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

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.320 | and I'm a professor of neurobiology and ophthalmology

00:00:13.120 | at Stanford School of Medicine.

00:00:15.000 | Today, my guest is Dr. Charles Zucker.

00:00:17.560 | Dr. Zucker is a professor of biochemistry

00:00:19.720 | and molecular biophysics and of neuroscience

00:00:22.320 | at Columbia University School of Medicine.

00:00:25.160 | Dr. Zucker is one of the world's leading experts

00:00:27.680 | in perception.

00:00:28.900 | That is how the nervous system converts physical stimuli

00:00:31.940 | in the world into events within the nervous system

00:00:35.220 | that we come to understand as our sense of smell,

00:00:38.360 | our sense of taste, our sense of vision,

00:00:40.520 | our sense of touch, and our sense of hearing.

00:00:43.080 | Dr. Zucker's lab is responsible for a tremendous amount

00:00:45.760 | of pioneering and groundbreaking work

00:00:47.960 | in the area of perception.

00:00:50.040 | For a long time, his laboratory worked on vision,

00:00:52.140 | defining the very receptors that allow

00:00:54.640 | for the conversion of light into signals

00:00:56.520 | that the rest of the eye and the brain can understand.

00:00:59.620 | In recent years, his laboratory has focused mainly

00:01:01.980 | on the perception of taste.

00:01:03.580 | And indeed, his laboratory is responsible

00:01:05.340 | for discovering many of the taste receptors,

00:01:08.020 | leading to our perception of things like sweetness,

00:01:11.040 | sourness, bitterness, saltiness, and umami,

00:01:14.420 | that is savoriness in food.

00:01:16.700 | Dr. Zucker's laboratory is also responsible

00:01:18.660 | for doing groundbreaking work on the sense of thirst.

00:01:21.620 | That is how the nervous system determines whether or not

00:01:24.320 | we should ingest more fluid or reject fluids

00:01:27.500 | that are offered to us.

00:01:28.900 | A key feature of the work from Dr. Zucker's laboratory

00:01:31.620 | is that it bridges the brain and body.

00:01:34.140 | As you'll soon learn from today's discussion,

00:01:36.300 | his laboratory has discovered a unique set

00:01:38.860 | of sugar-sensing neurons that exist,

00:01:41.380 | not just within the brain, but a separate set of neurons

00:01:43.860 | that sense sweetness and sugar within the body.

00:01:46.900 | And that much of the communication between the brain

00:01:49.120 | and body leading to our seeking of sugar

00:01:51.800 | is below our conscious detection.

00:01:53.820 | Dr. Zucker has received a large number of prestigious awards

00:01:56.560 | and appointments as a consequence

00:01:57.840 | of his discoveries in neuroscience.

00:01:59.880 | He is a member of the National Academy of Sciences,

00:02:02.220 | the National Academy of Medicine,

00:02:03.600 | and the American Association for the Advancement of Science.

00:02:06.300 | He is also an investigator

00:02:07.620 | with the Howard Hughes Medical Institute.

00:02:09.840 | For those of you that are not familiar

00:02:11.300 | with the so-called HHMI, the Howard Hughes Medical Institute,

00:02:14.380 | Howard Hughes Medical Institute investigators

00:02:16.420 | are selected on an extremely competitive basis.

00:02:19.420 | And indeed, they have to come back every five years

00:02:22.080 | and prove themselves worthy of being reappointed

00:02:25.400 | as Howard Hughes investigators.

00:02:27.360 | Dr. Zucker has been a Howard Hughes investigator since 1989.

00:02:31.980 | What all that means for you as a viewer

00:02:33.500 | and/or listener of today's podcast

00:02:35.580 | is that you are about to learn about the nervous system

00:02:38.320 | and its ability to create perceptions,

00:02:40.400 | in particular, the perception of taste and sugar-sensing

00:02:43.280 | from the world's expert on perception and taste.

00:02:47.000 | I'm certain that by the end of today's podcast,

00:02:49.560 | you're not just going to come away

00:02:50.600 | with a deeper understanding of our perceptions

00:02:52.660 | and our perception of taste in particular,

00:02:54.860 | but indeed, you will come away with an understanding

00:02:57.300 | of how we create internal representations

00:03:00.040 | of the entire world around us.

00:03:02.140 | And in doing so,

00:03:03.460 | how we come to understand our life experience.

00:03:06.200 | I'm pleased to announce that the Huberman Lab Podcast

00:03:08.060 | is now partnered with Momentous Supplements.

00:03:10.380 | We often talk about supplements on the Huberman Lab Podcast,

00:03:12.860 | and while supplements aren't necessary for everybody,

00:03:15.080 | many people derive tremendous benefit from them

00:03:17.220 | for things like enhancing the quality and speed

00:03:20.000 | with which you get into sleep,

00:03:21.560 | or for enhancing focus, or for hormone support.

00:03:24.580 | The reason we partnered with Momentous Supplements

00:03:26.380 | is several fold.

00:03:27.220 | First of all, their supplements

00:03:28.200 | are of the absolute highest quality.

00:03:29.960 | Second of all, they ship internationally,

00:03:32.200 | which is important because many of our podcast listeners

00:03:34.680 | reside outside the US.

00:03:36.320 | Third, many of the supplements that Momentous makes

00:03:39.160 | and most all of the supplements

00:03:40.720 | that we partnered with them directly on

00:03:42.560 | are single ingredient formulations.

00:03:44.680 | This is important for a number of reasons.

00:03:46.160 | First of all, if you're going to create a supplement protocol

00:03:48.380 | that's customized for your needs,

00:03:50.280 | you want to be able to figure out

00:03:51.520 | which supplement ingredients are most essential

00:03:53.520 | and only use those.

00:03:54.640 | And supplements that combine lots of ingredients

00:03:56.640 | simply won't allow you to do that.

00:03:58.460 | So in trying to put together a supplement protocol

00:04:00.720 | for yourself that's the most biologically effective

00:04:03.320 | and cost-effective, single ingredient formulations

00:04:06.000 | are going to be the most useful.

00:04:07.380 | If you'd like to see the supplements

00:04:08.520 | that we partnered with Momentous on,

00:04:10.280 | you can go to livemomentous.com/huberman.

00:04:13.240 | And there you'll see many of the supplements

00:04:15.380 | that we've talked repeatedly about

00:04:16.800 | on the Huberman Lab podcast episodes.

00:04:19.080 | I should mention that the catalog of supplements

00:04:21.520 | that are available at livemomentous.com/huberman

00:04:24.160 | is constantly being expanded.

00:04:25.940 | So you can check back there livemomentous.com/huberman

00:04:29.280 | to see what's currently available.

00:04:31.040 | And from time to time,

00:04:32.240 | you'll notice new supplements being added to the inventory.

00:04:34.820 | Before we begin, I'd like to emphasize that this podcast

00:04:37.340 | is separate from my teaching and research roles at Stanford.

00:04:40.100 | It is however, part of my desire and effort

00:04:42.080 | to bring zero cost to consumer information about science

00:04:44.620 | and science related tools to the general public.

00:04:47.220 | In keeping with that theme,

00:04:48.260 | I'd like to thank the sponsors of today's podcast.

00:04:51.000 | Our first sponsor is Thesus.

00:04:52.980 | Thesus makes custom nootropics.

00:04:55.220 | And for frequent listeners of this podcast,

00:04:57.700 | you may remember that I'm not a big fan

00:04:59.360 | of the word nootropics because the word nootropics

00:05:02.080 | means smart drugs or smart compound.

00:05:05.060 | And the reason I don't like that phrase

00:05:06.580 | is that the brain has many different circuits that it uses

00:05:09.640 | in order to perform things like focus or task switching

00:05:13.700 | or creativity.

00:05:14.980 | So the idea that there's a single thing

00:05:16.980 | that we would call a smart drug

00:05:18.660 | is simply not in concert with the biology.

00:05:21.980 | Well, Thesus understands this,

00:05:23.700 | and as a consequence has developed

00:05:25.460 | custom nootropic formulations

00:05:27.240 | that are tailored to your unique needs.

00:05:29.460 | So for instance,

00:05:30.580 | Thesus will allow you to try different blends

00:05:32.660 | over the course of a month and determine which blends

00:05:35.300 | of specific ingredients work best for you to focus

00:05:38.060 | or for you to gain motivation and energy for workouts

00:05:41.540 | or for cognitive work of some sort.

00:05:43.260 | I've been using Thesus custom nootropics

00:05:44.860 | for well over six months now,

00:05:46.700 | and they completely transformed the way

00:05:48.380 | that I do cognitive work

00:05:49.500 | and indeed the way that I do physical fitness.

00:05:52.620 | If you want to try

00:05:53.460 | your own personalized nootropic starter kit,

00:05:55.220 | you can go online to takethesus.com/huberman.

00:05:58.540 | There, you'll just do a brief three minute quiz

00:06:00.660 | and Thesus will send you four different formulas

00:06:02.640 | to try in your first month.

00:06:04.220 | That's takethesus.com/huberman

00:06:06.360 | and use the code Huberman at checkout

00:06:08.060 | to get 10% off your first box.

00:06:10.100 | Today's episode is also brought to us by Roca.

00:06:12.340 | Roca makes eyeglasses and sunglasses

00:06:14.520 | that are the absolute highest quality.

00:06:16.400 | The company was founded

00:06:17.240 | by two all American swimmers from Stanford

00:06:18.980 | and everything about Roca eyeglasses and sunglasses

00:06:21.500 | were designed with performance in mind

00:06:23.540 | and with the biology of the visual system in mind.

00:06:26.220 | I spent my lifetime working on the visual system

00:06:27.960 | and I can tell you that your visual system has to contend

00:06:30.140 | with a number of very important challenges

00:06:32.260 | in order to be able to see the world around you clearly.

00:06:34.620 | Things like adjusting for background illumination

00:06:36.680 | so that when you go from a sunny area to a shady area,

00:06:38.840 | you can see what's in front of you

00:06:40.020 | still with crystal clarity.

00:06:41.700 | Roca takes all of that into account

00:06:43.460 | when designing their eyeglasses and sunglasses.

00:06:45.860 | Their eyeglasses and sunglasses

00:06:47.060 | also have some unique qualities.

00:06:48.680 | For instance, because they were initially designed

00:06:50.960 | for performance with things like running and cycling,

00:06:53.700 | if you get sweaty, they won't fall off your face.

00:06:55.740 | Also, they're extremely lightweight.

00:06:57.380 | In fact, most of the time,

00:06:58.220 | I don't even remember that I'm wearing them.

00:07:00.020 | I wear Roca eyeglasses at night, so I wear readers

00:07:03.100 | and I wear sunglasses often during the day

00:07:04.900 | if it's very bright or if I'm driving.

00:07:06.940 | If you'd like to try Roca eyeglasses and sunglasses,

00:07:09.060 | you can go to Roca, that's R-O-K-A.com

00:07:11.620 | and enter the code Huberman to save 20% off your first order.

00:07:15.140 | Today's episode is also brought to us by Helix Sleep.

00:07:17.620 | Helix Sleep makes mattresses and pillows

00:07:19.340 | that are uniquely tailored to your sleep needs.

00:07:22.060 | I've talked repeatedly about the fact

00:07:23.900 | that sleep is the foundation of mental health,

00:07:25.740 | physical health, and performance.

00:07:27.380 | So getting adequate deep sleep is absolutely essential.

00:07:30.580 | Now, one of the key things to getting a great night's sleep

00:07:32.440 | is to make sure that the surface that you're sleeping on

00:07:34.620 | is the right one for you.

00:07:36.060 | Helix understands this and they've created a sleep quiz.

00:07:39.340 | That is, you go to their website and you fill out

00:07:41.860 | a brief quiz that asks questions like,

00:07:43.660 | do you sleep on your side, your back, your stomach?

00:07:45.600 | Do you tend to run hot or cold during the night?

00:07:47.140 | Maybe you don't know the answers,

00:07:48.120 | in which case you simply say you don't know.

00:07:50.360 | By taking that quiz, they will match you to a mattress

00:07:53.280 | that is ideal for your sleep needs.

00:07:55.580 | I took that quiz and I matched

00:07:56.980 | to the so-called Dusk D-U-S-K mattress,

00:07:59.180 | and I've been sleeping on that mattress for some time now,

00:08:01.220 | and it's the best sleep that I've ever had.

00:08:02.960 | So if you're interested in upgrading your mattress

00:08:04.600 | to one that's uniquely tailored to your sleep needs,

00:08:06.980 | you can go to helixsleep.com/huberman,

00:08:09.380 | take their two-minute sleep quiz,

00:08:10.620 | and they'll match you to a customized mattress,

00:08:12.380 | and you'll get up to $200 off any mattress order

00:08:15.240 | and two free pillows.

00:08:16.640 | They have a 10-year warranty,

00:08:17.820 | and you get to try out that mattress

00:08:19.100 | for 100 nights risk-free.

00:08:20.720 | They'll even pick it up for you if you don't love it,

00:08:22.540 | but I do believe that you will love it

00:08:24.040 | because you'll be sleeping far better than you have before.

00:08:26.460 | Again, if you're interested,

00:08:27.700 | you can go to helixsleep.com/huberman

00:08:30.220 | to get up to $200 off and two free pillows.

00:08:32.980 | And now for my discussion with Dr. Charles Zucker.

00:08:36.140 | Charles, thank you so much for joining me today.

00:08:38.880 | - My pleasure.

00:08:40.060 | - I want to ask you about many things

00:08:41.900 | related to taste and gustatory perception,

00:08:45.680 | but maybe to start off,

00:08:47.340 | and because you've worked on a number of different topics

00:08:49.540 | in neuroscience, not just taste,

00:08:51.420 | how do you think about perception?

00:08:54.780 | Or rather, I should say,

00:08:55.900 | how should the world and people think about perception,

00:09:00.260 | how it's different from sensation,

00:09:02.260 | and what leads to our experience of life

00:09:06.260 | in terms of vision, hearing, taste, et cetera?

00:09:09.420 | - So, you know, the brain is an extraordinary organ

00:09:14.420 | that weights maybe 2% of your body mass,

00:09:20.540 | yet it consumes anywhere between 25 to 30%

00:09:26.260 | of all of your energy and oxygen.

00:09:31.640 | And it gets transformed into a mind.

00:09:35.080 | And this mind changes the human condition.

00:09:40.400 | It changes, it transforms, you know, fear into courage,

00:09:47.180 | conformity into creativity,

00:09:51.520 | sadness into happiness.

00:09:54.780 | How the hell does that happen?

00:09:59.000 | Now, the challenge that the brain faces

00:10:01.760 | is that the world is made of real things.

00:10:05.900 | You know, this here is a glass,

00:10:07.940 | and this is a cord, and this is a microphone.

00:10:12.100 | But the brain is only made of neurons

00:10:14.820 | that only understand electrical signals.

00:10:17.580 | So how do you transform that reality

00:10:22.140 | into nothing that electrical signals

00:10:26.260 | that now need to represent the world?

00:10:29.800 | And that process is what we can

00:10:35.040 | operationally define as perception.

00:10:38.020 | In the senses, let's say olfactory,

00:10:43.360 | odor, taste, vision, you know,

00:10:46.320 | we can very straightforwardly separate

00:10:49.120 | detection from perception.

00:10:52.380 | Detection is what happens when you take a sugar molecule,

00:10:55.480 | you put it in your tongue,

00:10:57.480 | and then a set of specific cells

00:11:00.340 | now sense that sugar molecule.

00:11:03.140 | That's detection.

00:11:04.920 | You haven't perceived anything yet.

00:11:06.940 | That is just your cells in your tongue

00:11:09.300 | interacting with this chemical.

00:11:11.840 | But now that cell gets activated

00:11:13.680 | and sends a signal to the brain,

00:11:16.180 | and now detection gets transformed into perception.

00:11:20.180 | And it's trying to understand how that happens.

00:11:25.060 | That's been the maniacal drive

00:11:30.060 | of my entire career in neuroscience.

00:11:35.600 | How does the brain ultimately transform detection

00:11:38.660 | into perception so that it can guide actions and behaviors?

00:11:43.280 | Does that make sense?

00:11:45.520 | - Absolutely.

00:11:46.520 | And is a very clear and beautiful description.

00:11:49.340 | A sort of high-level question related to that.

00:11:52.460 | And then I think we can get into some of the

00:11:55.300 | intermediate steps.

00:11:56.680 | I think many people would like to know

00:11:58.980 | whether or not my perception of the color of your shirt

00:12:02.340 | is the same as your perception of the color of your shirt.

00:12:04.940 | - What an excellent question.

00:12:06.120 | Am I okay to interrupt you as you're,

00:12:08.840 | as I'm guessing what you're going?

00:12:10.520 | All right, very good.

00:12:11.360 | - Interruption is welcome on this podcast.

00:12:14.000 | The audience will always penalize me for interrupting you,

00:12:17.220 | and we'll never penalize you for interrupting me.

00:12:19.300 | - I like the one way penalizing.

00:12:22.020 | (laughing)

00:12:23.340 | Now, given what I told you before,

00:12:26.680 | that the brain is trying to represent the world

00:12:31.500 | based in nothing but the transformation of these signals

00:12:35.820 | into electrical, you know, languages

00:12:40.660 | that now neurons have to encode and decode.

00:12:43.740 | It follows that your brain is different than my brain.

00:12:47.980 | And therefore it follows that the way

00:12:50.180 | that you're perceiving the world

00:12:52.540 | must be different than mine,

00:12:54.180 | even when receiving the same sensory cues, okay?

00:12:58.100 | And I'll tell you about an experiment.

00:12:59.620 | It's a simple experiment, yet brilliant,

00:13:02.700 | that demonstrates why we perceive the world,

00:13:06.140 | how we perceive the world different.

00:13:09.500 | So in the world of vision, as you know, well know,

00:13:15.420 | we have three classes of photoreceptor neurons

00:13:19.320 | that sense three basic colors, red, blue, and green.

00:13:24.320 | Blue, green, and red, if we go, you know,

00:13:29.680 | from short to long wavelength.

00:13:31.460 | And these three are sufficient to accommodate

00:13:34.660 | the full visible spectra.

00:13:36.300 | I'm gonna take three light projectors,

00:13:40.660 | and I'm gonna project with one into a white screen,

00:13:43.480 | red light, and the other one, green light.

