If any goal that you achieved, whatever

it is, taking a drug, eating a food, u

getting a a partner or whatnot, um if

that was enough for you, right, then you

wouldn't keep living. You want that

system to keep tracking and once it gets

to one place, you want it to have

another place to which it could go.

Otherwise, you wouldn't live. Welcome to

the Huberman Lab podcast where we

discuss science and science-based tools

for everyday life.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stamford School of Medicine. My guest

today is Dr. Reed Montigue. Dr. Reed

Montigue is the director of the center

for human neuroscience research at

Virginia Tech. He is also an expert in

the science of motivation,

decision-making, and learning, and a

pioneer in developing methods to

directly measure levels of dopamine and

other neurom modulators in humans in

real time. Today, you'll learn how

dopamine really works. Not just to

regulate your levels of motivation.

We've all heard that before. But also to

teach you things. Dopamine is involved

in learning as well as persistence or

lack of persistence. As Reed will teach

you, most of what we hear and know about

dopamine is based on the idea that

dopamine levels go up or down depending

on our levels of expectations and then

what happens. But as he explains, most

aspects of life, work, school,

relationships, our pursuit of money,

etc. involve multiple milestones. We

work, we wait, then we get an outcome

that in turn informs the thing we do

next. Or maybe dopamine arrives suddenly

with no work involved at all. In other

words, dopamine levels are constantly

changing and that shapes not just what

you do now, but how you think about your

recent past and what you will do next.

So when we say dopamine is involved in

learning, today you are going to realize

that dopamine is teaching you how to

adjust your behavior. We of course

discuss how this knowledge can be

leveraged for better motivation and

decision-making, even better social

interactions. And we also discuss

serotonin and how dopamine and serotonin

work in sort of seessaw fashion and how

serotonin in particular teaches you

about unwanted outcomes. We also have a

discussion about SSRIs that you're going

to find fascinating. As Reed points out,

SSRIs increase levels of serotonin, but

often that serotonin gets used at the

dopamine synapses to reduce the

rewarding properties of dopamine. So

today's discussion about dopamine and

serotonin is going to be vastly

different than any that you've heard or

read about elsewhere. You're going to

learn how those neurom modulators work,

and you're going to learn how they

impact your everyday life and

decision-making. As we all know,

discussions about dopamine and serotonin

are everywhere nowadays. But in today's

episode, you're going to learn from a

top expert in the field what these

molecules truly do. And that's going to

help you better leverage your efforts,

introduce what we call deliberate

delays, and how to use tools like AI to

improve your levels of motivation and

your ability to learn through

neuroplasticity. Before we begin, I'd

like to emphasize that this podcast is

separate from my teaching and research

roles at Stanford. It is however part of

my desire and effort to bring zerocost

to consumer information about science

and science related tools to the general

public. In keeping with that theme,

today's episode does include sponsors.

And now for my discussion with Dr. for

Reed Montigue. Dr. Reed Montigue, great

to see you after all these 15 years.

>> 15 years. Um, you turned us down for a

job offer then.

>> I did. Um, but we both turned out okay.

So,

>> well, I hope so. We'll see.

>> Well, you certainly turned out okay and

uh you look great. It's always great to

see a colleague looking so fit and

healthy who also raised five children

successfully and uh all those things.

We'll talk a little bit about your life

and maybe uh your athletic life a little

bit later, but I want to talk about

dopamine. The world is obsessed with

dopamine. Now,

until very recently, people thought

about dopamine as a reward. Now, slowly,

people are starting to understand that

dopamine is involved with things other

than feeling good um such as motivation,

movement, etc. How do you think about

dopamine the neurom modulator and then

we'll move into the context in which you

study dopamine but when somebody says

what does dopamine do how do you think

and respond to that question

>> well it used to be that dopamine was

thought to equal pleasure dopamine goes

up you feel good dopamine goes down you

feel less good okay there's been an

explosion of work on it most of the new

work that's not psychological has been

out of the artificial intelligence world

what's now called artificial

intelligence. Um it's very clearly a

learning signal number one. So dopamine

fluctuations high and low control

learning. It's also playing multiple

roles. It plays a role in motivation and

it may also play a role in the way you

feel. Okay. It's it's less well

understood how the sort of mechanics of

what dopamine does for changing your

nervous system relates to your feeling

state. you can have a feeling state

that's good and see things um that don't

correlate with dopamine being the cause

of it.

>> Uh let's talk about dopamine in the

context of learning because that's

something that I think most people don't

associate with dopamine. Um what are a

few examples of what we know about

dopamine and its role in learning?

>> That's a world I can't even summarize in

a quick way. Uh people that work on

rodents now will um take a genetically

modified rodent and they will study the

way in which dopamine release correlates

with something the animal is learning.

The animal may learn to turn left when

it sees a light. It may learn to run

toward food. It may learn to run down a

maze. All kinds of learning tasks

associated with the animal are

associated with dopamine fluctuations in

your brain. Now these aren't

global. They're all over the place, but

there are different kinds of signals

that you can find in different spots in

your brain. Um, and we've begun to

understand dopamine as a central player

in the algorithms that your brain runs.

And that's where people like me, um, and

people like me, computational

neuroscientists, have made a connection.

And that's the connection between the

kinds of learning rules and learning

procedures that are installed in your

brain and installed in the brain of

every mobile creature on the planet and

dopamine fluctuations. So that's a

that's a strong connection that has been

worked out over the last 30 years. The

algorithms are well understood. What

wasn't well understood 30 years ago was

the kind of remarkable things those same

algorithms can learn. I'll come back

>> to that. I mean, there have been a bunch

of modern breakthroughs in what's called

reinforcement learning. And

reinforcement learning's main biology

partner is dopamine. It's the first big

hit. Now, you know, it's a area of

science. And so, what happens when you

have a a big finding that looks like it

explains a lot of things? Well, you

know, people come rushing in to sort of

beat it up. That's their job. That's

their job to hack away. Oh, is it really

this? Does it work the same in this

context and that context? Um but I think

the um description of what dopamine does

as a learning rule is pretty much true.

Let me give you an example. Um so

psychologists since the time of Pavlov

have understood what it means for an

animal to generate a prediction and to

compare it to an outcome. Okay, let let

me the example is so today's Wednesday.

Suppose and this is Rich Sutton's

example. Suppose I make a prediction

today that it's going to rain two inches

on Saturday. Okay. Now, we're going to

fast forward to tomorrow and I'm going

to update my prediction because I have

new knowledge and it's going to say I'm

it's going to rain 10 inches on

Saturday. Okay. There's been no

reinforcing feedback. It hasn't rained

yet because it's now Saturday yet. I'm

making a prediction about Saturday. But

there's a difference between this

expectation and that expectation.

Those differences

are encoded by dopamine. It's called a

the temporal difference error. Um, and

dopamine seems to code that before you

ever get to the terminal return. Imagine

that you were playing a game like

checkers. You make a move in the game

and you might make, I don't know, 40

moves before you win the game. And

suppose winning the game is the reward.

