Welcome to Huberman Lab Essentials,

where we revisit past episodes for the

most potent and actionable science-based

tools for mental health, physical

health, and performance.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stanford School of Medicine. And now for

my discussion with Dr. David Anderson.

David, great to be here and great to

finally sit down and chat with you.

>> Great to be here too. Thank you so much.

I want to start with something fairly

basic and that's the difference between

emotions and states. How should we think

about them and why might states be at

least as useful a thing to think about

if not more useful?

>> The short answer to your question is

that I see emotions as a type of

internal state in the sense that arousal

is also a type of internal state.

Motivation is a type of internal state.

Sleep is a type of internal state. They

change the input to output

transformation of the brain. When you're

asleep, you don't hear something that

you would hear if you were awake. So

from that broad perspective, I see

emotion as a class of state that

controls behavior. The reason I think

it's useful to think about it as a state

is it puts the focus on it as a

neurobiological process rather than as a

psychological process. Many people

equate emotion with feeling which is a

subjective sense that we can only study

in humans because to find out what

someone's feeling you have to ask them

and people are the only animals that can

talk that we can understand. That's how

I think about emotion. It's the if you

think of an iceberg it's the part of the

iceberg that's below the surface of the

water. The feeling part is the tip. What

are some of the other features of states

that represent below the tip of the

iceberg?

>> Right? There have been people who have

thought of emotions as having just

really two dimensions, a an arousal

dimension and a veilance dimension.

Ralph Adolf and I have tried to expand

that a little bit to think about

components of emotion, particularly

those that distinguish emotion states

from motivational states because they

are very closely related. One of those

important properties is persistence.

This is something that distinguishes

stated driven behaviors from simple

reflexes. Reflexes tend to terminate

when the stimulus turns off, like the

doctor hitting your knee with a hammer.

It initiates with the stimulus onset and

it terminates with the stimulus offset.

Emotions tend to outlast often the

stimulus that evoke them. If you're

walking along a trail here in Southern

California, you hear a rattlesnake

rattling, you're going to jump in the

air, your heart is going to continue to

beat and your palms sweat for a while

after it's slithered off in the bush and

you're going to be hypervigilant. If you

see something that even remotely looks

snake like a stick, you're going to

stop. Not all states have persistence.

So, for example, you think about hunger.

Once you've eaten, the state is gone.

You're not hungry anymore. But if you're

really angry and you get into a fight

with somebody, even after the fight is

over, you may remain riled up for a long

time and it takes you a while to calm

down. And then generalization is an

important component of emotion states um

that uh make them if they have been uh

triggered in one situation they can

apply to another situation. My favorite

example of that is you come home from

work and your kid is screaming. If you

had a good day at work you might pick it

up and and soothe it. And if you had a

bad day at work, you might react very

differently to it.

>> Like to talk a bit about aggression, the

beautiful work of Da Lin and others in

your lab. What are your thoughts on

aggression, how it's generated, the

neural circuit mechanisms, and some of

the variation in what we call

aggression? First of all, um the word

aggression

in my mind refers more to a description

of behavior than it does to an internal

state. Aggression could reflect an

internal state that we would call anger

in humans or could reflect fear or it

could reflect hunger if it's predatory

aggression. The work that Dau did when

she was in my lab, she found a way to

evoke aggression in mice using

optogenetics

to activate specific neurons in a region

of the hypothalamus, the ventromedial

hypothalamus, VH. Following first the

famous Nobel Prize-winning work uh of

Walter Hess, in Hess's original

experiments, he describes two types of

aggression that he evokes from cats

depending on where in the hypothalamus

he puts his electrode. One of which he

calls defensive rage. That's the ears

laid back, teeth bared and hissing. And

the other one is predatory aggression

where the the cat has its ears forward

and it's like batting with its paw at a

mouselike object like it wants to catch

it and eat it. If you think of

ventromedial hypothalamus like a pear

sitting on the ground, the fat part of

the pair near the ground is where the

aggression neurons are, but the upper

part of the pair has fear neurons. Fast

forward from that from a lot of work

from Dau now on her own at NYU and with

her postto Anna Gret Falconer there's

evidence that the type of fighting that

we were that we elicit when we stimulate

VMH is offensive aggression that is

actually rewarding to male mice.