00:13:47.940 | I'm gonna overlap the two beams,

00:13:49.960 | and on the screen, there'll be yellow.

00:13:51.860 | Okay, this is superposition

00:13:54.800 | when you have two beams of red and green.

00:13:58.940 | And then I'm gonna take a third projector,

00:14:01.660 | and I'm gonna put a filter that projects

00:14:03.860 | right next to that mixed beam, a spectrally pure yellow.

00:14:08.860 | And I'm gonna ask you to come to the red and green projectors

00:14:16.540 | and play with intensity knobs so that you can match

00:14:21.540 | that yellow that you're projecting

00:14:24.260 | to the spectrally pure next to it.

00:14:27.180 | Is this making sense?

00:14:28.300 | - Perfect sense.

00:14:29.140 | - And I'm going to write down the numbers

00:14:31.280 | in those two volume intensity knobs.

00:14:34.680 | And then I'm gonna ask the next person to do the same.

00:14:39.820 | And then I'm gonna ask every person around this area

00:14:43.060 | of Battery Park in New York to do the same.

00:14:46.900 | And guess what?

00:14:48.020 | We're gonna end up with thousands

00:14:50.860 | of different number combinations.

00:14:53.180 | - Amazing.

00:14:54.300 | - So for all of us, it's yellow enough

00:14:57.740 | that we can use a common language.

00:14:59.780 | But for every one of us,

00:15:02.820 | that yellow is gonna be ever so slightly differently.

00:15:07.120 | And so I think that simple psychological experiment

00:15:11.440 | beautifully illustrates how we truly perceive

00:15:14.640 | the world differently.

00:15:15.960 | - I love that example.

00:15:18.060 | And yet in that example, we know the basic elements

00:15:21.240 | from which color is created.

00:15:23.160 | If we migrate into a slightly different sense,

00:15:27.200 | let me pick a hard one, like--

00:15:30.060 | - Sound.

00:15:31.000 | - Sound or olfaction.

00:15:32.700 | - Yeah, very hard then to do an experiment

00:15:36.780 | that will allow us to get that degree of granularity

00:15:41.480 | and beautiful causality.

00:15:44.120 | Where we can show that A, produces and leads to B.

00:15:49.120 | If I give you the smell of a rose,

00:15:51.220 | you can describe it to me.

00:15:52.720 | If I smell the same rose, I can describe it also.

00:15:58.040 | But I have no way whether the two of us

00:16:00.880 | are experiencing the same.

00:16:03.060 | But it's close enough that we can both pretty much say

00:16:08.060 | that it has the following features or other determinants.

00:16:13.440 | But no question that your experience is different than mine.

00:16:19.760 | - The fact that it's good enough for us to both survive,

00:16:25.360 | that your perception of yellow and my perception of yellow,

00:16:28.160 | at least up until now,

00:16:29.000 | is good enough for us both to survive.

00:16:30.920 | - You got it.

00:16:31.840 | - It raises a thought about a statement made

00:16:35.300 | by a colleague of ours, Marcus Meister at Caltech.

00:16:39.500 | He's never been on this podcast,

00:16:40.800 | but in a review that I read by Marcus at one point,

00:16:45.500 | he said that the basic function of perception

00:16:48.360 | is to divide our behavioral responses

00:16:51.000 | into the outcomes downstream

00:16:55.420 | of three basic emotional responses.

00:16:58.980 | Yum, I like it.

00:17:01.420 | Yuck, I hate it.

00:17:03.440 | Or meh, whatever.

00:17:06.380 | What do you think about,

00:17:07.360 | I'm not looking to establish a debate

00:17:09.300 | between you and Marcus without Marcus here.

00:17:11.080 | - I understand.

00:17:11.920 | - But what I like about that is that it seems like the,

00:17:16.180 | we know the brain is a very economical organ in some sense,

00:17:20.220 | despite its high metabolic demands.

00:17:22.640 | And this variation in perception

00:17:25.700 | from one individual to the next at once seems like a problem

00:17:29.920 | because we're all literally seeing different things.

00:17:32.800 | And yet we function.

00:17:34.840 | We function well enough for most of us to avoid death

00:17:38.680 | and cliffs and eating poisons and so forth,

00:17:42.560 | and to enjoy some aspects of life, one hopes.

00:17:45.600 | So is there a general statement that we can make

00:17:49.040 | about the brain, not just as a organ to generate perception,

00:17:52.640 | not just as an organ to keep us alive,

00:17:54.920 | but also an organ that is trying to batch our behaviors

00:17:59.360 | into general categories of-

00:18:01.000 | - I think so, but, and again,

00:18:03.720 | I think the role of Marcus too.

00:18:06.880 | And I think he's right that, you know,

00:18:09.640 | broadly speaking, you could categorize a lot of behaviors

00:18:14.800 | falling into those two categories.

00:18:17.020 | And that's 100% likely to be the case

00:18:21.240 | for animals in the wild.

00:18:24.600 | We're, you know, the choices are not necessarily binary,

00:18:29.600 | but they're very unique and distinct.

00:18:33.820 | Do I wanna eat this?

00:18:37.320 | Do I wanna kill that?

00:18:39.080 | Do I wanna go there or do I wanna go here?

00:18:43.000 | We humans deviated from that world long ago

00:18:51.520 | and, you know, learn to experience life

00:18:56.320 | where we do things that we should not be doing.

00:19:00.960 | - Some of us more than others.

00:19:02.320 | - Exactly.

00:19:03.280 | You know, in my own world of taste,

00:19:07.480 | the likelihood that an animal in the wild

00:19:12.440 | will enjoy eating something bitter,

00:19:15.300 | it's inconceivable.

00:19:20.240 | Yet we, you know, love tonic water.

00:19:24.380 | We enjoy, we like living on the edge.

00:19:29.500 | We love enjoying experiences

00:19:32.920 | that makes us human.

00:19:38.840 | And that goes beyond that simple set of categories,

00:19:46.120 | which is yummy, yucky, ah, who cares?

00:19:51.120 | And so I think it's not a bad palette,

00:19:54.160 | but I think it's overly reductionist

00:19:59.160 | for certainly what we humans do.

00:20:04.340 | - I agree.

00:20:05.180 | And since we're here in New York,

00:20:06.440 | I can say that the many options,

00:20:08.960 | the extensive variety of food, flora and fauna in New York

00:20:15.240 | explains a lot of the more nuanced behaviors

00:20:18.160 | that we observe.

00:20:19.880 | Let's talk about taste because while you've done

00:20:23.880 | extensive work in the field of vision,

00:20:25.800 | and it's a topic that I love,

00:20:28.840 | you could spend all day on, taste is fascinating.

00:20:32.440 | First of all, I'd like to know why you migrated

00:20:35.000 | from studying vision to studying taste.

00:20:38.160 | And perhaps in that description,

00:20:39.520 | you could highlight to us why we should think about

00:20:42.260 | and how we should think about the sense of taste.

00:20:46.320 | - My goal has always been to understand,

00:20:48.240 | as I highlighted before, how the brain does its magic.

00:20:51.080 | What part, you might wonder?

00:20:54.660 | Ideally, I like to help contribute to understand all of it.

00:20:58.520 | How do you encode and decode emotions?

00:21:04.580 | How do you encode and decode memories and actions?

00:21:07.900 | How do you make decisions?

00:21:10.860 | How do you transform detection into perception?

00:21:14.600 | And the list goes on and on.

00:21:17.100 | But one of the key things in science, as you know,

00:21:23.100 | is ensuring that you always ask the right question

00:21:27.280 | so that you have a possibility of answering it.

00:21:31.280 | Because if the question cannot be tractable

00:21:35.440 | or reduced to an experimental path that helps you resolve it

00:21:40.440 | then we end up doing some really fun science

00:21:43.580 | but not necessarily answering the important problem

00:21:47.060 | that we want to study.

00:21:48.280 | Make sense?

00:21:50.700 | All right.

00:21:51.540 | - From a first person perspective, yes.

00:21:54.320 | The hardest question, the most important question is,

00:21:57.220 | what question are you going to try and answer?

00:22:00.080 | - And so, for example, I will have to understand

00:22:03.820 | the neural basis of empathy.

00:22:09.200 | - It's a big market for that.

00:22:10.840 | - 100%, but I wouldn't even know.

00:22:13.140 | I mean, at the molecular level, that's what we do.

00:22:15.780 | How do the circuits in your brain create that sense?

00:22:20.560 | I have no clue how to do it.

00:22:23.400 | I can come up with ways to think about it,

00:22:25.180 | but I like to understand what in your brain

00:22:29.500 | makes someone a great philanthropist.

00:22:31.840 | What is the neural basis of love?

00:22:37.080 | I wouldn't even know where to begin.

00:22:40.320 | So if I want to begin to study these questions

00:22:42.680 | about brain function that can cover so many aspects

00:22:46.680 | of the brain, I need to choose a problem

00:22:51.060 | that affords me that window.

00:22:52.920 | But in a way that I can ask questions that give me answers.

00:22:56.860 | And among the senses that have the capacity

00:23:02.760 | of transforming detection into perception

00:23:06.200 | of being stories, memories, of creating emotions,

00:23:11.000 | of giving you different actions and perceptions

00:23:15.800 | as a function of the internal state.

00:23:18.520 | When you're hungry, things taste very differently

00:23:21.040 | than when you're sated.

00:23:22.680 | How, why?

00:23:24.240 | When you taste something, you now remember

00:23:27.080 | this amazing meal you had with your first date.

00:23:30.040 | How does that happen?

00:23:31.280 | All right.

00:23:32.120 | So if I want to begin to explore all of these things

00:23:36.720 | that the brain does, I felt I have to choose

00:23:40.880 | a sensory system that affords some degree of simplicity

00:23:45.880 | in the way that the input output relationships

00:23:53.400 | are put together and in a way that still can be used

00:23:56.760 | to ask every one of these problems that the brain

00:24:00.040 | has to ultimately compute, encode, and decode.

00:24:04.060 | And what was remarkable about the taste system

00:24:08.380 | at the time that I began working on this

00:24:10.800 | is that nothing was known about the molecular basis of taste.

00:24:17.260 | We knew that we could taste what has been usually defined

00:24:22.600 | as the basic taste qualities.

00:24:25.840 | Sweet, sour, bitter, salty, and umami.

00:24:30.840 | Umami is a Japanese word that means yummy, delicious.

00:24:36.360 | And that's in nearly every animal species,

00:24:39.800 | the taste of amino acids.

00:24:42.160 | And in humans, it's mostly associated with the taste of MSG,

00:24:47.160 | monosodium glutamate, one amino acid in particular.

00:24:50.800 | - What are, just by way of example,

00:24:52.600 | some foods that are rich in the umami-evoking stimulation?

00:24:57.560 | - Seaweed, tomatoes, cheese.

00:25:02.120 | And it's a great, great flavor enhancer.

00:25:06.440 | It enriches our sensory experience.

00:25:09.160 | And so the beautiful thing of the system

00:25:11.880 | is that the lines of input are limited to five.

00:25:16.040 | You know, sweet, sour, bitter, salty, and umami.

00:25:20.160 | And each of them has a predetermined meaning.

00:25:24.560 | You are born liking sugar and disliking bitter.

00:25:29.440 | You have no choice.

00:25:31.520 | These are hard-wired systems.

00:25:34.020 | But of course, you can learn to dislike sugar

00:25:39.160 | and to like bitters, see?

00:25:41.720 | But in the wild, let's take humans out of the equation, eh?

00:25:46.660 | These are 100% predetermined.

00:25:50.520 | You're born with that specific valence value

00:25:55.520 | for each taste of sweet, umami, and low salt

00:26:01.340 | are attractive taste qualities.

00:26:04.200 | They evoke appetitive responses.

00:26:07.820 | I wanna consume them.

00:26:08.940 | And bitter and sour are innately predetermined

00:26:16.080 | to be aversive.

00:26:18.080 | - Could I interrupt you just briefly

00:26:19.460 | and ask a question about that exact point?

00:26:22.600 | For something to be appetitive to,

00:26:24.760 | and some other taste to be aversive,

00:26:28.180 | and for those to be hard-wired,

00:26:30.540 | can we assume that the sensation of very bitter,

00:26:35.300 | or of activation of bitter receptors in the mouth

00:26:37.860 | activates a neural circuit that causes closing of the mouth,

00:26:43.300 | retraction of the tongue, and retraction of the body,

00:26:46.480 | and that the taste of something sweet

00:26:48.200 | might actually induce more licking?

00:26:50.900 | - 100%, you got it.

00:26:53.260 | The activation of the receptors in the tongue

00:26:56.820 | that recognize sweet versus the ones that recognize bitter

00:27:01.480 | activate an entirely behavioral program.

00:27:04.280 | And that program that we can refer as appetitiveness,

00:27:10.320 | or aversion, it's composed of many different subroutines.

00:27:15.320 | In the case of bitter, it's very easy to actually look at,

00:27:20.780 | see them happening in animals,

00:27:22.960 | because the first thing you do is you stop licking,

00:27:25.680 | then you put a unhappy face, then you squint your eyes,

00:27:30.680 | and then you start gagging.

00:27:32.480 | And that entire thing happens

00:27:36.020 | by the activation of a bitter molecule

00:27:38.880 | in a bitter sensing cell in your tongue.

00:27:41.100 | - It's incredible.

00:27:42.700 | - It's, again, the magic of the brain,

00:27:44.980 | how it's able to encode and decode

00:27:48.980 | these extraordinary actions and behaviors

00:27:51.340 | in response of nothing but a simple,

00:27:53.480 | very unique sensory stimuli.

00:27:58.480 | Now, let me say that this palette of five basic tastes

00:28:02.560 | accommodates all the dietary needs of the organism.

00:28:05.980 | Sweet to ensure that we get the right amount of energy.

00:28:10.220 | Umami to ensure that we get proteins

00:28:14.780 | and that essential nutrient.

00:28:16.460 | Salt, the three appetitive ones to ensure

00:28:19.740 | that we maintain our electrolyte balance.

00:28:21.980 | Bitter to prevent the ingestion of toxic, nauseous chemicals.

00:28:28.120 | Nearly all bitter tasting things out in the wild

00:28:31.540 | are bad for you.

00:28:34.220 | And sour, most likely to prevent the ingestion

00:28:37.100 | of spoiled, acid, fermented foods.

00:28:42.100 | And that's it.

00:28:44.700 | That is the palette that we deal with.

00:28:48.220 | Now, of course, there's a difference

00:28:49.540 | between basic taste and flavor.

00:28:52.640 | Flavor is the whole experience.

00:28:55.800 | Flavor is the combination of multiple tastes

00:28:58.620 | coming together, together with smell,

00:29:02.180 | with texture, with temperature, with the look of it

00:29:07.180 | that gives you what you and I would call

00:29:09.300 | the full sensory experience.

00:29:11.420 | But we scientists need to reduce the problem

00:29:15.660 | into its basic elements so we can begin to break it apart

00:29:19.880 | before we put it back together.

00:29:21.780 | So when we think about the sense of taste

00:29:25.140 | and we try to figure out how these lines of information

00:29:29.200 | go from your tongue to your brain

00:29:30.880 | and how they signal and how they get integrated

00:29:33.600 | and how they trigger all these different behaviors,

00:29:36.560 | we look at them as individual qualities.

00:29:39.480 | So we give the animal sweet or we give them a bitter,

00:29:41.960 | we give them sour.

00:29:43.260 | We avoid mixes because the first stage of discovery

00:29:48.260 | is to have that clarity as to what you're trying to extract

00:29:56.120 | so that you can hopefully, meaningfully make a difference

00:29:59.560 | by being able to figure out how is it

00:30:02.860 | that A goes to B to C and to D.

00:30:06.080 | Does this make sense?

00:30:06.920 | - Yeah, almost like the primary colors

00:30:08.600 | to create the full array of the color spectrum.

00:30:11.360 | - Exactly.

00:30:12.780 | - Before I ask you about the first and second

00:30:15.380 | and third stages of taste and flavor perception,

00:30:18.660 | is there any idea that there may be more than five?

00:30:22.720 | - There is, for example, what about fat?

00:30:27.100 | - I love the taste.

00:30:28.160 | - I love fat too.

00:30:29.000 | - And I love the texture of fat,

00:30:30.520 | especially if it's slightly burnt.

00:30:32.740 | Like in South America, when I visited Buenos Aires,

00:30:36.240 | I found that at the end of a meal, they would take a steak,

00:30:38.760 | the trimming off the edge of the steak, burn it slightly,

00:30:42.680 | and then serve it back to me.

00:30:44.080 | And I thought, that's disgusting.

00:30:46.320 | And then I tasted it and it's delightful.

00:30:49.080 | - It is.

00:30:49.920 | - There's nothing quite like it.

00:30:51.880 | - This goes back to this notion before

00:30:53.680 | that we like to live on the edge.

00:30:55.380 | And we like to do things that we should not be doing

00:30:58.840 | with Andrew.

00:30:59.680 | But on the other hand, look at those muscles.

00:31:02.840 | [both laughing]

00:31:05.500 | - I don't suggest anyone eat pure fat.

00:31:08.800 | The listeners of this podcast will immediately,

00:31:10.440 | I'm sure there'll be a YouTube video soon

00:31:12.240 | that I like eating pure fat.

00:31:13.600 | I'm not in on a ketogenic diet, et cetera,

00:31:15.920 | but fat is tasty.

00:31:19.540 | - It is.

00:31:20.380 | - As evidenced by the obesity problem

00:31:22.760 | that exists in this country.

00:31:23.600 | - We'll talk about that in a little bit

00:31:25.400 | about the gut brain axis.

00:31:27.800 | I think it'll be important to cover it

00:31:30.040 | because it's the other side of the taste system.

00:31:32.620 | And so, so missing tastes, you know, one is fat.

00:31:38.600 | Although like you clearly highlighted,

00:31:42.440 | a lot of fat taste, in quotation marks,

00:31:46.520 | is really the feeling of fat rolling on your tongue.

00:31:52.960 | And so there is a compelling argument

00:31:57.760 | that a lot of what we call fat taste,

00:32:00.720 | it's really mechanosensory.

00:32:04.580 | It's somatosensory cells, cells that are not responding

00:32:09.480 | to taste, but they're responding to mechanical stimulation

00:32:14.260 | of fat molecules rolling on the tongue

00:32:17.020 | that gives you that perception of fat.