Well, you may have some prediction. Your

brain makes a prediction when you play

board position to board position that

you're going to win the game. And that's

a fluctuating quantity. That's a

different kind of learning rule. The

kind of learning rule that psychologists

talk about that you think about in your

everyday life is it's going to rain two

inches today. Okay, how much did it

rain? Okay, so that's a comparison

between an outcome and your expectation.

What Rich Sutton and Andy Barto did was

said, well, what you really want to do

is you want to stick between there your

next prediction. So you want successive

predictions. Okay. And why is that a

good model for animals? Well, because if

you're an animal and you're wandering

around foraging,

um, mainly you're not finding anything.

You're going from position to position

to position to position position, but

you're learning and dopamine is encoding

those signals. I'm so glad you said the

word foraging because I want to hover on

the theme of foraging uh, in the context

of human decision-m and learning and

behavior. So to stay with uh your

description, Saturday rolls around.

Let's say it doesn't rain. Let's say the

person doesn't want it to rain. They're

not a farmer. Uh they want to go to the

beach on Saturday.

>> Now we can talk about reward prediction

error, right? The difference between the

expectation when it actually happens.

>> Okay, let me let me interrupt and

correct that a bit. The reward

prediction error that people talk about

dopamine representing is the prediction

error that you get for every single step

whether or not you've received reward.

That's kind of diffused out in the

psychology literature as you have an

expectation and you have a reward.

>> It may be positive, negative or zero.

>> And what you do is you make an error

there.

>> That was understood in the 60s and 70s.

It's called the Rcoro Wagner rule um

1972.

That's how the system should learn. The

fact is though that doesn't model

reality very well. Reality doesn't give

you feedback like that every time.

Reality often gives you long stretches

of nothing. The insight I think of

Sutton and Barto in their algorithm was

well a better algorithm for learning

continuously is to take successive

predictions and to say that's a learning

rule. Obviously it's a learning rule of

the outcome when you get an outcome when

it's not zero. But it's successive

predictions. It's like why that should

be such a deep idea is not clear to me.

What is clear to me from data is an

algorithm based on that is installed in

Bbrains,

C slug brains all the way up to human

brains. There are these temporal

difference

reward prediction errors. And um so I

guess I'm sitting here trying to

backwash the old version of it which is

people say in a kind of uh vernacular

way oh it's the difference between your

expectations and the reward. Um

yes when that happens but most of the

time that's not happening in which case

it's the it's the ongoing difference

between your expectation and your next

expectation. So it's fluctuations in

your expectation as you move through the

world.

the Deep Mind guys in London who beat

the world go playing champion and made

Alpha Fold and won Nobel prizes and I

mean they're starting in 2015 they just

had this unbelievable series of hits.

They used the Sutton and Barto

algorithm. They trained those systems

where uh people would make the players

computer players would make hundreds of

board position changes before you ever

got to the end of the game. and update

and learn based on that. They threw

other tricks into I'm not going to get

technical about it. So there's a

difference. It's not just expectation

and outcome. It's expectation next

expectation

current outcome

>> and that is what rolls through and that

is what we see installed in we have a

paper uh this week coming out on

honeybee brains where you can show the

same sorts of learning rules in honeybee

brains. uh in honeybee brains it's

probably octopamine not dopamine. Um but

the other thing to say about dopamine is

it's not just dopamine. It's very clear

that lots of neurom modulators like that

are fluctuating with learning and

motivation and probably the whole

symphony of them that creates motivation

states and things like that.

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to get up to $400 off. Okay. So, I want

to pin up a a few rules uh so that um

people can move along this because I

think um most people and including me

who learned about dopamine through you

know neuroscience textbooks and lectures

and um papers and so forth um have been

fed this overly simplistic model of

expectation versus reward or lack of

reward expectation outcome. So, just to

remind people, dopamine reward

prediction error. If you, you know, the

dopamine system loves novelty,

especially positive novelty, right? You

don't think you're going to have a great

meal someplace that turns out to be

spectacular versus you're really

expecting a place to be great. Your

friend says it's terrific and then it's

okay. And you get dopamine um codes for

a lot of the expectation reward

relationship. What you're telling us is

that in most scenarios, it's more

interesting than that. there's an

updating of expectation before the final

answer comes in and dopamine is coding

for that. I'd like to um take this word

foraging and apply it to a real world

scenario in humans and then maybe we can

uh use a combination of what's known and

you'll also tell us where uh it might be

conjecture to kind of paint this picture

uh in an intuitive way for people. I

have a friend um and she's on the dating

market now. She will occasionally call

me and ask me, you know, like, "How do I

decode this text message or this

interaction?" I try and offer my

support, uh, where I can. Um, but the

conversations often go something like

this. Met so- and so. Uh, they seem

really great. They seem really busy and

they set a plan for like a month from

now. Is that weird? You're like, "All

right. Well, you know," and I give my my

interpretation. I say, "Well, you know,

he's nice. They've set a concrete plan.

You know, this and that. Like person's

busy, you know, this and that." Um, I

also hear the, "Hey, you know, met

someone, they're really, really

terrific." And I say, "Hey, listen. The

last time you said this, like two weeks

later, it was how do I get out of seeing

this person again?" So, like, go slow.

Like, collect data slowly. And I'm not

going to say I'm always right, but

almost inevitably it's three days later

or 3 weeks later it's like, "Oh my

goodness, how do I get out of this

thing?" Right? So, in some sense, it's

what you're saying, right? There's a

foraging for a healthy thing in life, a

mate. This has happened since the

beginning of time, although not with

apps. Um there's updating of expectation

based on experience and communication.

And I think this is a really beautiful

example of foraging in the context of

updating expectations because and one

could argue what is the final reward. Is

it marriage? Is it whatever? Okay,

that's that's subjective. But I think we

all can intuitively understand this

example

>> um either by experience or by

observation.

So for someone, this person who gets

excited about someone they just met,

right? Then meets them and is

increasingly excited, but it's unclear

where it's going to go, then finds out

as life goes that, oh, they're not

perfect. There's this thing. Can I live

with that? So there the I think of this

as like a sawtooth of dopamine going

through their system. Is that statement

accurate that dopamine and other neurom

modulators are encoding the sort of

expectation of success or lack of

success without actually knowing what

the final end point is? Exactly that and

that's the insight of Sutton and Barto

and when I first heard about this I I

learned about it from Peter Diane when I

was a posttock and we both arrived at

the Sulk Institute together something

about it captured me because all of a

sudden it's not this um okay you

understand expectation and outcome I

mean businesses understand that yeah

you're disappointed you expected to have

a quarterly return of X and you had Why?

That's less. You expected it to be low.

It was more. That's But that's really

rare. I studied hard. I wanted an A. I

got an A minus.

>> Yeah. But the reality is embedded in

this little simple continuous learning

update rule. Um uh it's called temporal

difference reinforcement learning. Um is

the fact that in the world these

expectations are going through their own

trajectory. All right. And that's what

dopamine is coding for. Any learning

rule should code for the surprising

outcome.

>> You you you have an expectation for an

outcome and either high or low of that.

Every learning rule should do that. And

the psychologist had that kind of

figured out 40 years ago, 50 years ago.

But it doesn't quite work because it

won't account for the way animals learn.

