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

0:00 Welcome to Huberman Lab Essentials,

0:01 [music] where we revisit past episodes for the most

0:04 potent and actionable science-based tools for mental health,

0:08 physical health, and performance.

0:11 I'm Andrew Huberman, and I'm a professor of neurobiology

0:14 and ophthalmology at Stanford School of Medicine.

0:17 And now, for my discussion with Dr.

0:19 Charles Zucker.

0:20 Charles, thank you so much for joining me today.

0:23 My pleasure.

0:24 I want to ask you about many things related to taste and gustatory perception,

0:29 but maybe to start off,

0:31 and because you've worked on a number of different topics in neuroscience,

0:34 not just taste, how should the world and people think about perception,

0:39 how it's different from sensation,

0:41 and what leads to our experience of life in terms of vision,

0:47 hearing, taste, et cetera?

0:48 The world is made of real things.

0:51 You know, this here is a glass.

0:54 And this is a cord, and this is a microphone.

0:57 But the brain is only made of neurons that only understand electrical signals.

1:04 So, how do you transform that reality into nothing

1:09 but electrical signals that now need to represent the world?

1:17 And that process is we can is what we can operationally define as perception.

1:24 In the senses, let's say olfactory, odor, taste, vision,

1:31 you know, we can very straightforwardly separate detection from perception.

1:37 Detection is what happens when you take a sugar molecule,

1:41 you put it in your tongue,

1:43 and then a set of specific cells now sense that sugar molecule.

1:48 That's detection.

1:50 You haven't perceived anything yet.

1:52 That is just your cells in your tongue interacting with this chemical.

1:57 But now that cell gets activated and sends a signal to the brain.

2:01 And now detection gets transformed into perception.

2:07 And it's trying to understand how that happens.

2:10 That's been the the maniacal drive of the of my entire career in neuroscience.

2:21 How does the brain ultimately transform detection into perception

2:25 so that it can guide actions and behaviors?

2:29 So if I want to begin to explore all of these things that the brain does,

2:35 I felt I have to choose a sensory system that affords some degree

2:42 of simplicity in the way that the input output relationships are put together.

2:51 And in a way that still can be used to ask every one

2:54 of these problems that the brain has to ultimately compute, encode, and decode.

3:01 And what what's remarkable about the taste system at the time that I began

3:05 working on this, is that nothing was known about the molecular basis of taste.

3:14 You know, we knew that we could taste what has

3:17 been usually defined as the the five basic taste qualities,

3:21 sweet, sour, bitter, salty, and umami.

3:27 Umami is a Japanese word that means yummy, delicious.

3:32 And that's the and nearly every animal species the taste of amino acids.

3:38 And in humans, it's mostly associated with the taste of MSG,

3:43 monosodium glutamate, one amino acid in particular.

3:47 And so the beautiful thing of the system is

3:48 that the lines of input are limited to five.

3:53 and each of them has a predetermined meaning.

3:57 You're born with that specific valence value for each taste of sweet,

4:05 umami, and low salt are attractive taste qualities.

4:10 They evoke appetitive responses.

4:13 I want to consume them.

4:15 And bitter and sour are innately predetermined to be aversive.

4:23 In the case of bitter, it's very easy to actually look at see them happening

4:28 in animals because the first thing you do is you stop licking.

4:32 Then you put an unhappy face.

4:35 Then you squint your eyes and then you start gagging.

4:40 Okay?

4:40 And that entire thing happens by the activation of a bitter

4:44 molecule in a bitter sensing cell in your tongue.

4:47 It's incredible.

4:49 It's It's again the magic of the brain.

4:51 You know how how [clears throat] it it's able to encode and decode

4:55 these extraordinary actions and behaviors in response

4:58 of nothing but a simple very, you know, unique sensory stimuli.

5:05 This palette of five basic tastes accommodates

5:08 all the dietary needs of the organism.

5:11 Sweet to ensure that we get the right amount of energy.

5:15 Umami to ensure that we get proteins and other essential nutrients.

5:21 Salt, the three appetitive ones to ensure

5:23 that we maintain our electrolyte balance.

5:26 Bitter to prevent the ingestion of toxic noxious chemicals.

5:30 Nearly all bitter tasting, you know, things out in the wild are bad for you.