00:32:20.380 | - I love the idea that there is a perception of fat

00:32:23.060 | regardless of whether or not there's a dedicated receptor

00:32:26.180 | for fat, mostly because it's evoking sensations

00:32:30.660 | and imagery of the taste of slightly burnt fat.

00:32:34.420 | - For example, and another one, you know,

00:32:36.900 | you could argue is metallic taste.

00:32:39.220 | You know, I know exactly what it tastes like.

00:32:42.000 | You know, if you ask me to explain it,

00:32:44.060 | I will have a hard time.

00:32:46.580 | You know, what are the palettes of that color

00:32:50.420 | that can allow me to define it?

00:32:51.980 | I wouldn't be easy, but I know precisely

00:32:55.860 | what it tastes like.

00:32:56.700 | You know, take a penny, put it in your mouth

00:32:59.660 | and you know what it tastes like, yeah?

00:33:01.380 | - Or blood. - Or blood.

00:33:02.380 | That's another very good example.

00:33:04.160 | And is there really, you know, a receptor for metallic taste

00:33:10.100 | or it's nothing but this magical combination

00:33:13.220 | of the activation of the existing lines.

00:33:16.700 | Think of it as lines of information,

00:33:18.340 | just separate lines by the keys of a piano, yeah?

00:33:21.600 | Sweet, sour, bitter, salty, you play the key

00:33:24.300 | and you activate that one chord.

00:33:26.580 | And that one chord in the case of a piano leads to a note,

00:33:29.860 | you know, a tune, and in the case of taste

00:33:32.860 | leads to an action and a behavior.

00:33:34.680 | But you play many of them together and something emerges

00:33:38.880 | that it's different than any one of the pieces.

00:33:43.840 | And it's possible that metallic, for example,

00:33:48.280 | represents the combination of the activity

00:33:50.960 | just in the right ratio of these added lines.

00:33:55.960 | - Makes sense.

00:33:57.740 | And it actually provides a perfect,

00:33:59.160 | your example of the piano provides a perfect segue

00:34:01.600 | for what I'd like to touch on next,

00:34:04.320 | which is if you would describe the sequence of neural events

00:34:10.840 | leading to a perceptual event of taste.

00:34:13.240 | And I'm certain that somewhere in there

00:34:15.560 | you will embed an answer to the question

00:34:19.100 | of whether or not we indeed have different taste receptors

00:34:22.600 | distributed in different locations on our tongue

00:34:26.160 | or elsewhere in the mouth.

00:34:27.520 | - Yes, so let's start by debunking that old tale and myth.

00:34:32.520 | - Who came up with that?

00:34:38.820 | - There are many views, but the most prevalent

00:34:41.840 | is that there was an original drawing

00:34:45.920 | describing the sensitivity of the tongue to different tastes.

00:34:50.920 | So imagine I can take a Q-tip.

00:34:54.480 | This is a thought experiment, yeah?

00:34:57.760 | And I'm gonna dip that Q-tip in salt and in quinine

00:35:02.400 | as something bitter and glucose as something sweet.

00:35:06.640 | And I'm gonna take that Q-tip, ask you to stick your tongue

00:35:10.100 | out and start moving it around your tongue

00:35:13.320 | and ask you, what do you feel?

00:35:15.480 | And then I'm going to change the concentration

00:35:20.480 | of the amount of salt or the amount of bitter

00:35:24.600 | and ask, can I get some sort of a map of sensitivity

00:35:28.320 | to the different tastes?

00:35:29.660 | And the argument that has emerged is that

00:35:35.000 | there is a good likelihood that the data

00:35:38.060 | was simply mistranslated as it was being drawn.

00:35:41.700 | And of course that led to an entire industry.

00:35:46.600 | This is the way you maximize your wine experience

00:35:51.540 | because now we're going to form the vessel

00:35:55.320 | that you're gonna drink from so that it acts maximally

00:35:58.920 | on the receptors which happen all right.

00:36:02.220 | Now, there is no tongue map, all right?

00:36:07.220 | We have taste buds distributed in various parts of the tongue

00:36:12.320 | so there is a map on the distribution of taste buds.

00:36:17.320 | But each taste bud has around 100 taste receptor cells.

00:36:22.300 | And those taste receptor cells can be of five types,

00:36:25.780 | sweet, sour, bitter, salty or umami.

00:36:31.040 | And for the most part, all taste buds

00:36:36.040 | have the representation of all five taste qualities.

00:36:41.140 | Now, there's no question that there is a slight bias

00:36:43.640 | for some tastes.

00:36:44.800 | Like, bitter is particularly enriched

00:36:48.320 | at the very back of your tongue.

00:36:50.100 | And there is a teleological basis for that,

00:36:53.320 | actually a biological basis for that.

00:36:56.040 | That's the last line of defense

00:36:57.840 | before you swallow something bad.

00:37:00.000 | And so, let's make sure that the very back of your tongue

00:37:05.000 | has plenty of these bad news receptors

00:37:08.520 | so that if they get activated,

00:37:11.320 | you can trigger a gagging reflex

00:37:13.960 | and get rid of this that otherwise may kill you, okay?

00:37:18.920 | - That's good sense.

00:37:19.800 | - But the notion that all sweet is in the front

00:37:23.720 | and salt is on the side, it's not real.

00:37:28.720 | Not real.

00:37:30.720 | And there, go ahead.

00:37:31.880 | - Oh, I was just gonna ask, are there,

00:37:33.640 | first of all, thank you for dispelling that myth.

00:37:35.880 | - Yes.

00:37:36.720 | - And we will propagate that information

00:37:38.360 | as far and wide as we can

00:37:40.240 | 'cause I think that's the number one myth related to taste.

00:37:43.600 | The other one is,

00:37:44.640 | are there taste receptors anywhere else in the mouth?

00:37:47.760 | For instance, on the lips. - Yeah, the palate.

00:37:49.400 | The palate, not the lips.

00:37:50.640 | So, it's in the far range at the very back

00:37:54.360 | of the oral cavity, the tongue and the palate.

00:37:58.600 | And the palate is very rich in sweet receptors.

00:38:02.320 | - I'll have to pay attention to this

00:38:03.480 | the next time I eat something sweet.

00:38:05.200 | - Whether you pull it up, yeah?

00:38:07.520 | Now, the important thing is that

00:38:12.520 | after the receptors for these five, the detectors,

00:38:17.840 | the molecules that sends sweet, sour, beet, and salt to mommy,

00:38:22.200 | these are receptors, proteins,

00:38:24.280 | found on the surface of taste receptor cells

00:38:26.840 | that interact with these chemicals.

00:38:29.280 | And once they interact,

00:38:30.440 | then they trigger the cascade of events,

00:38:33.480 | biochemical events inside the cell

00:38:35.740 | that now sends an electrical signal

00:38:37.880 | that says there is sweet here or there is salt here.

00:38:42.880 | Now, having these receptors

00:38:44.560 | and my laboratory identify the receptors

00:38:47.160 | for all five basic taste classes,

00:38:49.600 | sweet, beet, salt, to mommy, and most recently sour,

00:38:52.840 | now completing the palate,

00:38:55.520 | you can now use these receptors

00:38:57.240 | to really map where are they found in the tongue

00:39:00.480 | in a very rigorous way.

00:39:02.660 | This is no longer about using a Q-tip

00:39:05.160 | and trying to figure out what you're feeling,

00:39:09.240 | but rather what you have in your tongue.

00:39:12.080 | This is not a guess.

00:39:15.720 | This is now a physical map

00:39:18.600 | that says the sweet receptors are found here.

00:39:22.480 | The bitter are found here.

00:39:23.840 | And when you do that, you find that in fact,

00:39:25.940 | every taste pad throughout your oral cavity

00:39:30.680 | has receptors for all of the basic taste classes.

00:39:35.220 | - Amazing.

00:39:36.440 | And as it turns out,

00:39:38.120 | and I'm sure you'll tell us important

00:39:39.680 | in terms of thinking about how the brain computes

00:39:43.120 | and codes and decodes this thing we call taste.

00:39:46.180 | I'm going to inject a quick question

00:39:47.960 | that I'm sure is on many people's minds

00:39:50.040 | before we get back into the biological circuit,

00:39:52.840 | which is many people, including myself,

00:39:54.960 | are familiar with the experience

00:39:56.160 | of drinking a sip of tea or coffee that is too hot

00:39:59.320 | and burning my tongue is the way I would describe it.

00:40:03.380 | Horrible.

00:40:04.220 | And then disrupting my sense of taste

00:40:06.120 | for some period of time afterward.

00:40:07.880 | - Yes.

00:40:08.780 | - When I experienced that phenomenon,

00:40:12.040 | that unfortunate phenomenon,

00:40:13.560 | have I destroyed taste receptors that regenerate

00:40:17.080 | or have I somehow used temperature

00:40:20.640 | to distort the function of the circuit

00:40:22.560 | so that I no longer taste the way I did before?

00:40:26.120 | - Excellent question.

00:40:27.200 | And the answer is both.

00:40:29.120 | It turns out that your taste receptors

00:40:32.680 | only leave for around two weeks.

00:40:35.140 | And this, by the way, makes sense

00:40:38.380 | because here you have an organ, the tongue,

00:40:41.220 | that is continuously exposed

00:40:46.040 | to everything you could range from the nicest

00:40:48.200 | to the most horrible possible thing.

00:40:50.160 | - Use your imagination.

00:40:51.400 | (laughing)

00:40:52.760 | - And so you need to make sure

00:40:56.600 | that these cells are always coming back in a way

00:40:59.600 | that I can re-experience the world in the right way.

00:41:03.080 | And there are other organs

00:41:04.920 | that have the same underlying logic, okay?

00:41:08.960 | Your gut, your intestines are the same way.

00:41:11.360 | Yeah, amazing.

00:41:12.620 | Again, they're receiving everything that you ingest,

00:41:16.560 | God forbid what's there,

00:41:19.760 | from the spiciest to the most horrible tasting,

00:41:24.080 | so the most delicious.

00:41:25.820 | And again, those intestinal cells whose role is

00:41:29.700 | to ultimately take all these nutrients

00:41:32.880 | and bring them into the body,

00:41:34.940 | also renewal in a very, very fast cycle.

00:41:39.940 | Olfactory neurons in your nose is the other example.

00:41:47.960 | So then A, yes, you're burning a lot of your cells

00:41:51.640 | and it's over for those.

00:41:54.680 | The good news is that they're gonna come back.

00:41:57.480 | But we know that when you burn yourself with tea,

00:41:59.660 | they come back within 20 minutes, 30 minutes, an hour.

00:42:04.660 | And these cells are not renewing in that timeframe.

00:42:09.560 | They're not listening to your needs.

00:42:11.520 | They have their own internal clock.

00:42:16.240 | And so you are really affecting,

00:42:21.240 | you're damaging them in a way that they can recover.

00:42:25.540 | And then they come back

00:42:27.780 | and you also damage your somatosensory cells.

00:42:30.380 | These are the cells that feel things, not taste things.

00:42:35.300 | And then, you know, you wait half an hour or so,

00:42:39.840 | and then, my goodness, thank God, it's back to normal.

00:42:44.480 | - And most of the time, I don't even notice the transition,

00:42:47.500 | realizing, as you tell me.

00:42:49.140 | And later, I'll ask you about the relationship

00:42:51.640 | between odor and taste.

00:42:54.720 | But as a next step along the circuit,

00:42:58.880 | let's assume I ingest some,

00:43:00.700 | let's keep it simple, a sweet taste.

00:43:03.240 | - Let's make it even simpler,

00:43:06.600 | but at the same time, perhaps more informative.

00:43:11.440 | - Let's compare and contrast sweet and bitter

00:43:15.080 | as we follow their lines from the tongue to the brain.

00:43:18.100 | So the first thing is that the two evoke

00:43:22.560 | diametrically opposed behaviors.

00:43:25.120 | If we have to come up with two sensory experiences

00:43:28.320 | that represent polar opposites, it will be sweet and bitter.

00:43:31.320 | There are not two colors that represent polar opposites

00:43:33.720 | because, you know, you could say black and white,

00:43:35.680 | they are polar opposites.

00:43:36.760 | One detects only one thing,

00:43:37.920 | the other one detects everything.

00:43:40.580 | But they don't evoke different behaviors.

00:43:44.900 | - Even the political parties have some over them.

00:43:47.440 | - Sweet and bitter are the two opposite ends

00:43:51.000 | of the sensory spectra.

00:43:52.400 | Now, a taste can be defined by two features.

00:43:58.580 | Again, I'm a reductionist, so I'm reducing it in a way

00:44:04.200 | that I think is easier to follow the signal.

00:44:07.700 | And the two features are its quality

00:44:10.260 | and its valence.

00:44:13.020 | And valence with a little V,

00:44:16.160 | that's what we say in Spanish with a V,

00:44:18.680 | means the value of that experience, all right?

00:44:25.680 | Or in this case of that stimuli.

00:44:30.080 | And you take sweet, sweet has a quality,

00:44:35.080 | an identity, and that's what you and I will refer to

00:44:38.640 | as the taste of sweet.

00:44:40.480 | We know exactly what it tastes like.

00:44:42.480 | But sweet also has a positive valence,

00:44:47.580 | which makes it incredibly attractive and appetitive.

00:44:53.280 | But it's attractive and appetitive,

00:44:55.380 | as I'll tell you in a second,

00:44:56.720 | independent of its identity and quality.

00:45:00.760 | In fact, we have been able to engineer animals

00:45:04.280 | where we completely remove the valence from the stimuli.

00:45:08.140 | So these animals can taste sweet,

00:45:10.800 | can recognize it as sweet, but it's no longer attractive.

00:45:15.800 | It's just one more chemical stimuli.

00:45:19.520 | And that's because the identity and the valence

00:45:24.360 | are encoded in two separate parts of the brain.

00:45:27.180 | In the case of bitter, again, it has, on the one hand,

00:45:33.460 | its identity, its quality.

00:45:35.480 | And you know exactly what bitter tastes like.

00:45:38.840 | - I can taste it now, even as you describe it.

00:45:41.420 | - But it also has a valence, and that's a negative valence,

00:45:45.200 | because it evokes aversive behaviors.

00:45:48.740 | Are we on?

00:45:50.880 | - Absolutely. - All right.

00:45:51.760 | - And it comes to mind, I remember telling some kids recently

00:45:54.080 | that we're gonna go get ice cream, and it was interesting.

00:45:55.920 | They looked up and they started smacking their lip,

00:45:57.740 | like, you know, they'll actually evoke-

00:46:00.560 | - The anticipatory response, absolutely.

00:46:03.860 | When we talk about the gut brain, maybe we'll get there.

00:46:07.300 | So then the signals, if we follow now these two lines,

00:46:10.840 | they're really like two separate keys

00:46:13.100 | at the two ends of this keyboard.

00:46:15.340 | And you press one key and you activate this cord.

00:46:21.180 | So you activate the sweet cells throughout your oral cavity,

00:46:25.100 | and they all converge into a group of sweet neurons.

00:46:29.260 | In the next station, which is still outside the brain,

00:46:35.280 | is one of the taste ganglia.

00:46:37.080 | These are the neurons that innervate your tongue

00:46:40.960 | and the oral cavity.

00:46:42.560 | - Where do they sit approximately?

00:46:44.040 | - Around there. - Yeah, right here

00:46:45.440 | around the lymph nodes, more or less.

00:46:47.240 | - You got it.

00:46:48.060 | And there are two main ganglia that innervate

00:46:54.100 | the vast majority of all taste buds in the oral cavity.

00:46:59.100 | And then from there, that sweet signal

00:47:02.540 | goes onto the brainstem.

00:47:04.760 | The brainstem is the entry of the body into the brain.

00:47:08.880 | And there are different areas of the brainstem,

00:47:12.920 | and there are different groups of neurons in the brainstem,

00:47:15.760 | and there's this unique area,

00:47:17.640 | in a unique topographically defined location

00:47:22.640 | in the rostral side of the brainstem

00:47:29.340 | that receives all of the taste input.

00:47:32.680 | - A very dense area of the brain.

00:47:34.520 | A very rich area of the brain, exactly.

00:47:39.000 | And from there, the sweet signal goes to this other area,

00:47:42.760 | higher up on the brainstem.

00:47:45.560 | And then it goes through a number of stations

00:47:51.000 | where that sweet signal goes from sweet neuron

00:47:54.040 | to sweet neuron to sweet neuron

00:47:56.800 | to eventually get to your cortex.

00:48:00.280 | And once it gets to your taste cortex,

00:48:03.140 | that's where meaning is imposed into that signal.

00:48:08.140 | It's then, and only then, this is what the data suggests,

00:48:13.560 | that now you can identify this as a sweet stimuli.

00:48:20.500 | - And how quickly does that all happen?

00:48:22.680 | - You know, the timescale of the nervous system,

00:48:27.280 | it's fast, yeah?

00:48:30.280 | And so-- - Within less than a second.

00:48:32.040 | - Yeah, absolutely, yeah.

00:48:33.600 | - I rarely mistake bitter for sweet.

00:48:36.440 | Maybe with respect to people and my own poor judgment,

00:48:39.440 | but not with respect to taste.

00:48:41.960 | - Yeah, and in fact, we can demonstrate this

00:48:44.700 | because we can stick electrodes

00:48:46.800 | at each of these stations conceptually, yeah?

00:48:50.340 | And we can stimulate the tongue

00:48:51.940 | and then we can record the signals,

00:48:53.920 | pretty much time log to stimulus delivery.

00:48:57.360 | You deliver the stimuli and within a fraction of a second,

00:49:01.460 | you see now the response in these following stations.

00:49:05.680 | Now it gets to the cortex, yeah?

00:49:08.060 | And now in there, you impose meaning to that taste.

00:49:12.600 | There's an area of your brain

00:49:14.900 | that represents the taste of sweet in taste cortex

00:49:19.900 | and a different area that represents the taste of bitter.

00:49:25.460 | In essence, there is a topographic map

00:49:29.000 | of these taste qualities inside your brain.

00:49:31.340 | Now we're gonna do a thought experiment, all right?

