back to indexDr. Charles Zuker: The Biology of Taste Perception & Sugar Craving | Huberman Lab Podcast #81
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman,
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and I'm a professor of neurobiology and ophthalmology
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at Stanford School of Medicine.
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Today, my guest is Dr. Charles Zucker.
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Dr. Zucker is a professor of biochemistry
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and molecular biophysics and of neuroscience
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at Columbia University School of Medicine.
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Dr. Zucker is one of the world's leading experts
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That is how the nervous system converts physical stimuli
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in the world into events within the nervous system
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that we come to understand as our sense of smell,
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our sense of taste, our sense of vision,
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our sense of touch, and our sense of hearing.
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Dr. Zucker's lab is responsible for a tremendous amount
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of pioneering and groundbreaking work
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in the area of perception.
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For a long time, his laboratory worked on vision,
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defining the very receptors that allow
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for the conversion of light into signals
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that the rest of the eye and the brain can understand.
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In recent years, his laboratory has focused mainly
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on the perception of taste.
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And indeed, his laboratory is responsible
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for discovering many of the taste receptors,
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leading to our perception of things like sweetness,
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sourness, bitterness, saltiness, and umami,
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that is savoriness in food.
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Dr. Zucker's laboratory is also responsible
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for doing groundbreaking work on the sense of thirst.
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That is how the nervous system determines
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whether or not we should ingest more fluid
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or reject fluids that are offered to us.
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A key feature of the work from Dr. Zucker's laboratory
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is that it bridges the brain and body.
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As you'll soon learn from today's discussion,
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his laboratory has discovered a unique set
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of sugar-sensing neurons that exist
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not just within the brain, but a separate set of neurons
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that sense sweetness and sugar within the body.
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And that much of the communication between the brain
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and body leading to our seeking of sugar
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is below our conscious detection.
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Dr. Zucker has received a large number
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of prestigious awards and appointments
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as a consequence of his discoveries in neuroscience.
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He is a member of the National Academy of Sciences,
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the National Academy of Medicine,
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and the American Association for the Advancement of Science.
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He is also an investigator
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with the Howard Hughes Medical Institute.
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For those of you that are not familiar
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with the so-called HHMI, the Howard Hughes Medical Institute,
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Howard Hughes Medical Institute investigators
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are selected on an extremely competitive basis,
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and indeed they have to come back every five years
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and prove themselves worthy of being reappointed
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as Howard Hughes investigators.
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Dr. Zucker has been a Howard Hughes investigator since 1989.
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What all that means for you as a viewer
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and or a listener of today's podcast
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is that you are about to learn about the nervous system
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and its ability to create perceptions,
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in particular, the perception of taste and sugar-sensing
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from the world's expert on perception and taste.
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I'm certain that by the end of today's podcast,
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you're not just going to come away
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with a deeper understanding of our perceptions
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and our perception of taste in particular,
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but indeed you will come away with an understanding
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of how we create internal representations
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of the entire world around us,
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and in doing so, how we come to understand
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our life experience.
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I'm pleased to announce that the Huberman Lab Podcast
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is now partnered with Momentous Supplements.
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We often talk about supplements on the Huberman Lab Podcast,
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and while supplements aren't necessary for everybody,
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many people derive tremendous benefit from them
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for things like enhancing the quality and speed
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with which you get into sleep,
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or for enhancing focus, or for hormone support.
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The reason we partnered with Momentous Supplements
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First of all, their supplements
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Second of all, they ship internationally,
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which is important because many of our podcast listeners
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Third, many of the supplements that Momentous makes,
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and most all of the supplements
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This is important for a number of reasons.
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If you'd like to see the supplements
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that we partnered with Momentous on,
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you can go to livemomentous.com slash Huberman,
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and there you'll see many of the supplements
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that we've talked repeatedly about
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on the Huberman Lab Podcast episodes.
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I should mention that the catalog of supplements
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is constantly being expanded.
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So you can check back there livemomentous.com slash Huberman
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to see what's currently available.
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And from time to time,
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you'll notice new supplements being added to the inventory.
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Before we begin, I'd like to emphasize that this podcast
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is separate from my teaching and research roles at Stanford.
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It is however, part of my desire and effort
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to bring zero cost to consumer information about science
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and science related tools to the general public.
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In keeping with that theme,
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I'd like to thank the sponsors of today's podcast.
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Our first sponsor is Thesis.
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you may remember that I'm not a big fan
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And the reason I don't like that phrase
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Today's episode is also brought to us by Roca.
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Roca makes eyeglasses and sunglasses
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that are the absolute highest quality.
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The company was founded by two all American swimmers
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from Stanford and everything about Roca eyeglasses
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and with the biology of the visual system in mind.
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I spent my lifetime working on the visual system
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and I can tell you that your visual system has to contend
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in order to be able to see the world around you clearly.
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Helix Sleep makes mattresses and pillows
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And now for my discussion with Dr. Charles Zucker.
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Charles, thank you so much for joining me today.
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I want to ask you about many things related to taste
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and gustatory perception, but maybe to start off,
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and because you've worked on a number of different topics
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in neuroscience, not just taste,
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how do you think about perception?
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Or rather, I should say, how should the world
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and people think about perception,
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how it's different from sensation,
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and what leads to our experience of life
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in terms of vision, hearing, taste, et cetera?
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So, you know, the brain is an extraordinary organ
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that weights maybe 2% of your body mass,
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yet it consumes anywhere between 25 to 30%
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of all of your energy and oxygen.
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And it gets transformed into a mind.
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And this mind changes the human condition.
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It make, it changes, it transforms, you know,
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fear into courage, conformity into creativity,
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sadness into happiness.
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How the hell does that happen?
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Now, the challenge that the brain faces
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is that the world is made of real things.
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You know, this here is a glass,
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and this is a cord, and this is a microphone.
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But the brain is only made of neurons
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that only understand electrical signals.
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So how do you transform that reality
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into nothing but electrical signals
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that now need to represent the world?
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And that process is what we can operationally
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define as perception.
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In the senses, let's say olfactory, other, taste, vision,
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you know, we can very straightforwardly separate
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detection from perception.
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Detection is what happens when you take a sugar molecule,
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you put it in your tongue, and then a set of specific cells
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now sense that sugar molecule.
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You haven't perceived anything yet.
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That is just your cells in your tongue
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interacting with this chemical.
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But now that cell gets activated
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and sends a signal to the brain.
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And now detection gets transformed into perception.
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And it's trying to understand how that happens.
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That's been the maniacal drive
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of my entire career in neuroscience.
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How does the brain ultimately transform detection
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into perception so that it can guide actions and behaviors?
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Does that make sense?
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And is a very clear and beautiful description.
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A sort of high level question related to that.
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And then I think we can get into some of the
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intermediate steps.
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I think many people would like to know whether or not
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my perception of the color of your shirt
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is the same as your perception of the color of your shirt.
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What an excellent question.
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Am I okay to interrupt you as I'm guessing
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what you're going?
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All right, very good.
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Interruption is welcome on this podcast.
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The audience will always penalize me for interrupting you
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and we'll never penalize you for interrupting me.
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I like the one way penalizing.
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Now, given what I told you before,
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that the brain is trying to represent the world
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based in nothing but the transformation of these signals
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into electrical, you know, languages
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that now neurons have to encode and decode.
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It follows that your brain is different than my brain
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and therefore it follows
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that the way that you're perceiving the world
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must be different than mine,
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even when receiving the same sensory cues, okay?
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And I'll tell you about an experiment.
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It's a simple experiment, yet brilliant,
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that demonstrates why we perceive the world,
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how we perceive the world different.
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So in the world of vision, as you well know,
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we have three classes of photoreceptor neurons
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that sense three basic colors, red, blue, and green.
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Blue, green, and red, if we go, you know,
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from short to long wavelength.
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And these three are sufficient
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to accommodate the full visible spectra.
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I'm gonna take three light projectors
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and then when I project with one into a white screen,
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a red light and the other one, green light,
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I'm gonna overlap the two beams
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and on the screen to be yellow.
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Okay, this is superposition
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when you have two beams of red and green.
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And then I'm gonna take a third projector
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and I'm gonna put a filter that projects
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right next to that mixed beam, a spectrally pure yellow.
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Okay, and I'm gonna ask you
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to come to the red and green projectors
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and play with the intensity knobs
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so that you can match that yellow that you're projecting
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to the spectrally pure next to it.
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Is this making sense?
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And I'm going to write down the numbers
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in those two volume intensity knobs.
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And then I'm gonna ask the next person to do the same.
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And then I'm gonna ask every person
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around this area of Battery Park in New York to do the same.
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We're gonna end up
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with thousands of different number combinations.
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So for all of us, it's yellow enough
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that we can use a common language.
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But for every one of us,
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that yellow is gonna be ever so slightly differently.
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And so I think that simple psychological experiment
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beautifully illustrates
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how we truly perceive the world differently.
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I love that example.
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And yet in that example, we know the basic elements
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from which color is created.
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If we migrate into a slightly different sense,
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let me pick a hard one, like-
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Sound or olfaction.
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Very hard then to do an experiment
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that will allow us to get that degree of granularity
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and beautiful causality,
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where we can show that A produces and leads to B.
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If I give you the smell of a rose,
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you can describe it to me.
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If I smell the same rose, I can describe it also.
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But I have no way whether the two of us
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are experiencing the same.
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But it's close enough that we can both
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pretty much say that it has the following,
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you know, features or other determinants.
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But no question that your experience
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is different than mine.
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The fact that it's good enough for us to both survive,
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that your perception of yellow and my perception of yellow,
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at least up until now,
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is good enough for us both to survive,
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raises a thought about a statement made
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by a colleague of ours, Marcus Meister at Caltech.
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He's never been on this podcast,
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but in a review that I read by Marcus at one point,
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he said that the basic function of perception
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is to divide our behavioral responses
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into the outcomes downstream
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of three basic emotional responses.
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What do you think about,
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I'm not looking to establish a debate
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between you and Marcus without Marcus here.
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But what I like about that is that it seems like the,
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we know the brain is a very economical organ in some sense,
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despite its high metabolic demands.
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And this variation in perception
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from one individual to the next,
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at once seems like a problem
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because we're all literally seeing different things.
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And yet we function.
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We function well enough for most of us
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to avoid death and cliffs and eating poisons and so forth,
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and to enjoy some aspects of life, one hopes.
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So is there a general statement
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that we can make about the brain,
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not just as a organ to generate perception,
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not just as an organ to keep us alive,
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but also an organ that is trying to batch our behaviors
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into general categories of outcome?
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I think so, but, and again,
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I think the role of Marcus too.
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And I think he's right that,
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broadly speaking, you could categorize a lot of behaviors
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falling into those two categories.
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And that's 100% likely to be the case
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for animals in the wild,
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where the choices are not necessarily binary,
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but they're very unique and distinct.
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Do I wanna eat this?
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Do I wanna kill that?
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Do I wanna go there or do I wanna go here?
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And we humans deviated from that world long ago
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and learned to experience life
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where we do things that we should not be doing.
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Some of us more than others.
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You know, in my own world of taste,
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the likelihood that an animal in the wild
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will enjoy eating something bitter,
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it's inconceivable.
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Yet we, you know, love tonic water.
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We enjoy, we like living on the edge.
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We love enjoying experiences
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that makes us human.
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And that goes beyond that simple set of categories,
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which is yummy, yucky, ah, who cares?
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And so I think it's not a bad palette,
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but I think it's overly reductionist
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for certainly what we humans do.
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And since we're here in New York,
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I can say that the many options,
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the extensive variety of food, flora, and fauna in New York
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explains a lot of the more nuanced behaviors
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Let's talk about taste because while you've done
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extensive work in the field of vision,
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and it's a topic that I love,
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you could spend all day on, taste is fascinating.
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First of all, I'd like to know why you migrated
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from studying vision to studying taste.
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And perhaps in that description,
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you could highlight to us why we should think about
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and how we should think about this sense of taste.
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My goal has always been to understand,
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as I highlighted before, how the brain does its magic.
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You know, what part you might wonder.
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Ideally, I like to help contribute to understand all of it.