It won't let you chain events. So for

example, if I show a light and go to and

train on a reward with an outcome and I

use that expectation outcome learning

rule, it won't chain back to something

that predicts a light. Suppose a sound

predicts a light and we know the light

predicted the outcome. Now I ask the

question, well, what happens to the

sound? Well, we know people learn.

They'll they'll associate the sound with

the outcome. It's Pavlovian. Yeah. But

those learning rules won't do that. They

learn the wrong thing. They just do.

It's just not well appreciated. Now,

>> back when we were trying to associate

that learning rule with dopamine, there

was we were mainly working on it in a in

a kind of theoretical way, like if you

had a signal, what would it need to look

like? Where might you find this in

biology? I remember my our adviser,

Terry Sonowski, who's been on your show,

I think he said something like, "There

are these diffuse ascending systems.

They deliver these transmitters. you

guys go work on that.

>> Sounds like

his episode was spectacularly received.

>> Oh, great. Well, I mean, and he was it

was the most open,

>> inviting environment, but of course, all

the problems given out were impossible

to solve. And I I remember just

thinking, what? But um the first um

inroad was realizing that it matched uh

what Sutton had written down not so many

years before. Sutton got his PhD I think

in ' 84. I think he published the paper

in ' 88. Um I was we were doing this in

1990

and we ran into a guy's data on dopamine

signaling bull from Schultz. We didn't

know him. We ran and we could explain

every figure in every paper he published

and we just thought, okay, that's not an

accident. Okay, fast forward. We're in

generation three now. We're going to

come all the way forward. um people

doing very fancy, very detailed

experiments in rodents where you can

control where you um where dopamine

neurons are going to fire, when they're

going to fire. You can control reward,

okay? You can just control a lot of

things. And so, uh it's clearly more

than that. It's that and some other

stuff, but that's central core. I I I

don't see any good reason to throw away

that little explanation there. Back in

1990, the complaint was, "Well, that's

really cool. It matches these traces in

a arcane um journal of physiology paper.

What good is that? Reinforcement

learning like that can't learn anything.

The problem with that was at the time it

was right. Like there were no systems

that had done anything amazing. Now

they've done everything and it's it's

insane how good it was.

>> You're talking about the AI. That

algorithm that I just described with my

hands waving is the same thing that

David Silver and the Deep Mind Guys did

when they made the world champion

GoPlaying program and it beat the world

champion and that particular game had uh

expert advice built into it. Okay. And

they removed all that and then they

trained it from scratch. It's called

Alph Go Zero. And then that game was was

amazing. this item. It's never been

beaten. It basically beats the history

of Go. And so that as an example,

it's such an amazing that's a

breakthrough. Anybody that knows that

side now, that's the

>> that's the AI side. That's the

algorithm. But that same algorithm is

installed in your head.

>> It's installed in the head of a song

bird.

>> The interesting thing that's going on

now is this kind of convergence, right?

They're these they're these little

gremlins in in your brain stem that run

that algorithm. Okay,

they've now been externalized and put

into a computer program that now does

things that supersede us. It's a little

interesting convergence. It's the only

thing I know of that's sort of crawled

out of your mind into a program and now

the program is doing things that we

couldn't imagine before. And it matches

the biology. I mean, you can see this in

creatures as old as honeybees and

drosopha and whatnot. So,

>> okay. So, a couple of things. Uh, one

comment and a couple questions. Uh,

first comment, um, I'm just going to

say, uh, so that you don't feel you have

to. Um, everyone should know that when

Reed says dopamine is responsible for X,

Y, and Z, there are many other chemicals

in the brain likely involved as well.

>> Other chemicals. And dopamine has

multiple functions.

>> Yeah. Yeah. I I just

>> like anything in biology.

>> Yeah. We should just embed that's up on

the chalkboard now so that if you want

to mention it again, you can, but don't

feel obligated to. People, we're talking

about dopamine through a narrow cone

here, but certainly serotonin,

acetylcholine, norepinephrine, peptides

we haven't even discovered or understand

yet are are contributing. Dopamine is

clearly a major player. I want to step

back to a um a human example, a non-AII

example with the understanding of what

you just said, which is that the

algorithms that AI is running are based

on the same algorithms that neurons in

our brain stem are using to deploy

dopamine, which I I don't know of an

example like that in the world. Do you?

>> I don't. I mean

>> where we've discovered the nature of an

algorithm once we externalize it

>> we write in code and then it takes a few

very special groups to all of a sudden

have giant breakthroughs using that same

algorithm

>> and those breakthroughs are going to end

up pumping information back into our

head and so we live in an it's an

interesting recursion there

>> um I don't know what will come about

>> yeah the fact that we took biological

learning rules and gave them to a

computer essentially um and the computer

then can beat our own use of the

biological learning rules um is pretty

spectacular and I think it's a little

scary but I want to shove that for for

it is a little scary

>> later in the discussion I I want to

return to um the dating example

>> you're going to hang this dating example

around my neck

>> I think that um and and we can partner

it with another example which

>> dating example is good you you you go

along in an interaction with somebody

you pick up new knowledge about them on

Thursday you don't necessarily even see

them. It changes your expectations of

them. You pick up some new knowledge on

Saturday. You run into a co-orker of

theirs. They say, "Oh, I hear you're

seeing so and so. Did you know blah blah

blah blah blah?" You get a new changes

changes your view. So, what I want to

know is what is dopamine doing in the

context of the constantly updated

expectations?

We know that dopamine is involved in

motivation.

Are the changes in expectation

modifying motivation to either move

forward um become more pessimistic,

more optimistic or stay neutral?

>> That's a great question. So, uh

expectations change. Those changes in

expectation encoded by positive and

negative fluctuations in dopamine. Where

does motivation come in? Uh Todd Braver

and John Cohen had an idea about that

and I think Matt Botven Venick too and

that is those prediction errors are

perfect signals for deciding how

motivated you should be. How much should

you want a thing by measuring uh AC

across those kinds of signals. And if

you were doing an experiment, you were

trying to look at dopamine. Depending on

the time scale you looked at,

>> you might see little changes in it that

correlated with fluctuating

expectations. And you might see

something as a kind of an envelope, a

slower changing thing, which is the kind

of experiment you might do in a

experimental psychology setup. And that

would look like it correlated with

motivation with all these little

>> wandering things going on underneath.

That's the sense in which it could do

both functions. We are told that

dopamine is what we're seeking as we go

through a social media environment or we

go through a dating environment or we go

through a financial environment that

we're investing or investing time in.

But as you mentioned, dopamine is

not just that, you know, at the finish

line. We've known this for a while now.

It's part of the neural circuitry uh

algorithm that's driving us forward or

causing us to pause. But is it fair to

say that any system, whether whether

it's a social media platform or it's um

another form of business, whether they

consciously realize it or not, and they

probably do, it's built on trying to

constantly update our expectations so

that we keep playing the game, so that

we stay in the forging mode. Because if

you think about it, it's an infinite

scroll. There is no final outcome. If

there was a final outcome, you wouldn't

keep living. You want that system to

keep tracking and once it gets to one

place, you want it to have another place

to which it could go. Otherwise, you

wouldn't live.

