Essentials: The Biology of Taste Perception & Sugar Craving | Dr. Charles Zuker
3/5/202635 mincomplete
0:00Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and
0:05actionable science -based tools for mental health, physical health, and performance.
0:11I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of
0:16Medicine. And now for my discussion with Dr.
0:19Charles Zucker. Charles, thank you so much for joining me today.
0:23My pleasure. I want to ask you about many things related to taste and gustatory
0:28perception, but maybe to start off, and because you've worked on a number of different
0:32topics in neuroscience, not just taste, how should the world and people think about perception,
0:39how it's different from sensation, and what leads to our experience of life in terms
0:46of vision, hearing, taste, et cetera?
0:48The world is made of real things.
0:51You know, this here is a glass, and this is a cord, and this is
0:56a microphone, but the brain is only made of neurons that only understand electrical signals.
1:03So how do you transform that reality into nothing that electrical signals that now need
1:12to represent the world? And that process is what we can operationally define as perception.
1:24In the senses, let's say olfactory, odor, taste, vision, you know, we can very straightforwardly
1:33separate detection from perception. Detection is what happens when you take a sugar molecule, you
1:41put it in your tongue, and then a set of specific cells now sense that
1:47sugar molecule. That's detection. You haven't perceived anything yet.
1:52That is just your cells in your tongue interacting with this chemical.
1:57But now that cell gets activated and sends a signal to the brain, and now
2:02detection gets transformed into perception.
2:06And it's trying to understand how that happened.
2:09that's been the maniacal drive of my entire career in neuroscience.
2:20How does the brain ultimately transform detection into perception so that it can guide actions
2:27and behaviors? So if I want to begin to explore all of these things that
2:32the brain does, I felt I have to choose a sensory system that affords some
2:42degree of simplicity in the way that the input -output relationships are put together and
2:51in a way that still can be used to ask every one of these problems
2:54that the brain has to ultimately compute, encode, and decode.
3:01And what was remarkable about the taste system at the time that I began working
3:06on this is that nothing was known about the molecular basis of taste.
3:13You know, we knew that we could taste what has been usually defined as the
3:18five basic taste qualities. Sweet, sour, bitter, salty, and umami.
3:26Umami is a Japanese word that means yummy, delicious.
3:32And that's nearly every animal species, the taste of amino acids.
3:37And in humans, it's mostly associated with the taste of MSG, monosodium glutamate, one amino
3:45acid in particular. And so the beautiful thing of the system is that the lines
3:49of input are limited to five.
3:52And each of them has a predetermined meaning.
3:56You're born with that specific valence, value, for each taste.
4:04Sweet, umami, and low salt are attractive taste qualities.
4:10They evoke appetitive responses. I want to consume them.
4:15And bitter and sour are innately predetermined.
4:20determined to be aversive. In the case of bitter, it's very easy to actually look
4:27at, see them happening in animals, because the first thing you do is you stop
4:31licking, then you put unhappy face, then you squint your eyes, and then you start
4:38gagging. And that entire thing happens by the activation of a bitter molecule in a
4:46bitter sensing cell in your tongue.
4:47It's incredible. It's, again, the magic of the brain, you know, how it's able to
4:54encode and decode these extraordinary actions and behaviors in response of nothing but a simple,
5:00very unique sensory stimuli. This palate of five basic tastes accommodates all the dietary needs
5:10of the organism. Sweet, to ensure that we get the right amount of energy.
5:15Umami, to ensure that we get proteins, another essential nutrient.
5:21Salt, the three appetitive ones, to ensure that we maintain our electrolyte balance.
5:26Bitter, to prevent the ingestion of toxic, nauseous chemicals.
5:30Nearly all bitter tasting, you know, things out in the wild are bad for you.
5:36And sour, most likely to prevent the ingestion of spoiled, mineral, acid, fermented foods.
5:45And that's it. That is the palate that we deal with.
5:49Now, of course, there's a difference between basic taste and flavor.
5:54Flavor is the whole experience.
5:56Flavor is the combination of multiple tastes coming together, together with smell, with texture, with
6:04temperature, with the look of it that gives you what you and I would call
6:10the full sensory experience. But we scientists need to reduce the problem into its basic
6:17elements so we can begin to break it apart before we put it back together.
6:22So when we think about the sense of taste and we try to figure out
6:27how these lines of information go from your tongue to your brain and how.
6:31They signal and how they get integrated and how they trigger all these different behaviors.
6:37We look at them as individual qualities.