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You know, how do you encode and decode emotions?
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How do you encode and decode memories and actions?
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How do you make decisions?
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How do you transform detection into perception?
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And the list goes on and on.
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But one of the key things in science, as you know,
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is ensuring that you always ask the right question
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so that you have a possibility of answering it.
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Because if the question cannot be tractable
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or reduced to an experimental path
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that helps you resolve it,
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then we end up doing some really fun science,
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but not necessarily answering the important problem
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that we want to study.
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From a first person perspective, yes.
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The hardest question, the most important question is,
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what question are you going to try and answer?
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What question are you going to try and answer?
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And so, for example,
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I will have to understand the neural basis of empathy.
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It's a big market for that.
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100%, but I wouldn't even know.
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I mean, at the molecular level, that's what we do.
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How do the circuits in your brain create that sense?
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I have no clue how to do it.
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I can come up with ways to think about it,
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but I like to understand what in your brain
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makes someone a great philanthropist.
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What is the neural basis of love?
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I wouldn't even know where to begin.
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So if I want to begin to study these questions
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about brain function,
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that can cover so many aspects of the brain,
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I need to choose a problem that affords me that window.
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But in a way that I can ask questions that give me answers.
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And among the senses that have the capacity
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of transforming detection into perception
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of being stories, memories, of creating emotions,
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of giving you different actions and perceptions
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as a function of the internal state.
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When you're hungry, things taste very differently
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than when you're sated.
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When you taste something, you now remember
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this amazing meal you had with your first date.
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How does that happen?
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All right, so if I want to begin to explore
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all of these things that the brain does,
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I felt I have to choose a sensory system
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that affords some degree of simplicity
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in the way that the input-output relationships
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are put together, and in a way that still can be used
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to ask every one of these problems
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that the brain has to ultimately compute, encode,
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And what was remarkable about the taste system
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at the time that I began working on this,
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is that nothing was known about the molecular basis of taste.
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We knew that we could taste what has been usually defined
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as the basic taste qualities,
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sweet, sour, bitter, salty, and umami.
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Umami is a Japanese word that means yummy, delicious.
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And that's nearly every animal species
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the taste of amino acids.
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And in humans, it's mostly associated
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with the taste of MSG, monosodium glutamate,
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one amino acid in particular.
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What are, just by way of example,
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some foods that are rich in the umami-evoking stimulation?
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Seaweed, tomatoes, cheese.
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And it's a great, great flavor enhancer.
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It enriches our sensory experience.
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And so the beautiful thing of the system
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is that the lines of input are limited to five.
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You know, sweet, sour, bitter, salty, and umami.
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And each of them has a predetermined meaning.
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You are born liking sugar and disliking bitter.
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You have no choice.
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These are hardwired systems.
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But of course, you can learn to dislike sugar
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and to like bitters.
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But in the wild, let's take humans out of the question.
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These are 100% predetermined.
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You're born with that specific valence value
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for each taste of sweet, umami, and low salt
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are attractive taste qualities.
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They evoke appetitive responses, I want to consume them.
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And bitter and sour are innately
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predetermined to be aversive.
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Could I interrupt you just briefly
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and ask a question about that exact point?
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For something to be appetitive to,
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and some other taste to be aversive,
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and for those to be hardwired,
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can we assume that the sensation of very bitter,
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or of activation of bitter receptors in the mouth
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activates a neural circuit that causes closing of the mouth,
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retraction of the tongue, and retraction of the body,
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and that the taste of something sweet
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might actually induce more licking?
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The activation of the receptors in the tongue
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that recognize sweet versus the ones
link |
that recognize bitter activate an entire behavioral program.
link |
And that program that we can refer as appetitiveness
link |
or aversion, it's composed of many different subroutines.
link |
In the case of bitter, it's very easy
link |
to actually look at, see them happening in animals
link |
because the first thing you do is you stop licking,
link |
then you put unhappy face, then you squint your eyes,
link |
and then you start gagging, right?
link |
And that entire thing happens by the activation
link |
of a bitter molecule in a bitter sensing cell in your tongue.
link |
It's, again, the magic of the brain,
link |
you know, how it's able to encode and decode
link |
these extraordinary actions and behaviors
link |
in response of nothing but a simple,
link |
very, you know, unique sensory stimuli.
link |
Now, let me say that this palette of five basic tastes
link |
accommodates all the dietary needs of the organism.
link |
Sweet to ensure that we get the right amount of energy.
link |
Umami to ensure that we get proteins
link |
and that essential nutrient.
link |
Salt, the three appetitive ones,
link |
ensure that we maintain our electrolyte balance.
link |
Bitter to prevent the ingestion of toxic, nauseous chemicals.
link |
Nearly all bitter tasting, you know,
link |
things out in the wild are bad for you.
link |
And sour, most likely to prevent the ingestion of spoiled,
link |
acid, fermented foods.
link |
That is the palette that we deal with.
link |
Now, of course, there's a difference
link |
between basic taste and flavor.
link |
Flavor is the whole experience.
link |
Flavor is the combination of multiple tastes coming together
link |
together with smell, with texture, with temperature,
link |
with the look of it that gives you what you and I
link |
would call the full sensory experience.
link |
But we scientists need to reduce the problem
link |
into its basic elements so we can begin to break it apart
link |
before we put it back together.
link |
So when we think about the sense of taste
link |
and we try to figure out how these lines of information
link |
go from your tongue to your brain
link |
and how they signal and how they get integrated
link |
and how they trigger all these different behaviors,
link |
we look at them as individual qualities.
link |
So we give the animal sweet or we give them a bitter,
link |
we give them sour, we avoid mixes
link |
because the first stage of discovery
link |
is to have that clarity as to what you're trying to extract
link |
so that you can hopefully meaningfully make a difference
link |
by being able to figure out how is it
link |
that A goes to B to C and to D.
link |
Does this make sense?
link |
Yeah, almost like the primary colors
link |
to create the full array of the color spectrum.
link |
Before I ask you about the first and second and third stages
link |
of taste and flavor perception,
link |
is there any idea that there may be more than five?
link |
There is, for example.
link |
And I love the texture of fat,
link |
especially if it's slightly burnt.
link |
In South America, when I visited Buenos Aires,
link |
I found that at the end of a meal, they would take a steak,
link |
the trimming off the edge of the steak,
link |
burn it slightly, and then serve it back to me.
link |
And I thought, that's disgusting.
link |
And then I tasted it, and it's delightful.
link |
There's nothing quite like it.
link |
This goes back to this notion before
link |
that we like to live on the edge, yeah?
link |
And we like to do things that we should not be doing, Andrew.
link |
But on the other hand, look at those muscles.
link |
The, I don't suggest anyone eat pure fat.
link |
The listeners of this podcast will immediately,
link |
I'm sure there'll be a YouTube video soon
link |
that I like eating pure fat.
link |
I'm not in on a ketogenic diet, et cetera.
link |
As evidenced by the obesity problem
link |
that exists in this country.
link |
We'll talk about that in a little bit
link |
about the gut brain axis.
link |
I think it'll be important to cover it
link |
because it's the other side of the taste system.
link |
And so missing tastes, one is fat.
link |
Although, like you clearly highlighted,
link |
a lot of fat taste, in quotation marks,
link |
is really the feeling of fat rolling on your tongue.
link |
And so there is a compelling argument
link |
that a lot of what we call fat taste
link |
is really mechanosensory.
link |
It's somatosensory cells,
link |
cells that are not responding to taste,
link |
but they're responding to mechanical stimulation
link |
of fat molecules rolling on the tongue
link |
that gives you that perception of fat.
link |
I love the idea that there is a perception of fat
link |
regardless of whether or not
link |
there's a dedicated receptor for fat.
link |
Mostly because it's evoking sensations and imagery
link |
of the taste of slightly burnt fat.
link |
For example, and another one,
link |
you could argue it's metallic taste.
link |
I know exactly what it tastes like.
link |
If you ask me to explain it, I will have a hard time.
link |
What are the palettes of that color
link |
that can allow me to define it, I wouldn't be easy,
link |
but I know precisely what it tastes like.
link |
Take a penny, put it in your mouth,
link |
and you know what it tastes like, yeah?
link |
Or blood, that's another very good example.
link |
And is there really a receptor for metallic taste,
link |
or it's nothing but this magical combination
link |
of the activation of the existing lines.
link |
Think of it as lines of information, just separate lines,
link |
by the keys of a piano, yeah?
link |
Sweet, sour, bitter, salty, umami,
link |
you play the key and you activate that one chord.
link |
And that one chord in the case of a piano
link |
leads to a note, you know, a tune,
link |
and in the case of taste, leads to an action and a behavior.
link |
But you play many of them together and something emerges
link |
that it's different than any one of the pieces.
link |
And it's possible that metallic, for example,
link |
represents the combination of the activity
link |
just in the right ratio of these added lines.
link |
It makes sense, and it actually provides a perfect,
link |
your example of the piano provides a perfect segue
link |
for what I'd like to touch on next,
link |
which is if you would describe the sequence
link |
of neural events leading to a perceptual event of taste.
link |
And I'm certain that somewhere in there
link |
you will embed an answer to the question
link |
of whether or not we indeed have different taste receptors
link |
distributed in different locations on our tongue
link |
or elsewhere in the mouth.
link |
Yes, so let's start by debunking that old tale and myth.
link |
Who came up with that?
link |
There are many views, but the most prevalent
link |
is that there was an original drawing
link |
describing the sensitivity of the tongue to different tastes.
link |
So imagine I can take a Q-tip.
link |
This is a thought experiment, yeah?
link |
And I'm gonna dip that Q-tip in salt and in quinine
link |
or something bitter and glucose or something sweet.
link |
And I'm gonna take that Q-tip,
link |
ask you to stick your tongue out
link |
and start moving it around your tongue
link |
and ask you what do you feel.
link |
And then I'm going to change the concentration
link |
of the amount of salt or the amount of bitter
link |
and ask can I get some sort of a map of sensitivity
link |
to the different tastes, yeah?
link |
And the argument that has emerged
link |
is that there is a good likelihood
link |
that the data was simply mistranslated
link |
as it was being drawn.
link |
And of course that led to an entire industry.
link |
This is the way you maximize your one-to-one.
link |
Why in experience?
link |
Because now we're going to form the vessel
link |
that you're gonna drink from
link |
so that it acts maximally on the receptors which happen.
link |
All right, now there is no tongue map, all right?
link |
We have taste buds distributed in various parts of the tongue
link |
so there is a map on the distribution of taste buds.
link |
But each taste bud has around 100 taste receptor cells
link |
and those taste receptor cells can be of five types,
link |
sweet, sour, bitter, salty or umami.
link |
And for the most part,
link |
all taste buds have the representation
link |
of all five taste qualities.
link |
Now there's no question that there is a slight bias
link |
Like bitter is particularly enriched
link |
at the very back of your tongue.
link |
And there is a teleological basis for that
link |
and actually a biological basis for that.
link |
That's the last line of defense
link |
before you swallow something bad.
link |
And so let's make sure that the very back of your tongue
link |
has plenty of these bad news receptors
link |
so that if they get activated,
link |
you can trigger a gagging reflex and get rid of this
link |
that otherwise may kill you, okay?
link |
That's good sense.
link |
But the notion that all sweet is in the front
link |
and salt is on the side, it's not real.
link |
And there, go ahead.
link |
Oh, I was just going to ask, are there,
link |
first of all, thank you for dispelling that myth
link |
and we will propagate that information
link |
as far and wide as we can
link |
because I think that's the number one myth related to taste.
link |
The other one is, are there taste receptors anywhere else
link |
in the mouth, for instance, on the lips?
link |
The palate, not the lips.
link |
So it's in the far range at the very back
link |
of the oral cavity, the tongue and the palate.
link |
And the palate is very rich in sweet receptors.
link |
I'll have to pay attention to this
link |
the next time I eat something sweet.
link |
Whether you pull it up, yeah?
link |
Now, the important thing is that, you know,
link |
after the receptors for these five,
link |
the detectors, the molecules that sends
link |
sweet sour beet and salt to mommy,
link |
these are receptors, proteins found on the surface
link |
of taste receptor cells that interact with these chemicals.