>> Probably one insight into why it's in

every mobile creature's brain on the

planet. So if any goal that you

achieved, whatever it is, taking a drug,

eating a food, u getting a a partner or

whatnot, um if that was enough for you,

right, then probably be a hard, you

know, that's not the way your nervous

system works. Your nervous system keeps

pushing you forward. That's what you're

working for. You're working for this

push forward drive.

the mapping that onto dopamine hits um

is um it's not wrong, it's just blunt.

It's just a blunt way to say it. It's

not wrong, but it is blunt. It's a blunt

way to say it. You you you move around

with expectations before you get any

sort of big unexpected hit.

>> This is why I don't like the phrase or

the words dopamine hits because it

implies it's like a reward that gets

trickled into you.

>> But it is true you get a hit. Mhm.

>> It is true that there's this unexpected

reward

>> that you that your expectations, your

series of expectations did not

anticipate and that augments that is the

learning rule. That's that's what we

think uh the the dopamine fluctuations

are encoding. And so it does both jobs.

It it lets you update and learn and it

codes for the kind of motivation you

should have. And when you're surprised,

those are extra hits. So it it's not

wrong to say that. It's just incomplete.

>> I'm going to ask you to speculate a

little bit here, but speculate within

the context of what you know about

dopamine, which is a lot. Um, let's take

any of the different examples that I

threw out on the table for us, and we

artificially ramp up levels of dopamine

with, let's not say, a drug of of abuse

like methamphetamine or something, but

you know, we throw a little bit of a

dopamineergic stimulant into the

picture. Does that just raise the the

kind of the height of the saw tooth? Uh

does it change any of this? For

instance, if um uh this person who goes

out on a date on the second or third

date, they go to something that like

maybe a show that's spectacularly good.

Okay. How does that change the dynamics

when you know it's now it's now there's

an association with this person, an

event, but let's say that they're

flooded with dopamine. Let's take a drug

out of the picture. the the the

experience generated more dopamine. Does

it shape their expectation and

motivation around that person? If you

raise expectations and these code these

are coded by changes in dopamine, then

in fact that's that's sort of a tonic

question. That's sort of a tonic phase.

>> You explain tonic. Most people are think

tonic.

>> Well, so slower changing. Okay. So I see

a show. It makes me very excited. Uh I

have the well fills up with a little

more water. Okay. And it's sitting here.

So now the little hits on are on top of

that. Or I see something that depletes

it. I take a drug and some drugs deplete

dopamine.

>> Or they went to a play and it sucked.

>> Yeah. It's disappointing or it's sad.

>> He's got bad taste.

>> Yeah. Yeah. It just runs in your mind.

So So that can lower the levels and that

changes the way in which um the

fluctuations have an impact on learning.

Okay. Parkinson's disease is a condition

where by the time you show up with

symptoms in the doctor's office, you've

lost 70 to 75% of your dopamine neurons

in your brain stem. Those are the only

source of dopamine in your brain except

for a tiny pathway in your hypothalamus

and pituitary.

>> Well, there's sorry retinal biologist in

me. They're doing things totally

unrelated to any of this. They're

controlling adapt adaptation of light

levels.

>> Yeah, light level adaptations and um

certainly in goldfish. Uh um yeah, those

are actually very interesting. I won't

talk I won't talk about them.

>> So you got the the dopamineergic brain

stem neurons that degenerate in uh

>> by the time you're feeling so stiff uh

starting to have tremors all the parts

of the flat facy flat affect and um and

somebody's gets you to a doctor you're

you're in the 70 to 75%

loss. Okay. So what does that mean? Now

all of a sudden these and and dopamine

neurons in your brain stem or maybe

80,000 neurons per side, 160,000

neurons, that's like nothing. They send

dopamine delivering wires, biological

wires throughout your entire brain and

down your spinal cord making hundreds of

millions of connections. But now you've

shrunk those down. And so the one thing

that happens is it's very noisy. there's

not so many neurons to to code for it.

There's no smooth changes in it and the

no the noise floor relative to what you

could generate as a signal gets really

really high.

Well, one of the things that we think

dopamine is involved in in terms of

information processing is valuing the

world computing if you will the value of

taking this action or that action, the

value of grabbing this and putting it in

my mouth and drinking water etc. Okay?

And the Parkinson state is sort of like

a flat value function. You can't really

see differential value in things. As you

look around the world, you expect the

system to fluctuate for you to tell you

if I were to do this stuff or if I were

to do that stuff, if I were to look at

that, etc. It gives you a fluctuation,

but you can't read it. The downstream,

>> it's too noisy.

>> It's too noisy. You can't read it.

>> The downstream system just has to act as

it did before. It says, "Oh,

everything's of equal value. Just stay

stay put."

So I've always thought about Parkinson's

as an active freezing disease that the

nervous system is doing exactly what it

would do if because it takes energy to

transition from where you are to doing

the next thing. Why do that if it's

there's nothing more valuable there.

This comes back to the idea of it

pushing you through the world. It

doesn't habituate because it has to keep

your behavior going or else you're going

to die. I don't think it's a

coincidence. In fact, I know it's not.

That dopamine is involved in learning,

motivation, feelings, and movement

among a few other more minor roles. Uh,

everything about physical movement is

intuitive to us. You move forward, you

move back, you move side to side, you

stay put. Okay? like movement, the idea

that that levels of dopamine in in a

moment and what you're referring to as

the tonic kind of um baseline, what I

call baseline levels of dopamine

>> as opposed to spikes on top of that um

predict whether or not you'll move

forward, how much resistance there is to

moving forward, these kinds of things.

But I think for a lot of people it might

be useful to think about dopamine in the

context of thought movement, right? And

motivation is is sort of a a a version

of forward movement. You know, in if I

think about am I motivated to do

something? I don't I no longer like the

word motivated. I decided I like the

word a sense of urgency. You could have

a low level of urgency, moderate or high

level of urgency. Urgency I define as um

sort of a persistent resilient

motivation, right? And the reason I

prefer urgency to motivation is that a

sense of urgency is is more intuitive I

think to most people. we kind of know

when we feel we have to do something, we

really want to do it or like it's we

don't really want to do it or we're

procrastinating. Whereas motivation is

this just kind of like catchall term for

how motivated are you? They think

intrinsic motivation, extrinsic

motivation. So when I think about a

sense of urgency, I think about a sense

of a need and readiness to move the body

and or move thoughts in a particular

direction. Do we think that dopamine is

involved in moving thoughts and

decision-m in a particular direction?

>> We exactly think that.

>> Okay. Thank you. I wasn't asking you to

validate my my non- theory theory. I

just I want I think that dopamine is

thrown around so much nowadays that we

don't even really understand what

motivation is, let alone how dopamine

would be playing this this

>> it's very clear dopamine and the other

neurom modulators are involved in um

stabilizing and sustaining brain states.

