that the input output relationships are put together.

I mean, a way that still can be used to ask everyone of these problems that the brain has to ultimately compute and code 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 basic taste qualities. Sweet, sour, bitter, salty, and umami. Umami is a Japanese word that means yummy delicious and that's nearly every animal species the taste of amino acids. And in humans is 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 repetitive responses. I want to consume them. And bitter and sour are innately predetermined to be a vericive.

In the case of bitter is very easy to actually look at, see them happening in animals because the first thing you do is you stop leaking.

Then you put, uh, unhappy face, then you're squint your eyes and then you start guardian. And that entire thing happens by the activation of a bitter molecule in a bitter sense in selling your tongue. It's incredible. 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, you know, a unique sensory stimuli.

Sweet to ensure that we get the right amount of energy, umami to ensure that we get proteins and that essential nutrient.

“Salt, the three repetitive ones, 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 spoil acid, fermented foods. And that's it. That is the palette that we deal with. Now, of course, there's a difference between basic taste and flavor. Flavor is the whole experience. Flavor is the combination of multiple tastes coming together together with smell, with texture, with temperature, with the look of it that gives you what you and I would call the full sensory experience. But but we scientists need to reduce the problem into 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 can integrate it and how they trigger all these different behaviors, we look at them as individual qualities. So we give them a sweet, or we give them a bitter, we give them sour, we avoid mixes.

“Think of the lines of information, just separate lines, by the kiss of a piano, yeah?”

Sweet, sour, bitter, salty, Miami, 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. And if you're a regular listener of the Hubertman Lab podcast, you've no doubt heard me talk about the vitamin mineral probiotic drink AG1. And if you've been on the fence about it, now's an awesome time to give it a try.

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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 buds has around a hundred taste receptor cells. And those taste receptors cells can be of five types, sweet, sour, bitter, salty, or mommy. 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 enrich 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 after the receptors for these five detectors, the molecules that sense sweet, sour, bitter, salty mommy,”

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 by the chemical events inside itself that now sense 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.

The first thing is that the two invoke diametrically opposed behaviors. If we have to come up with two sensory experience, a 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.

These are the neurons that innovate your tongue and the oral cavity. Where do they set approximately? They're all there. Yeah, right here, around there. The lymph nodes more or less, you got it. And there are two main ganglia that innovate 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 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, this sweet signal goes to this other area higher up on the brain stem and then it goes through a number of stations where that sweet signal goes from sweet neuron to sweet neuron to 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 these as a sweet stimuli.

And how quickly does that all happen? You know, the timescale of the nervous system, it's fast, yeah? And we're in the last one a second. Yeah. And in fact, we can demonstrate this because we can stick electrodes at each of these stations.

You deliver this stimuli and within a fraction of a second. You see now their response in this following stations. Now it gets to the cortex.

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 this is there is a topographic map of this taste quality, this 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 taste.”

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.

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 early childhood? So taste, we just told you that, you know, pre-determined hardwired. But pre-determined hardwired doesn't mean that it's not modulated by learning or experience. It only means that you are born like in sweet and this like in 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, in the case of coffee, of course, it's cafe in activating a whole group of neurotransmitter systems that give you that high associated with coffee. So yes, the taste system is changeable, it's malleable, and it's subjected to learning and experience.

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

Where does this, this, the sensitizing happens? That's the term that we use it. I think it, happening at multiple stations. It's happening at the receptor level, IE, the cells in your tongue that are sensing that sugar. As you activate this receptor and it's triggering 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.

From the term to the ganglia, from the ganglia to the first station in the brainstem, a set of stations in the brainstem to the thalamus, then to the cortex.

So there are multiple steps that this signal is struggling. Now you might say, "Why if this is a label line, why do we 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 side to give it plasticity and modulation. I'm going to give you one example 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. Our electrolyte balance requires salt.