link |
And once they interact, then they trigger
link |
the cascade of events, biochemical events inside the cell
link |
that now sends an electrical signal that says,
link |
there is sweet here, or there is salt here.
link |
Now having these receptors and my laboratory identify
link |
the receptors for all five basic taste classes,
link |
sweet, bitter, salt, to mommy, and most recently sour,
link |
now completing the palate,
link |
you can now use these receptors to really map
link |
where are they found in the tongue in a very rigorous way.
link |
This is no longer about using a Q-tip
link |
and trying to figure out what you're feeling,
link |
but rather what you have in your tongue.
link |
This is not a guess, this is now a physical map
link |
that says the sweet receptors are found here.
link |
The bitter are found here, and when you do that,
link |
you find that in fact, every taste pad
link |
throughout your oral cavity has receptors
link |
for all of the basic taste classes.
link |
And as it turns out, and I'm sure you'll tell us,
link |
important in terms of thinking about how the brain
link |
computes and codes and decodes this thing we call taste.
link |
I'm going to inject a quick question
link |
that I'm sure is on many people's minds
link |
before we get back into the biological circuit,
link |
which is many people, including myself,
link |
are familiar with the experience of drinking a sip of tea
link |
or coffee that is too hot, and burning my tongue
link |
is the way I would describe it.
link |
And then disrupting my sense of taste
link |
for some period of time afterward.
link |
When I experienced that phenomenon,
link |
that unfortunate phenomenon,
link |
have I destroyed taste receptors that regenerate,
link |
or have I somehow used temperature
link |
to distort the function of the circuit
link |
so that I no longer taste the way I did before?
link |
Excellent question, and the answer is both.
link |
It turns out that your taste receptors
link |
only leave for around two weeks.
link |
And this, by the way, makes sense
link |
because here you have an organ, the tongue,
link |
that is continuously exposed to everything
link |
you could range from the nicest
link |
to the most horrible possible things.
link |
Use your imagination.
link |
you need to make sure that these cells
link |
are always coming back in a way
link |
that I can re-experience the world in the right way.
link |
And there are other organs
link |
that have the same underlying logic, okay?
link |
Your gut, your intestines are the same way.
link |
Again, they're receiving everything that you ingest,
link |
God forbid what's there,
link |
from the spiciest, you know,
link |
to the most horrible tasting, so the most delicious.
link |
And again, those intestinal cells
link |
whose role is to ultimately take all these nutrients
link |
and bring them into the body,
link |
also renewal in a very, very fast cycle.
link |
Olfactory neurons in your nose is the other example.
link |
So then, A, yes, you're burning a lot of your cells
link |
and it's over for those.
link |
The good news is that they're gonna come back.
link |
But we know that when you burn your cell with tea,
link |
they come back, you know,
link |
within 20 minutes, 30 minutes, an hour.
link |
And these cells are not renewing in that timeframe.
link |
They're not listening to your needs.
link |
They have their own internal clock.
link |
And so, you are really affecting,
link |
you're damaging them in a way that they can recover.
link |
And then they come back
link |
and you also damage your somatosensory cells.
link |
These are the cells that feel things, not taste things.
link |
And then, you know, you wait half an hour or so,
link |
and then, my goodness, thank God, it's back to normal.
link |
And most of the time, I don't even notice the transition,
link |
realizing, as you tell me,
link |
and later, I'll ask you about the relationship
link |
between odor and taste.
link |
But as a next step along the circuit,
link |
let's assume I ingest some,
link |
let's keep it simple, a sweet taste.
link |
Let's make it even simpler,
link |
but at the same time, perhaps more informative.
link |
Let's compare and contrast sweet and bitter
link |
as we follow their lines from the tongue to the brain.
link |
So, the first thing is that the two evoke
link |
diametrically opposed behaviors.
link |
If we have to come up with two sensory experience
link |
that represent polar opposites, it will be sweet and bitter.
link |
There are not two colors that represent polar opposites
link |
because, you know, you could say black and white,
link |
they are polar opposites, one detects only one thing,
link |
the other one detects everything.
link |
But they don't evoke different behaviors,
link |
even political parties have some over them.
link |
Sweet and bitter are the two opposite ends
link |
of the sensory spectra.
link |
Now, a taste can be defined by two features.
link |
Again, I'm a reductionist, so I'm reducing it
link |
in a way that I think is easier to follow the signal.
link |
And the two features are its quality and its valence.
link |
And valence with a little V, that's what we say in Spanish,
link |
with a V, yeah, means the value of that experience.
link |
Or in this case of that stimuli.
link |
And you take sweet, sweet has a quality, an identity,
link |
and that's what you and I will refer to
link |
as the taste of sweet.
link |
We know exactly what it tastes like.
link |
But sweet also has a positive valence,
link |
which makes it incredibly attractive and appetitive.
link |
But it's attractive and appetitive,
link |
as I'll tell you in a second,
link |
independent of its identity and quality.
link |
In fact, we have been able to engineer animals
link |
where we completely remove the valence from the stimuli.
link |
So these animals can taste sweet,
link |
can recognize it as sweet, but it's no longer attractive.
link |
It's just one more chemical stimuli.
link |
And that's because the identity and the valence
link |
are encoded in two separate parts of the brain.
link |
In the case of bitter, again, it has, on the one hand,
link |
its identity, its quality.
link |
And you know exactly what bitter tastes like.
link |
I can taste it now, even as you describe it.
link |
But it also has a valence, and that's a negative valence,
link |
because it evokes aversive behaviors.
link |
And it comes to mind, I remember telling some kids recently
link |
that we're going to go get ice cream,
link |
and it was interesting.
link |
They looked up and they started smacking their lip,
link |
like, you know, they'll actually evoke-
link |
The anticipatory response, absolutely.
link |
When we talk about the gut brain, maybe we'll get there.
link |
So then the signals, if we follow now these two lines,
link |
they're really like two separate keys
link |
at the two ends of this keyboard.
link |
And you press one key and you activate this cord.
link |
So you activate the sweet cells throughout your oral cavity
link |
and they all converge into a group of sweet neurons
link |
in the next station, which is still outside the brain,
link |
the brain is one of the taste ganglia.
link |
These are the neurons that innervate your tongue
link |
and the oral cavity.
link |
Where do they sit approximately?
link |
Yeah, right here around the lymph nodes, more or less.
link |
And there are two main ganglia that innervate
link |
the vast majority of all taste buds in the oral cavity.
link |
And then from there, that sweet signal
link |
goes onto the brainstem.
link |
The brainstem is the entry of the body into the brain.
link |
And there are different areas of the brainstem
link |
and there are different groups of neurons in the brainstem.
link |
And there's this unique area,
link |
in a unique topographically defined location
link |
in the rostral side of the brainstem
link |
that receives all of the taste input.
link |
A very dense area of the brain.
link |
A very rich area of the brain, exactly.
link |
And from there, the sweet signal goes to this other area
link |
higher up on the brainstem.
link |
And then it goes through a number of stations
link |
where that sweet signal goes from sweet neuron
link |
to sweet neuron to sweet neuron
link |
to eventually get to your cortex.
link |
And once it gets to your taste cortex,
link |
that's where meaning is imposed into that signal.
link |
It's then, and only then, this is what the data suggests,
link |
that now you can identify this as a sweet stimuli.
link |
And how quickly does that all happen?
link |
You know, the timescale of the nervous system, it's fast.
link |
Within less than a second.
link |
Yeah, absolutely, yeah.
link |
I rarely mistake bitter for sweet.
link |
Maybe with respect to people and my own poor judgment,
link |
but not with respect to taste.
link |
Yeah, and in fact, we can demonstrate this
link |
because we can stick electrodes
link |
at each of these stations conceptually, yeah?
link |
And we can stimulate the tongue
link |
and then we can record the signals
link |
pretty much time log to stimulus delivery.
link |
You deliver the stimuli
link |
and within a fraction of a second,
link |
you see now the response in these following stations.
link |
Now it gets to the cortex here.
link |
And now in there, you impose meaning to that taste.
link |
There's an area of your brain
link |
that represents the taste of sweet in taste cortex
link |
and a different area that represents the taste of bitter.
link |
In essence, there is a topographic map
link |
of these taste qualities inside your brain.
link |
Now we're gonna do a thought experiment, all right?
link |
Now, if this group of neurons in your cortex
link |
really represents the sense of sweet
link |
and this added different group of neurons in your brain
link |
represents the taste, the perception of bitter,
link |
then we should be able to do two things.
link |
First, I should be able to go into your brain,
link |
somehow silence those neurons,
link |
find a way to prevent them from being activated
link |
and I can give you all the sweet you want
link |
and you'll never know that you're tasting sweet.
link |
And conversely, I should be able to go into your brain,
link |
come up with a way to activate those neurons
link |
when I'm giving you absolutely nothing
link |
and you're gonna think
link |
that you're getting that full percept.
link |
And that's precisely what we have done
link |
and that's precisely what you get.
link |
This of course is in the brain of mice.
link |
But presumably in humans it would work similar.
link |
Absolutely the same, zeroed out.
link |
I have no questions.
link |
So this attests to two important things.
link |
The first to the predetermined nature of the sense of taste
link |
because it means I can go to these parts of your brain
link |
in the absence of any stimuli
link |
and have you throw the full behavioral experience.
link |
In fact, when we activate in your cortex
link |
these bitter neurons, the animal can start gagging.
link |
But it's drinking only water.
link |
But the animal thinks that it's getting a bit of stimuli.
link |
And so, and the second, just to finish the line
link |
so that it doesn't sound like it teaches two things
link |
and then I only give you one lesson,
link |
is that it substantiates this capacity of the brain
link |
to segregate, to separate in these nodes of action
link |
the representation of these two diametrically opposed
link |
percepts, which is sweet, for example, versus bitter.
link |
The reason I say amazing, and that is also amazing
link |
You told us earlier, and you're absolutely correct,
link |
of course, that at the end of the day,
link |
whether or not it's one group of neurons over here
link |
and another group of neurons over there,
link |
which is the way it turns out to be,
link |
electrical activity is the generic common language
link |
of both sets of neurons.
link |
So that raises the question for me of whether or not
link |
those separate sets of neurons are connected to areas
link |
of the brain that create this sense of valence
link |
or whether or not they're simply created, connected,
link |
excuse me, to sets of neurons that evoke distinct behaviors
link |
of moving towards and inhaling more and licking or aversive.
link |
Are we essentially interpreting our behavior
link |
and our micro responses?
link |
Or are micro responses and our behaviors
link |
the consequence of the percept?
link |
Excellent, excellent question.
link |
So first the answer is they go into an area of the brain
link |
where valence is imposed.
link |
And that area is known as the amygdala.
link |
And the sweet neurons go to a different area
link |
than the bitter neurons.
link |
Now, I wanna do a thought experiment
link |
because I think your audience might appreciate this.
link |
Let's say I activate this group of neurons
link |
and the animal increases licking
link |
and I'm activating the sweet neurons.
link |
And so that's expected because now it's, you know,
link |
tasting this water as if it was sugar.
link |
Now, this is Moses transforming water into wine.
link |
In this case, we're gonna, and today is Passover.
link |
So then it's an appropriate, you know, example.
link |
We're transforming it into sweet, yeah?
link |
But how do I know, how do I know that activating them
link |
is evoking a positive feeling inside, a goodness,
link |
a satisfaction, oh, I love it,
link |
versus I'm just increasing licking,
link |
which is the other option because all we're seeing
link |
is that the animal is licking more
link |
and we're trying to infer that that means
link |
that he's feeling something really good versus,
link |
That piano line is going back straight into the tongue
link |
and all he's doing is forcing it to move faster.
link |
Well, we can actually separate this by doing experiments
link |
that allow us to fundamentally distinguish them.
link |
And imagine the following experiment.
link |
I'm gonna take the animal and I'm gonna put them
link |
inside a box that has two sides.
link |
And the two sides have features that make them different.
link |
One has yellow little toys, the other one has green toys.
link |
One has little, you know, black stripes,
link |
the other one has blue stripes.