Okay, that's why they're thought to be

involved in seizures, right? One thing

you have to do with the brain state is

kind of hold on to it a bit. It's got to

have a dwell time, right? Let's call

that a thought. Boom. Okay. Uh and then

it it goes forward or changes and then

it may come back to that. Okay? So

thinking and sequencing through what you

would call thoughts is something that

these systems are clearly intimately

related to. And there are a lot of great

groups now that are exploring this in in

mice models and theoretical models as

well. Um so I think you tie the words

together pretty well. Um in an animal

that has to keep moving to stay alive

and that's all animals. Um it has to

know how valuable is it? How motivated

should I be? How much should I want a

thing? Right? um the calculations that

we think the algorithms are affecting in

your in your brain are exactly those.

And so we can have these conversations

at the level of these psychology words

which are interesting and pertinent to

the way looking at an animal behave. But

now we're starting to pull it apart at

the level of what is this computing? How

fast is it computing it? How did it

update it? And now we can build

artificial systems based on that. Um and

I think um there was a paper in 2004 by

David Reddish talking about um addiction

as a computational disease gone arai

where you keep feeding system um a level

of dopamine by putting a drug in that c

blocks its re-uptake that it can't

anticipate, right? And so it keeps

chasing that and it never gets there.

when people have ADHD, even low what

low-level ADHD

um or they take a drug that um increases

dopamine, do you think that it makes

more things in the world sticky, meaning

uh mentally sticky, like we we naturally

just will latch on to more things when

our levels of dopamine are elevated.

We'll forage more randomly or do we

forage more narrowly? Because the whole

notion of ADHD is that they they the

whole like oh squirrel like that's the

kind of generic example is that someone

with ADHD um the theory is that their

dopamineergic systems are disregulated.

These drugs, almost all of them, right,

whether or not it's rolin or aderall or

these other drugs, they raise levels of

dopamine and norepinephrine. Oh, yes.

And somehow put people into a more

narrow trench of of focus or give them a

little bit more selectivity in terms of

what um what paths they decide to

forage.

>> Yeah. I suspect, if you made me guess,

that it's stabilizing brain states and

thought sequences in a way that's um

narrow and it doesn't divert. Does that

surprise you that increasing dopamine

would do that?

>> No. Bees do this. Okay. So, when you're

a forager bee, uh you come back and you

do a little dance in the hive and it

tells the hive uh other foragers where

to go find the nectar source. Okay. And

it's a it's a whole language. People

have worked that out. It tells you fly

this far with the sun here and there's a

polarization.

>> It's an amazing phenomenon.

>> Yeah. Yeah. that the bees go back and

they literally they do this dance the

waggle

>> and they feel the the the waggle dance

on the bee and by feeling it they know

where to go wild

>> well it's a language you can decode I

mean it's been decoded it's very to some

degree

>> when you look at bees I know this

because I've been working with a bee guy

Brian Smith at Arizona State University

for the last few years I've known him my

whole career but I've now has some

methodology that lets him make

measurements of dopamine and serotonin

and norepinephrine in bees while they do

odor learning. And um he has bees on an

axis. Okay, way over here are the ADD

bees, let's call them. And way over here

are the concentration bees.

>> Okay, and it relates to a chemical

that's related to dopamine called

octopamine, but it's a ratio of

octopamine to it's called tyramine.

That's like dopamine and serotonin if

you were talking about primates. The

ADDBs, they they feel the waggle dance

and they start, you know, they start

running for the nectar and then they get

distracted. You know, they're the

four-year-old.

>> A lot of adults like that nowadays, too.

>> They and they can't. Of course, what

they do by being distracted is they

explore more. Okay. And then the ones on

the far end over here, um, they fly

right to the nectar source.

>> Okay? So, you need both. you need.

That's called exploitation. This one's

exploiting where the nectar source is.

It's going to get it. It's going to

bring it back to the hive. And the the

sort of add guys are the um explorers.

They're looking for new information, new

nectar sources, etc. Well, your mind

kind of, as blunt as that is, your your

mind plays this dichotomy

>> in the same individual. You think that

we have this ADHD like mode and a more

focused mode. you've got multiple bees

inside your head.

>> One of them is making you into the

explorer and and that's really really

valuable sometimes. Okay. And companies

they they keep these people around.

These are the uh lateral thinkers and

you know you just have to you know feed

them enough. Um and then you have the

people that can really follow

instructions and follow the best course

of action and whatnot. And you need all

that.

>> Need all that. And this distribution of

abilities is built into all of us, but

it's different across us. You know, if I

was looking at an oak leaf and I told

you, what about this little wiggle? It's

it's the wiggle in our software design

for motivation and learning. Um, it's

very effective to sometimes be the

explorer

and other times you have to be able to

follow the chain of this is going to

lead you to the thing that you want.

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to get started today. What you're

describing is a sort of ADHD like mode

inside of all of us as well as a highly

focused mode inside all of us. You're

also I I think I hear you correctly in

um thinking that you're also describing

the fact that some people are very

strongly ADHD mode and other people are

very strongly focused. Um they're very

linear uh

>> taskbased task.

>> They can really uh form a task, hold it

in mind, a task stays there. You know,

lots of lots of athletes are that way.

They set a goal um and they set multiple

scales of goals. They set some goal, you

know, this is where I want to be in two

years. Okay, to get there, I'm going to

have to do, you know, I'm going have to

crawl through, you know, hell to get

there in two years and I have to do

these things and I'm going to wake up

again tomorrow morning and again and

again and again and these goals have to

be reconstituted and pursued. Um, if

you, you know, wanted to go play in the

NBA and then all of a sudden six months

into that you decided you want to go do

ice hockey, well that's a problem.

That's a person who can't

>> can't focus.

>> We all know these people. One question I

have and we can only speculate here is

you know there's a lot of uh ideas now

that social media but when I say social

media I don't want to knock on I teach

and learn on social media. I what I

mainly thinking about is um short very

short form video. There's this idea out

there that it's quote unquote giving

everybody ADHD. Now, I don't actually

think that's true, but I could imagine

that if we have this continuum of

honeybee like modes in our uh in our

brains that if we repeatedly engage in a

kind of rapid turnover of stimula like

you get when you scroll a Tik Tok or a

you know YouTube shorts or something

like that, I mean there's a very

frequent updating of lots of different

contexts um and information that those

circuits might get stronger And that the

circuits that uh allow you to move from

node to node and route to a goal,

updating as necessary, understanding and

integrating expectations and rewards and

failures and all the above, right? The

athlete example, the academic example,

any life, navigating relation, all the

the stuff that we think of as building a

solid life, right? You could imagine

that some of that rapid updating and

foraging could undermine the circuitry.

>> No, you build your ADHD muscle. Is there

any evidence maybe from related or or or

other experiments entirely that show

that if you give people a task where

they have to update very quickly that

you shift the the sort of state of the

brain toward seeking that more and and

doing that more easily than you do kind

of like long long haul uh distant reward

type stuff. I don't know the answer to

that in people, but I do know about

training artificial systems to do it.

And you have to be very careful to

control the mix so that it doesn't

overtrain on some on one of these two

possibilities. If we're going to divide

these two possibilities, chase a goal,

chase everything that flies along,

right? And you don't want to do either

one of those things. You have to balance

that. And sometimes you have to impose

constraints to make that happen in an

artificial network. It's a more

complicated problem in people. I mean I

can imagine I know lots of settings for

being ADD is an absolute requirement.

>> Can you give me a few examples?