5:36 And sour most likely to prevent the ingestion of spoil acid.

5:42 Yeah?

5:43 Fermented foods.

5:45 And that's it.

5:46 That is the palate that we deal with.

5:49 Now, of course, there's a difference between basic taste and flavor.

5:54 Flavor is the whole experience.

5:56 Flavor is the combination of multiple

5:58 tastes coming together together with smell,

6:02 with texture, with temperature, with the look of it,

6:08 that gives you what you and I would call the full sensory experience, eh?

6:12 But but we scientists need to reduce the the problem into its basic elements

6:17 so we can begin to break it apart before we put it back together.

6:22 So, when we think about the sense of taste,

6:25 and we try to figure out how these lines

6:29 of information go from your tongue to your brain,

6:31 and how they signal, and how they get integrated,

6:34 and how they trigger all these different behaviors,

6:37 we look at them as individual qualities, eh?

6:40 So, we give the animal sweet, or we give them a bitter, we give them sour.

6:43 We avoid mixes.

6:47 Think of it as lines of information, yeah?

6:48 Separate lines, like the keys of a piano, yeah?

6:51 Sweet, sour, bitter, salty, umami.

6:53 You play that key and you activate that one chord.

6:56 And that one chord, in the case of a piano, leads to a note, you know, a tune.

7:01 And in the case of taste, leads to an action and a behavior.

7:05 If you would describe the sequence of neural

7:08 events leading to a perceptual event of taste,

7:12 We have taste buds distributed in various parts of the tongue.

7:16 So, there is a map on the distribution of taste buds.

7:21 But each taste bud has around 100 taste receptor cells.

7:26 And those taste receptor cells can be of five types, yeah?

7:32 Sweet, sour, bitter, salty, or umami.

7:35 And for the most part,

7:39 all taste buds have the representation of all five taste qualities.

7:45 Now, there's no question that there is a slight bias for some taste.

7:49 Like bitter is particularly enriched at the very back of your tongue.

7:55 And there is a teleological basis

7:57 for that, actually a biological basis for that.

8:00 That's the last line of defense before you swallow something bad.

8:06 And so let's make sure that the very back

8:08 of your tongue has plenty of these bad news receptors.

8:13 So that if they get activated, you can trigger a gagging reflex and get

8:19 rid of these that otherwise may kill you.

8:22 The important thing is that, you know,

8:24 after the receptors for these five the the detectors,

8:28 the molecules that sense sweet, sour, bitter, salt, umami, these are receptors,

8:34 proteins found on the surface of taste

8:36 receptor cells that interact with these chemicals.

8:40 And once they interact, then they trigger the cascade of events,

8:44 biochemical events inside the cell,

8:46 that now sends an electrical signal that says

8:50 there is sweet here or there is salt here.

8:53 Let's compare and contrast sweet and bitter as we

8:57 follow their lines from the tongue to the brain.

9:00 So the first thing is that the two evoke diametrically opposed behaviors.

9:05 If we have to come up

9:06 with two sensory experience that represent polar opposites,

9:10 it would be sweet and bitter.

9:11 So then the signals, if we follow now these two lines,

9:14 they're really like two separate keys at the two ends of this keyboard.

9:19 And you press one key and you activate this chord,

9:23 so you activate the sweet cells throughout your oral cavity.

9:27 And they all converge into a group of sweet neurons in the next station,

9:33 which is still outside the brain.

9:36 It's one of the taste ganglia.

9:38 These are the neurons that innervate your tongue and the oral cavity.

9:42 Where do they sit approximately?

9:44 Are there some

9:44 Around there, yeah.

9:45 Right here around the the lymph nodes, more or less?

9:47 You got it.

9:48 And there are two main ganglia that innervate the vast

9:52 majority of all taste buds in the oral cavity.

9:57 And then from there, that sweet signal goes onto the brain stem.

10:03 The brain stem is the entry of the body into the brain.

10:07 And there are different areas of the brain stem,

10:10 and there are different groups of neurons in the brain stem,

10:13 and this is a unique area in a unique topographically defined location

10:20 in the rostral side of the brain stem that receives all of the taste input.

10:26 A very dense area of the brain.

10:28 A very rich area of the brain, exactly.