>> They like it.

>> They like it. male mice will learn to

poke their nose or press a bar to get

the opportunity to beat up a subordinate

male mouse. It has a positive veilance.

So it's become clear that if you want to

call it the state of aggressiveness

is multifaceted. It depends on the type

of aggression and it involves different

sorts of circuits. Why do you think

there would be such a close positioning

of neurons that can elicit such

divergent states and behaviors? I mean,

you're talking about this pear-shaped

structure where the neurons that

generate fear are cheekto jowlel with

the neurons that generate offensive

aggression. If you think from an

evolutionary perspective, it might have

been the case that defensive behaviors

and fear arose before offensive

aggression because animals first and

foremost have to defend themselves from

predation by other animals. And maybe

it's only when they're comfortable with

having warded off predation and made

themselves safe that they can start

about start to think about who's going

to be the alpha male in in my group

here. And so it could be that if you

think that brain regions and cell

populations evolved by duplication and

modification of preexisting

cell populations.

that might be the way that those regions

wound up next to each other. But I think

there must be a functional part as well.

So one thing we know about offensive

aggression is that strong fear shuts it

down. Whereas defensive aggression, at

least in rats, is actually enhanced by

fear. It's one of the big differences

between defensive aggression and

offensive aggression. And maybe these

two regions are close to each other to

facilitate inhibition of aggression by

fe the fear neurons. We know for a fact

that if we deliberately stimulate those

fear neurons at the top of the pair,

when two animals are involved in a

fight, it just stops the fight, dead in

its tracks, and they go off into the

corner and freeze. So, at least

hierarchically, it seems like fear is

the dominant behavior over offensive

aggression. I think that's the way I

tend to think about why these neurons

are are all mixed up together. And it's

not just fight and flight. There are

also metabolic neurons that are mixed

together in VMH as well. One of the

concepts that you've raised in your

lectures before is this idea of a sort

of hydraulic pressure or maybe it was

Conrad Conrad I can't speak now excuse

me Conrad Lauren Barton who talked about

a kind of hydraulic pressure towards

behavior. What's really driving

hydraulic pressure toward a given state?

>> One way that is helpful, at least for

me, to break this question apart and

think about it is to distinguish

homeostatic

behaviors that is needbased behaviors

where the pressure is built up because

of a need like I'm hungry, I need to

eat, I'm thirsty, I need to drink, I'm

hot, I need to get to a cold place. is

basically the thermostat model of your

brain. You have a set point and then if

the temperature gets too hot, you turn

on the AC and if the temperature gets

too cold, you turn on the heater and you

put yourself back to the set point. You

can think of this accumulated hydraulic

pressure either being based on something

that you were deprived of creating an

accumulating need or something that you

want to do building up a uh a drive or a

pressure to do that. And the natural way

to think about that at least for me is

as gradual increases in neural activity

in a particular region of the brain. So

for example in the area of the brain of

the hypothalamus that controls feeding

Scott Sternson and others have shown

that the hungrier you get the higher the

level of activity in that region in the

brain and then when you eat boom the

activity goes right back down again. And

I think in the case of aggression, our

data and others show that the more

strongly you drive this region of the

brain optogenetically,

the more of just a hair trigger you need

to set the animal off to get it to

fight. VMH projects to about 30

different regions in the brain and it

gets input from about 30 different

regions. So I kind of see it as both an

antenna and a broadcasting center. It's

like a satellite dish that takes in

information from different sensory

modalities, smell, maybe vision,

mechanical uh mechano sensation and then

it sort of synthesizes and integrates

that into a fairly lowdimensional as the

computational people call it uh

representation of this pressure to

attack. And it broadcasts that all over

the brain to trigger all these systems

that have to be brought into play. If

the animal is going to engage in

aggression because aggression is a very

risky thing for an animal to engage in.