>> Combat

>> combat rapid decision-making kind of the

fighter pilot u situational knowledge.

Now what do they do to prepare for that?

By the way, my dad was a captain in the

Navy and I have lots of combat examples

in my head. Um well they they practice

they practice they practice being

surprised. They practice being hungry

and you know they they put themselves

under stress and all so that when that

happens they don't have to run through

every possibility and you're they're

very effective but that requires

training that requires an enormous

amount of mental training. It's all it's

it's all about the mental game. Yeah,

it's a good example. Uh we've had a

couple of experts in ADHD on here and um

all of them have agreed that um children

and adults with ADHD, mild or severe,

can focus very intensely on things they

really enjoy and are interested in. It's

not a lack of ability to focus. It's

that the um there's a lot of choppy

terrain to get into that narrow mode of

focus unless it's something they love.

You give a kid with ADHD a video game

they love, they'll drop right in as if

it was, you know, the most focused

you've ever seen them.

>> Anytime you have to do rapid fire

decision-m, I think you would want

somebody who was able to at least train

up to that level there.

>> Do you worry about the overexposure to

um you know

>> frequent media?

>> Yeah, these media. I have a lot of kids

and so

like every parent, my main nemesis is

screen time. Okay, I'm trying to figure

out how to monitor it, measure it,

restrict it, and you know, and basically

my kids are smarter than me and they're

they're more nimble and they they move

faster than I I mean, so it's a battle

I'm losing. Um, so I've decided that the

only way I can combat it is to lose it,

but lose it a little more effectively

toward my side. So, um, but I have to

admit when I see YouTube shorts,

>> these little, you know, like, oh, look

at this person. He built a house out of

Jell-O and it's falling over now. Okay,

look at this other person. There's a

parakeet poke poke. I mean, it it's

mindnumbing to me, right? Well, there

isn't a lot of long-term learning. I,

you know, one of the things that I

define learning by as uh useful learning

is did I reflect on it again at a point

later in time? You know, the other day I

was on social media and I actually saw a

clip. It was on a friend of mine who has

a podcast um Steven Bartlett and he was

interviewing a guest and um this speak

gets right to the heart of this

conversation. You know, a lot of stuff

flies by a lot of wisdom type advice,

you know, health advice, all the you

know, it's constant barrage, but this

one stuck with me. It's interesting. Um

he asked the guy, "What's the meaning of

life?" People ask this on podcasts. I

won't ask you that today. That's that's

a Lex Freedman question. When you go on

Lex's podcast, he you can answer it to

him, but I won't ask you that. But

Stephen asked this guy, I forget who it

was, so forgive me. You know, what do

you think the point of life is? And the

guy said, "It's to learn to enjoy the

passage of time." And I thought, "That's

pretty awesome. I would add to it and

also engage in behaviors that buy you

more time, you know, is it make sure you

don't undermine your the time piece of

it." But, you know, it was something

that flew by on social media, but stuck

with me. Mhm.

>> It is exceedingly rare that a short clip

provides entertainment or information

that really stays with me that I reflect

on it later. Whereas when I read a book,

it's exceedingly rare that I don't have

five or 10 things underlined per chapter

that I go back to later.

>> It takes a while to read a book.

>> That's the thing. You it takes a

deliberative set of intentional actions

to read a book. That's the difference in

the modality. So, one thing that uh this

speaks to then is I've wondered whether

activities that require effort that may

or may not include reward but that

include effort and that are a little bit

slower and effort and slower tend to go

hand in hand um not always. Uh whether

or not that is part of the mechanism

that strengthens a circuit. Does effort

strengthen an algorithm?

uh in other words um if I get on social

media it's very easy to scroll scroll

scroll scroll scroll short form video

content doesn't take any effort um so

and in fact there's no learning involved

all you have to do is move your thumb

but there's really no learning involved

whereas if I have to do something if I

have to puzzle into do a puzzle to get

in or if I have to solve something or

think about something or grapple with

something that is where the learning

occurs what's the relationship between

if that we know between effort and

dopamine. There is a good bit of work

now where people look at the amount of

effort an animal has to do to accomplish

a task. Let me just go back to something

you just said which was interesting.

When you have to do effort um it's

easier to learn something because it

slows you down. I don't know whether

effort is itself the cause or whether

the fact that effort is slow

>> and so it slows it down. Maybe we could

design an experiment to

>> maybe slowing it down. It immediately

gave me this idea. Um,

>> so that's true in simple experiments

with rodents, but you know, rodents

can't read very well. I've never seen a

rodent that I admired that could manage

a cell phone

>> very well. And you know, even the

rodents that can read are kind of flat

effectively and all. I mean, rodent is a

terrible model for this really. I I I

wouldn't even do the experiment in

rodent. to do the experiment in a human.

>> Yeah.

>> Where you can with a few words set a

human in a certain state and you know go

or you can make them hungry or you can

you know you can put a human into a

mental state by just asking them to

think about X Y and Z and have various

controls to account for that. I have to

admit that when I look at

the generation we're concerned about

I've just read this book the anxious

generation.

>> Oh yeah. Jonathan was on this podcast

>> and I was on a MacArthur network um

neuroscience and law with him for a

while and he he's just a extremely

clearheaded

person really um always made me think

about things on the other hand I don't

know um other than the comparison to

others and the speed at which social

media lets you do that and I have you

know I have girls mainly four girls and

one boy Um,

I don't know what it's doing to him

exactly. We We all Okay. I I don't think

anybody does. I think we all suspect

there's features of it that aren't good.

And yet, it's like we're trying to hold

back the tsunami. I mean, it's just the

water's going past us. And so, I think

the only way to

uh deal with it is kind of fly by wire.

um you know when a little fire starts

over here and somebody says oh this

really causes a depression in mood and

it's these features of it then we can go

react to that and all but it's very hard

to know what it's going to do globally

it's it's it's it's evolving with its

own it feels like it's independent

>> of anything we do and so I I I I think

it's going to have to be a re sort of a

>> get in front of it reaction you can't

for example my kid just got a cell

phone. She's 13. She was the last,

according to her, and she's the reporter

here. She's the last seventh grader in

her school to get a cell phone. And but

the the raw fact was she I'm being left

out of all the discussions and whatnot.

And the answer was that that is true.

She is being left out. Their their mode

of choice is Snapchat now.

>> Um

well, there's a lot of downside to

Snapchat. And um so now I'm the I my

nervous system and my physiology is now

hooked to her blizzard of time requests

on my phone. It did, you know, I turned

it off before I came in here. Um on the

plane flying over the country, I'm

denying things and giving 15 minutes and

whatnot. So um

Jonathan has real prescriptions for how

to fix that. He has good suggestions for

how to fix that. But

the collective action thing is, you

know, collective actions are hard

because, you know, they're collections

of humans and you just can't get people

to all do something at once. There's

always a defector.