link |
So the animal can tell the two halves.
link |
I take the mouse, put them inside this arena,
link |
this play arena, and it will explore
link |
and poach around both sides with equal frequency.
link |
And now what I'm going to do is I'm gonna activate
link |
these neurons, these sweet neurons,
link |
every time the animal is on the side with the yellow stripes.
link |
And if that is creating a positive internal state,
link |
what would the animal now want to do?
link |
It will want to stay on the side with the yellow stripes.
link |
There's no leaking here.
link |
The animal is not extending its tongue
link |
every time I'm activating these neurons, okay?
link |
This is known as a place preference test.
link |
And it's generally used, it's just one form
link |
of many different tests to demonstrate
link |
that the activation of a group of neurons in the brain
link |
is imposing, for example,
link |
a positive versus a negative valence.
link |
Whereas if I do the same thing
link |
by activating the bitter neurons,
link |
the animal will actively want now to stay away from the side
link |
where these neurons are being activated.
link |
And that's precisely what we see.
link |
And that's precisely what we see.
link |
Many people, including myself,
link |
are familiar with the experience of going to a restaurant,
link |
eating a variety of foods,
link |
and then, fortunately it doesn't happen that often,
link |
but then feeling very sick.
link |
I learned coming up in neuroscience
link |
that this is one strong example of one trial learning,
link |
that from that point on,
link |
it's not the restaurant or the waitress
link |
or the waiter or the date,
link |
but it's my notion of it had to have been the shrimp
link |
that leads me to then want to avoid shrimp
link |
in every context, maybe even shrimp powder.
link |
For a very long time.
link |
I can imagine all the evolutionarily adaptive reasons
link |
why this such a phenomenon would exist.
link |
Do we have any concept of where in this pathway that exists?
link |
We know actually a significant amount at a general level.
link |
In fact, more than shrimp,
link |
oysters are even a more dramatic example.
link |
One bad oyster is all you need
link |
to be driven away for the next six months.
link |
I think because of the texture alone
link |
is something that one learns to overcome.
link |
I actually really enjoy oysters.
link |
I despise mussels, despise shrimp,
link |
not the animal, but the taste,
link |
and yet oysters, for some reason,
link |
I've yet to have a bad experience.
link |
It's like uni, by the way.
link |
Texture is hard to get over,
link |
but once you get over, it's delicious.
link |
That's what they tell me.
link |
We were both in San Diego at one point,
link |
and I'll give a plug to Sushi Ota
link |
is kind of the famous little city,
link |
and they have amazing uni,
link |
and I've tried it twice, and I'm 0 for 2.
link |
Somehow the texture outweighs
link |
any kind of the deliciousness
link |
that people report.
link |
It's a very acquired taste, yeah?
link |
You know, I grew up in Chile.
link |
That's where the accent comes from,
link |
in case anyone wonder.
link |
And you know, by the time I came here
link |
to graduate school, I was 19, too old
link |
to, you know, overcome my heavy Chilean accent.
link |
So here I am, 40 years, 50 years late, not quite, 40 plus.
link |
We appreciate it. And I still sound
link |
like I just came off the boat.
link |
So in Chile, you don't drink beer
link |
when you're young, you drink wine.
link |
You know, Chile is a huge wine producer.
link |
So when I came to the US,
link |
all of my, you know, classmates,
link |
you know, were drinking beer
link |
because they, you know, they had finished college
link |
where they were all, you know, beer drinking,
link |
and, you know, graduate school,
link |
you're working 18 hours a day, every day.
link |
The way they, you know, relax,
link |
let's go and have some beers.
link |
And beer is cheaper.
link |
And beer is cheap.
link |
And we were being clearly underpaid, may I add.
link |
It's an acquired taste.
link |
It was too late by then.
link |
And here I am, you know, 60 plus.
link |
And if you take all the beer I've drunk in my entire life,
link |
I would say they add to less than an eight ounce
link |
in glass of water.
link |
Impressive. Well, your health is probably better for it.
link |
Your physical health, anyway.
link |
So, you know, it goes back to, you know, acquired taste.
link |
This is the connection to uni and to oysters.
link |
Now, going back to the one trial learning,
link |
you know, this is the great thing about our brains.
link |
Certain things we need to repeat
link |
a hundred times to learn them.
link |
Hello, operator, can I have the phone number
link |
for sushi ota, please?
link |
And then she'll give it to you over the phone,
link |
at least in the old days.
link |
And then you need to repeat it to yourself
link |
over and over and over over the next minute
link |
so you can dial sushi ota.
link |
And five minutes later, it's gone.
link |
That's what we call working memory.
link |
Then there is the short-term memory.
link |
And if we're lucky, by the end of the day,
link |
we remember where it is.
link |
And then there is the long-term memory.
link |
We remember the birthdays of every one of our children
link |
for the rest of our lives.
link |
Well, there are events that a single event is so traumatic
link |
that it activates the circuits in a way
link |
that it's a one trial learning.
link |
And the taste system is literally
link |
at the top of that food chain.
link |
And there is a phenomenon known
link |
as conditioned taste aversion.
link |
You can pair an attractive stimuli
link |
with a really bad one.
link |
And you can make an animal begin to vehemently dislike,
link |
for example, sugar.
link |
And that's because you've conditioned the animals
link |
to now be averse to this otherwise nice taste
link |
because it's been associated with malaise.
link |
And when you do that, now you could begin to ask,
link |
what has changed in the signal as it travels
link |
from the tongue to the brain in a normal animal
link |
versus an animal where you have now transformed sweet
link |
from being attractive to being aversive?
link |
And this is the way now you begin to explore
link |
how the brain changes the nature, the quality,
link |
the meaning of a stimuli as a function of its state.
link |
I have a number of questions related to that,
link |
all of which relate to this idea of context.
link |
Because you mentioned before that flavor
link |
is distinct from taste because flavor involves smell,
link |
texture, temperature, and some other features.
link |
Ooni, sea urchin being a good example of,
link |
I can sense the texture.
link |
It actually, yeah, I won't describe what it reminds me of
link |
for various reasons.
link |
The ability to place context on into,
link |
to insert context into a perception
link |
or rather to insert a perception into context
link |
And there's an element of kind of mystery about it,
link |
but if we start to think about some of the more nuanced
link |
that we like to live at the edge, as you say,
link |
how many different tastes on the taste dial,
link |
to go back to your analogy earlier, the color dial,
link |
do you think that there could be
link |
for something as fixed as bitter?
link |
So for instance, I don't think I like bitter tastes,
link |
but I like some fermented foods
link |
that seem to have a little bit of sour
link |
and have a little bit of that briny flavor.
link |
How much plasticity do you think there is there,
link |
and in particular across the lifespan?
link |
Because I think one of the most salient examples
link |
of this is that kids don't seem to like certain vegetables,
link |
but they all are hardwired to like sweet tastes.
link |
And yet you could also imagine
link |
that one of the reasons why they may eventually grow
link |
to incorporate vegetables is because of some knowledge
link |
that vegetables might be better for them.
link |
So is there a change in the receptors,
link |
the distribution, the number, the sensitivity, et cetera,
link |
that can explain the transition
link |
from wanting to avoid vegetables
link |
to being willing to eat vegetables,
link |
simply in childhood to early development?
link |
I'm gonna take the question slightly differently,
link |
but I think it will illustrate the point.
link |
And I'm gonna just use the difference
link |
between the olfactory system
link |
and the taste system to make the point.
link |
Taste system, five basic palates,
link |
sweet, sour, bitter, salt, and umami.
link |
Each of them has a predetermined identity.
link |
We know exactly what, and valence.
link |
These are attractive, these are aversive.
link |
In the olfactory system,
link |
it's claimed that we can smell millions of different others.
link |
Yet, for the most part,
link |
none of them have an innate predetermined meaning.
link |
In the olfactory system,
link |
meaning is imposed by learning and experience,
link |
even the smell of smoke.
link |
So I'm gonna give you, I'm gonna make it differently.
link |
There are a handful of the millions of others
link |
that were claimed that you could immediately tell me
link |
these are aversive and these are attractive.
link |
So vomit, it's not correct because I can assure you
link |
that there are cultures and societies
link |
where things which are far less appealing than vomit
link |
do not evoke an aversive reaction.
link |
Sulfur would be maybe a universal.
link |
I'm not talking pheromones, okay?
link |
Pheromones are in a different category
link |
that trigger innate responses.
link |
But nearly every other
link |
is afforded meaning by learning and experience.
link |
And that's why you like broccoli and I despise broccoli
link |
because I remember my mother forcing me to eat broccoli.
link |
Same sensory experience, all right.
link |
This accommodates two important things.
link |
In the case of taste, you have neurons at every station
link |
that are for sweet, for sour, for bitter,
link |
for salty and umami.
link |
It's only five classes.
link |
So it's not gonna take a lot of your brain.
link |
If we can in fact smell a million others
link |
and every one of us have others
link |
had to have predetermined meaning,
link |
there's not gonna be enough brain
link |
just to accommodate that one sense.
link |
And so evolution in its infinite wisdom
link |
evolve a system where you put together a pathway
link |
and a cortex, olfactory cortex,
link |
where you have the capacity to associate every other
link |
in a specific context that now gives it the meaning.
link |
Now let's go back to the original question then.
link |
So other than clearly plastic, mega plastic
link |
because it's fundamental basis and neural organization.
link |
But taste, we just told you
link |
that's predetermined hardwired.
link |
But predetermined hardwired doesn't mean
link |
that it's not modulated by learning or experience.
link |
It only means that you are born liking sweet
link |
and disliking bitter.
link |
And we have many examples of plasticity,
link |
beer being one example.
link |
So why do we learn to love beer is in coffee?
link |
It's because it has an associated gain to the system
link |
and that gain to the system,
link |
that positive valence that emerges
link |
out of that negative signal is sufficient
link |
to create that positive association.
link |
And in the case of beer, of course, is alcohol.
link |
The feeling good that we get after
link |
is more than sufficient to say,
link |
I wanna have more of this.
link |
And in the case of coffee, of course,
link |
is caffeine activating a whole group
link |
of neurotransmitter systems
link |
that give you that high associated with coffee.
link |
So yes, this taste system is changeable.
link |
It's malleable and is subjected to learning and experience.
link |
But unlike the olfactory system,
link |
it's restricted in what you could do with it
link |
because its goal is to allow you
link |
to get nutrients and survive.
link |
The goal of the olfactory system is very different.
link |
It's being used, not in our case,
link |
but in every animal species,
link |
to identify friend versus foe,
link |
to identify ecological niches they wanna be in.
link |
So it plays a very broad role
link |
that then requires that it be set up,
link |
organized and function in a very different type of context.
link |
Taste is about can we get the nutrients we need to survive?
link |
And can we ensure that we are attracted
link |
to the ones we need?
link |
And we're averse to the ones that are going to kill us.
link |
I'm being overly simplistic and reductionist,
link |
but I think it illustrates a huge difference
link |
between these two chemosensory systems.
link |
I don't think you're being overly simplistic.
link |
I think it illustrates the key intractable nature
link |
of this system and the way you've approached it.
link |
And I think it's important for people to hear that
link |
because everybody, as we are,
link |
it's mystified with empathy and love, et cetera.
link |
So in fairness to that,
link |
I'm going to ask a sort of a high level question
link |
or abstract question.
link |
This was based on a conversation I had
link |
with a former girlfriend
link |
where we were talking about chemistry between individuals.
link |
Very complicated topic on the one hand,
link |
but on the other hand,
link |
quite simple in that certain people, for whatever reason,
link |
evoke a tremendous sense of arousal,
link |
for lack of a better word, between two people,
link |
At least for some period of time.
link |
I didn't know this was that kind of a podcast.
link |
No, well, the reason I,
link |
but this has to do with taste because she said something,
link |
I think in part to maybe irritate me a bit,
link |
but we were commenting
link |
not about our own experience of each other,
link |
but of someone that she was now very excited about.
link |
We're on good terms.
link |
what do you think it is, this thing of chemistry?
link |
So maybe she was trying to, you know.
link |
Warn you of what's coming.
link |
Warn me of what's coming.