It could wind up losing and it could

wind up getting killed and and so its

brain constantly has to make a

costbenefit analysis of whether to

continue on that path or to back off. As

we're talking about aggression and

mating behavior, I think hormones. One

of the common myths that's out there and

I think that persists is that

testosterone makes animals and humans

aggressive and estrogen makes animals

placid and kind or emotional. And as we

both know, nothing could be further from

the truth. The specific hormones that

are involved in generating aggression

via VMH

are things other than testosterone.

Could you tell us a little bit more

about that because there's some

interesting surprises in there.

>> When we finally identified the neurons

in VMH that control aggression with a

molecular marker, we found out that that

marker was the estrogen receptor. Other

labs have shown that the estrogen

receptor in adult male mice is necessary

for aggression. If you knock out the

gene in VMH, they don't fight. And it's

been shown and a lot of this is work

from your colleague Ner Sha at Stanford

who is one of my former PhD students

that if you castrate a mouse uh and it

loses the abil ability to fight, not

only can you rescue fighting with a

testosterone implant, but you can rescue

it with an estrogen implant. So you can

bypass completely the requirement for

testosterone to restore aggressiveness

to the mice. And as you say, it's

because many of the effects of

testosterone, although not all, many of

them are mediated by its conversion to

estrogen by a process called

aromatization.

It's carried out by an enzyme called

aromatase. In fact, people may have most

of your listeners may have heard of

aromatase because aromatase inhibitors

are widely used in female humans as

adgivant chemotherapy for breast cancer.

what's involved in female aggression

that's unique from the pathways that

generate male aggression.

>> So, uh we and other labs have studied

this in both mice and also in fruit

flies. One thing in mice that is

distinguishes aggression and females

from males is that male mice are pretty

much ready to fight at the drop of a

hat. Female mice only fight when they

are nurturing and nursing their pups

after they've delivered a litter. And

there is a window there where they

become hyperaggressive.

After their pups are weaned, that

aggressiveness goes away. So this is

pretty remarkable that you take a virgin

female mouse and expose it to a male and

her response is to become sexually

receptive and to mate with him. And now

you let her have her pups and you put

the same male or another male mouse in

the cage with her and instead of trying

to mate with him, she attacks him. We

recently showed in a paper, this is work

from one of my students, Mongu Leu, that

within VMH in females, there are two

clearly divisible subsets of estrogen

receptor neurons. and she showed that

one of those subsets controls fighting

and the other one controls mating. This

gets into the whole issue of neurons

that are present in females but not in

males. So this is already showing you

some complexity. The male mouse VMH has

both male specific aggression neurons

and generic aggression neurons. And then

the female VMH, the mating cells are

only found in females. they are female

specific and not found in the male

brain. And so we're trying to find out

what these sex specific populations of

neurons are doing. But that indicates

that that is some of the mechanism by

which different sexes show different

behaviors. If one observes the mating

behaviors of different animals, we know

that there's a tremendous range of

mating behaviors in humans. Um there can

be no aggressive component, there could

be aggressive component. Humans have all

sorts of kinks and fetishes and

behaviors and most of which probably has

never been documented because most of

this happens in private. With that said,

when you look at mating behavior of

various animals, you see an aggressive

component sometimes but not always. Is

it species specific? Is it context

specific? And more generally, do you

think that there um is cross talk

between these different neuro neuronal

populations and the animal itself might

be kind of confused about what's going

on? I can't really speak to the issue of

whether this is species specific because

I'm not a naturalist or a zoologologist.