>> Well, I think as long as we're also

training the other more slow, effortful

type integration of knowledge. Um, I

mean, it'd be wonderful if social media

had settings where I could click

entertainment. I would just get

entertainment stuff and then I knew how

long I was doing that versus educate me

because I do learn a lot from social

media and I certainly try and learn on

social media. Um, and this what may

sound like kind of a trivial statement

the other day and learn to enjoy the

passage of time was what sat with me in

some way that felt important to me at

that moment and um I've been reflecting

on it through a couple of different

lenses. We're obviously not going to

solve this problem. I am curious about

speed versus effort when foraging. Let's

take it back to the dating example. This

person's gonna kill me for I'm not going

to reveal who she is, but you know, I

said, listen, I've noticed this pattern

over time. You discount people early or

you get very excited and then it always

kind of kind of ends up in the same

place where you're like, uh, why did I

do that? And I was like, well, let's,

you know, so maybe run a different

algorithm, maybe start to collect data a

little bit more slowly or maybe, you

know, see them more frequently for like

two weeks and then make a decision so

it's not you didn't waste so much time.

Still more frequently means more time,

but not overtime, you know. So, um, we

can change our our mode of foraging. I I

personally put social media on an old

phone and it goes in a supermax prison

uh lockbox that you can't code out of

for 22 hours a day. You do that to

yourself.

>> I do. And not

>> like the person that can't avoid eating

chocolate. K, you lock the chocolate.

>> It wasn't that. I just I'd read this

paper that was published recently that

said that if your phone is upside down

on a table or in your bag in the same

room, it lowers cognitive performance.

Even if you're not aware of the phone,

then you it's it's pulling resources.

It's pulling resources to it's pulling

resources. if it's in another room, it

seems that your cognitive performance

returns to its previously higher levels.

So, I thought that's pretty good. So, I

started keeping my phone in the other

room. Um, and I thought, how how much

further can I take this? So, I think

that the physical distance from things

that's non-negotiable

feels really good to somebody like me.

>> Out of sight, out of mind,

>> maybe. Although, I want to bring this

back to dopamine. uh you know can the

dopamine system learn to uh to get

motivation states and pleasure from

resisting things. I think of a

pathologic version of this might be we

did an episode on anorexia where food is

rewarding for most people but for people

who have true anorexia

um the reward system seems to enter a

state where uh resisting food becomes

the reward.

>> Control feels good. Yeah, control feels

good and but there's po anorexia

obviously the most dangerous and deadly

psychiatric illness of all the

psychiatric illnesses but but resisting

your phone um to get other work done and

to be more present for people in my life

including myself but you know that seems

like a good thing. So can the dopamine

system um encode reward for resisting

behaviors as much as it can for

indulging behaviors?

>> Yes. I mean, I think anorexia is a good

example of it. It feels good to resist

and they do it pathologically. It's such

a dangerous disorder. Um,

>> but in a healthy sense, like I'll reveal

now that you were a a fairly

accomplished dathlete. Um, so that meant

getting to practice, doing things, but

did you ever feel like I'm going to bed

early when everybody else is staying up

late? I'm getting stronger. Oh, I

relished the whole I'm running this

tennis court hill while all those other

soft guys are, you know, asleep and I'm

throwing up on top of the hill. Yeah,

that was a that was a thing. And it

meant when you got in a tough spot, um I

was a wrestler all through high school.

>> Yeah, they're sickos.

>> Yeah, they're sickos. Yeah. And but

you're never in better shape than when

you're active wrestler. um you

have to put up with things that are

really demanding on you like you like

having your air cut off. So the main

thing you do when your air is cut off is

don't panic. Well, that's not you you

know you're not pre-built to not panic.

So you have to learn how to do that.

That was the most important thing I did

in wrestling. Just learn to stay calm,

think about where your weight was and

all that. Um it's the same thing for

people that study a lot. I think people

that study a lot want to be better than

the people that don't study a lot. I

mean, they want the idea of achieving a

goal. Um, that's hard for other people

to do. And the most healthy version of

that is without any regard to what

anybody else is doing. The person who

just this is the life I live and these

are my standards and I'm quiet with them

and I'm going to go do this thing and it

doesn't matter what anybody else thinks.

And you hope that for your children, you

hope they get to be a person like that.

Um, anyway, I can tell you my kids

school, just to circle back, their

collective action is to completely

disallow phones during the school day

>> is junior high school.

>> They go to a school that's K through 12.

Mhm.

>> Um you have put it up when you get there

and I think 3:30 is when you can

activate to call for a ride or whatever.

>> Um and it's off. It's off. It's a f the

Well, I like the head of school.

>> Uh but her that's the best decision

she's ever made. I mean that that's a

great decision. Um and now they're

wrestling with what do we do with AI in

the school? How are we going to let

these kids interface with these systems

that are smarter than us? More

interesting, no less. I want to talk

about AI. Um but before we go there um I

think you've painted a really nice

picture of dopamine and the various

things it does and even just this early

statement that you made that dopamine is

is fluctuating according to our constant

updating not just expectation reward but

expectation expectation expectation

expectation maybe the reward never comes

maybe it does let's talk about serotonin

because not in every case but at least

in some cases my understanding is that

serotonin is fluctuating in the opposite

direction to dopamine at least in animal

studies it see these are some

interesting in

>> human studies too

>> great so educate us about serotonin in

this context because I know it's a huge

topic right a habit that people that

work on neurom modulators I'll name a

few dopamine serotonin norepinephrine

acetylcholine

histamine

um probably on the order of let's say 15

to 20 let's say and then there are a lot

of peptides and all but the big three

dopamine serotonin norepinephrine

um learning and motivation uh active

inhibition

um attention that's what people would

say ep norepinephrine and epinephrine or

controlling attentional states serotonin

tells you to get ready to wait like you

put an animal uh you put a piece of

cheese over an area of a table and

there's an electrified grid on the

table. The animal knows it's

electrified. He really they see the

cheese, they want the some rodent. Uh

they see the cheese, they want the

cheese, but the light is on that means

that the grit is active and they're not

super hungry, so they wait, but you

know, there's a part of their nervous

system that's making that hard. Active

waiting.

um which also suggests another set of

things for serotonin that it's uh

learning about negative things. Dopamine

is learning about positive things or the

absence of negative things or the Okay,

so there's there's ambiguity in there

because the experiments aren't all that

clear yet. There's an enormous amount of

work going on in humans. We are the only

group who records sub-second levels of

dopamine and serotonin in conscious

human beings while they do things.

Reward motivated tasks, social

interactions with other people, uh

various kinds of visual perceptual

tasks, looking at emotional

u pictures, positive, negative, and

neutral and whatnot. The theme that

emerges from that is dopamine and

serotonin are opponent to one another.

When dopamine goes up, serotonin goes

down. When serotonin goes up, dopamine

goes down. We could talk about those

events as being for positive events or

anticipation of positive events.

Dopamine goes up and serotonin goes down

and opponent see that. um at your own

institution, Rob Malinka has a a set of

beautiful results in rodents where the

learning that they see in the animal

requires that kind of opponency and I

mean it's a definitive experiment in the

rodent. Um, it's harder to do these

things in humans because you can do

simple things in humans. That's fine.

But humans can sit and have an idea and

it can generate these kinds of signals

and they can run through the ideas. And

so that that's a hard thing to both get

our hands around and to do in a

controlled setting. And so that's why

it's been ambiguous. But the first time

we were able to measure dopamine and

serotonin concurrently, they look

opponent and they look opponent all over

the place. They're old ideas

uh from the 60s and 70s about opponent

systems in this sort of a effective

processing space. Dopamine has now

inherited the positive part of that and

serotonin the negative part of that.