6:39So we give the animals sweet or we give them a bitter, we give them
6:43sour. We avoid mixes. Think of it as lines of information, separate lines, like the
6:49keys of a piano. Sweet, sour, bitter, salty umami.
6:53You play the key and you activate that one chord.
6:56And that one chord, in the case of a piano, leads to a note, you
7:00know, a tune. And in the case of taste, leads to an action and a
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7:56If you would, describe the sequence of neural events leading to a perceptual event of
8:02taste. We have taste baths distributed in various parts of the tongue.
8:07So there is a map on the distribution of taste baths.
8:12But each taste bath has around 100 taste receptor cells.
8:16And those taste receptor cells can be of five types.
8:23Sweet, sour, bitter, salty, or umami.
8:26And for the most part, all taste baths have the representation of all five taste
8:35qualities. Now, there's no question that there is a slight bias for some tastes.
8:40Like, bitter is particularly... and reach at the very back of your tongue.
8:46And there is a teleological basis for that, actually a biological basis for that.
8:51That's the last line of defense before you swallow something bad.
8:56And so let's make sure that the very back of your tongue has plenty of
9:01these bad news receptors so that if they get activated, you can trigger a gagging
9:08reflex and get rid of these that otherwise may kill you.
9:13The important thing is that, you know, after the receptors for these five, the detectors,
9:20the molecules that sends sweet, sour, beta, salt, umami, these are receptors, proteins found on
9:26the surface of taste receptor cells that interact with these chemicals.
9:30And once they interact, then they trigger the cascade of events, biochemical events inside the
9:37cell that now sends an electrical signal that says there is sweet here or there
9:43is salt here. Let's compare and contrast sweet and bitter as we follow their lines
9:50from the tongue to the brain.
9:51So the first thing is that the two evoke diametrically opposed behaviors.
9:56If we have to come up with two sensory experiences that represent polar opposites, it
10:01will be sweet and bitter.
10:02So then the signals, if we follow now these two lines, they're really like two
10:07separate keys at the two ends of this keyboard.
10:10And you press one key and you activate this cord.
10:14So you activate the sweet cells throughout your oral cavity and they all converge into
10:20a group of sweet neurons.
10:22In the next station, which is still outside the brain, is one of the taste
10:27ganglia. These are the neurons that innervate your tongue and the oral cavity.
10:34Where do they sit approximately?
10:35Around there. Yeah, right here, around the lymph nodes, more or less.
10:38You got it. And there are two main ganglia that innervate the vast majority of
10:45all taste buds in the oral cavity.
10:48And then from there, that sweet signal goes onto the brain stem.
10:53And there are two main mechanisms that have been used by being used by being
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10:55entry of the body into the brain.
10:58And there are different areas of the brainstem, and there are different groups of neurons
11:03in the brainstem, and there's this unique area in a unique topographically defined location in
11:11the rostral side of the brainstem that receives all of the taste input.
11:17A very dense area of the brain.
11:19A very rich area of the brain, exactly.
11:24And from there, the sweet signal goes to this other area, higher up on the
11:29brainstem. And then it goes through a number of stations where that sweet signal goes
11:35from sweet neuron to sweet neuron to sweet neuron to eventually get to your cortex.
11:43And once it gets to your taste cortex, that's where meaning is imposed into that
11:50signal. It's then, this is what the data suggests, that now you can identify this
11:58as a sweet stimuli. And how quickly does that all happen?
12:02You know, the time scale of the nervous system, it's fast.
12:06Within less than a second.
12:09Yeah. And in fact, we can demonstrate this because we can stick electrodes at each
12:13of these stations. You deliver the stimuli, and within a fraction of a second, you
12:18see now the response in these following stations.
12:22Now it gets to the cortex.
12:24And now in there, you impose meaning to that taste.
12:29There is an area of your brain that represents the taste of sweet in taste
12:36cortex, and a different area that represents the taste of bitter.
12:41In essence, there is a topographic map of these taste qualities inside your brain.
12:47How much plasticity do you think there is there?
12:49And in particular, across the lifespan.
12:51Because I think one of the most salient examples of this is that kids don't
12:55seem to like certain vegetables, but they all are hardwired to like sweet tastes.
13:01And yet, you could also imagine that one of the reasons why they may eventually
13:04Which means that a lot of them are along a wayward.
13:04just there, but for example, So this is the two people that Monklyn volatility just
13:05compared to China at history, you could lose their reputation.