Everyone 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 is incredibly aggressive. And we all know this because we're going to the ocean, and then when you get in your mouth, it's not that great. However, if I sold the pride view, now this incredibly high concentration of salt, one molar sodium chloride, becomes amazingly appetitive and attractive. What's going on in here? You're totally telling you, this is horrible, but you're brain is telling you you need it. And this is what we call the modulation of the taste system by the internal state.

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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 everyone 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 heart beats 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 an example. So, part-loving is classical experiments in conditioning, you know, associative conditioning. It would take a bell, it would ring the bell, every time it 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 celebrate. And we will call that, you know, neurologically speaking, an anticipatory response. Nures in the brain that formed that association now represent food is coming, and they're sending a signal to moral neurons to go into your salary very glance to squeeze them.

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

“In response to a bell, somehow the brain created his associations and their neurons in your brain now, that know food is coming.”

And send a signal somehow all the way down to your pancreas. 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 emerged from the vagal ganglia, the nodos ganglia. And so, it's the vagus nerve that it's innovating 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 to well do that."

And I should point out, as you will know, every organ, plain pancreas, they all must be monitored. I have not doubt that the cices 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 at the cice of metabolism. I believe obesity is at the cice of brain circuits, I do as well.”

And so, this is view that we have been working on for the longest time because the molecules that we're dealing with are in the body, not in the head. Let us to view, of course, these issues and problems has been 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 biggest nerve is made out of many thousands of fibers, so 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 ingenier mice that lack these receptors. So, in essence, this 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 animal goes samples, each one leaks a couple of leaks and then says, "Oh, that's the one I want because it's a petitive 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, this mice no longer have in their oral cavity any sensors that can detect sweetness, be that sugar molecule, be it an artificial sweetener with anything else that tastes sweet. And if you give this 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 their receptors for sweet, so that sweet bottle tastes yes like water.

But if I keep the mouse in that case, 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 learns that there is something in that bottle that makes me feel good and that is the bottle I want to consume.

So, we reason if this is true and is the God brain access that's driving sugar preference,

then this should be a group of neurons in the brain that are responding to pos ingestive sugar. And low and behold, we identify a group of neurons in the brain that does this and this neurons receive their input directly from the God brain access. So, we are going to be able to identify the God brain access. And we are going to identify the God brain access. And we are going to identify the God brain access.

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 you got to the point that it's going to be used, which is the God.

And now is since 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 God cells, the recognized sugar molecule. Send a signal and that signal is received by the God neuron directly, got it. And the sends a signal through the God brain access to the cell bodies of these neurons in the vagal ganglia. And from there to the brain stem to now trigger the preference for sugar. 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. I'd like to take a quick break and acknowledge one of our sponsors function. Last year I became a function member after searching for the most comprehensive approach to lab testing.

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“The key element of this circuit is that the sensors in the gut that recognize the sugar to not recognize artificial sweeteners is a completely different molecule that only recognizes the glucose molecule, not artificial sweeteners.”

As 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 access, they'll never satisfy the craving for sugar like sugar does. We have a mega problem with over-consumption of sugar and fat. We're facing a unique time in our evolution where the ceases of malnutrition are due to over-nutrition.

But I want to go back to the notion of this brain centers that are ultimately the ones that are being activated by this 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 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?”

Oh my god, this is so delicious, it's fatty or umami recognizing amino acids. So that's the liking pathway, but in the wisdom of evolution, that's good, but that's not quite good. You want to make sure that these things get to the place where they're needed. They are 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 would have never happened in nature.

And we not only find these things repetitive and palatable, but in addition, we are continuously reinforcing, you know, the one thing 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.”

Understanding the circuits is giving us important insights and how ultimately 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 to C to D and I think there's a lot more complexity to it. 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 in a way that we avoid what we're facing now, you know, as a society.

I mean, it's not that the over nutrition happens to be such a prevalent problem.

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 brain is is the key or the nervous system to be more accurate is the one of the key overlooked features.”

Is the RVter, ultimately is the RVter of many of these pathways? I'll be half 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.

It's 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. I'll do it again. We saw.

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