Opponent as you know is a a theme in the

nervous system. In the retina you have

color opponency, you have light and dark

opponency. These kinds of information

channels go all the way through to the

visual cortex. One other thing that's

interesting is that when you put SSRIs

on people um you prevent ser selective

serotonin reuptake inhibitors KAC

fluoxitine luxro um it blocks the

re-uptake of serotonin in the serotonin

terminals over a few weeks period you

have a clinical effect and you know for

some people it's a life changer It's

very heterogeneous. Um, but it pushes

serotonin into the dopamine terminals,

too. This is less well understood,

>> but you know, if you were a system and

you thought that the positive juice was

dopamine and the negative juice was

serotonin and you put the negative juice

in the positive terminals, then the

cells that control the release of that

are going to chatter for positive

things. You might start negatively

conditioning on things that you should

actually pursue and learn about. SSRIs

have helped a great number of people.

There have also been some devastatingly

tragic circumstances where SSRIs have

the theory is that they've accelerated

uh suicidality. They've accelerated

ahidonia. They they've created a lot of

problems. If we were to just take a step

back in terms of serotonin as learning

about negative things, if you could just

summarize these results for me AC

animals and and what the expectation

would be in humans. So, let's say that

somebody or an animal is learning a a

task where they get shocked. If one were

to artificially increase serotonin, does

that make somebody or an animal more or

less likely to code something as

negative?

>> Well, the idea would be it makes you

less likely to code something as

negative because you have less serotonin

in the serotonin terminals. And so if

they're communicating this information

about

>> more serotonin in the serotonin

terminals.

>> Gotcha. So if somebody takes an SSRI,

serotonin is increased and they have a

tough interaction at work.

Uh the idea is that they would encode

that cognitively as less bad

because there's an abundance of

serotonin or worse than it would be had

they not been on this drug. When you

increase serotonin

in your brain because you won't let it

be vacuumed out by the normal mechanisms

that clear it from your brain, then it

has the opportunity to be there longer

and it has the opportunity to go into

the dopamine terminals. This is

something we know. The the mechanisms

that suck dopamine out of the spaces of

your brain um will also bind to

serotonin and suck it out. Not quite as

well because it's tuned. It's called a

dopamine transporter. Um, and so

depending on what the downstream

parts of your brain think, then in fact

increasing serotonin could uh decrease

the serotonin in the serotonin terminals

by blocking the reuptake. I see. So

that's why you said it earlier. I tried

to correct you saying no, it's going to

increase serotonin because you're

blocking reuptake. You're saying no, it

pushes serotonin into the dopamine

terminals and this is why people might

not get as much reward from a positive

event. Correct.

>> When serotonin is elevated

pharmacologically,

>> there was a killer paper 20 years ago on

that where they showed they gave rodents

um some common SSRI they waited this

number of weeks and they went in there

to say where is the serotonin.

>> Okay. And what they showed was that the

dopamine transporter pathway was the

thing that was taking it into the

dopamine terminals because that's where

the dopamine transporters are. And so I

don't know where that's gone since then,

but that's a 20-year-old result. It's a

very clear result.

>> It was in a journal called Neuron. John

Danny was the senior author. He's at

Penn. Um was a remarkable paper. I don't

know that people have followed up in

humans. I actually think the only way to

follow up in humans is to kind of do

what we've been trying to do, which is

develop methods of measuring these

things in humans directly. Uh we've been

able to do it in people that are having

brain surgeries and they have an

affliction. They're going to have a

electrode put in their brain for various

reasons and they let us piggyback on

that. They consent obviously under

strict ethical guidelines. Um but we can

measure serotonin and dopamine when they

do a rewarding task or they play a game

that has a series of things that go on

back and forth with another person. um

which I like better

>> in the sense that that's a more natural

reward. Somebody does something to you

and you do something back to them.

Usually in our case they're economic

games.

>> This is encoded in money or the

expectation of the money that's going to

come and you can see strong opponency in

dopamine and serotonin signaling in the

amig deep structures in your brain.

these experiments, if people positively

anticipate

um because things are quote unquote

going well uh for them, uh you see

dopamine going up and you see serotonin

going down.

>> And if they're losing at this game or

they feel like the game isn't going well

for them in some way, um there's more

uncertainty perhaps. Serotonin goes up

and dopamine goes down.

>> Yes.

>> Interesting. And then there's state

changes in your brain that can be

induced by, for example, making somebody

hungry

>> where we don't really know how to

explain what we're seeing, but they

still show opponency. What would you say

uh being hungry does to the dynamics for

let's just take them one at a time,

dopamine, does dopamine still increase

for positive events when people are

hungry?

>> No. No. Not in rodent in rodent model. I

can talk about rodent models. We are

actually in the middle of doing

something like that now where people

come in in the morning hungry. Uh in

this case, these are people with

epilepsy that have wires in their head.

Um and we do an experiment on them when

they're right before they're going to

eat. And then we repeat the experiment

after they've eaten. But in rodents it's

very clear

uh I guess at the level of the amydala

if you make a rodent hungry then you can

show that dopamine will encode um

something like punishment prediction

errors not reward prediction errors. In

other words it does it's like it flips

its role. It's like if you're in a how

hungry do you have to be? I don't know

how it feels to be a hungry rat but um

imagine that it put it in an emergency

state.

>> Okay. So, it's not just a kind of like

like I mean I don't do any formal

intermittent fasting, but I usually eat

my first meal somewhere around

between 10:00 and noon. Uh, and at 9:00

a.m. I'm like mildly hungry. I could

eat, but I'm

>> by four. You would be hungry.

>> I'd be really hungry.

>> You'd be you'd feel it. You'd feel what

we've all felt when we're hungry.

>> And um this is a guy called Mark

Anderman at Harvard.

>> Oh, yeah. I know Mark. Yeah.

>> So, he puts animals in starvation states

and he shows that dopamine will encode

aversive events, aversive errors. very

clear result.

>> So folks,

>> I know this because he called me. I

mean, we we we met.

>> So when your kid boyfriend or girlfriend

is hungry and you're going to a show or

you're going someplace, you got to feed

them if they want to uh if you want them

to enjoy the time. I mean, that's sort

of obvious on the one hand, but I don't

think we really

>> Oh, it's even better than that. There's

an Israeli paper from I don't know about

10 years ago where they looked at judges

and the judgments that were made if you

hadn't eaten versus judgments that you

made that you had eaten and you really

want a judge that's had a good lunch.

>> Very interesting. So general state of

stress because hunger is a form of

stress.

>> Yes.

uh drives the direction of the dopamine

um to either reinforce positive things

or reinforce negative. Yeah. Cuz think

about it. If you get to a state where

you're really starving, things have not

been going well for a long time.

You've been making really bad decisions.

The creek dried up. The, you know, some

forest fire came through and ruined your

your foraging area or whatever. things

are going really really bad, are you

going to really sit around and wait for

the the rewards? The main thing you want

to do is stay alive. If you don't stay