10:32 And from there, the sweet signal goes to this other area,

10:36 higher up on the brain stem,

10:39 and then it goes through a number of stations where that sweet signal goes

10:44 from sweet neuron to sweet neuron to sweet

10:48 neuron to eventually get to your cortex.

10:52 And once it gets to your taste cortex,

10:55 that's where meaning is imposed into that signal.

11:00 It's then, this is what the data suggests,

11:05 that now you can identify this as a sweet stimuli.

11:09 And how quickly does that all happen?

11:11 You know, the time scale of the nervous system, it's fast, yeah?

11:16 And so less than a second.

11:18 Yeah.

11:18 And then, in fact, we can demonstrate this because

11:20 we can stick electrodes at each of these stations.

11:24 You deliver the stimuli, and within a fraction of a second,

11:27 you see now the response in these following stations.

11:31 Now it gets to the cortex, yeah?

11:34 And now, in there, you impose meaning to that taste.

11:38 There's an area of your brain that represents

11:43 the taste of sweet in taste cortex,

11:46 and a different area that represents the taste of bitter.

11:50 In essence, there is a topographic map

11:53 of these taste qualities inside your brain.

11:56 How much plasticity do you think there is there,

11:58 and in particular across the lifespan?

12:00 Because I think one of the most salient examples

12:02 of this is that kids don't seem to like certain vegetables,

12:07 but they all are hardwired to like sweet tastes.

12:10 And yet, you could also imagine that one of the reasons why they may eventually

12:14 grow to incorporate vegetables is because of some

12:17 knowledge that vegetables might be good for you.

12:19 better for them.

12:20 Is there a change in the receptors that can explain the transition from wanting

12:25 to avoid vegetables to being willing to eat

12:27 vegetables simply in childhood to to early development?

12:31 taste, we just told you that's, you know, predetermined, hardwired.

12:35 But, predetermined hardwired doesn't mean that's

12:37 not modulated by learning or experience.

12:41 It only means that you're born liking sweet and disliking bitter.

12:47 And we have many examples of plasticity.

12:50 Coffee, it has an associated gain to the system.

12:55 And that gain to the system,

12:57 that positive valence that emerges out of that negative

13:01 signal is sufficient to create that positive association.

13:06 And in the case of coffee, of course,

13:08 it's caffeine activating a whole group of neurotransmitter systems

13:12 that give you that that that high associated with coffee.

13:16 So, yes, this taste system is changeable,

13:18 it's malleable, and it's subjected to learning and experience.

13:22 Can you imagine a sort of system by which people could leverage that.

13:28 Where does this this desensitizing happens?

13:32 That's the term that we use, eh?

13:34 I think it's happening at multiple stations.

13:39 It's happening at the receptor level.

13:42 I.E.

13:44 the cells in your tongue that are sensing that sugar.

13:48 As you activate this receptor and it's

13:50 triggering activity after activity after activity,

13:54 eventually you exhaust the receptor.

13:56 Again, I'm using terms which are extraordinarily loose.

14:00 The receptor gets to a point where

14:03 it undergoes a set of changes, chemical changes,

14:08 where it now signals far less efficiently or it

14:13 even gets removed from the surface of the cell.

14:17 And that is a huge side of this modulation.

14:21 And then the next, I believe, is the integrated, again,

14:25 loss of signaling that happens by continuous activation

14:29 of the circuit at each of these different neural stations.

14:33 From the tongue to the ganglia,

14:34 from the ganglia to the first station in the brain stem,

14:37 a second station in the brain stem, to the thalamus, then to the cortex.

14:43 So, there are multiple steps that this signal is traveling.

14:46 Now, you might say, "Why, if this is a labeled line,

14:48 why do you need to have so many stations?" And that's because the taste

14:53 system is so important to ensure that you get what you need to survive,

14:58 that it has to be subjected to modulation by the internal state.

15:03 And each of these nodes provides a new

15:06 site to give it plasticity and modulation.

15:10 I'm going to give you one example of of how

15:13 the internal state changes the way the taste system works.

15:16 Salt is very appetitive at low concentrations.

15:22 And that's because we need it.

15:24 It's our electrolyte balance requires salt.