link |
I have a feeling something about it is in smell
link |
and something about it is actually in taste,
link |
literally the taste of somebody's breath.
link |
That's the way she described it.
link |
And I thought that it was a very interesting example
link |
for a number of reasons,
link |
but in particular,
link |
because it gets to the merging of odor and taste,
link |
but also to the idea that,
link |
of course, the context of a new relationship,
link |
and in fact, they're both attractive people, et cetera.
link |
There's a whole context there,
link |
but I've had the experience of
link |
the odor of somebody's breath being aversive,
link |
not because I could identify it as aversive.
link |
Because you just didn't like it.
link |
But because it just didn't like it.
link |
But that's because you associate it
link |
negative, you know, aversive reaction, by the way.
link |
There are certain perfumes to me that are aversive.
link |
And there are other scents,
link |
can recall scents of skin,
link |
of foods, et cetera,
link |
that are immensely repetitive.
link |
So I've experienced both sides of this equation myself.
link |
And she was describing this.
link |
And to me, more than tasting wine,
link |
which is the typical example,
link |
where people inhale it and then they drink it.
link |
To me, this seems like something that
link |
more people might be able to relate to.
link |
That certain things and people smell delicious.
link |
Even mothers describing the smell of their baby's head.
link |
I mean, you know, our own babies,
link |
when they're in their necks.
link |
That's the magical place.
link |
The back of their neck.
link |
I have a grandchild now.
link |
So I know exactly what Rio, that's his name, smells like.
link |
So more beautiful examples.
link |
It's always more fun to think about the beautiful,
link |
positive, the repetitive examples.
link |
The smell of the back of your grandson's neck.
link |
I mean, you couldn't,
link |
you could get more specific than that,
link |
but not a lot more specific.
link |
So what is going on in terms of
link |
the combination of odor and taste,
link |
given that these two systems are so different?
link |
And they come together.
link |
Ultimately, there is a place in the brain
link |
where they come together to integrate the two
link |
into what we would call, you know, that sensory experience.
link |
And I'll tell you an experiment that you could do
link |
that demonstrates this.
link |
I think it's good for your audience here
link |
to get a sense of how we approach these problems
link |
so that we can get in a meaningful scientific answers.
link |
So we know where the olfactory cortex is in the brain.
link |
We know where the taste cortex is in the brain.
link |
They're in two different places.
link |
We can go to each of these two cortices,
link |
put color traces, we put green in one,
link |
we put red in the other,
link |
and we see where the colors go to.
link |
That's a reflection of where those neurons
link |
are projecting to into their next targets.
link |
Once they get the signal,
link |
where do they send the signal to?
link |
And then we reason that if odor and taste
link |
come together somewhere in the brain,
link |
we should find an area that now
link |
it's getting red and green color.
link |
And we found such an area.
link |
And next, we anticipated, we hypothesized
link |
that maybe this is the area in the brain of the mouse,
link |
corresponding area in the brain of humans,
link |
that integrates odor and taste.
link |
It's known, the term normally used
link |
is multisensory integration.
link |
And if this is true, we could do the following experiment.
link |
We can train a mouse to lick sweet and if they guess correctly
link |
that that is supposed to be sweet,
link |
they should go now to the right port,
link |
to the right side to get a water reward.
link |
If they go to the left when it was sweet,
link |
then they're incorrect and they get no reward.
link |
And they actually get a timeout.
link |
Now the mice are thirsty,
link |
so they're very motivated to perform.
link |
And if you repeat this task a hundred times,
link |
a hundred trials, incredibly enough,
link |
this animal learned to recognize the sweet
link |
and execute the right action.
link |
And by their action, we now are being told
link |
what that animal is tasting.
link |
We can make it more interesting
link |
and we can give him sweet and bitter
link |
and say if it's sweet, go to the right
link |
and if it's bitter, go to the left.
link |
And after you train him, this mice with 90% accuracy
link |
will tell you when you randomize now the stimuli,
link |
what was sweet and what was bitter.
link |
We can now do the same experiment,
link |
but now mix taste with odor.
link |
And say, if you got odor alone,
link |
go to the right or push this lever in mice.
link |
If you get taste alone,
link |
go to this other part or push this other lever.
link |
And if you get the two together, do this something else.
link |
And if you train the mice,
link |
the mice are able now to report back to you
link |
when it's sensing taste alone, odor alone or the mix.
link |
Now we can go to the brain of this mice
link |
and go to this area that we now uncover,
link |
discover as being the site of multi-sensor integration
link |
between taste and odor and silence it.
link |
Prevent it from being activated experimentally.
link |
And if that area really represented
link |
the integration of these two,
link |
the animal should still be able to recognize the taste alone.
link |
They still should be able to recognize the odor alone,
link |
but should be incapable now to recognize the mix.
link |
And exactly as predicted, that's exactly what you get.
link |
The brain is basically a series of engineered circuits.
link |
And our task is to figure out how can we extract
link |
this amazing architecture of these circuits
link |
in a way that we can begin to uncover
link |
the mysteries of the brain.
link |
And why certain people's breath tastes so good
link |
and other people's not so good.
link |
So I never answered that,
link |
but I told you how we can figure out
link |
where in the brain is happening.
link |
As we've been having this discussion,
link |
I thought a few times about similarities
link |
to the visual system or differences to the visual system.
link |
The visual system, there are a couple of phenomenon
link |
that I wonder if they also exist in the taste system.
link |
In the visual system, we know for instance,
link |
that if you look at something long enough
link |
and activate the given receptors long enough,
link |
that object will actually disappear.
link |
We offset this with little micro eye movements, et cetera,
link |
but the principle is a fundamental one,
link |
this habituation or desensitization.
link |
Everyone seems to call it something different,
link |
but you get the idea, of course.
link |
In the taste system, I'm certainly familiar
link |
with eating something very, very sweet
link |
for the first time in a long time,
link |
and it tastes very sweet,
link |
but a few more licks, a few more bites,
link |
and now it tastes not as sweet.
link |
With olfaction, I'm familiar with the odor in a room
link |
I don't like or I like, and then it disappearing.
link |
So similar phenomenon, where does that occur?
link |
And can you imagine a sort of a system
link |
by which people could leverage that?
link |
Because I do think that most people are interested
link |
in eating not more sugar, but less sugar.
link |
I think we have better ways to approach that,
link |
and we can transition from taste into these other circuits
link |
that makes sugar so extraordinarily impossible
link |
So where does this desensitizing happens?
link |
That's the term that we use.
link |
And it's, I think, happening at multiple stations.
link |
It's happening at the receptor level,
link |
i.e. the cells in your tongue that are sensing that sugar.
link |
As you activate this receptor,
link |
and it's triggering activity after activity after activity,
link |
eventually you exhaust the receptor.
link |
Again, I'm using terms which are extraordinarily loose.
link |
But for sake of this discussion, it's fine.
link |
For the sake of this discussion,
link |
the receptor gets to a point where it undergoes
link |
a set of changes, chemical changes,
link |
where it now signals far less efficiently,
link |
or it even gets removed from the surface of the cell.
link |
And now what will happen is that the same amount of sugar
link |
will trigger far less of a response.
link |
And that is a significant change.
link |
And that is a huge side of this modulation.
link |
And then the next, I believe,
link |
is the integrated, again, loss of signaling
link |
that happens by continuous activation of the circuit
link |
at each of these different neural stations.
link |
You know, there is from the tongue to the ganglia,
link |
from the ganglia to the first station in the brainstem,
link |
a second station in the brainstem,
link |
to the thalamus, then to the cortex.
link |
So there are multiple steps that this signal is traveling.
link |
Now, you might say, why, if this is a labeled line,
link |
why do you need to have so many stations?
link |
And that's because the taste system is so important
link |
to ensure that you get what you need to survive,
link |
that it has to be subjected to modulation
link |
by the internal state.
link |
And each of these nodes provides a new side
link |
to give it plasticity and modulation,
link |
not necessarily to change the way that something tastes,
link |
but to ensure that you consume more or less
link |
or differently of what you need.
link |
I'm gonna give you one example
link |
of how the internal state changes
link |
the way the taste system works.
link |
Salt is very appetitive at low concentrations,
link |
and that's because we need it.
link |
Our electrolyte balance requires salt.
link |
Every one of their neurons uses salt
link |
as the most important of the ions,
link |
you know, with potassium to ensure that
link |
you can transfer these electrical signals
link |
within and between neurons.
link |
But at high concentrations, let's say ocean water,
link |
it's incredibly aversive.
link |
And we all know this because we've gone to the ocean,
link |
and then when you get it in your mouth,
link |
it's not that great.
link |
However, if I salt deprive you,
link |
and we can do this in experimental models quite readily,
link |
now this incredibly high concentration of salt,
link |
one molar sodium chloride,
link |
becomes amazingly appetitive and attractive.
link |
What's going on in here?
link |
Your tongue is telling you this is horrible,
link |
but your brain is telling you,
link |
I don't care, you need it.
link |
And this is what we call the modulation
link |
of the taste system by the internal state.
link |
And presumably if one is hungry enough,
link |
even uni will taste good.
link |
Just kidding, to me.
link |
You hit it right on the money.
link |
No, no, this is exactly correct.
link |
Or if you're thirsty and hungry,
link |
you suppress hunger,
link |
so that you don't waste water molecules in digesting food.
link |
Because if you're thirsty and you have no water,
link |
you will die within a week or so.
link |
But you can go on a hunger strike
link |
as long as you have water for months,
link |
because you're gonna eat up all your energy reserves.
link |
Water is a different story.
link |
So you could see that there are multiple layers
link |
at which the taste system that guides our drive
link |
and our motivation to consume the nutrients we need
link |
has to be modulated in response to the internal state.
link |
And of course, internal state itself
link |
has to be modulated by the external world.
link |
And so that, I think, is a reason why
link |
what could otherwise would have been
link |
an incredibly simple system from the tongue
link |
to the cortex in one, yes, wire, it's not.
link |
Because you have to ensure that at each step,
link |
you give the system that level of flexibility,
link |
or what we call in neuroscience, plasticity.
link |
I think we're headed into the gut.
link |
But I have a question that has just been on my mind
link |
for a bit now, because I was drinking this water,
link |
and it has essentially no taste.
link |
And it has essentially no taste.
link |
Is there any kind of signal for the absence of taste
link |
despite having something in the mouth?
link |
And here is why I ask.
link |
What I'm thinking about is saliva.
link |
And while it's true that if I eat
link |
a lot of very highly palatable foods,
link |
that does change how I experience more bland foods.
link |
I must confess when I eat
link |
a lot of these highly processed foods,
link |
I don't particularly like them.
link |
I tend to crave healthier foods,
link |
but that's probably for contextual reasons
link |
about nutrients, et cetera.
link |
But I could imagine an experiment where-
link |
Is there a taste of no taste?
link |
Is there a taste of no taste?
link |
Because in the visual system there is, right?
link |
You close the eyes and you start getting increases
link |
in activity in the visual system,
link |
as opposed to decreases, which often surprises people.
link |
But there are reasons for that,
link |
because everything is about signal to noise,
link |
signal to background.
link |
It's a good question.
link |
I can tell you that most of our work
link |
is trying to focus on how the taste system works,
link |
not how it doesn't work.
link |
I know you're being playful.
link |
And I knew when inviting you here today,
link |
I was setting myself up for it.
link |
I actually, on a different-
link |
We're trying to learn things.
link |
All right, listen, I was weaned in this system of,
link |
and I'll say it here for the second.
link |
Actually, I recorded a podcast recently
link |
with a very prominent podcast, Lex Friedman Podcast.
link |
And I made reference to the so-called
link |
New York Neuroscience Mafia.
link |
I won't say whether or not we are sitting in the presence
link |
of the New York Neuroscience Mafia member,
link |
I know the sorts of ribbing that they provide.
link |
For those listening,
link |
this is the kind of hazing that happens,
link |
benevolent hazing in academia.
link |
It's a sign of love.
link |
He's going to tell me that.
link |
And it's always about the science in the end.
link |
It's an interesting question.
link |
Look, I don't know the answer,
link |
and I don't even know how I would explore it
link |
in a way that it will rigorously teach me.