13:05grow to incorporate vegetables is because of some knowledge that vegetables might be good for
13:10you, better for them. Is there a change in the receptors that can explain the
13:14transition from wanting to avoid vegetables to being willing to eat vegetables simply in childhood
13:20to early development? It says, we just told you that's, you know, predetermined hardwired, but
13:26predetermined hardwired doesn't mean that's not modulated by learning or experience.
13:31It only means that you are born like in sweet and dislike in bitter.
13:37And we have many examples of plasticity.
13:41Coffee, it has an associated gain to the system.
13:45And that gain to the system, that positive valence that emerges out of that negative
13:52signal is sufficient to create that positive association.
13:57And in the case of coffee, of course, is caffeine activating a whole group of
14:01neurotransmitter systems that give you that high associated with coffee.
14:07So yes, this taste system is changeable, it's malleable, and it's subjected to learning and
14:12experience. Can you imagine a sort of a system by which people could leverage that?
14:19Where does this desensitizing happens?
14:23That's the term that we use.
14:25I think it happening at multiple stations.
14:29It's happening at the receptor level, i .e.
14:35the cells in your tongue that are sensing that sugar.
14:39As you activate this receptor and it's triggering activity after activity after activity, eventually you
14:45exhaust the receptor. Again, I'm using terms which are extraordinarily loose.
14:51The receptor gets to a point where it undergoes a set of changes, chemical changes,
14:58changes, where it now signals far less efficiently, or it even gets removed from the
15:06surface of the cell. And that is a huge side of this modulation.
15:12And then the next, I believe, is the integrated, again, loss of signaling that happens
15:18by continuous activation of the circuit at each of these different neural stations from the
15:24tongue to the ganglia from the ganglia to the first station in the brainstem a
15:28second station in the brainstem to the thalamus then to the cortex so there are
15:34multiple steps that this signal is traveling now you might say why if this is
15:38a label line why do you need to have so many stations and that's because
15:43the taste system is so important to ensure that you get what you need to
15:48survive that it has to be subjected to modulation by the internal state and each
15:54of these nodes provides a new site to give it plasticity and modulation i'm going
16:02to give you one example of of how the internal state changes the way the
16:06taste system works salt is very appetitive at low concentrations and that's because we need
16:14it it's our electrolyte balance requires salt every one of their neurons uses salt as
16:20the most important of the ions you know with potassium to ensure that you can
16:25transfer these electrical signals within and between neurons but at high concentrations let's say ocean
16:32water is incredibly aversive and we all know this because we've gone to the ocean
16:37and then when you get it in your mouth it's not that great however if
16:41i salt deprive you now this incredibly high concentration of salt one molar sodium chloride
16:48becomes amazingly appetitive and attractive what's going on in here your tongue is telling you
16:56this is horrible but your brain is telling you you need it and this is
17:02what we call the modulation of the taste system by the internal state i'd like
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18:40I'd love for you to talk about the aspects of gut brain signaling that drive
18:45our, or change our perceptions and behaviors that are completely beneath our awareness.
18:50You know, the brain needs to monitor the state of every one of our organs.
18:57It has to do it.
18:58This is the only way that the brain can ensure that every one of those
19:03organs are working together in a way that we have healthy physiology.
19:08This is a two -way highway where the brain is not only monitoring, but is
19:15now modulating back what the body needs to do.
19:20And that includes all the way from monitoring the frequency of heartbeats and the way
19:26that inspiration and aspirations in the breathing cycle operate to what happens when you ingest
19:33sugar and fat. Let me give you an example.
19:37So Pavlov in his class, Classical experiments in conditioning, you know, associative conditioning.
19:42He would take a bell, it would ring the bell every time he was going
19:47to feed the dog. Eventually, the dog learned to associate the ringing of the bell
19:52with food coming. The dog now, in the presence of the bell alone, will start
19:58to salivate. And we will call that, you know, neurologically speaking, an anticipatory response.
20:04Neurons in the brain that form that association now represent food is coming.
20:10And they're sending a signal to motor neurons to go into your salivary glands to
20:15squeeze them. So you release, you know, saliva because you know food is coming.
20:22But what's even more remarkable is that those animals are also releasing insulin in response
20:29to a bell. Somehow the brain created these associations and there are neurons in your
20:34brain now. That no food is coming.
20:37And send a signal somehow all the way down to your pancreas.
20:40That now it says release insulin because sugar is coming down.
20:45Now the main highway that is communicating the state of the body with the brain
20:51is a specific bundle of nerves.
20:53Which emerge from the vagal ganglia, the nodos ganglia.
20:57And so it's the vagus nerve that it's innervating the majority of the organs in
21:03your body. It's monitoring their function, sending a signal to the brain.