Uh I've seen like you have in the wild

for example lions when they mate I've

seen them in Africa. There's often a

biting component of that as well. One of

the things that surprised us when we

identified neurons in VMHVL that control

aggression in males is that within that

population there is a subset of neurons

that is activated by females during male

female mating encounters. There's some

evidence that those female selective

neurons in VMH are part of the mating

behavior. If you shut them down, the

animals don't mate as effectively as

they otherwise would. U what happens

when you stimulate them, we don't yet

know because we don't have a way to

specifically do that without activating

the male aggression neurons. But I think

they must be there for a reason because

VMH is not traditionally the brain

region to which male sexual behavior has

been assigned. That's another area

called the medial preoptic area. And

there we have shown that there are

neurons that definitely stimulate mating

behavior. In fact, if we activate those

mating neurons in a male while it's in

the middle of attacking another male, it

will stop fighting, start singing to

that male, and start to try to mount

that male until we shut those neurons

off. So those are the make, love, not

war neurons. And VMH are the make, war,

not love neurons. And there are dense

interconnections

between these two nuclei which are very

close to each other into the in the

brain. But it's also possible that there

are some cooperative interactions

between those structures as well as uh

antagonistic interactions. And the

balance of whether it's the cooperative

or antagonistic interactions that are

firing at any given moment in a mating

encounter, as you suggest, may determine

whether a a moment of of uh of uh quital

bliss among two lions may suddenly turn

into a snap or a growl and a bearing of

fangs. We don't know that but certainly

the substrate the wiring is there for

that to happen. When we made that

discovery initially, it it raised the

question in my mind whether uh some

people that are serial rapists, for

example, uh and engage in sexual

violence might in some level have their

wires crossed in some way that that

these states that are supposed to be

pretty much separated and mutually

antagonistic are not and are actually

more rewarding and reinforcing. I'd love

to talk about this structure because it

seems to be involved in everything which

is the P A the perryqueductal gray. It's

been studied in the context of pain.

It's been studied in the context of the

so-called lordosis response the the

receptivity or arching of the back of

the female to receive intrammission and

mating from the male. In particular, I

want to know is there some mechanism of

pain modulation and control during

fighting and or mating? And the reason I

ask is that um while I'm not a combat

sports person, years ago, I did did a

little bit of martial arts and it always

was um impressive to me how little it

hurt to get punched during a fight and

how much it hurt afterwards, right? So

there clearly is some indogenous pain

control

>> um that then wears off and then you feel

beat up.

>> Y

>> what's P A doing visav pain and what's

pain doing visav these other behaviors?

So, I think of P A like a old-fashioned

telephone switchboard. There are calls

coming in and then the cables have to be

punched into the right hole to get the

information to be routed to the right

recipient on the other end of it.

Because pretty much every type of innate

behavior you can think of has had the

pag implicated. In cross-section, the

pag kind of looks like the water in a

toilet when you're standing over an open

toilet bowl. And if you imagine a clock

face projected onto that, it's like the

pag has sectors from 1 to 12, maybe even

more of them. And in each of those

sectors, you find different neurons from

the hypothalamus are projecting. So it

could turn out that there is a

topographic arrangement along the dorsal

vententral axis of the PAG and the

medial axis of the PAG that determines

the type of behavior that will be

emitted when neurons in that region are

stimulated. And I think sort of all of

the evidence is pointing in that

direction but by no means has it been

mapped out. Now the thing that you

mentioned about it not hurting when you

got beat up during martial arts. There

is a well-known phenomenon called

fearinduced

uh analesia

where when an animal is in a high state

of fear like if it's trying to defend

itself there is a suppression of pain

responses and I'm not sure completely

about the mechanisms and how well that's

understood but for example the adrenal

gland has a peptide in it that is

released from the adrenal medela which

controls the fightor-flight responses

and that peptide has analesic

activities.

what is

>> it's called boine adrenal medularary

peptide of 22 amino acid residues and I

only know about it because it activates

a receptor that we discovered many years

ago that's involved in pain and we

thought it promoted pain but it turns

out that this actually inhibits pain.