link |
Let me tell you why I'm asking,
link |
and then I'll offer an experiment
link |
that I'd love to see someone in your class do.
link |
I'm thinking about saliva.
link |
No, no, no, but that we know,
link |
that we can figure it out, actually.
link |
But the question is whether or not
link |
the saliva in a fed state
link |
is distinct from the saliva in an unfed state,
link |
such that it modulates-
link |
The sensitivity of the receptors.
link |
That experiment has been done, no.
link |
And so the answer is no.
link |
Yeah, and the way you could do the experiment
link |
is because we use artificial saliva.
link |
There's such a thing.
link |
I know there's artificial tears, but-
link |
No, no, we, I don't mean that you go to Walgreens
link |
and you get, I mean, we in my laboratory,
link |
we know the composition of saliva,
link |
and so you can make such a thing.
link |
And you can take, you know, taste cells in culture
link |
or in a tongue where you wash it out of,
link |
and then you can apply artificial saliva.
link |
And what happens is that the system
link |
is being engineered to desensitize,
link |
to become agnostic for saliva to become invisible.
link |
And there is no difference on the state of the animal.
link |
Well, this is the reason to do experiments.
link |
So it doesn't defeat any grand hypothesis.
link |
It's just a pure curiosity.
link |
You know that curiosity kills the cut, yeah?
link |
But saves the career of a scientist.
link |
Every single time.
link |
That's what drives us.
link |
Every single time.
link |
It's the story of our lives.
link |
Okay, so if it's not saliva, and apparently it is not,
link |
what about internal state?
link |
And what aspects of the internal milieu are relevant?
link |
Because there's autonomic, there's asleep and awake,
link |
One of the questions that I got from hundreds of people
link |
when I solicited questions in advance of this episode was,
link |
why do I crave sugar when I'm stressed, for instance?
link |
And that could be contextual,
link |
but what are the basic elements?
link |
Because it makes us feel good, by the way.
link |
We'll get to that.
link |
That's the answer.
link |
It activates what I'm going to generically refer to
link |
as reward pleasure centers in a way
link |
that dramatically changes our internal state.
link |
This is, you know, why do we eat a gallon of ice cream
link |
when we're very depressed?
link |
In fact, this is a good segue
link |
to go into this entirely different world, yeah?
link |
Of the body telling your brain what you need
link |
in important things like sugar and fat, yeah?
link |
Okay, but anyways, go ahead.
link |
You were going to ask something.
link |
Well, no, I would like to discuss the most basic elements
link |
of internal state, in particular,
link |
the ones that are below our conscious detection.
link |
And this is a, of course, is a segue
link |
into this incredible landscape,
link |
which is the gut-brain axis,
link |
which I think 15 years ago was almost a,
link |
maybe it was a couple posters at a meeting.
link |
And then now I believe you and others,
link |
there are companies, there have companies,
link |
there are active research programs, there's,
link |
and beautiful work.
link |
Maybe you could describe some of that work
link |
that you and others have been involved in.
link |
And a lot of the listeners of this podcast
link |
will have heard of the gut-brain axis,
link |
and there are a lot of misconceptions
link |
about the gut-brain axis.
link |
Many people think that this means
link |
that we think with our stomach
link |
because of the quote-unquote gut feeling aspect,
link |
but I'd love for you to talk about the aspects
link |
of gut-brain signaling that drive our,
link |
or change our perceptions and behaviors
link |
that are completely beneath our awareness.
link |
So let me begin maybe by stating
link |
that the brain needs to monitor
link |
the state of every one of our organs.
link |
This is the only way that the brain can ensure
link |
that every one of those organs are working together
link |
in a way that we have healthy physiology.
link |
Now, this monitoring of the brain
link |
has been known for a long time,
link |
but I think what hadn't been fully appreciated,
link |
that this is a two-way highway
link |
where the brain is not only monitoring,
link |
but is now modulating back what the body needs to do.
link |
And that includes all the way from monitoring
link |
the frequency of heartbeats
link |
and the way that inspiration and aspirations
link |
in the breathing cycle operate
link |
to what happens when you ingest sugar and fat.
link |
Now, let me give you an example again
link |
of how the brain can take
link |
what we would refer to contextual associations
link |
and transform it into incredible changes
link |
in physiology and metabolism.
link |
So Pavlov in his classical experiments
link |
in conditioning, you know, associative conditioning,
link |
he would take a bell, it would ring the bell
link |
every time he was going to feed the dog.
link |
And eventually the dog learned to associate
link |
the ringing of the bell with food coming.
link |
Now, the first incredible finding he made
link |
is the fact that the dog now,
link |
in the presence of the bell alone,
link |
will start to salivate.
link |
And we will call that, you know, neurologically speaking,
link |
an anticipatory response.
link |
Okay, I could understand it, I get it.
link |
You know, neurons in the brain that form that association
link |
now represent food is coming
link |
and they're sending a signal to motor neurons
link |
to go into your salivary glands to squeeze them
link |
so you release, you know, saliva
link |
because you know food is coming.
link |
But what's even more remarkable
link |
is that those animals are also releasing insulin
link |
in response to a bell.
link |
This illustrates one part of this two-way highway,
link |
the highway going down.
link |
Somehow the brain created these associations
link |
and there are neurons in your brain now
link |
that know food is coming
link |
and send a signal somehow all the way down to your pancreas
link |
that now it says release insulin
link |
because sugar is coming down.
link |
All right, this goes back to the magic of the brain.
link |
It's a never-ending source of both joy and intrigue.
link |
How the hell do they do this?
link |
Okay, I mean the neurons, eh?
link |
I mean the neurons, eh?
link |
I share your delight and fascination.
link |
There's not a day or a lecture
link |
or some talks are better than others
link |
or a talk where I don't sit back and just think
link |
it's absolutely amazing.
link |
Now over the past, I don't know, dozen years
link |
and with great force over the last five years.
link |
Now the main highway that is communicating
link |
the state of the body with the brain
link |
has been uncovered,
link |
has been what we now refer to as the gut-brain axis
link |
and the highway is a specific bundle of nerves
link |
which emerge from the vagal ganglia, the nodos ganglia
link |
and so it's the vagus nerve
link |
that it's innervating the majority
link |
of the organs in your body.
link |
It's monitoring their function,
link |
sending a signal to the brain
link |
and now the brain going back down and saying
link |
this is going all right, do this
link |
or this is not going so well, do that.
link |
And I should point out, as you well know,
link |
every organ, spleen, pancreas, lungs.
link |
They all must be monitored.
link |
Otherwise, in fact, you know, I now,
link |
I have no doubt that diseases that we have
link |
normally associated with metabolism, physiology
link |
and even immunity are likely to emerge
link |
as diseases, conditions, states of the brain.
link |
I don't think obesity is a disease of metabolism.
link |
I believe obesity is a disease of brain circuits.
link |
I do as well and so this view that we have,
link |
you know, been working on for the longest time
link |
because, you know, the molecules that we're dealing with
link |
are in the body, not in the head.
link |
You know, led us to view, of course,
link |
these issues and problems as being one
link |
of metabolism, physiology and so forth.
link |
They remain to be the carriers of the ultimate signal
link |
but the brain ultimately appears to be the conductor
link |
of this orchestra of physiology and metabolism.
link |
All right, now let's go to the gut, brain and sugar.
link |
No, I mean, the vagus nerve has, in popular culture,
link |
has been kind of converted into this single meaning
link |
of calming pathways, mostly because,
link |
I actually have to tip my hat to the yogic community
link |
was among the first to talk about vagus on and on and on.
link |
There are calming pathways that are, you know,
link |
so-called parasympathetic pathways within the vagus
link |
but I think that the more we learn about the vagus,
link |
the more it seems like an entire set of neural connections
link |
as opposed to one nerve.
link |
I just wanted to just mention that
link |
because I think a lot of people have heard
link |
about the vagus, turns out experimentally in the laboratory,
link |
many neuroscientists will stimulate the vagus
link |
to create states of alertness and arousal
link |
when animals or even people, believe it or not,
link |
are close to dying or going into coma.
link |
Stimulation of the vagus is one of the ways
link |
to wake up the brain, counter to the idea
link |
that it's just this way of calming oneself down.
link |
And also, of course, I mean,
link |
one has to be cautious there in that.
link |
So the vagus nerve is made out of many thousands of fibers.
link |
You know, individual fibers that make this gigantic bundle
link |
and it's likely, as we're speaking,
link |
that each of these fibers carries
link |
a slightly different meaning, okay?
link |
Not necessarily one by one,
link |
maybe five fibers, 10 fibers, 22, all right.
link |
But they carry meaning that's associated
link |
with their specific task.
link |
This group of fibers is telling the brain
link |
about the state of your heart.
link |
This group of fiber is telling the brain
link |
about the state of your gut.
link |
This is telling your brain about its nutritional state.
link |
This, your pancreas, this, your lungs.
link |
And they are, again, to make the same simple example,
link |
simple example, the keys of this piano.
link |
Yes, you're right, there is a lot of data
link |
showing that activating the entire vagal bundle
link |
has very meaningful effect in a wide range of conditions.
link |
In fact, it's being used to treat untractable depression.
link |
A little stimulator, epileptic seizures.
link |
But again, there are thousands of fibers
link |
carrying different functions.
link |
So to some degree, this is like turning the lights
link |
on the stadium because you need to illuminate
link |
where you lost your keys under your seat.
link |
Yet 10,000 volts of 1,000 watts each have just come on.
link |
Only one of these is pointing to where.
link |
And so I'm lucky enough that one of them
link |
happened to point to my site.
link |
So here you activate the bundle, thousands of fibers.
link |
I'm lucky enough that some of those happen to do something
link |
to make a meaningful difference in depression
link |
or to make a meaningful difference in epileptic.
link |
But it should not be misconstrued as arguing
link |
that this broad activation has any type
link |
of selectivity or specificity.
link |
We're just lucky enough that among all the things
link |
that are being done, some of those happen to change
link |
the biology of these processes.
link |
Now, the reason this is relevant because the magic
link |
of this gut-brain axis is the fact that you have
link |
these thousands of fibers really doing different functions.
link |
And our goal, and along with many other great scientists,
link |
including Steve Liverless that started a lot
link |
of this molecular dissection on this vagal gut-brain
link |
communication line at Harvard,
link |
is trying to uncover what are each of those lines doing?
link |
What are each of those keys of this piano playing?
link |
What's the latest there?
link |
Just as a brief update, I know Steven Liverless,
link |
I think I was there when he got his Howard Hughes
link |
and I did not, so that was fun.
link |
Always great to get beat by excellent people.
link |
First of all, I'm happy you did them
link |
because that way you can focus on this amazing podcast.
link |
Thank you, that's very gracious of you.
link |
It always feels better, it's not good,
link |
to get beat out by excellent people.
link |
Steven is second to none and he is defining,
link |
as you said, the molecular constituents
link |
of different elements of these many, many fibers.
link |
Is there an update there?
link |
Are they finding multiple parallel pathways?
link |
They are, they are.
link |
Some that control heartbeat,
link |
some that control the respiratory cycle,
link |
some that might be involved in a gastric movement,
link |
you know, this notion that you're full
link |
and you feel full in part because your gut gets distended,
link |
your stomach, for example,
link |
and then there are little sensors that are reading that
link |
and telling the brain you're full.
link |
Yeah, so the text books will soon change
link |
on the basis of the liberalese and other work.
link |
In essence, I think we are learning enough
link |
about these lines that could really help put together
link |
this holistic view of, you know, how the brain,
link |
it's truly changing body physiology, metabolism, and immunity.
link |
The part that hasn't been yet developed
link |
and that it needs a fair amount of work,
link |
but it's an exciting, thrilling, you know,
link |
journey of discovery is how the signal comes back
link |
to now change that biology.
link |
You know, the example I gave you before with Pavlov's dog.
link |
Yeah, all right, I figure out, you know,
link |
how the association created this link between the belt,
link |
but then how does the brain tell the path?
link |
How does the brain tell the pancreas
link |
to release in the right amount of insulin?