15:27 Every one of their neurons uses salt

15:29 as the most important of the ions, you know,

15:31 with potassium to ensure that you can

15:34 transfer these electrical signals within and between neurons.

15:37 But at high concentrations, let's say ocean water is incredibly aversive.

15:44 And we all know this because we go into the ocean

15:46 and then when you get it in your mouth, it's not that great.

15:49 However, if I salt deprive you, now this incredibly high concentration of salt,

15:55 1 molar sodium chloride, becomes amazingly appetitive and attractive.

16:02 What's going on in here?

16:04 Your tongue is telling you this is horrible,

16:06 but your brain is telling you you need it.

16:09 And this is what we call the modulation

16:13 of the taste system by the internal state.

16:17 I'd love you to talk about the aspects of gut-brain signaling that drive

16:21 our or change our perceptions and behaviors

16:24 that are completely beneath our awareness.

16:26 Yes.

16:27 You know, the brain needs to monitor the state of every one of our organs.

16:33 It has to do it.

16:35 This is the only way that the brain can ensure that every one

16:39 of those organs are working together in a way that we have healthy physiology.

16:45 That this is a two-way highway where the brain is not only monitoring,

16:51 but is now modulating back what the body needs to do.

16:57 And that includes all the way from monitoring

17:00 the frequency of heartbeats and the way that inspiration

17:04 and aspirations in the breathing cycle operate

17:07 to what happens when you ingest sugar and fat.

17:11 Let me give you a an example.

17:13 So, Pavlov in his classical experiments in conditioning,

17:16 you know, associative conditioning, he would take a bell,

17:21 he would ring the bell every time he was going to feed the dog.

17:25 Eventually, the dog learned to associate

17:28 the ringing of the bell with food coming.

17:30 The dog now, in the presence of the bell alone, will start to salivate.

17:35 And we will call that, you know,

17:37 neurologically speaking, an anticipatory response.

17:41 Neurons in the brain that form that association now represent food is coming,

17:46 and they're sending a signal to motor neurons to go

17:50 into your salivary glands to squeeze them so you release,

17:54 you know, you know, saliva because, you know, food is coming.

17:59 But what's even more remarkable is that those animals

18:02 are also releasing insulin in response to a bell.

18:07 Somehow, the brain created these associations,

18:09 and there are neurons in your brain now

18:11 that know food is coming and send a signal somehow

18:15 all the way down to your pancreas that now

18:17 it says release insulin because sugar is coming down.

18:21 Now, the main highway that is communicating the state

18:25 of the body with the brain is a specific bundle of nerves,

18:30 which emerge from the vagal ganglia, the nodose ganglia.

18:34 And so is the vagus nerve that is

18:36 innervating the majority of the organs in your body.

18:41 It's monitoring their function, sending a signal to the brain,

18:45 and now the brain going back down and saying, "This is going all right,

18:50 do this, or this is not going so well, do that." And I should point out,

18:54 as you well know, every organ, spleen, pancreas, lung,

18:59 They all must be monitored.

19:02 I have no doubt that diseases

19:04 that we have normally associated with metabolism, physiology,

19:09 and even immunity are likely to emerge as diseases,

19:15 conditions, states of the brain.

19:18 I don't think obesity is a disease of metabolism.

19:21 I believe obesity is a disease of brain circuits.

19:25 I do as well.

19:26 Yeah?

19:26 And so this this view that we have you know

19:29 been working on for the longest time because you know,

19:34 the molecules that we're dealing with are in the body, not in the head.

19:37 You know, let us to you know,

19:39 to view of course these issues and problems as being one of metabolism,

19:44 physiology, and so forth.

19:45 They remain to be the carriers of the ultimate signal.

19:50 But the brain ultimately appears to be

19:53 the conductor of this orchestra of physiology and metabolism.

19:58 Now let's go to the gut-brain and sugar.

20:01 The vagus nerve is made out of many

20:04 thousands of fibers that make this gigantic bundle.

20:08 And it's likely as we're speaking that each of these fibers

20:12 they carry meaning that's associated with their specific task.

20:17 This group of fibers is telling the brain about the state of your heart.

20:22 This group of fibers is telling the brain about the state of your gut.

20:27 This is telling your brain about its nutritional state.

20:31 They are again to make the same simple example, the keys of this piano.