00:49:36.240 | Now, if this group of neurons in your cortex

00:49:39.620 | really represents the sense of sweet

00:49:41.920 | and this added different group of neurons in your brain

00:49:46.020 | represents the taste, the perception of bitter,

00:49:51.020 | then we should be able to do two things.

00:49:55.780 | First, I should be able to go into your brain,

00:49:58.760 | somehow silence those neurons,

00:50:03.020 | find a way to prevent them from being activated

00:50:06.500 | and I can give you all the sweet you want

00:50:09.900 | and you'll never know that you're tasting sweet.

00:50:12.380 | And conversely, I should be able to go into your brain,

00:50:18.300 | come up with a way to activate those neurons

00:50:21.740 | while I'm giving you absolutely nothing

00:50:25.140 | and you're gonna think

00:50:27.080 | that you're getting that full percept.

00:50:29.860 | And that's precisely what we have done

00:50:34.060 | and that's precisely what you get.

00:50:36.740 | This of course is in the brain of mice.

00:50:39.220 | - But presumably in humans, it would work similar.

00:50:41.540 | - Absolutely the same, zeroed out.

00:50:44.180 | I have no questions.

00:50:45.900 | So this attests to two important things.

00:50:50.080 | The first to the predetermined nature of the sense of taste

00:50:55.560 | because it means I can go to these parts of your brain

00:50:58.980 | in the absence of any stimuli

00:51:01.200 | and have you throw the full behavioral experience.

00:51:06.120 | In fact, when we activate in your cortex,

00:51:08.420 | these bitter neurons, the animal can start gagging

00:51:11.740 | but it's drinking only water

00:51:16.580 | but the animal thinks that it's getting a bit of stimuli.

00:51:23.380 | - This is amazing.

00:51:25.140 | And so, and the second, just to finish the line

00:51:27.560 | so that it doesn't sound like it teaches two things

00:51:30.200 | and then I only give you one lesson,

00:51:31.960 | is that it substantiates this capacity of the brain

00:51:40.760 | to segregate, to separate in these nodes of action,

00:51:45.800 | the representation of these two diametrically opposed

00:51:50.240 | percepts, which is sweet, for example, versus bitter.

00:51:55.000 | The reason I say amazing and that is also amazing

00:51:58.400 | is the following.

00:51:59.440 | You told us earlier and you're absolutely correct,

00:52:02.740 | of course, that the end of the day,

00:52:05.880 | whether or not it's one group of neurons over here

00:52:07.800 | and another group of neurons over there,

00:52:10.340 | just the way it turns out to be,

00:52:11.900 | electrical activity is the generic common language

00:52:16.520 | of both sets of neurons.

00:52:18.640 | So that raises the question for me

00:52:20.320 | of whether or not those separate sets of neurons

00:52:23.160 | are connected to areas of the brain

00:52:24.920 | that create this sense of valence

00:52:28.200 | or whether or not they're simply created, connected,

00:52:30.840 | excuse me, to sets of neurons that evoke distinct behaviors

00:52:34.440 | of moving towards and inhaling more and licking or aversive.

00:52:37.760 | Are we essentially interpreting our behavior

00:52:40.400 | and our micro responses or are micro responses

00:52:44.080 | and our behaviors the consequence of the percept?

00:52:46.320 | - Excellent, excellent question.

00:52:48.540 | So first the answer is they go into an area of the brain

00:52:53.540 | where valence is imposed and that area is known

00:52:58.540 | as the amygdala and the sweet neurons go to a different area

00:53:06.260 | than the bitter neurons.

00:53:08.660 | Now, I wanna do a thought experiment

00:53:10.500 | because I think your audience might appreciate this.

00:53:12.760 | Let's say I activate this group of neurons

00:53:16.600 | and the animal increases licking

00:53:18.600 | and I'm activating the sweet neurons

00:53:22.060 | and so that's expected because now it's, you know,

00:53:24.940 | tasting this water as if it was sugar.

00:53:28.700 | Now, this is Moses transforming water into wine.

00:53:32.120 | In this case, we're gonna, and today is Passover

00:53:34.300 | so then it's an appropriate, you know, example.

00:53:37.500 | We're transforming it into sweet, yeah?

00:53:42.420 | But how do I know, how do I know that activating them

00:53:47.520 | is evoking a positive feeling inside, a goodness,

00:53:52.160 | a satisfaction, I love it versus I'm just increasing licking

00:53:57.160 | which is the other option because all we're seeing

00:54:01.200 | is that the animal is licking more

00:54:02.800 | and we're trying to infer that that means

00:54:05.680 | that he's feeling something really good versus you know what?

00:54:08.960 | That piano line is going back straight into the tongue

00:54:11.720 | and all he's doing is forcing it to move faster.

00:54:15.720 | Well, we can actually separate this by doing experiments

00:54:19.640 | that allow us to fundamentally distinguish them.

00:54:22.100 | And imagine the following experiment.

00:54:26.080 | I'm gonna take the animal and I'm gonna put them

00:54:28.260 | inside a box that has two sides

00:54:31.520 | and the two sides have features that make them different.

00:54:35.520 | One has yellow little toys, the other one has green toys.

00:54:40.520 | One has little, you know, black stripes,

00:54:43.720 | the other one has blue stripes.

00:54:45.320 | So the animal can tell the two halves.

00:54:48.400 | I take the mouse, put them inside this arena,

00:54:51.200 | this play arena and it will explore

00:54:54.880 | and poach around both sides with equal frequency.

00:54:58.860 | And now what I'm going to do is I'm gonna activate

00:55:02.040 | these neurons, these sweet neurons,

00:55:05.000 | every time the animal is on the side with the yellow stripes

00:55:15.160 | and if that is creating a positive internal state,

00:55:20.160 | what would the animal now want to do?

00:55:24.040 | It will want to stay on the side with the yellow stripes.

00:55:29.040 | There's no leaking here.

00:55:31.180 | The animal is not extending its tongue

00:55:33.320 | every time I'm activating these neurons, okay?

00:55:36.320 | This is known as a place preference test

00:55:39.320 | and it's generally used, it's just one form

00:55:42.960 | of many different tests to demonstrate

00:55:47.520 | that the activation of a group of neurons in the brain

00:55:53.680 | is imposing, for example,

00:55:56.320 | a positive versus a negative valence.

00:55:59.780 | Whereas if they do the same thing

00:56:01.560 | by activating the bitter neurons,

00:56:03.440 | the animal will actively want now to stay away from the side

00:56:07.920 | where these neurons are being activated

00:56:12.360 | and that's precisely what you see.

00:56:13.840 | - And that's precisely what we see.

00:56:16.400 | - Many people including myself are familiar

00:56:18.440 | with the experience of going to a restaurant,

00:56:20.500 | eating a variety of foods

00:56:23.040 | and then fortunately it doesn't happen that often

00:56:25.240 | but then feeling very sick.

00:56:27.600 | I learned coming up in neuroscience

00:56:29.540 | that this is one strong example of one trial learning

00:56:34.540 | that from that point on, it's not the restaurant

00:56:38.560 | or the waitress or the waiter or the date

00:56:42.480 | but it's my notion of it had to have been the shrimp

00:56:47.240 | that leads me to then want to avoid shrimp in every context,

00:56:50.280 | maybe even shrimp powder.

00:56:52.080 | - You got it.

00:56:53.000 | - For a very long time.

00:56:54.400 | I can imagine all the evolutionarily adaptive reasons

00:56:57.600 | why this such a phenomenon would exist.

00:57:00.440 | Do we have any concept of where in this pathway that exists?

00:57:03.720 | - We know actually a significant amount at a general level.

00:57:08.720 | In fact, more than shrimp,

00:57:12.840 | oysters are even a more dramatic example.

00:57:15.800 | One bad oyster is all you need

00:57:19.400 | to be driven away for the next six months.

00:57:22.160 | - I think because of the texture alone

00:57:24.040 | is something that one learns to overcome.

00:57:25.720 | I actually really enjoy oysters.

00:57:27.640 | I despise mussels, despise shrimp,

00:57:31.480 | not the animal but the taste

00:57:33.480 | and yet oysters, for some reason,

00:57:35.240 | I've yet to have a bad experience.

00:57:36.880 | - It's like uni by the way, texture is hard to get over

00:57:40.400 | but once you get over, it's delicious.

00:57:43.200 | - That's what they tell me.

00:57:44.760 | We were both in San Diego at one point

00:57:46.480 | and I'll give a plug to Sushi Ota

00:57:48.720 | is kind of the famous little-- - Oh my goodness.

00:57:50.280 | - And they have amazing uni and I've tried it twice

00:57:53.240 | and I'm oh for two.

00:57:55.560 | Somehow the texture outweighs any kind of the deliciousness

00:57:59.120 | that people report.

00:57:59.960 | - It's a very acquired taste, it's like beer.

00:58:03.440 | - I grew up in Chile.

00:58:05.760 | That's where the accent comes from in case anyone wonder.

00:58:08.560 | And by the time I came here to graduate school,

00:58:12.280 | I was 19, too old to overcome my heavy Chilean accent.

00:58:17.280 | So here I am 40 years, 50 years late, not quite, 40 plus.

00:58:24.040 | - We appreciate it.

00:58:24.880 | - And I still sound like I just came off the boat.

00:58:28.080 | So in Chile, you don't drink beer when you're young.

00:58:31.640 | You drink wine, Chile is a huge wine producer.

00:58:34.560 | So when I came to the US, all of my classmates

00:58:40.800 | were drinking beer because they had finished college

00:58:45.040 | where they were all beer drinking and graduate school,

00:58:49.520 | you're working 18 hours a day every day.

00:58:52.840 | The way they relax, let's go and have some beers.

00:58:55.960 | - And beer is cheaper.

00:58:57.000 | - And beer is cheap.

00:58:57.880 | And we were being clearly underpaid, may I add.

00:59:01.320 | I couldn't do it.

00:59:05.640 | It's an acquired taste.

00:59:07.520 | It was too late by then.

00:59:09.560 | And here I am, you know, 60 plus.

00:59:12.600 | And if you take all the beer I've drunk in my entire life,

00:59:16.120 | I would say they add to less than an eight ounce

00:59:20.000 | in glass of water.

00:59:21.400 | - Impressive.

00:59:22.240 | Well, your health is probably better for it.

00:59:24.000 | - I'm not sure.

00:59:24.840 | - Your physical health anyway.

00:59:27.760 | - It goes back to, you know, acquired taste.

00:59:30.640 | This is the connection to uni and to oysters.

00:59:33.240 | Now going back to the one trial learning.

00:59:36.320 | You know, this is the great thing about our brains.

00:59:38.840 | Certain things we need to repeat a hundred times

00:59:41.240 | to learn them.

00:59:42.520 | Hello operator, can I have the phone number

00:59:45.160 | for sushi ota please?

00:59:47.160 | And then she'll give it to you over the phone,

00:59:49.440 | at least in the old days.

00:59:51.240 | And then you need to repeat it to yourself

00:59:54.120 | over and over and over over the next minute

00:59:55.960 | so you can dial sushi ota.

00:59:58.040 | And five minutes later, it's gone.

01:00:03.080 | That's what we call working memory.

01:00:05.320 | Then there is the short-term memory.

01:00:08.480 | We park our car and if we're lucky by the end of the day,

01:00:12.160 | we remember where it is.

01:00:14.080 | And then there is the long-term memory.

01:00:16.680 | We remember the birthdays of every one of our children

01:00:19.920 | for the rest of our lives.

01:00:22.640 | Well, there are events that a single event is so traumatic

01:00:26.200 | that it activates the circuits in a way

01:00:30.520 | that it's a one trial learning.

01:00:32.960 | And the taste system is literally

01:00:36.440 | at the top of that food chain.

01:00:38.280 | And there is a phenomenon known as condition taste aversion.

01:00:43.360 | You can pair an attractive stimuli with a really bad one.

01:00:52.560 | And you can make an animal begin to vehemently

01:00:56.360 | dislike, for example, sugar.

01:00:58.440 | And that's because you've conditioned the animals

01:01:02.960 | to now be averse to this otherwise nice taste

01:01:07.960 | because it's been associated with malaise.

01:01:11.640 | And when you do that, now you could begin to ask,

01:01:13.920 | why does change in the signal as it travels from the tongue

01:01:19.440 | to the brain in a normal animal versus an animal

01:01:23.680 | where you have now transformed sweet

01:01:26.120 | from being attractive to being aversive?

01:01:28.840 | And this is the way now you begin to explore

01:01:31.520 | how the brain changes the nature, the quality,

01:01:36.440 | the meaning of a stimuli as a function of its state.

01:01:41.440 | - I have a number of questions related to that,

01:01:48.020 | all of which relate to this idea of context.

01:01:51.120 | Because you mentioned before that flavor

01:01:54.380 | is distinct from taste because flavor involves smell,

01:01:56.760 | texture, temperature, and some other features.

01:01:59.860 | Ooni, sea urchin being a good example of,

01:02:02.380 | I can sense the texture.

01:02:05.300 | It actually, yeah, I won't describe

01:02:07.400 | what it reminds me of for various reasons.

01:02:11.360 | The ability to place context on into,

01:02:15.440 | to insert context into a perception

01:02:17.520 | or rather to insert a perception into context is so powerful.

01:02:22.520 | And there's an element of kind of mystery about it,

01:02:27.240 | but if we start to think about some of the more nuance

01:02:30.760 | that we like to live at the edge, as you say,

01:02:33.100 | how many different tastes on the taste dial,

01:02:39.320 | to go back to your analogy earlier, the color dial,

01:02:41.640 | do you think that there could be

01:02:42.800 | for something as fixed as bitter?

01:02:45.920 | So for instance, I don't think I like bitter taste,

01:02:49.420 | but I like some fermented foods

01:02:51.680 | that seem to have a little bit of sour

01:02:53.360 | and have a little bit of that briny flavor.

01:02:56.660 | How much plasticity do you think there is there,

01:02:58.580 | and in particular across the lifespan?

01:03:01.000 | Because I think one of the most salient examples of this

01:03:03.280 | is that kids don't seem to like certain vegetables,

01:03:07.520 | but they all are hardwired to like sweet tastes.

01:03:11.200 | And yet you could also imagine that one of the reasons

01:03:13.760 | why they may eventually grow to incorporate vegetables

01:03:17.620 | is because of some knowledge

01:03:18.840 | that vegetables might be better for them.

01:03:21.580 | So is there a change in the receptors,

01:03:25.720 | the distribution, the number, the sensitivity, et cetera,

01:03:28.140 | that can explain the transition

01:03:30.200 | from wanting to avoid vegetables

01:03:32.160 | to being willing to eat vegetables

01:03:34.160 | simply in childhood to early development?

01:03:37.480 | - I'm going to take the question slightly differently,

01:03:39.600 | but I think it would illustrate the point.

01:03:41.840 | And I'm gonna just use the difference

01:03:46.840 | between the olfactory system and the taste system

01:03:49.700 | to make the point.

01:03:50.760 | Taste system, five basic palates.

01:03:54.700 | Sweet sour, bitter salt, and umami.

01:03:56.360 | Each of them has a predetermined identity.

01:03:58.680 | We know exactly what, and valence.

01:04:01.480 | These are attractive, these are aversive.

01:04:04.440 | In the olfactory system,

01:04:05.800 | it's claimed that we can smell millions of different others.

01:04:11.160 | Yet, for the most part,

01:04:14.040 | none of them have an innate predetermined meaning.

01:04:19.040 | In the olfactory system,

01:04:21.920 | meaning is imposed by learning and experience,

01:04:26.080 | even the smell of smoke.

01:04:27.440 | So I'm gonna give you, I'm gonna make it differently.

01:04:30.600 | There are a handful of the millions of others

01:04:34.360 | that were claimed that you could immediately tell me

01:04:38.640 | these are aversive and these are attractive.

01:04:41.680 | - Vomit.

01:04:42.800 | - So vomit, it's not correct because I can assure you

01:04:47.580 | that there are cultures and societies

01:04:50.440 | where things which are far less appealing than vomit

01:04:54.160 | do not evoke an aversive reaction.

01:04:56.080 | - Really? - Really.

01:04:57.360 | Sulfur would be maybe a universal.

01:05:00.080 | I'm not talking pheromones, okay?

01:05:01.640 | Pheromones are in a different category

01:05:03.400 | that trigger innate responses.

01:05:06.640 | But nearly every other is afforded meaning

01:05:11.640 | by learning and experience.

01:05:14.200 | And that's why you like broccoli and I despise broccoli

01:05:18.460 | because I remember my mother forcing me to eat broccoli.

01:05:22.960 | Same sensory experience, all right.

01:05:25.700 | This accommodates two important things.

01:05:30.880 | In the case of taste,

01:05:32.000 | you have neurons at every station that are for sweet,

01:05:35.140 | for sour, for bitter, for salty and umami.

01:05:37.600 | It's only five classes.

01:05:38.880 | So it's not gonna take a lot of your brain.

01:05:41.080 | If we can in fact smell a million others

01:05:44.080 | and every one of us have others

01:05:45.280 | had to have predetermined meaning,

01:05:47.500 | there's not gonna be enough brain

01:05:49.120 | just to accommodate that one sense.

01:05:52.600 | And so evolution in its infinite wisdom,

01:05:57.300 | evolve a system where you put together a pathway

01:06:03.340 | and a cortex, olfactory cortex,

01:06:05.800 | where you have the capacity to associate every other

01:06:11.440 | in a specific context that now gives it the meaning.

01:06:17.340 | Now, let's go back to the original question then.

01:06:23.800 | So other than clearly plastic, mega plastic,

01:06:28.160 | because it's fundamental basis and neural organization.

01:06:33.700 | But taste, we just told you

01:06:34.940 | that's predetermined hardwired.

01:06:37.340 | But predetermined hardwired doesn't mean

01:06:39.180 | that it's not modulated by learning or experience.

01:06:43.340 | It only means that you are born liking sweet

01:06:47.580 | and disliking bitter.

01:06:49.220 | And we have many examples of plasticity,

01:06:53.820 | beer being one example.

01:06:56.220 | So why do we learn to love beer?

01:06:58.340 | It's in coffee.

01:06:59.980 | It's because it has an associated gain to the system.

01:07:04.980 | And that gain to the system,

01:07:09.600 | that positive valence that emerges

01:07:12.320 | out of that negative signal is sufficient

01:07:15.720 | to create that positive association.