link |
Okay, so tell me, tell me,
link |
let me tell you about the gut-brain axis
link |
and our insatiable appetite for sugar and fat.
link |
Insatiable for sugar and quenchable for fat.
link |
And this is a story about the fundamental difference
link |
between liking and wanting.
link |
Liking sugar is the function of the taste system.
link |
And it's not really liking sugar, it's liking sweet.
link |
Wanting sugar, our never-ending appetite for sugar,
link |
is the story of the gut-brain axis, liking versus wanting.
link |
And this is work of my own laboratory,
link |
you know, that began long ago
link |
when we discovered the sweet receptors.
link |
And you can now engineer mice that lack these receptors.
link |
So in essence, these animals will be unable to taste sweet.
link |
A life without sweetness, how horrible.
link |
And if you give a normal mouse a bottle containing sweet,
link |
and we're gonna put either sugar
link |
or an artificial sweetener, all right?
link |
They both are sweet.
link |
They have slightly different tastes,
link |
but that's simply because artificial sweeteners
link |
have some off tastes.
link |
But as far as the sweet receptor is concerned,
link |
they both activate the same receptor,
link |
trigger the same signal.
link |
And if you give an animal an option
link |
of a bottle containing sugar or a sweetener versus water,
link |
this animal will drink 10 to one
link |
from the bottle containing sweet.
link |
That's the taste system.
link |
Animal Go samples each one, leaks a couple of leaks,
link |
and then says, uh-uh, that's the one I want
link |
because it's a pettative and because I love it.
link |
So it prefers sugar to artificial sweetener?
link |
No, no, no, no, no.
link |
Equally artificial sweetener.
link |
In this experiment, this experiment,
link |
I'm gonna put only sweet in one bottle,
link |
and it could be either sugar or artificial sweetener.
link |
It doesn't matter which one.
link |
Okay, we're gonna do the next experiment
link |
where we separate those two.
link |
For now, it's sweet versus water.
link |
And sweet means sweet, not sugar.
link |
Sweet means anything that tastes sweet, all right?
link |
And sugar is one example, and splenda is another example.
link |
Aspartame, monk fruit, stevia, doesn't matter.
link |
Yeah, I mean, there's some that only humans can taste,
link |
mice cannot taste because their receptors
link |
between humans and mice are different.
link |
But we have put the human receptor into mice.
link |
We engineer mice, and we completely humanize
link |
this mouse's taste world, all right?
link |
But for the purpose of this conversation,
link |
we're only comparing sweet versus water.
link |
An option, my goodness, they will leak to know
link |
from the sweet side, 10 to one at least versus the water.
link |
All right, now we're gonna take the mice
link |
and we're gonna genetically engineer it
link |
to remove the sweet receptors.
link |
So these mice no longer have in their oral cavity
link |
any sensors that can detect sweetness,
link |
be that sugar molecule, be it an artificial sweetener,
link |
be it anything else that tastes sweet.
link |
And if you give these mice an option between
link |
sweet versus water, sugar versus water,
link |
artificial sweetener versus water,
link |
it will drink equally well from both
link |
because it cannot tell them apart
link |
because it doesn't have the receptors for sweet,
link |
so that sweet bottle tastes just like water.
link |
Makes sense. Very good.
link |
Now we're gonna do the experiment with sugar.
link |
From now on, let's focus on sugar.
link |
So I'm gonna give a mouse now, sugar versus water.
link |
Normal mouse will drink from the sugar, sugar, sugar, sugar,
link |
very little from the water.
link |
Knock out the sweet receptors, eliminate them.
link |
Mouse can no longer tell them apart
link |
and they will drink from both.
link |
But if I keep the mouse in that cage for the next 48 hours,
link |
something extraordinary happens when I come 48 hours later
link |
and I see what the mouse is leaking or drinking from.
link |
That mouse is drinking almost exclusively
link |
from the sugar bottle. How could this be?
link |
It cannot taste it, doesn't have sweet receptors.
link |
During those 48 hours, the mouse learn
link |
that there is something in that bottle
link |
that makes me feel good.
link |
And that is the bottle I want to consume.
link |
Now, how does the mouse identify that bottle?
link |
It does so by using other sensory features.
link |
The smell of the bottle, the texture of the solution inside,
link |
sugar at high concentrations is kind of goopy.
link |
The sadness in which the bottle is in the cage.
link |
It doesn't matter what, but the mouse realize
link |
there is something there that makes me feel good
link |
and that's what I want.
link |
And that is the fundamental basis
link |
of our unquenchable desire and our craving for sugar
link |
and is mediated by the gut brain axis.
link |
The first clue is that it takes a long time to develop.
link |
Immediately suggesting a post-ingestive effect.
link |
So we reason if this is true and it's the gut brain axis
link |
that's driving sugar preference,
link |
then there should be a group of neurons in the brain
link |
that are responding to post-ingestive sugar.
link |
And lo and behold, we identify a group of neurons
link |
in the brain that does this and these neurons
link |
receive their input directly from the gut brain axis.
link |
From other neurons.
link |
And so what's happening is that sugar is recognized normally
link |
by the tongue, activates an repetitive response.
link |
Now you ingest it and now it activates a selective group
link |
of cells in your intestines that now send a signal
link |
to the brain via the vagal ganglia that says,
link |
I got what I need.
link |
The tongue doesn't know that you got what you need.
link |
It only knows that you tasted it.
link |
This knows that it got to the point
link |
that it's going to be used, which is the gut.
link |
And now it sends the signal to now reinforce
link |
the consumption of this thing
link |
because this is the one that I needed.
link |
Sugar, source of energy.
link |
And are these neurons in the gut?
link |
So these are not neurons in the gut.
link |
So these are gut cells that recognize the sugar molecule,
link |
send a signal and that signal is received
link |
by the vagal neuron directly.
link |
And this sends a signal through the gut brain axis
link |
to the cell bodies of these neurons in the vagal ganglia
link |
and from there to the brain stem
link |
to now trigger the preference for sugar.
link |
One, you mentioned that these cells that detect sugar
link |
within the gut are actually within the intestine.
link |
You didn't say stomach, which surprised me.
link |
I always think gut as stomach, but of course intestines.
link |
They're intestine because that's where
link |
all the absorption happens.
link |
So you want the signal.
link |
You see, you want the brain to know
link |
that you had successful ingestion and breakdown
link |
of whatever you consume into the building blocks of life.
link |
And you know, glucose, amino acids, fat.
link |
And so you wanna make sure that once they are in the form
link |
that intestines can now absorb them
link |
is where you get the signal back saying,
link |
this is what I want, okay?
link |
Now, let me just take it one step further.
link |
And this now sugar molecules activates
link |
this unique gut brain circuit
link |
that now drives the development of our preference for sugar.
link |
Now, a key element of this circuit is that the sensors
link |
in the gut that recognize the sugar
link |
do not recognize artificial sweeteners at all.
link |
Right, because their nutrient value
link |
is uncoupled from the taste.
link |
Generically speaking, one can make that,
link |
but it's because it's a very different type of receptor.
link |
Turns out that it's not the tongue receptors
link |
being used in the gut.
link |
It's a completely different molecule
link |
that only recognizes the glucose molecule,
link |
not artificial sweeteners.
link |
This has a profound impact on the effect
link |
of ultimately artificial sweeteners
link |
in curbing our appetite,
link |
our craving, our insatiable desire for sugar.
link |
Since they don't activate the gut brain axis,
link |
they'll never satisfy the craving for sugar like sugar does.
link |
And the reason I believe that artificial sweeteners
link |
have failed in the market to curve our appetite,
link |
our need, our desire for sugar
link |
is because they beautifully work on the tongue,
link |
the liking, the desire for sugar.
link |
The liking to recognize sweet versus non-sweet,
link |
but they fail to activate the key sensors in the gut
link |
that now inform the brain,
link |
you got sugar, no need to crave anymore.
link |
So the issue of wanting,
link |
can we relate that to a particular set of neurochemicals
link |
upstream of, so the pathway is,
link |
so glucose is activating these cells in the gut
link |
through the vagus that's communicated
link |
through presumably the nodose ganglion
link |
and up into the brainstem.
link |
And from there, where does it go?
link |
Yeah, where does it go
link |
and what is the substrate of wanting?
link |
I, you know, of course I think molecules like dopamine,
link |
craving, there's a book even called
link |
The Molecule of More, et cetera, et cetera.
link |
Dopamine is a very diabolical molecule, as you know,
link |
because it evokes both a sense of pleasure-ish,
link |
but also a sense of desiring more, of craving.
link |
So if I understand you correctly,
link |
artificial sweeteners, and I agree,
link |
are failing as a means to satisfy sugar craving
link |
at the level of nutrient sensing.
link |
And yet if we trigger this true sugar evoked
link |
wanting pathway too much, and we've all experienced this,
link |
then we eat sugar and we find ourselves
link |
wanting more and more sugar.
link |
Now that could also be insulin dysregulation,
link |
but can we uncouple those?
link |
Yeah, I mean, look,
link |
if we have a mega problem
link |
with overconsumption of sugar and fat,
link |
we're facing a unique time in our evolution
link |
where diseases of malnutrition are due to overnutrition.
link |
I mean, how nuts is that, eh?
link |
I mean, historically, diseases of malnutrition
link |
have always been linked to undernutrition.
link |
And so we need to come up with strategies
link |
that can meaningfully change
link |
the activation of these circuits
link |
that control our wanting,
link |
certainly in the populations at risk.
link |
And this gut-brain circuit
link |
that ultimately, you know, it's the lines of communication
link |
that are informing the brain,
link |
the presence of intestinal sugar in this example.
link |
It's a very important target in the way we think about
link |
is there a way that we can meaningfully
link |
modulate these circuits?
link |
So I make your brain think that you got satisfied
link |
with sugar, even though I'm not giving you sugar.
link |
So that immediately raises the question,
link |
are the receptors for glucose in these gut cells
link |
susceptible to other things that are healthier for us?
link |
That's very good, excellent idea.
link |
And I think an important goal
link |
will be to come up with a strategy
link |
and identify those very means
link |
that allow us to modulate the circuits
link |
in a way that, certainly for all of those
link |
where this is a big issue,
link |
it can really have a, you know, dramatic impact
link |
in improving human health.
link |
I could be wrong about this and I'm happy to be wrong.
link |
I'm often wrong and told I'm wrong.
link |
That we have cells within our gut
link |
that don't just sense sugar, glucose, to be specific,
link |
but also cells within our gut
link |
that sense amino acids and fatty acids.
link |
I could imagine a scenario where one could train themselves
link |
to feel immense amounts of satiety
link |
from the consumption of foods
link |
that are rich in essential fatty acids, amino acids,
link |
perhaps less caloric
link |
or less insulin-disregulating than sugar.
link |
I'll use myself as an example.
link |
I've always enjoyed sweets, but in the last few years,
link |
for some reason, I've started to lose my appetite for them,
link |
probably because I just don't eat them anymore.
link |
At first, that took some restriction.
link |
Now I just don't even think about it.
link |
Yeah, and you're not reinforcing the circuits.
link |
And so you're, in essence, are removing yourself,
link |
but you tend to be the exception.
link |
You know, we have a huge,
link |
a huge, incredible large number of people
link |
that are being continuously exposed
link |
to highly processed foods, yeah?
link |
And hidden, so-called hidden sugars.
link |
They don't even have to be hidden.
link |
You know, it's right there.
link |
Hiding in plain sight.
link |
So much is made of hidden sugars
link |
that we often overlook that they are,
link |
there are also the overt sugars.
link |
Yeah, I mean, we can have a long discussion
link |
on the importance of coming up with strategies,
link |
you know, that could meaningfully change public health
link |
when it comes to nutrition.
link |
But I want to just go back to the notion of, you know,
link |
these brain centers that are ultimately
link |
the ones that are being activated
link |
by these essential nutrients.
link |
So sugar, fat, and amino acids
link |
are building blocks of our diets.
link |
And this is across all animal species.
link |
So it's not unreasonable then to assume
link |
that dedicated brain circuits would have evolved
link |
to ensure their recognition,
link |
their ingestion, and the reinforcement
link |
that that is what they need.