21:09And now the brain going back down and saying, this is going all right.
21:14Do this or this is not going so well.
21:16Do that. And I should point out, as you well know, every organ, spleen, pancreas,
21:22lungs. They all must be monitored.
21:25I have no doubt that diseases that we abnormally associated with metabolism, physiology, and even
21:33immunity are likely to emerge as diseases, conditions, states of the brain.
21:41I don't think obesity is a disease of metabolism.
21:44I believe obesity is a disease of brain circuits.
21:48Yes, I do as well.
21:49And so this view that we have, you know, been working on for the longest
21:55time, because, you know, the molecules that we're dealing with are in the body, not
22:00in the head, you know, led us to, you know, to view, of course, these
22:04issues and problems as being one of metabolism, physiology and so forth.
22:09They remain to be the carriers of the ultimate signal, but the brain ultimately appears
22:16to be the conductor of this orchestra of physiology and metabolism.
22:22Now, let's go to the gut, brain and sugar.
22:25The vagus nerve is made out of many thousands of fibers that make this gigantic
22:31bundle. And it's likely, as we're speaking, that each of these fibers, they carry meaning
22:37that's associated with their specific task.
22:41This group of fibers is telling the brain about the state of your heart.
22:46This group of fiber is telling the brain about the state of your gut.
22:50This is telling your brain about its nutritional state.
22:55They are, again, to make the same simple example, the keys of this piano.
23:02Now, the reason this is relevant, because the magic of this gut -brain axis is
23:08the fact that you have these thousands of fibers really doing different functions.
23:13Okay, let me tell you about the gut -brain axis and our insatiable appetite for
23:20sugar. This is work of my own laboratory that began long ago when we discovered
23:27the sweet receptors. You can now engineer mice that lack these receptors.
23:33So, in essence, these animals will be unable to taste sweet.
23:38And if you give a normal mouse a bottle containing sweet, and we're going to
23:44put either sugar or an artificial sweetener.
23:47All right? They both are sweet.
23:49They have slightly different tastes.
23:51But that's simply because artificial sweeteners have some off -tastes.
23:59But as far as the sweet we see...
24:00Tepteries concern, they both activate the same receptor, trigger the same signal, and if you
24:06give an animal an option of a bottle containing sugar or a sweetener versus water,
24:12this animal will drink 10 to 1 from the bottle containing sweet.
24:17That's the taste system. Animal goes, samples each one, licks a couple of licks, and
24:22then says, uh -uh, that's the one I want because it's appetitive and because I
24:26love it. Now we're going to take the mice and we're going to genetically engineer
24:31it to remove the sweet receptors.
24:34So these mice no longer have in their oral cavity any sensors that can detect
24:39sweetness, be it a sugar molecule, be it an artificial sweetener, be it anything else
24:44that tastes sweet. And if you give these mice an option between sweet versus water,
24:50it will drink equally well from both because it cannot tell them apart because it
24:54doesn't have the receptors for sweet, so that sweet bottle tastes just like water.
24:58But if I keep the mouse in that cage for the next 48 hours, something
25:04extraordinary happens when I come 48 hours later, that mouse is drinking almost exclusively from
25:11the sugar bottle. During those 48 hours, the mouse learned that there is something in
25:19that bottle that makes me feel good.
25:23And that is the bottle I want to consume.
25:26And that is the fundamental basis of our unquenchable desire and our craving for sugar
25:35and is mediated by the gut -brain axis.
25:38So we reason if this is true and it's the gut -brain axis that's driving
25:45sugar preference, then there should be a group of neurons in the brain that are
25:51responding to post -ingestive sugar.
25:55And lo and behold, we identify a group of neurons in the brain that does
25:58this, and these neurons receive their input directly from the gut -brain axis.
26:05And so what's happening is that sugar is recognized normally by the tongue.
26:10Man SURPRIED! 2 5 i Thank you.
26:11Activates an appetitive response. Now you ingest it.
26:15And now it activates a selective group of cells in your intestines that now send
26:22a signal to the brain via the vagal ganglia that says, I got what I
26:28need. The tongue doesn't know that you got what you need.
26:31It only knows that you tasted it.
26:34This knows that it got to the point that it's going to be used, which
26:38is the gut. And now it sends the signal to now reinforce the consumption of
26:45this thing because this is the one that I needed, sugar, source of energy.
26:51So these are gut cells that recognize the sugar molecule.
26:54I see. Send a signal, and that signal is received by the vagal neuron directly.