01:07:19.200 | And in the case of beer, of course, is alcohol.

01:07:21.840 | The feeling good that we get after

01:07:25.200 | is more than sufficient to say,

01:07:27.400 | I wanna have more of this.

01:07:29.780 | And in the case of coffee, of course,

01:07:31.280 | is caffeine activating a whole group

01:07:33.180 | of neurotransmitter systems that give you

01:07:35.940 | that high associated with coffee.

01:07:39.340 | So yes, this taste system is changeable,

01:07:41.920 | it's malleable, and it's subjected

01:07:44.100 | to learning and experience.

01:07:46.220 | But unlike the olfactory system,

01:07:48.940 | it's restricted in what you could do with it,

01:07:53.160 | because its goal is to allow you

01:07:57.100 | to get nutrients and survive.

01:07:59.540 | The goal of the olfactory system is very different.

01:08:02.600 | It's being used, not in our case,

01:08:04.740 | but in every animal species,

01:08:06.760 | to identify friend versus foe,

01:08:09.720 | to identify mate,

01:08:12.540 | to identify ecological niches they wanna be in.

01:08:18.840 | So it plays a very broad role

01:08:22.960 | that then requires that it be set up,

01:08:25.800 | organized, and function

01:08:27.840 | in a very different type of context.

01:08:30.540 | Taste is about, can we get the nutrients

01:08:33.260 | we need to survive?

01:08:35.140 | And can we ensure that we are attracted

01:08:36.900 | to the ones we need, and we're averse

01:08:39.500 | to the ones that are going to kill us?

01:08:41.400 | I'm being overly simplistic and reductionist,

01:08:44.420 | but I think it illustrates a huge difference

01:08:47.260 | between these two chemosensory systems.

01:08:50.580 | - I don't think you're being overly simplistic.

01:08:52.960 | I think it illustrates the key intractable nature

01:08:56.760 | of this system and the way you've approached it,

01:08:59.600 | and I think it's important for people to hear that,

01:09:01.860 | because everybody, as we are,

01:09:04.020 | is mystified with empathy and love, et cetera.

01:09:07.400 | So in fairness to that,

01:09:09.280 | I'm gonna ask a sort of a high-level question

01:09:12.920 | or abstract question.

01:09:14.160 | This was based on a conversation I had

01:09:16.880 | with a former girlfriend,

01:09:18.500 | where we were talking about chemistry

01:09:20.820 | between individuals.

01:09:22.240 | Very complicated topic on the one hand,

01:09:26.180 | but on the other hand, quite simple

01:09:29.260 | in that certain people, for whatever reason,

01:09:32.200 | evoke a tremendous sense of arousal,

01:09:34.980 | for lack of a better word, between two people,

01:09:37.820 | one would hope.

01:09:38.660 | At least for some period of time.

01:09:42.660 | - I didn't know this was that kind of a podcast.

01:09:44.940 | - No, well, the reason I,

01:09:47.260 | but this has to do with taste,

01:09:48.660 | because she said something,

01:09:49.880 | I think in part to maybe irritate me a bit,

01:09:53.600 | but we were commenting not about our own experience

01:09:57.480 | of each other,

01:09:58.640 | but of someone that she was now very excited about.

01:10:03.200 | We're on good terms.

01:10:04.340 | And she said, "What do you think it is,

01:10:08.780 | this thing of chemistry?"

01:10:10.120 | So maybe she was trying to, you know.

01:10:12.160 | - Warn you of what's coming.

01:10:13.800 | - Warn me of what's coming.

01:10:15.120 | And she said, "I have a feeling something about it

01:10:17.760 | is in smell and something about it is actually in taste."

01:10:23.320 | Literally the taste of somebody's breath.

01:10:25.540 | That's the way she described it.

01:10:27.440 | And I thought that it was a very interesting example

01:10:31.000 | for a number of reasons,

01:10:32.640 | but in particular,

01:10:33.580 | because it gets to the merging of odor and taste,

01:10:37.340 | but also to the idea that,

01:10:39.800 | of course, the context of a new relationship,

01:10:42.320 | I'm assuming, and in fact,

01:10:43.820 | they're both attractive people, et cetera.

01:10:45.500 | There's a whole context there,

01:10:46.680 | but I've had the experience of the odor of somebody's breath

01:10:52.960 | being aversive,

01:10:53.800 | not because I could identify it as aversive.

01:10:57.260 | - Because you just didn't like it.

01:10:58.100 | - But because it just didn't like it.

01:11:01.160 | - But that's because you associate it with other others

01:11:06.160 | that trigger that negative aversive reaction, by the way.

01:11:13.460 | - Absolutely.

01:11:16.920 | There are certain perfumes to me that are aversive.

01:11:19.000 | - You got it.

01:11:19.840 | - There are other scents, I can recall,

01:11:23.360 | scents of skin, of foods, et cetera,

01:11:26.060 | that are immensely repetitive.

01:11:28.240 | So I've experienced both sides of this equation myself,

01:11:31.420 | and she was describing this,

01:11:32.840 | and to me, more than tasting wine,

01:11:35.680 | which is the typical example,

01:11:37.160 | where people inhale it and then they drink it,

01:11:39.300 | to me, this seems like something

01:11:40.760 | that more people might be able to relate to,

01:11:43.160 | that certain things and people smell delicious.

01:11:47.480 | Even mothers describing the smell of their baby's head.

01:11:49.920 | - Of course, a mother in mass.

01:11:51.920 | I mean, our own babies when they're in their necks,

01:11:55.320 | that's the magical place.

01:11:56.800 | - Their neck.

01:11:57.640 | - The back of their neck.

01:11:58.600 | - There you go.

01:11:59.440 | - Oh my goodness.

01:12:00.520 | I have a grandchild now,

01:12:01.540 | so I know exactly what Rio, that's his name, smells like.

01:12:05.460 | - Okay, so more beautiful examples.

01:12:07.360 | It's always more fun to think about the beautiful,

01:12:09.180 | positive, the repetitive examples.

01:12:11.520 | The smell of the back of your grandson's neck.

01:12:15.120 | - Yes.

01:12:15.960 | - You could get more specific than that,

01:12:17.800 | but not a lot more specific.

01:12:19.120 | So what is going on in terms of the combination

01:12:23.080 | of odor and taste,

01:12:24.600 | given that these two systems are so different?

01:12:27.600 | - Yes, and they come together.

01:12:31.620 | Ultimately, there is a place in the brain

01:12:35.700 | where they come together to integrate the two

01:12:39.960 | into what we would call that sensory experience.

01:12:45.200 | And I'll tell you an experiment that you could do

01:12:48.180 | that demonstrates this.

01:12:49.760 | I think it's good for your audience here

01:12:53.940 | to get a sense of how we approach these problems

01:12:56.280 | so that we can get meaningful scientific answers.

01:12:59.080 | So we know where the olfactory cortex is in the brain.

01:13:05.080 | We know where the taste cortex is in the brain.

01:13:07.040 | They're in two different places.

01:13:09.160 | We can go to each of these two cortices,

01:13:13.720 | put color traces, we put green in one,

01:13:17.480 | we put red in the other,

01:13:18.940 | and we see where the colors go to.

01:13:21.920 | That's a reflection of where those neurons

01:13:24.040 | are projecting to into their next targets.

01:13:29.040 | Once they get the signal,

01:13:30.240 | where do they send the signal to?

01:13:32.220 | And then we reason that if odor and taste come together

01:13:37.440 | somewhere in the brain,

01:13:38.920 | we should find an area that now

01:13:40.560 | it's getting red and green color.

01:13:43.700 | And we found such an area.

01:13:45.940 | And next, we anticipated, we hypothesized

01:13:51.100 | that maybe this is the area in the brain of the mouse,

01:13:55.220 | corresponding area in the brain of humans,

01:13:57.460 | that integrates odor and taste.

01:14:02.460 | It's known, the term normally used

01:14:05.620 | is multisensory integration.

01:14:08.020 | And if this is true, we could do the following experiment.

01:14:12.900 | We can train a mouse to lick sweet,

01:14:17.900 | and if they guess correctly

01:14:23.940 | that that is supposed to be sweet,

01:14:25.820 | they should go now to the right port,

01:14:29.780 | to the right side to get a water reward.

01:14:32.720 | If they go to the left when it was sweet,

01:14:38.100 | then they're incorrect and they get no reward.

01:14:42.140 | And they actually get a time out.

01:14:44.820 | Now the mice are thirsty,

01:14:46.580 | so they're very motivated to perform.

01:14:48.980 | And if you repeat this task a hundred times,

01:14:52.400 | a hundred trials, incredibly enough,

01:14:55.080 | this animal learned to recognize the sweet

01:14:58.020 | and execute the right action.

01:15:00.060 | And by their action, we now are being told

01:15:05.020 | what that animal is tasting.

01:15:07.040 | We can make it more interesting

01:15:09.300 | and we can give them sweet and bitter

01:15:10.760 | and say if it's sweet, go to the right

01:15:12.660 | and if it's bitter, go to the left.

01:15:14.360 | And after you train them, this mice with 90% accuracy

01:15:18.500 | will tell you when you randomize now the stimuli,

01:15:22.220 | what was sweet and what was bitter.

01:15:24.220 | All right.

01:15:25.580 | We can now do the same experiment,

01:15:27.480 | but now mix taste with odor.

01:15:31.000 | And say, if you got odor alone,

01:15:38.380 | go to the right or push this lever in mice.

01:15:43.380 | If you get taste alone, go to this other part

01:15:47.080 | or push this other lever.

01:15:48.480 | And if you get the two together, do this something else.

01:15:53.560 | And if you train the mice,

01:15:55.020 | the mice are able now to report back to you

01:15:57.700 | when it's sensing taste alone, odor alone or the mix.

01:16:02.700 | Make sense?

01:16:05.840 | - Makes sense.

01:16:06.660 | - So we can go to the brain of these mice

01:16:09.340 | and go to this area that we now uncover, discover

01:16:13.780 | as being the site of multi-sensor integration

01:16:17.140 | between taste and odor and silence it.

01:16:21.140 | Prevent it from being activated experimentally.

01:16:25.740 | And if that area really represented

01:16:29.520 | the integration of these two,

01:16:31.600 | the animal should still be able to recognize the taste alone.

01:16:35.140 | They still should be able to recognize the odor alone,

01:16:38.180 | but should be incapable now to recognize the mix.

01:16:42.980 | And exactly as predicted, that's exactly what you get.

01:16:48.980 | All right?

01:16:50.220 | - The brain is basically a series of engineered circuits.

01:16:54.460 | Complex, you got it.

01:16:56.000 | And our task is to figure out how can we extract

01:17:03.140 | this amazing architecture of these circuits

01:17:07.380 | in a way that we can begin to uncover

01:17:10.020 | the mysteries of the brain.

01:17:12.980 | - And why certain people's breath tastes so good

01:17:15.940 | and other people's not so good.

01:17:18.780 | - So I never answered that,

01:17:20.020 | but I told you how we can figure out

01:17:22.100 | where in the brain is happening.

01:17:24.660 | - As we've been having this discussion,

01:17:27.420 | I thought a few times about similarities

01:17:31.100 | to the visual system or differences to the visual system.

01:17:34.100 | The visual system, there are a couple of phenomenon

01:17:36.260 | that I wonder if they also exist in the taste system.

01:17:41.120 | In the visual system, we know, for instance,

01:17:42.680 | that if you look at something long enough

01:17:44.580 | and activate the given receptors long enough,

01:17:47.020 | that object will actually disappear.

01:17:49.340 | We offset this with little micro eye movements, et cetera,

01:17:51.740 | but the principle is a fundamental one,

01:17:53.740 | this habituation or desensitization.

01:17:55.780 | Everyone seems to call it something different,

01:17:57.660 | but you get the idea, of course.

01:18:00.860 | In the taste system, I'm certainly familiar

01:18:04.140 | with eating something very, very sweet

01:18:05.860 | for the first time in a long time,

01:18:07.900 | and it tastes very sweet.

01:18:09.860 | But a few more licks, a few more bites,

01:18:11.620 | and now it tastes not as sweet.

01:18:13.320 | With olfaction, I'm familiar with the odor in a room

01:18:16.900 | I don't like or I like, and then it disappearing.

01:18:18.900 | So similar phenomenon.

01:18:20.200 | Where does that occur?

01:18:23.060 | And can you imagine a sort of system

01:18:28.960 | by which people could leverage that?

01:18:31.600 | Because I do think that most people

01:18:33.840 | are interested in eating not more sugar, but less sugar.

01:18:37.740 | - I think we have better ways to approach that,

01:18:39.680 | and we can transition from taste into these other circuits

01:18:44.520 | that makes sugar so extraordinarily impossible

01:18:49.520 | not to consume.

01:18:53.540 | - Impossible.

01:18:54.800 | - Exactly.

01:18:56.840 | So where does this desensitizing happens?

01:19:01.840 | That's the term that we use.

01:19:03.420 | And it's, I think, happening at multiple stations.

01:19:09.400 | It's happening at the receptor level,

01:19:15.540 | i.e. the cells in your tongue that are sensing that sugar.

01:19:20.100 | As you activate this receptor,

01:19:23.300 | and it's triggering activity after activity after activity,

01:19:27.020 | eventually you exhaust the receptor.

01:19:29.780 | Again, I'm using terms which are extraordinarily loose.

01:19:33.720 | - But for sake of this discussion, it's fine.

01:19:36.700 | - For the sake of this discussion,

01:19:37.540 | the receptor gets to a point

01:19:41.680 | where it undergoes a set of changes, chemical changes,

01:19:45.100 | where it now signals far less efficiently,

01:19:50.620 | or it even gets removed from the surface of the cell.

01:19:54.660 | And now what will happen is that the same amount of sugar

01:19:59.340 | will trigger far less of a response.

01:20:02.700 | And that is a huge side of this modulation.

01:20:08.040 | And then the next, I believe,

01:20:10.820 | is the integrated, again, loss of signaling

01:20:14.620 | that happens by continuous activation of the circuit

01:20:18.380 | at each of these different neural stations.

01:20:20.860 | You know, there is from the tongue to the ganglia,

01:20:23.720 | from the ganglia to the first station in the brainstem,

01:20:26.740 | a second station in the brainstem,

01:20:29.100 | to the thalamus, then to the cortex.

01:20:32.220 | So there are multiple steps that this signal is traveling.

01:20:35.140 | Now, you might say, why, this is a label line,

01:20:37.840 | why do you need to have so many stations?

01:20:41.020 | And that's because the taste system is so important

01:20:43.780 | to ensure that you get what you need to survive,

01:20:48.020 | that it has to be subjected to modulation

01:20:50.900 | by the internal state.

01:20:53.140 | And each of these nodes provides a new side

01:20:57.280 | to give it plasticity and modulation,

01:21:00.860 | not necessarily to change the way that something tastes,

01:21:04.060 | but to ensure that you consume more or less

01:21:09.500 | or differently of what you need.

01:21:12.840 | I'm gonna give you one example

01:21:14.220 | of how the internal state changes

01:21:16.400 | the way the taste system works.

01:21:18.100 | Salt is very appetitive at low concentrations,

01:21:24.320 | and that's because we need it.

01:21:26.860 | It's our electrolyte balance requires salt,

01:21:31.000 | every one of their neurons uses salt

01:21:33.060 | as the most important of the ions,

01:21:35.300 | you know, with potassium to ensure

01:21:36.900 | that you can transfer these electrical signals

01:21:40.260 | within and between neurons.

01:21:44.380 | But at high concentrations, let's say ocean water,

01:21:48.440 | it's incredibly aversive.

01:21:50.800 | And we all know this because we've gone to the ocean

01:21:52.720 | and then when you get it in your mouth, it's not that great.

01:21:56.360 | However, if I salt deprive you,

01:22:00.200 | and we can do this in experimental models quite readily,

01:22:05.160 | now this incredibly high concentration of salt,

01:22:10.240 | one molar sodium chloride becomes amazingly appetitive

01:22:15.040 | and attractive.

01:22:15.940 | What's going on in here?

01:22:19.160 | Your tongue is telling you this is horrible,

01:22:22.480 | but your brain is telling you, I don't care, you need it.

01:22:27.380 | And this is what we call the modulation of the taste system

01:22:34.720 | by the internal state.

01:22:37.640 | - And presumably if one is hungry enough,

01:22:39.400 | even uni will taste good.

01:22:41.400 | Just kidding to me. - You hit it right

01:22:42.640 | on the money, no, no, this is exactly correct.

01:22:45.980 | Or if you're thirsty and hungry, you suppress hunger

01:22:50.980 | so that you don't waste water molecules in digesting food.

01:22:56.520 | Why?

01:22:58.240 | Because if you're thirsty and you have no water,

01:23:01.360 | you will die within a week or so.

01:23:03.260 | But you can go on a hunger strike as long as you have water

01:23:09.120 | for months, because you're gonna eat up

01:23:12.240 | all your energy reserves.

01:23:14.560 | Water is a different story.

01:23:16.040 | So you could see that there are multiple layers at which

01:23:21.000 | the taste system that guides our drive and our motivation

01:23:27.320 | to consume the nutrients we need has to be modulated

01:23:32.360 | in response to the internal state.

01:23:35.780 | And of course, internal state itself has to be modulated

01:23:39.000 | by the external world.

01:23:42.160 | And so that I think is a reason why,

01:23:44.740 | what could otherwise would have been

01:23:46.000 | an incredibly simple system from the tongue

01:23:49.320 | to the cortex in one gas wire, it's not.

01:23:53.800 | Because you have to ensure that at each step,

01:23:57.560 | you give the system that level of flexibility

01:24:01.440 | or what we call in neuroscience, plasticity.

01:24:04.000 | - I think we're headed into the gut.

01:24:06.860 | - All right.

01:24:07.700 | - I have a question that has just been on my mind

01:24:10.920 | for a bit now, because I was drinking this water

01:24:14.960 | and it has essentially no taste.

01:24:16.960 | - Yes.

01:24:18.300 | - Is there any kind of signal for the absence of taste

01:24:21.880 | despite having something in the mouth?

01:24:23.520 | And here is why I ask, what I'm thinking about is saliva.

01:24:28.040 | And while it's true that if I eat a lot

01:24:30.640 | of very highly palatable foods,

01:24:33.060 | that does change how I experience more bland foods.