link |
And indeed, you know, animals evolved these two systems.
link |
One is the taste system that allows you to recognize them
link |
and trigger these predetermined hardwired
link |
immediate responses, yes?
link |
Oh my goodness, this tastes so good, it's so sweet.
link |
I personally have a sweet tooth, may I add.
link |
And you know, oh my God, this is so delicious,
link |
it's fatty or umami recognizing amino acids.
link |
So that's the liking pathway, yeah?
link |
But in the wisdom of evolution,
link |
that's good but doesn't quite do it.
link |
You want to make sure that these things
link |
get to the place where they are needed.
link |
And they are not needed in your tongue.
link |
They are needed in your intestines
link |
where they are going to be absorbed
link |
as the nutrients that will support life.
link |
And the brain wants to know this.
link |
And it wants to know it in a way
link |
that it can now form the association
link |
between that that I just tasted
link |
is what got where it needs to be
link |
and it makes me feel good.
link |
And so now, next time that I have to choose,
link |
what should I eat, that association now guides me to,
link |
that's the one I want.
link |
I want that fruit, not that fruit.
link |
I want those leaves, not those leaves
link |
because these are the ones that activate the right circuits
link |
that ensure that the right nutrients
link |
got to the right place and told the brain,
link |
this is what I want and need.
link |
One thing that intrigues me and puzzles me
link |
is that this effect took a couple of days, at least in mice.
link |
And the sensation, sorry, the perception of taste
link |
is immediate and yet this is a slow system.
link |
And so in a beautiful way, but in a kind of mysterious way,
link |
the brain is able to couple the taste of a sweet drink
link |
with the experience of nutrient extraction in the gut
link |
under a context where the mouse and the human
link |
is presumably ingesting other things,
link |
smelling other mice, smelling other people.
link |
That's incredible.
link |
Yeah, but you have to think of it not as humans.
link |
Remember, we inherited the circuits of our ancestors
link |
and they, through evolutionary, from their ancestors.
link |
And we haven't had that many years
link |
to have fundamentally changed
link |
in many of these hardwired circuits.
link |
So forget, as humans, let's look at animals in the wild,
link |
okay, which is easier now to comprehend the logic.
link |
Why should this take a long time of continued reinforcement
link |
given that I can taste it in a second?
link |
You wanna make sure that this source of sugar,
link |
for example, in the wild is the best, is the richest,
link |
is the one where I get the most energy
link |
for the least amount of extraction,
link |
the least amount of work.
link |
I wanna identify rich sources of sugar.
link |
And if the system simply responds immediately
link |
to the first sugar that gets to your gut,
link |
you're gonna form the association
link |
with those sources of food,
link |
which are not the ones that you should be eating from.
link |
Don't fall in love with the first person you encounter.
link |
Oh my goodness, exactly.
link |
And so evolutionarily, by having the taste system
link |
giving you the immediate recognition,
link |
but then by forcing this gut brain access
link |
to reinforce it only when sustained,
link |
you know, repeated exposure has informed the brain,
link |
you don't wanna form the association before.
link |
And so, you know, when we remove it from the context of,
link |
you know, we just go to, you know, the supermarket.
link |
We're not hunting there in the wild where I need to form.
link |
And so what's happening is that highly processed foods
link |
are hijacking, you know,
link |
co-opting the circuits in a way
link |
that it would have never happened in nature.
link |
And then we not only find these things
link |
appetitive and palatable,
link |
but in addition, we are continuously reinforcing,
link |
you know, the wanting in a way that,
link |
oh my God, this is so great.
link |
What do I feel like eating?
link |
Let me have more of this.
link |
You've just forever changed the way
link |
that I think about supermarkets and restaurants.
link |
There are, understanding this fast signaling
link |
and this slower signaling and the utility of having both
link |
makes me realize that supermarkets and restaurants
link |
are about the most unnatural thing for our system ever.
link |
Almost the equivalent of living in small villages
link |
with very few suitable mates
link |
versus online dating, for instance.
link |
Look, I'm not gonna make a judgment call there
link |
because they do serve an important purpose.
link |
I like restaurants too.
link |
Yeah, and so do supermarkets, thank God.
link |
I think they're not the culprits.
link |
Yeah, I think the culprits of course, you know,
link |
are reliance on foods that are not necessarily healthy.
link |
Now, going back to the supermarket,
link |
they don't fall in love with the first, they need to work.
link |
You know, you take a tangerine
link |
and you take an extract of tangerine
link |
that you used to cook that spike, let's say with sugar
link |
and you equalize in both where they both provide
link |
the same amount of calories.
link |
If you eat them both,
link |
they're gonna have a very different effect
link |
in your gut brain axis and your system.
link |
Once you make the extract and you process it
link |
and you add it, process sugar, you know, to use it now
link |
to cook, to add, to make it really sweet tangerine thing.
link |
Now you're providing now a fully ready to use
link |
broken down source of sugar in the tangerine
link |
that sugar it's mixed in the complexity
link |
of a whole set of other chemical components,
link |
fiber, long chains of sugar molecules
link |
that need a huge amount of work by your stomach,
link |
your gut system to break it down.
link |
So you're using a huge amount of energy to extract energy.
link |
And the balance, it's very different
link |
than when I take this process, highly extracted tangerine.
link |
By the way, I use tangerines because I had a tangerine
link |
just before I came here.
link |
Delicious, they are delicious.
link |
And so this goes back to the issue of supermarkets.
link |
And so to some degree, you know, A, given a choice,
link |
you don't wanna eat processed, highly processed foods
link |
because everything's already been broken down for you.
link |
And so your system has no work.
link |
And so you're co-opting, hijacking the circuits
link |
in a way that they're being activated at a timescale
link |
that normally wouldn't happen.
link |
This is why I often feel that,
link |
and I think a lot of data are now starting
link |
to support the idea that while indeed
link |
the laws of thermodynamics apply,
link |
calories ingested versus calories burned
link |
is a very real thing, right?
link |
That the appetite for certain foods
link |
and the wanting and the liking are phenomena
link |
of the nervous system, brain and gut,
link |
as you've beautifully described,
link |
and that that changes over time
link |
depending on how we are receiving these nutrients.
link |
Look, we have a lot of work to do.
link |
I'm talking as a society.
link |
I'm not talking about you and I.
link |
We also have a lot of work to do.
link |
Now, I think understanding the circuits
link |
is giving us important insights
link |
and how ultimately and hopefully
link |
we can improve human health
link |
and make a meaningful difference.
link |
Now, it's very easy to try to connect the dots,
link |
A to B, B to C, C to D.
link |
And I think there's a lot more complexity to it,
link |
but I do think that the lessons that are emerging
link |
out of understanding how the circuits operate
link |
can ultimately inform how we deal with our diets
link |
in a way that we avoid what we're facing now as a society.
link |
I mean, it's nuts that the overnutrition
link |
happens to be such a prevalent problem.
link |
And I also think the training of people
link |
who are thinking about metabolic science
link |
and metabolic disease is largely divorced
link |
from the training of the neuroscientist
link |
No one field is to blame,
link |
but I fully agree that the brain is the key
link |
or the nervous system to be more accurate
link |
is one of the key overlooked features.
link |
Is the arbitrary, ultimately is the arbiter
link |
of many of these pathways.
link |
As a final question and one which is simply
link |
to entertain my curiosity
link |
and the curiosity of the listeners,
link |
what is your absolute favorite food?
link |
Taste, I should say.
link |
Taste, to distinguish between taste
link |
and the nutritive value or lack thereof.
link |
Yes, look, we, unlike every animal species,
link |
eat for the enjoyment of it.
link |
It doesn't happen in the wild.
link |
Most animals eat when they need to eat.
link |
Doesn't mean they don't enjoy it,
link |
but it's a completely different story.
link |
I have too many favorite foods
link |
because I enjoy the sensory experience.
link |
Rather than the food itself,
link |
to me is the whole thing.
link |
It's from the present.
link |
Look, there've been these experiments done
link |
I'm gonna take a salad made out of 11 components
link |
and I'm gonna mix them all up in potpourri
link |
of greens and other things here.
link |
And in the other one,
link |
I'm gonna present it in a beautiful arrangement
link |
and I'm gonna put it behind a glass cabinet
link |
and I'm gonna sell them.
link |
And I'm gonna sell one for $2 and one for $8.
link |
Precisely the same ingredients,
link |
exactly the same amount of each.
link |
Ultimately, you're gonna mix them.
link |
They're all gonna be the same.
link |
And people will pay the $8 because you know what?
link |
It evokes a different person.
link |
It gives you the feel that,
link |
oh my goodness, I'm gonna enjoy that salad.
link |
So going back to what is my favorite food.
link |
To me, eating is really a sensory journey.
link |
I don't mean the everyday,
link |
let me have some chicken wings because I'm hungry.
link |
But every piece I think has an important evoking sensory role.
link |
And so in terms of categories of food,
link |
I grew up in Chile, so meat is always been,
link |
but I eat it so seldom now.
link |
Yeah, because I know that's not necessarily
link |
the healthiest thing.
link |
Red meat I'm talking about, yeah?
link |
And so I grew up eating it every day.
link |
I'm talking seven days a week.
link |
Chile and Argentina, that's the mainstay of our diet, yeah?
link |
Now maybe I have red meat, I know,
link |
once every four weeks.
link |
Part of it is because I haven't had it in four weeks.
link |
But I love sushi, but I love the art of sushi.
link |
The whole thing, the way it's presented,
link |
it changes the way you taste it.
link |
I love ethnic food in particular.
link |
You're in the right place.
link |
That was the main reason I wanted to come to New York.
link |
No, I'm just kidding.
link |
There's also that Columbia University that's-
link |
I came here because I wanted to be with people
link |
that are thinking about the brain
link |
the same way that I like to think,
link |
can we solve this big problem?
link |
This big question.
link |
And certainly you're making amazing strides
link |
in that direction.
link |
And I love your answer because it really brings together
link |
the many features of the circuitries
link |
and the phenomenon we've been talking about today,
link |
which is that while it begins with sensation and perception,
link |
ultimately it's the context,
link |
and that context is highly individual
link |
to person, place, and time,
link |
and many, many other things.
link |
On behalf of myself and certainly
link |
on behalf of all the listeners,
link |
I want to thank you, first of all,
link |
for the incredible work that you've been doing now
link |
for decades in vision, in taste,
link |
and in this bigger issue of how we perceive
link |
and experience life.
link |
It's a truly pioneering and incredible work.
link |
And I feel quite lucky to have been on the sidelines
link |
seeing this over the years and hearing the talks
link |
and reading the countless beautiful papers,
link |
but also for your time today to come down here
link |
and talk to us about what drives you
link |
and the discoveries you've made.
link |
Thank you ever so much.
link |
Thank you for having me.
link |
We'll do it again.
link |
Thank you for joining me today
link |
for my discussion about perception
link |
and in particular, the perception of taste
link |
with Dr. Charles Zucker.
link |
If you're learning from and or enjoying this podcast,
link |
please subscribe to our YouTube channel.
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That's a terrific zero cost way to support us.
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In addition, please subscribe to the podcast
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And on Spotify and Apple,
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If you have feedback for us in terms of comments
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or topics or guests that you'd like us to cover
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please put those in the comment section on YouTube.
link |
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On today's episode of the Huberman Lab Podcast,
link |
we didn't talk about supplements,
link |
but on many previous episodes of the Huberman Lab Podcast,
link |
we talk about supplements that are useful for sleep,
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for focus, for hormone support,
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and other aspects of mental health,
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physical health, and performance.
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If you're interested in some of those supplements,
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you can go to livemomentus.com slash Huberman
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We also have a newsletter in which we spell out protocols
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If you'd like to check those out,
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Go to the menu and look for the Neural Network Newsletter.
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And if you'd like examples of previous newsletters,
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Once again, thank you for joining me today
link |
in my discussion with Dr. Charles Zucker
link |
about the biology of perception
link |
and the biology of the perception of taste in particular.
link |
I hope you found that discussion
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to be as enriching as I did.
link |
And last, but certainly not least,
link |
thank you for your interest in science.