It's like an endogenous analesic.

Whether this is happening, this type of

analesia is happening when an animal is

engaged in offensive aggression or in

mating behavior. I don't know, but it

certainly is possible. And I don't know

whether these uh analesic mechanisms are

happening in the PAG. They could also be

happening a little further down in the

spinal cord. The PAG is really

continuous with the spinal cord. If you

just follow it down towards the tail of

an animal, you will wind up in the

spinal cord. And so it could be that

there are influences acting at many

levels on pain in the pag and in the

spinal cord as well. And it may well be

known. I just don't know it. I want to

distinguish clearly between things that

are not known that I know are unknown

which is in a fairly small area where I

have expertise from things that may be

known but I'm ignorant of them because I

just don't have a broad enough knowledge

base to know that. Tell us about

tachikinan.

I've talked about this a couple times on

different podcast episodes because of

its relationship to social isolation. My

understanding is that tachikinanine is

present in flies and mice and in humans

and may do similar things in those

species. So tachyin is uh refers to a

family of related neuropeptides. So

these are brain chemicals. They're

different from dopamine and serotonin in

that they're not small organic

molecules. They're actually short pieces

of protein that are directly encoded by

genes that are active in specific

neurons and not in others. And when

those neurons are active, those

neuropeptides are released together with

classical transmitters like glutamate.

Whatever tackyins have been famously

implicated in pain, particularly

tachikin 1, which is called substance P,

one of the original pain modulating.

This is something that promotes

inflammatory pain. And so we did a a

screen unbiased screen of peptides and

found indeed that one of the tachikinins

Drosopha tachiinan those neurons when

you activate them strongly promote

aggression and it depends on the release

of tachikinanine. Now the interesting

thing is that in flies just like in

people and practically any other social

animal that shows aggression, social

isolation increases aggressiveness. So

putting a violent prisoner in solitary

confinement is absolutely the worst most

counterproductive thing you could do to

them. And indeed we found in flies that

social isolation increases the level of

tachikinan in the brain. And if we shut

that gene down, it prevents the

isolation from increasing aggression. So

since my lab also works on mice, it was

natural to see whether tachie kinins

might be upregulated in social isolation

and whether they play a role in

aggression. And this is work done by a

former postoc Moriel Zelikovsky now at

University of Salt Lake City in Utah.

And she found remarkably that when mice

are socially isolated for two weeks,

there is this massive upregulation of

tachikinan 2 in their brain. In fact, if

you tag the peptide with a green

fluorescent protein from a jellyfish,

genetically the brain looks green when

the mice are socially isolated because

there's so much of this stuff released.

And she went on to show that that

increase in tachi kynanin is responsible

for the effect of social isolation to

increase aggressiveness and to increase

fear and to increase anxiety. And in

fact there are drugs that block the

receptor for tachiein which were tested

in humans and abandoned because they had

no efficacy in the tests that they were

analyzed for. If you give those drugs to

a socially isolated mouse, it blocks all

of the effects of social isolation. It

blocks the aggression. It blocks the

increased fear and the increased

anxiety. And that Moriel described it.

The mice just look chill. It's not a

seditive, which is really important.

It's not that the mice are going to

sleep. Most remarkably is once you

socially isolate a mouse and it becomes

aggressive, you can never put it back in

its cage with its brothers from its

litter because it will kill them all

overnight. But if you give it this drug

which is called osanotonant that black

blocks tachikinanine too that mouse can

be returned to the cage with its

brothers and will not attack them and

seems to be happy about that for the

rest of the time. So, this is an

incredibly powerful effect of this drug.

And I've been really interested in

trying to get pharmaceutical companies

to test this drug, which has a really

good safety profile in humans, in

testing it in people who are subjected

to social isolation stress or

bereavement stress. But it's just very

difficult for economic reasons to find a

way to get somebody to test that. As

long as we're talking about humans, I'd

love to get your thoughts about human

studies of emotion. I know you wrote

this book with Ralph Adolf. You have

this new book. There are books that are

worth reading and then there are books

that are important and I think this book

is truly important for the general

population to read and understand.