01:24:37.600 | I must confess when I eat a lot

01:24:39.000 | of these highly processed foods,

01:24:40.540 | I don't particularly like them.

01:24:41.740 | I tend to crave healthier foods,

01:24:43.120 | but that's probably for contextual reasons

01:24:44.880 | about nutrients, et cetera.

01:24:46.960 | But I could imagine an experiment where-

01:24:50.580 | - Is there a taste of no taste?

01:24:52.200 | - Right, is there a taste of no taste?

01:24:53.640 | Because in the visual system there is, right?

01:24:56.220 | You close the eyes and you start getting increases

01:24:58.520 | in activity in the visual system as opposed to decreases,

01:25:01.020 | which often surprises people.

01:25:02.580 | But there are reasons for that because everything

01:25:04.720 | is about signal to noise, signal to background.

01:25:07.160 | And it's a good question.

01:25:09.160 | I can tell you that most of our work is trying to focus

01:25:11.880 | on how the taste system works, not how it doesn't work.

01:25:16.880 | - Well, but- - I know, yes we do.

01:25:19.160 | - I know you're being playful.

01:25:20.280 | And I knew when inviting you here today,

01:25:21.720 | I was setting myself up for it.

01:25:23.400 | I actually, on a different-

01:25:25.080 | - We're trying to learn things.

01:25:26.200 | - Yeah, I know. - However-

01:25:27.280 | - All right, listen, I was weaned in this system of,

01:25:30.680 | and I'll say it here for the second.

01:25:32.560 | Actually, I recorded a podcast recently

01:25:34.800 | with a very prominent podcast at Lex Friedman Podcast.

01:25:37.560 | And I made reference to the so-called

01:25:39.160 | New York Neuroscience Mafia.

01:25:41.560 | I won't say whether or not we are sitting in the presence

01:25:43.980 | of the New York Neuroscience Mafia member,

01:25:46.240 | but in any event, I know the sorts of ribbing

01:25:49.980 | that they provide.

01:25:51.160 | For those listening, this is the kind of hazing that happens,

01:25:54.160 | benevolent hazing in academia.

01:25:57.040 | I'm the target.

01:25:57.880 | - Of course, it's- - It's a sign of love.

01:26:00.520 | - Exactly. - He's gonna tell me that.

01:26:02.160 | - And it's always about the science in the end.

01:26:04.520 | - Right, but-

01:26:05.840 | - It's an interesting question.

01:26:07.360 | Look, I don't know the answer.

01:26:10.960 | And I don't even know how I would explore it

01:26:15.960 | in a way that it will rigorously teach me.

01:26:20.960 | But-

01:26:24.720 | - Let me tell you why I'm asking,

01:26:27.800 | and then I'll offer an experiment

01:26:29.400 | that I'd love to see someone in your class do.

01:26:32.160 | I'm thinking about saliva.

01:26:33.560 | - Yes, no, no, no, but that we can figure it out.

01:26:36.600 | - Right, but the question is whether or not

01:26:38.800 | the saliva in a fed state is distinct from the saliva

01:26:43.800 | in an unfed state, such that it modulates-

01:26:47.880 | - It's not.

01:26:48.720 | - The sensitivity of the receptors.

01:26:49.560 | - That experiment has been done, no.

01:26:50.560 | - It has been done.

01:26:51.400 | And so the answer is no.

01:26:52.460 | - It's not, yeah.

01:26:53.300 | And the way you could do the experiment

01:26:54.800 | is because we use artificial saliva.

01:26:58.260 | - There's such a thing.

01:26:59.100 | I know there's artificial tears, but-

01:27:00.720 | (laughing)

01:27:01.660 | - No, no, we, I don't mean that you go to Walgreens

01:27:04.860 | and you get, I mean, we in my laboratory,

01:27:07.900 | we know the composition of saliva,

01:27:09.780 | and so you can make such a thing.

01:27:12.040 | And you can take, you know, taste cells in culture

01:27:17.040 | or in a tongue where you wash it out of,

01:27:20.420 | and then you can apply artificial saliva.

01:27:23.340 | And what happens is that the system is being engineered

01:27:26.820 | to desensitize, to become agnostic,

01:27:31.820 | for saliva to become invisible.

01:27:35.520 | And there is no difference on the state of the animal.

01:27:40.380 | - Great, well, this is the reason to do experiments.

01:27:42.020 | - Yeah, absolutely.

01:27:42.860 | - So it doesn't defeat any grand hypothesis.

01:27:44.820 | It's just a pure curiosity.

01:27:47.340 | So-

01:27:48.160 | - You know that curiosity kills the cut, yeah?

01:27:49.940 | - I do.

01:27:50.780 | (laughing)

01:27:53.020 | But saves the career of a scientist.

01:27:56.500 | - Every single time.

01:27:57.340 | - That's what drives us, absolutely.

01:27:58.860 | - Every single time.

01:27:59.700 | - It's the story of our lives.

01:28:00.740 | - Exactly.

01:28:01.740 | Okay, so if it's not saliva, and apparently it is not,

01:28:05.340 | what about internal state?

01:28:09.700 | And what aspects of the internal milieu are relevant?

01:28:14.000 | Because there's autonomic, there's asleep and awake,

01:28:16.180 | there's stress.

01:28:17.140 | One of the questions that I got from hundreds of people

01:28:20.260 | when I solicited questions in advance of this episode was,

01:28:22.980 | why do I crave sugar when I'm stressed, for instance?

01:28:26.140 | And that could be contextual,

01:28:27.220 | but what are the basic elements?

01:28:28.820 | - Because it makes us feel good, by the way.

01:28:30.700 | We'll get to that.

01:28:31.540 | That's the answer.

01:28:33.200 | It activates what I'm going to generically refer to

01:28:38.200 | as reward pleasure centers

01:28:43.180 | in a way that dramatically changes our internal state.

01:28:48.180 | This is, you know, why do we eat a gallon of ice cream

01:28:50.680 | when we're very depressed, yeah?

01:28:53.460 | In fact, this is a good segue

01:28:55.100 | to go into this entirely different world, yeah?

01:28:59.800 | Of the body telling your brain what you need,

01:29:04.800 | in important things like sugar and fat, yeah?

01:29:11.020 | Okay, but anyways, go ahead.

01:29:12.440 | You were going to ask something.

01:29:13.580 | - Well, no, I would like to discuss

01:29:15.720 | the most basic elements of internal state,

01:29:19.820 | in particular, the ones that are below

01:29:21.560 | our conscious detection.

01:29:23.140 | And this is, of course, is a segue

01:29:26.820 | into this incredible landscape,

01:29:29.180 | which is the gut-brain axis,

01:29:31.060 | which I think 15 years ago was almost a,

01:29:35.540 | maybe it was a couple posters at a meeting.

01:29:38.340 | And then now I believe you and others,

01:29:41.740 | there are companies, there have companies,

01:29:44.140 | there are active research programs, and beautiful work.

01:29:49.140 | Maybe you could describe some of that work

01:29:50.800 | that you and others have been involved in.

01:29:52.740 | And a lot of the listeners of this podcast

01:29:56.440 | will have heard of the gut-brain axis,

01:29:58.300 | and there are a lot of misconceptions

01:30:00.580 | about the gut-brain axis.

01:30:01.580 | Many people think that this means

01:30:03.140 | that we think with our stomach

01:30:04.740 | because of the quote-unquote gut feeling aspect,

01:30:08.740 | but I'd love for you to talk about

01:30:10.380 | the aspects of gut-brain signaling

01:30:12.740 | that drive or change our perceptions and behaviors

01:30:15.820 | that are completely beneath our awareness.

01:30:18.300 | - Yes, excellent.

01:30:19.780 | So let me begin maybe by stating

01:30:24.620 | that the brain needs to monitor

01:30:29.260 | the state of every one of our organs.

01:30:32.620 | It has to do it.

01:30:35.960 | This is the only way that the brain can ensure

01:30:39.300 | that every one of those organs are working together

01:30:44.440 | in a way that we have healthy physiology.

01:30:49.320 | Now, this monitoring of the brain

01:30:52.680 | has been known for a long time,

01:30:55.320 | but I think what hadn't been fully appreciated,

01:30:57.680 | that this is a two-way highway

01:31:00.220 | where the brain is not only monitoring,

01:31:03.080 | but is now modulating back what the body needs to do.

01:31:09.080 | And that includes all the way from monitoring

01:31:13.880 | the frequency of heartbeats

01:31:16.120 | and the way that inspiration and aspirations

01:31:19.540 | in the breathing cycle operate

01:31:21.400 | to what happens when you ingest sugar and fat.

01:31:25.700 | Now, let me give you an example again

01:31:32.780 | of how the brain can take

01:31:37.780 | what we would refer to contextual associations

01:31:45.700 | and transform it into incredible changes

01:31:49.200 | in physiology and metabolism.

01:31:51.040 | Remember Pavlov?

01:31:54.180 | So Pavlov, in his classical experiments

01:31:56.760 | in conditioning, associative conditioning,

01:32:00.180 | he would take a bell, it would ring the bell

01:32:03.940 | every time he was going to feed the dog.

01:32:06.180 | And eventually, the dog learned to associate

01:32:10.760 | the ringing of the bell with food coming.

01:32:13.600 | Now, the first incredible finding he made

01:32:18.600 | is the fact that the dog now,

01:32:21.880 | in the presence of the bell alone,

01:32:24.440 | will start to salivate.

01:32:25.940 | And we will call that, neurologically speaking,

01:32:30.640 | an anticipatory response.

01:32:32.900 | Okay, I could understand it.

01:32:35.600 | I get it.

01:32:36.440 | Neurons in the brain that form that association

01:32:40.360 | now represent food is coming

01:32:42.840 | and they're sending a signal to motor neurons

01:32:46.760 | to go into your salivary glands to squeeze them

01:32:50.040 | so you release saliva because you know food is coming.

01:32:55.040 | But what's even more remarkable

01:32:58.040 | is that those animals are also releasing insulin

01:33:01.320 | in response to a bell.

01:33:05.260 | Okay.

01:33:08.540 | This illustrates one part of this two-way highway,

01:33:13.060 | the highway going down.

01:33:14.760 | Somehow the brain created these associations

01:33:18.260 | and there are neurons in your brain now

01:33:20.560 | that no food is coming and send a signal somehow

01:33:23.940 | all the way down to your pancreas

01:33:25.540 | that now it says release insulin

01:33:28.460 | because sugar is coming down.

01:33:31.560 | All right, this goes back to the magic of the brain.

01:33:35.460 | It's a never-ending source of both joy and intrigue.

01:33:40.320 | How the hell do they do this?

01:33:41.920 | Okay.

01:33:43.200 | I mean the neurons, eh?

01:33:44.240 | - No, I share your delight and fascination.

01:33:47.760 | There's not a day or a lecture

01:33:50.640 | or some talks are better than others

01:33:54.040 | or where I don't sit back and just think

01:33:56.400 | it's absolutely amazing.

01:33:57.960 | - How?

01:33:58.800 | - It's amazing, it's amazing.

01:34:01.140 | - Now, over the past dozen years,

01:34:04.960 | and with great force over the last five years.

01:34:08.020 | Now, the main highway that is communicating

01:34:12.860 | the state of the body with the brain

01:34:16.140 | has been uncovered,

01:34:19.060 | has been what we now refer to as the gut-brain axis,

01:34:23.680 | and the highway is a specific bundle of nerves,

01:34:27.780 | you know, which emerge from the vagal ganglia,

01:34:31.780 | the nodal ganglia, and so it's the vagus nerve

01:34:35.020 | that it's innervating the majority

01:34:39.200 | of the organs in your body.

01:34:40.960 | It's monitoring their function,

01:34:44.500 | sending a signal to the brain,

01:34:46.880 | and now the brain going back down and saying,

01:34:50.380 | this is going all right, do this,

01:34:52.200 | or this is not going so well, do that.

01:34:54.920 | - And I should point out, as you well know,

01:34:57.840 | every organ, spleen, pancreas, lung.

01:35:01.200 | - They all must be monitored.

01:35:03.900 | In fact, you know, I now, I have no doubt

01:35:09.180 | that diseases that we have normally associated

01:35:12.480 | with metabolism, physiology, and even immunity

01:35:17.440 | are likely to emerge as diseases,

01:35:23.200 | conditions, states of the brain.

01:35:25.940 | I don't think obesity is a disease of metabolism.

01:35:31.460 | I believe obesity is a disease of brain circuits.

01:35:35.740 | - I do as well. - Yeah?

01:35:37.160 | And so this view that we have, you know,

01:35:41.760 | been working on for the longest time,

01:35:44.220 | because, you know, the molecules that we're dealing with

01:35:47.500 | are in the body, not in the head, you know,

01:35:50.580 | led us to view, of course, these issues and problems

01:35:54.820 | as being one of metabolism, physiology, and so forth.

01:35:58.500 | They remain to be the carriers of the ultimate signal,

01:36:03.180 | but the brain ultimately appears to be the conductor

01:36:07.220 | of this orchestra of physiology and metabolism.

01:36:11.380 | All right, now let's go to the gut, brain, and sugar.

01:36:15.060 | May we?

01:36:17.660 | - Please, please.

01:36:19.780 | No, I mean, the vagus nerve has, in popular culture,

01:36:26.440 | has been kind of converted into this single meaning

01:36:31.440 | of calming pathways, mostly because,

01:36:35.100 | I actually have to tip my hat to the yogic community,

01:36:38.560 | was among the first to talk about vagus on and on and on.

01:36:43.020 | There are calming pathways, you know,

01:36:47.260 | so-called parasympathetic pathways within the vagus,

01:36:49.880 | but I think that the more we learn about the vagus,

01:36:52.740 | the more it seems like an entire set of neural connections

01:36:57.020 | as opposed to one nerve.

01:36:58.480 | I just wanted to just mention that

01:36:59.680 | because I think a lot of people have heard about the vagus.

01:37:02.000 | It turns out experimentally in the laboratory,

01:37:04.520 | many neuroscientists will stimulate the vagus

01:37:07.000 | to create states of alertness and arousal

01:37:10.020 | when animals or even people, believe it or not,

01:37:12.720 | are close to dying or going into coma.

01:37:14.920 | Stimulation of the vagus is one of the ways

01:37:16.740 | to wake up the brain, counter to the idea

01:37:19.580 | that it's just this way of calming oneself down.

01:37:22.320 | And also, of course, I mean,

01:37:24.040 | one has to be cautious there in that.

01:37:26.680 | So the vagus nerve is made out of many thousands of fibers,

01:37:31.680 | you know, individual fibers that make this gigantic bundle.

01:37:38.160 | And it's likely, as we're speaking,

01:37:40.440 | that each of these fibers carries

01:37:42.820 | a slightly different meaning, okay?

01:37:45.480 | Not necessarily one by one, maybe five fibers,

01:37:48.540 | 10 fibers, 22, all right.

01:37:50.560 | But they carry meaning that's associated

01:37:55.000 | with their specific task.

01:37:58.120 | This group of fibers is telling the brain

01:38:00.800 | about the state of your heart.

01:38:02.920 | This group of fiber is telling the brain

01:38:06.240 | about the state of your gut.

01:38:08.880 | This is telling your brain about its nutritional state.

01:38:13.040 | This, your pancreas.

01:38:14.960 | This, your lungs.

01:38:17.440 | And they are, again, to make the same simple example,

01:38:22.440 | the keys of this piano, okay?

01:38:26.420 | Yes, you're right, there is a lot of data

01:38:30.320 | showing that activating the entire vagal bundle

01:38:36.960 | has very meaningful effects in a wide range of conditions.

01:38:42.920 | In fact, it's being used to treat untractable depression.

01:38:47.920 | - Little stimulator.

01:38:50.180 | - Epileptic seizures.

01:38:53.500 | But again, there are thousands of fibers

01:38:57.760 | carrying different functions.

01:38:59.600 | So to some degree, you know, this is like

01:39:03.440 | turning the lights on the stadium

01:39:12.560 | because you need to illuminate

01:39:15.140 | where you lost your keys under your seat.

01:39:18.680 | Yet 10,000 volts of 1,000 watts each have just come on.

01:39:23.680 | Only one of these is pointing to where.

01:39:28.860 | And so I'm lucky enough that one of them

01:39:32.320 | happened to point to my side.

01:39:35.200 | So here you activate the bundle of thousands of fibers.

01:39:39.940 | I'm lucky enough that some of those

01:39:42.160 | happened to do something

01:39:43.820 | to make a meaningful difference in depression

01:39:48.040 | or to make a meaningful difference in epileptic.

01:39:51.580 | But it should not be misconstrue

01:39:54.720 | as arguing that this broad activation

01:39:59.080 | has any type of selectivity or specificity.

01:40:05.040 | We're just lucky enough

01:40:06.240 | that among all the things that are being done,

01:40:09.960 | some of those happen to change

01:40:12.200 | the biology of these processes.

01:40:14.640 | Now, the reason this is relevant,

01:40:16.980 | because the magic of this gut-brain axis

01:40:20.440 | is the fact that you have these thousands of fibers

01:40:24.560 | really doing different functions.

01:40:27.260 | And our goal, and along with many other great scientists,

01:40:37.280 | including Steve Liverless, that started a lot of,

01:40:40.480 | you know, this molecular dissection

01:40:43.080 | on this vagal gut-brain communication line at Harvard,

01:40:48.080 | is trying to uncover what are each of those lines doing?

01:40:54.520 | What are each of those keys of this piano playing?

01:40:57.900 | - What's the latest there?

01:41:00.160 | Just as a brief update, I know Stephen Lee release,

01:41:03.020 | I think I was there when he got his Howard Hughes

01:41:05.980 | and I did not.

01:41:06.820 | That was fun.

01:41:07.740 | Always great to get beat by excellent people.

01:41:10.100 | - First of all, I'm happy you did them

01:41:11.380 | because that way you can focus on this amazing podcast.

01:41:15.480 | - Thank you, that's very gracious of you.

01:41:18.040 | It's always feels better.

01:41:21.120 | It's not good to get beat out by excellent people.

01:41:23.220 | Stephen is second to none.

01:41:26.800 | And he is defining, as you said,

01:41:28.960 | the molecular constituents of different elements

01:41:31.960 | of these many, many fibers.

01:41:33.620 | Is there an update there?