26:59Got it. And it sends a signal through the gut -brain axis to the cell
27:05bodies of these neurons in the vagal ganglia and from there to the brainstem to
27:12now trigger the preference for sugar.
27:15You see, you want the brain to know that you had successful ingestion and breakdown
27:20of whatever you consume into the building blocks of life.
27:26And, you know, glucose, amino acids, fat.
27:30And so you want to make sure that once they are in the form, that
27:34the intestines can now absorb them is where you get the signal back saying, this
27:40is what I want. Okay?
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29:21Now, let me just take it one step further.
29:24This, now, sugar molecules activates this unique gut -brain circuit that now drives the development
29:32of our preference for sugar.
29:35A key element of this circuit is that the sensors in the gut that recognize
29:41the sugar do not recognize artificial sweeteners.
29:45It's a completely different molecule that only recognizes the glucose molecule, not artificial sweeteners.
29:53This has a profound impact on the effect of, ultimately, artificial sweeteners incurving our appetite,
30:04our craving, our insatiable desire for sugar.
30:08Since they don't activate the gut -brain axis, they'll never satisfy the craving for sugar,
30:14like sugar does. We have a mega problem with overconsumption of sugar and fat.
30:21We're facing a unique time in our evolution where diseases of malnutrition are due to
30:29overnutrition. Historically, diseases of malnutrition...
30:33have always been linked to undernutrition.
30:37But I want to just go back to the notion of, you know, these brain
30:41centers that are ultimately the ones that are being activated by these essential nutrients.
30:48So sugar, fat, and amino acids are building blocks of our diets.
30:56And this is across all animal species.
30:59So it's not unreasonable then to assume that dedicated brain circuits would have evolved to
31:07ensure their recognition, their ingestion, and the reinforcement that that is what I need.
31:15And indeed, you know, animals evolve these two systems.
31:20One is the taste system that allows you to recognize them and trigger these predetermined,
31:26hardwired, immediate responses, yes? You know, oh my God, this is so delicious.
31:31It's fatty or umami recognized in amino acids.
31:35So that's the liking pathway.
31:38But in the wisdom of evolution, that's good, but doesn't quite do it.
31:43You want to make sure that these things get to the place where they are
31:45needed. They are needed in your intestines where they are going to be absorbed as
31:50the nutrients that will support life.
31:52And the brain wants to know this.
31:57Highly processed foods are hijacking, you know, co -opting these circuits in a way that
32:05it would have never happened in nature.
32:07And then we not only find these things appetitive and palatable, but in addition, we
32:13are continuously reinforcing, you know, the wanting in a way that, oh my God, this
32:19is so great. What do I feel like eating?
32:20Let me have more of these.
32:22This is why I think a lot of data are now starting to support the
32:25idea that while indeed the laws of thermodynamics apply, calories ingested versus calories burned is
32:31a very real thing, right?
32:33The appetite for certain foods and the wanting and the liking are phenomena of the
32:41nervous system, brain and gut, as you've beautifully...
32:44described, and that that changes over time, depending on how we are receiving these nutrients.
32:51Absolutely. Understanding the circuits is giving us important insights and how ultimately, hopefully, we can
33:00improve human health and make a meaningful difference.
33:07Now, it's very easy to try to, you know, connect the dots, A to B,
33:14B to C, C to D, and I think there's a lot more complexity to
33:18it, but I do think that the lessons that are emerging out of understanding how
33:26the circuits operate can ultimately inform how we deal with our diets in a way
33:33that we avoid what we're facing now, you know, as a society.
33:37I mean, it's nuts that the over -nutrition happens to be such a prevalent problem.
33:44And I also think the training of people who are thinking about metabolic science and
33:49metabolic disease is largely divorced from the training of the neuroscientists and vice versa.
33:54No one field is to blame, but I fully agree that the brain is the
33:59key or the nervous system to be more accurate.
34:02It's the, one of the key overlooked features.
34:05It's the arbitrary, ultimately it's the arbiter of many of these pathways.
34:10On behalf of myself, and certainly on behalf of all the listeners, I want to
34:15thank you, first of all, for the incredible work that you've been doing now for
34:18decades in vision, in taste, and in this bigger issue of how we perceive and
34:23experience life. It's truly pioneering and incredible work.
34:28And I feel quite lucky to have been on the sidelines, seeing this over the
34:32years and hearing the talks and reading the countless beautiful papers, but also for your
34:37time today to come down here and talk to us about what drives you and
34:42the discoveries you've made. Thank you ever so much.
34:45It was great fun. Thank you for having me.
34:48I'll do it again. And I, we sold.
34:55For more information visit www .fema .org