20:38 Now, the reason this is relevant because the magic of this gut-brain axis

20:44 is the fact that you have

20:45 these thousands of fibers really doing different functions.

20:50 Okay, let me tell you about the gut-brain

20:53 axis and our insatiable appetite for sugar.

20:58 This is work of my own laboratory.

21:01 You know, that began long ago when we discovered the sweet receptors.

21:06 You can now engineer mice that lack these receptors.

21:10 So, in essence, these animals will be unable to taste sweet.

21:15 And if you give a normal mouse a bottle containing sweet,

21:20 and we're going to put either sugar or an artificial sweetener.

21:24 All right?

21:24 They both are sweet.

21:26 They have slightly different tastes,

21:28 but that's simply because artificial sweeteners have some off tastes.

21:35 But as far as the sweet receptor is concerned,

21:38 they both activate the same receptor, trigger the same signal.

21:42 And if you give an animal an option

21:44 of a bottle containing sugar or a sweetener versus water,

21:48 this animal will drink 10 to 1 from the bottle containing sweet.

21:54 That's the taste system.

21:55 It Animal goes, samples each one, licks a couple of licks, and then says,

21:59 "Uh-uh, that's the one I want because

22:01 it's appetitive and because I love it." Now, we're going to take the mice,

22:05 and we're going to genetically engineer it to remove the sweet receptors.

22:10 So, these mice no longer have in their oral

22:12 cavity any sensors that can detect sweetness.

22:16 Be that sugar molecule, be it an artificial sweetener,

22:20 be it anything else that tastes sweet.

22:22 And if you give these mice an option between sweet versus water,

22:26 it will drink equally well from both because it cannot tell them apart.

22:30 Because it doesn't have the receptors for sweet,

22:32 so that sweet bottle tastes just like water.

22:35 But if I keep the mouse in that cage for the next 48 hours,

22:40 something extraordinary happens when I come 48 hours later.

22:44 That mouse is drinking almost exclusively from the sugar bottle.

22:49 During those 48 hours, the mouse learned that there is something

22:55 in that bottle that makes me feel good,

22:59 and that is the bottle I want to consume.

23:02 And that is the fundamental basis of our unquenchable desire

23:09 and our craving for sugar and is mediated by the gut-brain axis.

23:15 So, we reason if this is true

23:18 and it's the gut-brain axis that's driving sugar preference,

23:23 then there should be a group of neurons

23:25 in the brain that are responding to post-ingestive sugar.

23:31 And lo and behold, we identify a group of neurons in the brain

23:34 that does this and these neurons receive

23:37 their input directly from the gut-brain axis.

23:41 And so, what's happening is that sugar is recognized normally by the tongue,

23:48 activates an appetitive response.

23:50 Now you ingest it and now it activates

23:53 a selective group of cells in your intestines

23:57 that now send a signal to the brain via the vagal ganglia that says,

24:03 "I got what I need." The tongue doesn't know that you got what you need.

24:08 It only knows that you tasted it.

24:10 This knows that it got to the point

24:12 that it's going to be used, which is the gut.

24:16 And now it sends the signal to now reinforce the consumption

24:21 of this thing because this is the one that I needed, sugar, source of energy.

24:27 So, these are gut cells that recognize the sugar molecule, I see,

24:31 send a signal and that signal is received by the vagal neuron directly.

24:35 Got it.

24:36 And this sends a signal through the gut-brain

24:39 axis to the cell bodies of these neurons in the vagal ganglia and from there

24:46 to the brainstem to now trigger the preference for sugar.

24:52 You see, you want the brain to know that you had successful

24:55 ingestion and breakdown of whatever you

24:58 consume into the building blocks of life.

25:03 And you know, glucose, amino acids,

25:05 fatty and so you want to make sure that once they are in the form

25:10 that intestines can now absorb them is where you get the signal back saying,

25:16 this is what I want.

25:17 Okay?

25:18 Now, let me just take it one step further.

25:20 This now sugar molecules activates this unique gut brain circuit

25:26 that now drives the development of our preference for sugar.

25:32 A key element of this circuit is that the sensors

25:36 in the gut that recognize the sugar do not recognize artificial sweeteners.