01:41:34.540 | Are they finding multiple parallel pathways?

01:41:37.040 | - They are, they are.

01:41:38.040 | Some that control heartbeat,

01:41:40.240 | some that control the respiratory cycle,

01:41:43.040 | some that might be involved in a gastric movement.

01:41:48.040 | You know, this notion that you're full

01:41:52.400 | and you feel full in part because your gut gets distended,

01:41:57.320 | your stomach, for example.

01:41:58.680 | And then there are little sensors that are reading that

01:42:02.880 | and telling the brain you're full, yeah.

01:42:06.720 | - So the textbooks will soon change

01:42:08.500 | on the basis of the liberalese and other work.

01:42:10.660 | - In essence, I think we are learning enough

01:42:13.820 | about these lines that could really help

01:42:18.820 | put together this holistic view of how the brain,

01:42:25.900 | it's truly changing body physiology, metabolism, and immunity.

01:42:33.280 | The part that hasn't been yet developed

01:42:36.800 | and that it needs a fair amount of work,

01:42:39.000 | but it's an exciting, thrilling journey of discovery

01:42:44.000 | is how the signal comes back to now change that biology.

01:42:50.080 | You know, the example I gave you before with Pavlov's dog.

01:42:53.000 | All right, I figure out, you know,

01:42:56.900 | how the association created this link between the bell,

01:43:00.680 | but then how does the brain tell the pancreas

01:43:03.000 | to release in the right amount of insulin?

01:43:07.860 | Okay, so tell me, (laughs)

01:43:10.760 | let me tell you about the gut-brain axis

01:43:15.760 | and our insatiable appetite for sugar and fat.

01:43:21.620 | Insatiable for sugar and quenchable for fat.

01:43:29.440 | And this is a story about the fundamental difference

01:43:34.440 | between liking and wanting.

01:43:38.920 | Liking sugar is the function of the taste system.

01:43:46.080 | And it's not really liking sugar, it's liking sweet.

01:43:55.680 | Wanting sugar, our never-ending appetite for sugar

01:44:00.680 | is the story of the gut-brain axis, liking versus wanting.

01:44:08.880 | And this work is work of my own laboratory,

01:44:14.360 | you know, that began long ago

01:44:16.520 | when we discovered the sweet receptors.

01:44:19.020 | And you can now engineer mice that lack these receptors.

01:44:26.000 | So in essence, these animals will be unable to taste sweet.

01:44:31.000 | A life without sweetness, how horrible.

01:44:35.680 | And if you give a normal mouse a bottle containing sweet,

01:44:42.160 | and we're gonna put either sugar or an artificial sweetener.

01:44:46.380 | All right, they both are sweet.

01:44:48.280 | They have slightly different tastes,

01:44:50.840 | but that's simply because artificial sweeteners

01:44:55.280 | have some off tastes.

01:44:57.600 | But as far as the sweet receptor is concerned,

01:45:00.580 | they both activate the same receptor,

01:45:02.980 | trigger the same signal.

01:45:04.700 | And if you give an animal an option

01:45:07.260 | of a bottle containing sugar or a sweetener versus water,

01:45:11.920 | this animal will drink 10 to one

01:45:14.600 | from the bottle containing sweet.

01:45:17.000 | That's the taste system.

01:45:19.120 | Animal goes, samples each one, leaks a couple of leaks,

01:45:21.800 | and then says, uh-uh, that's the one I want

01:45:24.120 | because it's repetitive and because I love it.

01:45:27.320 | - So it prefers sugar to artificial sweetener?

01:45:29.600 | - No, no, no, no, no.

01:45:30.960 | - Equally artificial. - In this experiment,

01:45:32.920 | this experiment, I'm gonna put only sweet in one bottle.

01:45:36.760 | And it could be either sugar or artificial sweetener.

01:45:39.320 | It doesn't matter which one.

01:45:41.000 | Okay, we're gonna do the next experiment

01:45:43.040 | where we separate those two.

01:45:44.360 | For now, it's sweet versus water.

01:45:46.600 | - Okay.

01:45:48.320 | - And sweet means sweet, not sugar.

01:45:51.200 | Sweet means anything that tastes sweet, all right?

01:45:54.800 | And sugar is one example, and Splenda is another example.

01:45:59.240 | - Aspartame, monk fruit, stevia, doesn't matter.

01:46:03.440 | - Yeah, I mean, there's some that only humans can taste,

01:46:06.480 | mice cannot taste because their receptors

01:46:09.940 | between humans and mice are different.

01:46:12.560 | But we have put the human receptor into mice.

01:46:16.960 | We engineer mice and we completely humanize

01:46:21.040 | this mouse's taste world, all right?

01:46:25.880 | But for the purpose of this conversation,

01:46:29.500 | we're only comparing sweet versus water.

01:46:31.460 | An option, my goodness, they will leak to know

01:46:35.760 | from the sweet side, 10 to one at least versus the water.

01:46:40.680 | Make sense?

01:46:42.520 | All right, now we're gonna take the mice

01:46:44.760 | and we're gonna genetically engineer it

01:46:47.580 | to remove the sweet receptors.

01:46:49.660 | So these mice no longer have in their oral cavity

01:46:53.720 | any sensors that can detect sweetness,

01:46:56.760 | be that sugar molecule, be it an artificial sweetener,

01:47:00.240 | be it anything else that tastes sweet.

01:47:02.080 | And if you give these mice an option

01:47:05.340 | between sweet versus water, sugar versus water,

01:47:09.400 | artificial sweetener versus water,

01:47:11.860 | it will drink equally well from both

01:47:13.540 | because it cannot tell them apart.

01:47:15.540 | Because it doesn't have the receptors for sweet,

01:47:17.280 | so that sweet bottle tastes just like water.

01:47:20.500 | Make sense?

01:47:22.520 | - Makes sense. - Very good.

01:47:23.820 | Now we're gonna do the experiment with sugar.

01:47:27.180 | From now on, let's focus on sugar.

01:47:29.120 | So I'm gonna give a mouse a home.

01:47:31.500 | Sugar versus water.

01:47:34.140 | Normal mouse will drink from the sugar, sugar, sugar, sugar,

01:47:38.660 | very little from the water.

01:47:41.000 | Knock out the sweet receptors, eliminate them.

01:47:44.220 | Mouse can no longer tell them apart

01:47:46.100 | and they will drink from both.

01:47:47.600 | But if I keep the mouse in that cage for the next 48 hours,

01:47:54.180 | something extraordinary happens when I come 48 hours later

01:47:59.940 | and I see what the mouse is leaking or drinking from.

01:48:03.740 | That mouse is drinking almost exclusively

01:48:06.880 | from the sugar bottle.

01:48:09.240 | How could this be?

01:48:11.060 | It cannot taste it.

01:48:12.520 | Doesn't have sweet receptors.

01:48:15.360 | During those 48 hours, the mouse learn

01:48:21.060 | that there is something in that bottle

01:48:23.760 | that makes me feel good.

01:48:26.200 | And that is the bottle I want to consume.

01:48:31.140 | Now, how does the mouse identify that bottle?

01:48:34.220 | It does so by using other sensory features.

01:48:38.020 | The smell of the bottle.

01:48:39.600 | The texture of the solution inside.

01:48:43.480 | Sugar at high concentrations is kind of goopy.

01:48:46.100 | The side-ness in which the bottle is in the cage.

01:48:51.840 | It doesn't matter what.

01:48:53.420 | But the mouse realize there is something there

01:48:56.800 | that makes me feel good and that's what I want.

01:49:00.700 | And that is the fundamental basis

01:49:05.700 | of our unquenchable desire and our craving for sugar

01:49:10.700 | and is mediated by the God brain axis.

01:49:14.420 | The first clue is that it takes a long time to develop.

01:49:18.380 | Immediately suggesting a post-ingestive effect.

01:49:23.880 | So we reason if this is true and it's the God brain axis

01:49:29.940 | that's driving sugar preference,

01:49:34.900 | then there should be a group of neurons in the brain

01:49:37.380 | that are responding to post-ingestive sugar.

01:49:41.880 | And lo and behold, we identify a group of neurons

01:49:45.260 | in the brain that does this and these neurons

01:49:48.140 | receive their input directly from the God brain axis.

01:49:53.140 | - From other neurons.

01:49:55.820 | - You got it.

01:49:56.660 | And so what's happening is that sugar

01:50:01.200 | is recognized normally by the tongue,

01:50:04.800 | activates an repetitive response.

01:50:08.240 | Now you ingest it and now it activates a selective group

01:50:12.300 | of cells in your intestines that now send a signal

01:50:17.300 | to the brain via the vagal ganglia

01:50:20.200 | that says I got what I need.

01:50:25.400 | The tongue doesn't know that you got what you need.

01:50:28.200 | It only knows that you tasted it.

01:50:30.900 | This knows that you got to the point

01:50:33.940 | that it's going to be used, which is the gut.

01:50:36.860 | And now it sends the signal to now reinforce

01:50:41.820 | the consumption of this thing

01:50:44.300 | because this is the one that I needed.

01:50:46.860 | Sugar, source of energy.

01:50:49.020 | - And are these neurons in the gut?

01:50:51.120 | - So these are not neurons in the gut.

01:50:53.600 | So these are gut cells that recognize the sugar molecule,

01:50:57.580 | send a signal and that signal is received

01:51:00.300 | by the vagal neuron directly.

01:51:02.020 | - Got it.

01:51:02.860 | - And this sends a signal through the gut brain axis

01:51:07.220 | to the cell bodies of these neurons in the vagal ganglia

01:51:11.500 | and from there to the brain stem

01:51:14.780 | to now trigger the preference for sugar.

01:51:18.660 | - Two questions.

01:51:19.580 | One, you mentioned that these cells that detect sugar

01:51:23.300 | within the gut are actually within the intestine.

01:51:25.660 | You didn't say stomach.

01:51:27.340 | - Which surprised me.

01:51:28.220 | I always think gut as stomach, but of course, intestine.

01:51:31.100 | - They're intestine because that's where

01:51:32.260 | all the absorption happens.

01:51:33.660 | So you want the signal.

01:51:35.380 | You see, you want the brain to know

01:51:36.620 | that you had successful ingestion and breakdown

01:51:41.280 | of whatever you consume into the building blocks of life.

01:51:45.400 | And you know, glucose, amino acids, fat.

01:51:50.060 | And so you want to make sure that once they are in the form

01:51:53.940 | that intestines can now absorb them,

01:51:57.300 | is where you get the signal back saying,

01:51:59.580 | this is what I want, okay?

01:52:01.620 | Now, let me just take it one step further.

01:52:04.120 | And this now, sugar molecules activates

01:52:09.940 | this unique gut brain circuit

01:52:12.540 | that now drives the development of our preference for sugar.

01:52:17.540 | Now, a key element of this circuit

01:52:23.700 | is that the sensors in the gut that recognize the sugar

01:52:28.580 | do not recognize artificial sweeteners at all.

01:52:33.180 | - Right, because their nutrient value

01:52:35.120 | is uncoupled from the taste.

01:52:37.040 | - Generically speaking, one can make that by this

01:52:42.260 | because it's a very different type of receptor.

01:52:44.220 | - I see.

01:52:45.060 | - It turns out that it's not the tongue receptors

01:52:46.620 | being used in the gut.

01:52:48.040 | It's a completely different molecule

01:52:50.540 | that only recognizes the glucose molecule,

01:52:54.360 | not artificial sweeteners.

01:52:56.420 | This has a profound impact on the effect

01:53:01.420 | of ultimately artificial sweeteners in curbing our appetite,

01:53:07.220 | our craving, our insatiable desire for sugar.

01:53:12.260 | Since they don't activate the gut brain axis,

01:53:18.080 | they'll never satisfy the craving for sugar like sugar does.

01:53:23.080 | And the reason I believe that artificial sweeteners

01:53:27.760 | have failed in the market to curve our appetite,

01:53:32.760 | our need, our desire for sugar

01:53:36.540 | is because they beautifully work on the tongue,

01:53:40.320 | the liking to recognize sweet versus non-sweet,

01:53:48.120 | but they fail to activate the key sensors in the gut

01:53:53.120 | that now inform the brain, you got sugar,

01:53:58.600 | no need to crave anymore.

01:54:01.720 | - So the issue of wanting, can we relate that

01:54:06.720 | to a particular set of neurochemicals upstream?

01:54:10.360 | So the pathway is, so glucose is activating

01:54:13.400 | these cells in the gut through the vagus

01:54:15.440 | that's communicated through presumably the nodose ganglion

01:54:19.860 | and up into the brainstem.

01:54:21.100 | - Very good, and from there, where does it go?

01:54:23.140 | - Yeah, where is it going?

01:54:23.980 | What is the substrate of wanting?

01:54:25.820 | I, you know, of course I think molecules like dopamine,

01:54:29.420 | craving, there's a book even called

01:54:31.480 | "The Molecule of More," et cetera, et cetera.

01:54:34.400 | Dopamine is a very diabolical molecule, as you know,

01:54:37.720 | because it evokes both a sense of pleasure-ish,

01:54:41.520 | but also a sense of desiring more, of craving.

01:54:44.920 | So if I understand you correctly,

01:54:47.440 | artificial sweeteners, and I agree,

01:54:49.800 | are failing as a means to satisfy sugar craving

01:54:53.140 | at the level of nutrient sensing.

01:54:55.920 | And yet, if we trigger this true sugar-evoked

01:55:02.640 | wanting pathway too much, and we've all experienced this,

01:55:07.320 | then we eat sugar and we find ourselves

01:55:09.560 | wanting more and more sugar.

01:55:10.900 | Now that could also be insulin dysregulation,

01:55:13.800 | but can we uncouple those?

01:55:15.660 | - Yeah, I mean, look.

01:55:16.820 | We have a mega problem

01:55:23.440 | with overconsumption of sugar and fat.

01:55:26.800 | You know, we're facing a unique time in our evolution

01:55:32.460 | where diseases of malnutrition are due to overnutrition.

01:55:38.680 | I mean, how nuts is that, eh?

01:55:42.600 | I mean, historically, diseases of malnutrition

01:55:46.040 | have always been linked to undernutrition.

01:55:49.200 | And so we need to come up with strategies

01:55:54.660 | that can meaningfully change

01:55:57.720 | the activation of these circuits that control our wanting,

01:56:05.580 | certainly in the populations at risk.

01:56:10.860 | And this gut-brain circuit that ultimately,

01:56:15.860 | it's the lines of communication that are informing the brain,

01:56:25.380 | the presence of intestinal sugar, in this example,

01:56:28.640 | it's a very important target in the way we think about,

01:56:34.380 | is there a way that we can meaningfully

01:56:36.060 | modulate these circuits?

01:56:37.980 | So I make your brain think that you got satisfied

01:56:42.980 | with sugar, even though I'm not giving you sugar.

01:56:47.520 | - So that immediately raises the question,

01:56:49.760 | are the receptors for glucose in these gut cells

01:56:53.640 | susceptible to other things that are healthier for us?

01:56:57.780 | - That's very good, excellent idea.

01:57:01.260 | And I think an important goal will be to come up

01:57:06.020 | with a strategy and identify those very means

01:57:11.020 | that allow us to modulate the circuits in a way that,

01:57:15.620 | certainly for all of those where this is a big issue,

01:57:20.560 | it can really have a dramatic impact

01:57:25.920 | in improving human health.

01:57:28.440 | - I could be wrong about this, and I'm happy to be wrong.

01:57:30.860 | I'm often wrong and told I'm wrong.

01:57:35.820 | That we have cells within our gut

01:57:38.000 | that don't just sense sugar, glucose, to be specific,

01:57:42.420 | but also cells within our gut

01:57:44.540 | that sense amino acids and fatty acids.

01:57:47.260 | I could imagine a scenario where one could train themselves

01:57:52.020 | to feel immense amounts of satiety

01:57:55.740 | from the consumption of foods

01:57:57.660 | that are rich in essential fatty acids, amino acids,

01:58:01.460 | perhaps less caloric or less insulin-disregulating

01:58:06.340 | than sugar.

01:58:07.300 | I'll use myself as an example.

01:58:09.540 | I've always enjoyed sweets, but in the last few years,

01:58:12.420 | for some reason, I've started to lose my appetite for them,

01:58:15.500 | probably because I just don't eat them anymore.

01:58:18.140 | At first, that took some restriction.

01:58:20.100 | Now I just don't even think about it.

01:58:21.900 | - Yeah, and you're not reinforcing the circuits.

01:58:24.920 | And so you're in essence are removing yourself,

01:58:28.820 | but you tend to be the exception.

01:58:32.580 | We have a huge, incredible large number of people

01:58:37.580 | that are being continuously exposed

01:58:41.260 | to highly processed foods.

01:58:43.740 | - And hidden, so-called hidden sugars.

01:58:46.580 | - They don't even have to be hidden.

01:58:48.640 | It's right there.

01:58:49.620 | - Hiding in plain sight.

01:58:51.140 | Yeah, I agree.

01:58:52.020 | So much is made of hidden sugars

01:58:54.220 | that we often overlook that they are.

01:58:57.060 | There are also the overt sugars.

01:58:58.860 | - Yeah, I mean, we can have a long discussion

01:59:02.060 | on the importance of coming up with strategies

01:59:05.700 | that could meaningfully change public health

01:59:10.080 | when it comes to nutrition.

01:59:11.780 | But I wanna just go back to the notion of these brain centers

01:59:18.200 | that are ultimately the ones that are being activated

01:59:23.200 | by these essential nutrients.

01:59:25.500 | So sugar, fat, and amino acids

01:59:28.100 | are building blocks of our diets.

01:59:33.100 | And this is across all animal species.

01:59:36.580 | So it's not unreasonable then to assume

01:59:39.780 | that dedicated brain circuits would have evolved

01:59:43.500 | to ensure their recognition,

01:59:46.780 | their ingestion, and the reinforcement

01:59:54.100 | that that is what I need.

01:59:56.800 | And indeed, you know, animals evolved these two systems.

02:00:03.740 | One is the taste system that allows you to recognize them

02:00:11.980 | and trigger these predetermined hardwired

02:00:15.140 | immediate responses, yes?

02:00:17.820 | Oh my goodness, this tastes so good, it's so sweet.

02:00:20.700 | I personally have a sweet tooth, may I add.