There's a heat map diagram in that book

of subjective reports that people gave

of where they experience an emotion or a

feeling sematic feeling in their body or

in their head or both when they are

angry sad calm lonely etc etc and I

wouldn't want people to think that those

heat maps were generated by any

physiological measurement because they

were not. How should we think about the

body in terms of states? And at some

point, I'd love for you to comment on

that heat map experiment. Uh this goes

back to uh something called the somatic

marker hypothesis that was proposed by

Antonio Damasio who is a neurologist at

USC. The idea that our subjective

feeling of a particular emotion is in

part associated with a sensation of

something happening in a particular part

of our body, the gut, the heart. If

there is a physiology underlying these

heat maps, it could reflect increased

blood flow to these different structures

and that in turn reflects communication

between the brain and the body and it's

birectional communication and it's

mediated by the peripheral nervous

system, the sympathetic and the

parasympathetic nervous system which

control heart rate for example, blood

vessel blood pressure and those nerves

Neurons receive input from the

hypothalamus and other blood uh brain

regions, central brain regions that

control their activity. And when the

brain is put in a particular state, it

activates sympathetic and

parasympathetic neurons which have

effects on the heart and on blood

pressure. These in turn feed back onto

the brain through the sensory system.

And uh a large part of this birectional

communication is also mediated through

the vagus nerve which many of your

listeners and viewers may have heard

about because it's become a topic of

intense activity. Now the vagus nerve is

a bundle of nerve fibers that comes out

basically of your skull, out of the

central nervous system and then sends

fibers in to your heart, your gut, all

sorts of visceral organs. That

information is both apherrant and

epherent. The veagal fibers sense things

that are happening in the body. So when

you're the reason you feel your stomach

tied up in knots if you're tense is that

those veagal fibers are sensing the

contraction of the gut muscles. They're

also aference which means that

information coming out of the brain can

influence those peripheral organs as

well. And there's work from a number of

labs just in the last 6 months or so

where people are starting to decode the

components of the different fibers in

the vagus nerve. And it's amazing how

much specificity is. There are specific

veagal nerves that go to the lung that

control breathing responses that go to

the gut that go to other organs. uh it's

almost like a set of color-coded lines

uh uh labeled lines for those things.

And now how those vagal aference play a

role in the playing out of emotion

states is a fascinating question that

people are just beginning to scrape the

surface of. But I think what's exciting

now is that people are going to be

developing tools that will allow us to

turn on or turn off specific subsets of

fibers within the vagus nerve and ask

how that affects particular emotional

behaviors. So you're absolutely right.

This brain body connection is critical

not just for the gut but for the heart,

for the lungs, for all kinds of other uh

parts of your body. And Darwin

recognized that as well. And I think

it's uh it's a central feature of

emotion state and I think what underlies

our subjective feelings of an emotion.

David, I have to say as a true fan of

the work that your lab has been doing

over so many decades. I know I speak on

behalf of a tremendous number of people

and I say thank you for taking time out

of your important schedule to share with

us what you've learned.

>> I really have appreciated your

questions. They're all they've all been

right on the money. You've hit all of

the critical important issues in this

field and you've you've uncovered what

is known, the little bit is known and

how much is not known. And I think it's

important to emphasize the unknown

things because that's what the next

generation of neuroscientists has to

solve. And so I hope this will help to

attract young people into this field

because it's so important particularly

for our understanding of mental illness

and mental health and and uh uh and

psychiatry. We've got to figure out how

emotion systems are controlled in a

causal way uh if we ever want to improve

on the psychiatric treatments that we

have now. And that's going to require

the next generation of people coming

into the field.

>> Absolutely. I second that. Well, thank

you. It's been a delight.

>> Thank you. Great. Really appreciate it.