25:42 It's a completely different molecule that only

25:44 recognizes the glucose molecule not artificial sweeteners.

25:50 This has a profound impact on the effect

25:55 of ultimately artificial sweeteners in curbing our appetite our craving,

26:02 our insatiable desire for sugar.

26:05 Since they don't activate the gut brain axis,

26:08 they'll never satisfy the craving for sugar like sugar does.

26:13 We have a mega problem with overconsumption of sugar and fat.

26:18 You know, we're facing a unique time in our evolution

26:21 where diseases of malnutrition are due to overnutrition.

26:27 Historically, diseases of malnutritions have

26:30 always been linked to undernutrition.

26:33 But I want to just go back to the notion of, you know,

26:37 these brain centers that are ultimately the ones

26:42 that are being activated by these essential nutrients.

26:45 So, sugar, fat, and amino acids are building blocks of our diets.

26:53 And this is across all animal species.

26:56 So, it's not unreasonable then to assume that dedicated

27:00 brain circuits would have evolved to ensure their recognition,

27:06 their ingestion, and their reinforcement that that is what I need.

27:12 And indeed, you know, animals evolved these two systems.

27:17 One is the taste system that allows you to recognize

27:20 them and trigger this predetermined hardwired immediate responses, yes?

27:26 You know, "Oh my god, this is so delicious.

27:28 It's fatty." Or umami, recognizing amino acids.

27:31 So, that's the liking pathway, yeah?

27:35 But in the wisdom of evolution, that's good, but doesn't quite do it.

27:39 You want to make sure that these things get to the place where they're needed.

27:42 They're needed in your intestines where they're going

27:45 to be absorbed as the nutrients that will support life.

27:50 And the brain wants to know this.

27:53 Highly processed foods are hijacking, you know,

27:58 co-opting the circuits in a way that we would have never happened in nature.

28:04 And then we not only find these things

28:06 up appetitive and palatable, but in addition,

28:09 we are continuously reinforcing, you know,

28:12 the wanting in a way that, "Oh my god, this is so great.

28:16 What do I feel like eating?

28:17 Let me have more of this." Well,

28:19 this is why I think a lot of data are now starting

28:21 to support the idea that while indeed the laws of thermodynamics apply,

28:25 calories ingested versus calories burned is a very real thing, right?

28:30 The appetite for certain foods and the the wanting

28:35 and the liking are phenomena of the nervous system.

28:39 Brain and gut, as you've beautifully described.

28:42 And that that changes over time depending

28:45 on how we are receiving these nutrients.

28:48 Absolutely.

28:48 Understanding the circuits is giving us important insights and how ultimately,

28:56 hopefully, we can improve human health and make a meaningful difference.

29:04 Now, it's very easy to try to, you know,

29:08 connect the dots, A to B, B to C, C to D.

29:12 And I think there's a lot more complexity to it.

29:17 But I do think that the lessons that are

29:18 emerging out of understanding how these circuits operate can

29:25 ultimately inform how we deal with our diets

29:29 in a way that we avoid what we're facing now, you know, as a society.

29:34 I mean, it's nuts that the overnutrition happens to be such a prevalent problem.

29:41 Yeah.

29:41 And I also think the training of people who are thinking about metabolic science

29:45 and metabolic disease is largely divorced

29:48 from the training of the neuroscientists and vice versa.

29:50 No one field is to blame,

29:52 but I fully agree that the the brain is is the key over or the nervous system,

29:57 to be more accurate, is the one of the key overlooked features.

30:02 Is the arbiter.

30:02 Ultimately, is the arbiter of many of these pathways.

30:07 On behalf of myself uh and certainly on behalf of all the listeners,

30:11 I want to thank you first of all for the incredible

30:14 work that you've been doing now for decades in vision,

30:17 in taste, and in this bigger issue of how we perceive and experience life.

30:22 It's uh truly pioneering and incredible work and I feel quite lucky to have been

30:27 on the sidelines seeing this over the years

30:29 and hearing the talks and reading the countless beautiful papers,

30:33 but also for your time today to come down here and talk

30:36 to us about what drives you and the discoveries you've made.

30:40 Thank you ever so much.

30:42 It was great fun.

30:43 Thank you for having me.

30:45 We'll do it again.

30:46 We [music] shall.