02:00:23.540 | And you know, oh my God, this is so delicious,

02:00:25.900 | it's fatty or umami, recognizing amino acids.

02:00:29.780 | So that's the liking pathway, yeah?

02:00:32.980 | But in the wisdom of evolution,

02:00:38.300 | that's good, but doesn't quite do it.

02:00:41.900 | You wanna make sure that these things get to the place

02:00:43.980 | where they're needed, and they're not needed in your tongue.

02:00:48.120 | They are needed in your intestines

02:00:51.460 | where they're going to be absorbed

02:00:53.700 | as the nutrients that will support life.

02:00:56.500 | And the brain wants to know this.

02:01:01.560 | And he wants to know it in a way

02:01:05.100 | that he can now form the association

02:01:07.940 | between that that I just tasted

02:01:11.620 | is what got where it needs to be,

02:01:16.020 | and it makes me feel good.

02:01:20.140 | And so now, next time that I have to choose

02:01:23.780 | what should I eat,

02:01:25.700 | that association now guides me to that's the one I want.

02:01:31.660 | I want that fruit, not that fruit.

02:01:34.960 | I want those leaves, not those leaves,

02:01:39.500 | because these are the ones that activate the right circuits,

02:01:42.780 | that ensure that the right nutrients

02:01:44.380 | got to the right place, and told the brain

02:01:47.940 | this is what I want and need.

02:01:50.860 | Are we on?

02:01:53.380 | - We're on.

02:01:54.740 | One thing that intrigues me and puzzles me

02:01:57.620 | is that this effect took a couple of days,

02:02:01.060 | at least in mice, and the sensation,

02:02:03.820 | ah, sorry, the perception of taste-

02:02:06.020 | - Is immediate.

02:02:06.860 | - Is immediate, and yet this is a slow system.

02:02:09.140 | And so in a beautiful way, but in a kind of mysterious way,

02:02:13.800 | the brain is able to couple the taste of a sweet drink

02:02:17.420 | with the experience of nutrient extraction in the gut

02:02:20.380 | under a context where the mouse and the human

02:02:24.800 | is presumably ingesting other things,

02:02:26.620 | smelling other mice, smelling other people.

02:02:29.060 | That's incredible.

02:02:30.260 | - Yeah, but you have to think of it not as humans.

02:02:33.300 | Remember, we inherited the circuits of our ancestors,

02:02:38.300 | and they, through evolutionary, from their ancestors.

02:02:44.860 | And we haven't had that many years

02:02:48.460 | to have fundamentally changed

02:02:50.800 | in many of these hard-wired circuits.

02:02:53.160 | So forget, as humans, let's look at animals in the wild,

02:02:57.940 | okay, which is easier now to comprehend the logic.

02:03:01.380 | Why should this take a long time of continual reinforcement,

02:03:08.620 | given that I can taste it in a second?

02:03:14.220 | You wanna make sure that this source of sugar,

02:03:16.860 | for example, in the wild, is the best, is the richest,

02:03:21.660 | is the one where I get the most energy

02:03:24.300 | for the least amount of extraction,

02:03:29.100 | the least amount of work.

02:03:32.060 | I wanna identify rich sources of sugar.

02:03:37.020 | And if the system simply responds immediately

02:03:40.900 | to the first sugar that gets to your gut,

02:03:43.460 | you're gonna form the association with those sources of food

02:03:48.460 | which are not the ones that you should be eating from.

02:03:52.620 | - Don't fall in love with the first person you encounter.

02:03:55.220 | - Oh my goodness, exactly.

02:03:58.380 | And so, evolutionarily, by having the taste system

02:04:02.780 | giving you the immediate recognition,

02:04:05.140 | but then by forcing this gut-brain axis

02:04:08.820 | to reinforce it only when sustained repeated exposure

02:04:13.820 | has informed the brain, this is the one.

02:04:20.280 | You don't wanna form the association before.

02:04:22.520 | And so, when we remove it from the context of,

02:04:27.380 | we just go to the supermarket.

02:04:30.980 | We're not hunting there in the wild where I need to form.

02:04:36.100 | And so, what's happening is that highly processed foods

02:04:41.100 | are hijacking, co-opting the circuits in a way

02:04:46.500 | that would have never happened in nature.

02:04:52.020 | And then we not only find these things

02:04:55.380 | appetitive and palatable, but in addition,

02:04:57.380 | we are continuously reinforcing the wanting

02:05:02.140 | in a way that, oh my God, this is so great.

02:05:04.240 | What do I feel like eating?

02:05:05.260 | Let me have more of these.

02:05:07.240 | - You've just forever changed the way

02:05:09.140 | that I think about supermarkets and restaurants.

02:05:12.460 | There are, understanding this fast signaling

02:05:16.460 | and this slower signaling and the utility of having both

02:05:19.160 | makes me realize that supermarkets and restaurants

02:05:23.700 | are about the most unnatural thing for our system ever.

02:05:28.140 | Almost the equivalent of living in small villages

02:05:31.980 | with very few suitable mates versus online dating,

02:05:35.260 | for instance.

02:05:36.100 | - Look, I'm not gonna make a judgment call there

02:05:38.100 | because they do serve an important purpose.

02:05:40.060 | - I like restaurants too.

02:05:41.300 | - Yeah, but, and so do supermarkets, thank God.

02:05:44.200 | I think they're not the culprits.

02:05:47.820 | I think the culprits, of course,

02:05:49.420 | are reliance on foods that are not necessarily healthy.

02:06:00.160 | - Now, going back to the supermarket,

02:06:03.120 | don't fall in love with the first, it need to work.

02:06:06.880 | You know, you take, you take a tangerine

02:06:10.880 | and you take an extract of tangerine

02:06:20.460 | that you used to cook that spike, let's say with sugar.

02:06:29.620 | And you equalize in both where they both provide

02:06:32.420 | the same amount of calories.

02:06:33.900 | If you eat them both,

02:06:36.820 | they're gonna have a very different effect

02:06:40.400 | in your gut brain axis and your system.

02:06:45.540 | Once you make the extract and you process it

02:06:48.080 | and you add it processed sugar, you know,

02:06:50.600 | to use it now to cook, to add,

02:06:52.920 | to make it really sweet, tangerine thing.

02:06:55.660 | Now you're providing now a fully ready to use,

02:07:00.220 | broken down source of sugar.

02:07:02.720 | In the tangerine, that sugar, it's mixed in the complexity

02:07:09.480 | of a whole set of other chemical components.

02:07:15.420 | Fiber, long chains of sugar molecules

02:07:20.180 | that need a huge amount of work by your stomach,

02:07:24.900 | your gut system to break it down.

02:07:29.060 | So you're using a huge amount of energy to extract energy.

02:07:34.060 | And the balance, it's very different

02:07:40.640 | than when I take this process, highly extracted tangerine.

02:07:45.640 | By the way, I use tangerines because I had a tangerine

02:07:48.940 | just before I came here.

02:07:50.100 | - Delicious, they are delicious.

02:07:52.940 | - And so this goes back to the issue of supermarkets.

02:07:57.940 | And so to some degree, you know, A, given a choice,

02:08:03.500 | you don't wanna eat processed, highly processed foods

02:08:05.580 | because everything's already been broken down for you.

02:08:08.920 | And so your system has no work.

02:08:11.100 | And so you are co-opting, hijacking the circuits

02:08:15.660 | in a way that they're being activated at a timescale

02:08:19.220 | that normally wouldn't happen.

02:08:22.240 | This is why I often feel that,

02:08:25.360 | and I think a lot of data are now starting to support

02:08:27.580 | the idea that while indeed the laws of thermodynamics apply,

02:08:31.380 | calories ingested versus calories burned

02:08:33.600 | is a very real thing, right?

02:08:35.760 | That the appetite for certain foods

02:08:42.020 | and the wanting and the liking are phenomena

02:08:47.420 | of the nervous system, brain and gut

02:08:49.880 | as you've beautifully described.

02:08:51.800 | And that that changes over time,

02:08:54.700 | depending on how we are receiving these nutrients.

02:08:57.460 | - Absolutely.

02:08:58.380 | Look, we have a lot of work to do.

02:09:03.380 | I'm talking as a society.

02:09:07.580 | I'm not talking about you and I.

02:09:09.940 | - We also have a lot of work to do.

02:09:12.100 | - No, I think understanding the circuits

02:09:16.540 | is giving us important insights

02:09:20.660 | and how ultimately and hopefully we can improve human health

02:09:25.280 | and make a meaningful difference.

02:09:28.620 | Now it's very easy to try to connect the dots,

02:09:35.740 | A to B, B to C, C to D.

02:09:38.640 | And I think there's a lot more complexity to it,

02:09:41.860 | but I do think that the lessons that are emerging

02:09:46.340 | out of understanding how the circuits operate

02:09:50.700 | can ultimately inform how we deal with our diets

02:09:55.700 | in a way that we avoid what we're facing now as a society.

02:10:03.740 | I mean, it's nuts that the over nutrition

02:10:07.120 | happens to be such a prevalent problem.

02:10:11.900 | - And I also think the training of people

02:10:13.660 | who are thinking about metabolic science

02:10:15.980 | and metabolic disease is largely divorced

02:10:18.580 | from the training of the neuroscientist and vice versa.

02:10:21.340 | No one field is to blame,

02:10:22.660 | but I fully agree that the brain is the key

02:10:26.740 | or the nervous system to be more accurate

02:10:29.540 | is one of the key overlooked features.

02:10:32.380 | - Is the arbitrary.

02:10:33.260 | Ultimately is the arbiter of many of these pathways.

02:10:38.280 | - As a final question and one which is simply

02:10:40.780 | to entertain my curiosity and the curiosity

02:10:43.880 | of the listeners, what is your absolute favorite food?

02:10:48.880 | - Oh my goodness.

02:10:50.260 | - Taste, I should say.

02:10:53.840 | - Yes.

02:10:55.100 | - Taste, to distinguish between taste

02:10:57.400 | and the nutritive value or lack thereof.

02:10:59.620 | - Yes, look, we, unlike every other animal species,

02:11:04.620 | eat for the enjoyment of it.

02:11:08.200 | It doesn't happen in the wild.

02:11:13.000 | Most animals eat when they need to eat.

02:11:15.160 | Doesn't mean they don't enjoy it,

02:11:19.020 | but it's a completely different story, yeah?

02:11:21.420 | I have too many favorite foods

02:11:27.780 | because I enjoy the sensory experience.

02:11:30.760 | Rather than the food itself, to me is the whole thing.

02:11:34.940 | It's from the present, look,

02:11:36.540 | there've been these experiments done in psychophysics, yeah?

02:11:39.260 | I'm gonna take a salad made out of 11 components.

02:11:42.480 | And I'm gonna mix them all up in potpourri of greens

02:11:47.480 | and other things here.

02:11:50.540 | I mean, the other one, I'm gonna present it

02:11:52.160 | in a beautiful arrangement and I'm gonna put it

02:11:54.240 | behind a glass cabinet and I'm gonna sell them.

02:11:57.060 | And I'm gonna sell one for $2 and one for $8.

02:12:00.080 | Precisely the same ingredients,

02:12:03.300 | exactly the same amount of each.

02:12:05.240 | Ultimately, you're gonna mix them,

02:12:07.500 | they're all gonna be the same.

02:12:10.620 | And people will pay the $8 because, you know what?

02:12:15.620 | It evokes a different person.

02:12:18.340 | It gives you the feel that, oh my goodness,

02:12:22.660 | I'm gonna enjoy that salad.

02:12:24.540 | So going back to what is my favorite food.

02:12:29.440 | To me, eating is really a sensory journey.

02:12:38.260 | I don't mean the everyday, let me have some chicken wings

02:12:42.340 | because I'm hungry.

02:12:43.640 | But every piece, I think, has an important

02:12:50.580 | evoking sensory role.

02:12:58.500 | And so, in terms of categories of food,

02:13:05.020 | I grew up in Chile, so meat has always been,

02:13:09.700 | but I eat it so seldom now.

02:13:13.940 | - Is that right?

02:13:14.780 | - Yeah, because I know that it's not necessarily

02:13:17.140 | the healthiest thing, red meat I'm talking about, yeah?

02:13:19.900 | And so I grew up eating it every day.

02:13:23.980 | I'm talking seven days a week, Chile and Argentina,

02:13:28.260 | that's the mainstay of our diet, yeah?

02:13:33.220 | Now maybe I have red meat, I know, once every four weeks.

02:13:38.220 | - And you enjoy it.

02:13:41.620 | - Oh, I love it.

02:13:42.760 | Part of it is because I haven't had it in four weeks, eh?

02:13:46.180 | But I love sushi, but I love the art of sushi.

02:13:51.180 | The whole thing, the way it's presented,

02:13:56.540 | it changes the way you taste it.

02:14:01.660 | I love ethnic food, in particular.

02:14:06.180 | - You're in the right place.

02:14:07.300 | - You got it.

02:14:08.140 | That was the main reason I wanted to come to New York.

02:14:10.460 | No, I'm just kidding.

02:14:12.000 | - There's also that Columbia University that's-

02:14:14.700 | - I came here because I wanted to be with people

02:14:18.100 | that are thinking about the brain the same way

02:14:20.740 | that I like to think, which, you know,

02:14:22.100 | can we solve this big problem, this big question?

02:14:26.180 | - And certainly you're making amazing strides

02:14:28.820 | in that direction.

02:14:29.740 | And I love your answer because it really brings together

02:14:33.420 | the many features of the circuitries

02:14:35.240 | and the phenomenon we've been talking about today,

02:14:36.940 | which is that while it begins with sensation and perception,

02:14:40.300 | ultimately it's the context,

02:14:41.880 | and that context is highly individual

02:14:44.020 | to person, place, and time, and many, many other things.

02:14:47.380 | On behalf of myself,

02:14:50.740 | and certainly on behalf of all the listeners,

02:14:52.740 | I want to thank you, first of all,

02:14:54.540 | for the incredible work that you've been doing now

02:14:56.180 | for decades in vision, in taste,

02:14:58.740 | and in this bigger issue of how we perceive

02:15:01.220 | and experience life.

02:15:03.020 | It's a truly pioneering and incredible work.

02:15:05.540 | And I feel quite lucky to have been on the sidelines

02:15:09.420 | seeing this over the years and hearing the talks

02:15:11.240 | and reading the countless beautiful papers,

02:15:14.260 | but also for your time today to come down here

02:15:17.240 | and talk to us about what drives you

02:15:19.300 | and the discoveries you've made.

02:15:21.100 | Thank you ever so much.

02:15:22.740 | - It was great fun.

02:15:24.420 | Thank you for having me.

02:15:25.940 | - We'll do it again.

02:15:26.780 | - We shall.

02:15:28.780 | - Thank you for joining me today

02:15:29.880 | for my discussion about perception,

02:15:31.820 | and in particular, the perception of taste

02:15:33.960 | with Dr. Charles Zucker.

02:15:35.820 | If you're learning from and/or enjoying this podcast,

02:15:38.340 | please subscribe to our YouTube channel.

02:15:40.060 | That's a terrific zero-cost way to support us.

02:15:42.500 | In addition, please subscribe to the podcast

02:15:44.620 | on Spotify and Apple.

02:15:46.420 | And on Spotify and Apple,

02:15:48.220 | you can leave us up to a five-star review.

02:15:50.480 | If you have feedback for us in terms of comments

02:15:53.260 | related to topics we've covered, or questions,

02:15:55.640 | or topics, or guests that you'd like us to cover

02:15:57.640 | on future episodes of the Huberman Lab Podcast,

02:16:00.040 | please put those in the comment section on YouTube.

02:16:02.340 | We do read all the comments.

02:16:04.120 | On today's episode of the Huberman Lab Podcast,

02:16:06.440 | we didn't talk about supplements,

02:16:07.700 | but on many previous episodes of the Huberman Lab Podcast,

02:16:10.660 | we talk about supplements that are useful for sleep,

02:16:12.740 | for focus, for hormone support,

02:16:14.220 | and other aspects of mental health,

02:16:15.820 | physical health, and performance.

02:16:17.600 | If you're interested in some of those supplements,

02:16:19.140 | you can go to livemomentus.com/huberman

02:16:21.820 | to see the catalog of supplements

02:16:23.480 | that we've helped them formulate,

02:16:24.820 | and that map directly onto specific protocols

02:16:27.520 | described on the Huberman Lab Podcast.

02:16:29.160 | Again, that's livemomentus.com/huberman.

02:16:31.920 | If you're not already following us on social media,

02:16:34.440 | we are @hubermanlab on Twitter and @hubermanlab on Instagram.

02:16:38.320 | And at both Twitter and Instagram,

02:16:40.900 | I cover science and science-related tools,

02:16:43.140 | some of which overlap with the content

02:16:44.680 | of the Huberman Lab Podcast,

02:16:45.960 | but much of which is distinct from the information

02:16:47.940 | contained in the Huberman Lab Podcast.

02:16:49.800 | We also have a newsletter in which we spell out protocols

02:16:52.760 | and some summaries from previous podcast episodes.

02:16:55.520 | If you'd like to check those out,

02:16:56.620 | you can go to hubermanlab.com, go to the menu,

02:16:59.300 | and you'll find the Neural Network Newsletter.

02:17:01.500 | You can sign up for that newsletter

02:17:02.700 | simply by providing an email.

02:17:04.340 | It's completely zero cost.

02:17:06.060 | We have a very strict privacy policy.

02:17:07.580 | We do not share your email with anybody.

02:17:09.360 | Again, that's hubermanlab.com.

02:17:11.000 | Go to the menu and look for the Neural Network Newsletter.

02:17:13.540 | And if you'd like examples of previous newsletters,

02:17:15.680 | you'll also find those at hubermanlab.com.

02:17:18.080 | Once again, thank you for joining me today

02:17:19.580 | in my discussion with Dr. Charles Zucker

02:17:21.700 | about the biology of perception

02:17:23.200 | and the biology of the perception of taste in particular.

02:17:25.880 | I hope you found that discussion

02:17:27.360 | to be as enriching as I did.

02:17:29.300 | And last, but certainly not least,

02:17:31.380 | thank you for your interest in science.

02:17:33.180 | [upbeat music]

02:17:35.760 | (upbeat music)

Dr. Charles Zuker: The Biology of Taste Perception & Sugar Craving | Huberman Lab Podcast #81

Chapters