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 ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. David Anderson.

Dr. Anderson is a professor of biology

at the California Institute of Technology,

often commonly referred to as Caltech University.

Dr. Anderson’s research focuses on emotions

and states of mind and body.

And indeed, he emphasizes how emotions

like happiness, sadness, anger, and so on

are actually subcategories

of what are generally governed by states.

That is, things that are occurring in the nervous system

in our brain and in the connections between brain and body

that dictate whether or not we feel good

about how we are feeling,

and that drive our behaviors.

That is, bias us to be in action or inaction

and strongly influence the way we interpret our experience

and our surroundings.

Today, Dr. Anderson teaches us, for instance,

why people become aggressive

and why that aggression can sometimes take the form of rage.

Also talk about sexual behavior

and the boundaries and overlap

between aggression and sexual behavior.

And that discussion about aggression and sexual behavior

also starts to focus on particular aspects

of neural circuits and states of mind and body

that govern things like, for instance,

male-male aggression versus male-female aggression

versus female-female aggression.

So today you will learn a lot

about the biological mechanisms

that govern why we feel the way we feel.

Indeed, Dr. Anderson is an author

of a terrific new popular book

entitled, The Nature of the Beast, How Emotions Guide Us.

I’ve read this book several times now.

I can tell you it contains so many gems

that are firmly grounded in the scientific research.

In fact, a lot of what’s in the book

contrasts with many of the common myths

about emotions and biology.

So whether or not you’re a therapist

or you’re a biologist

or you’re simply just somebody interested

in why we feel the way we feel

and why we act the way we act,

I cannot recommend the book highly enough.

Again, the title is The Nature of the Beast,

How Emotions Guide Us.

Today’s discussion also ventures into topics

such as mental health and mental illness.

And some of the exciting discoveries

that have been made by Dr. Anderson’s laboratory

and other laboratories,

identifying specific peptides, that is small proteins

that can govern whether or not people feel anxious

or less anxious, aggressive or less aggressive,

this is an important area of research

that has direct implications

for much of what we read about in the news,

both unfortunate and fortunate events,

and that will no doubt drive the future

of mental health treatments.

Dr. Anderson is considered one of the most pioneering

and important researchers in neurobiology of our time.

Indeed, he is a member of the National Academy of Sciences

and a Howard Hughes Medical Institute investigator.

I’ve mentioned the HHMI once or twice before

when we’ve had other HHMI guests on this podcast,

but for those of you that are not familiar,

the Howard Hughes Medical Institute

funds a small number of investigators

doing particularly high-risk, high-benefit work,

and it is an extremely competitive process

to identify those Howard Hughes investigators.

They’re essentially appointed,

and then every five years,

they have to compete against one another

and against a new incoming flock

of would-be HHMI investigators.

To get another five years of funding,

they are literally given a grade every five years

as to whether or not they can continue,

not continue, or whether or not they should worry

about being funded for an extended period of time.

Dr. Anderson has been an investigator

with the Howard Hughes Medical Institute since 1989.

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 zero cost to consumer information

about science and science-related tools

to the general public.

In keeping with that theme,

I’d like to thank the sponsors of today’s podcast.

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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.

Yeah, I have a ton of questions,

but I want to start with something fairly basic,

but that I’m aware is a pretty vast landscape,

and that’s the difference between emotions and states,

if indeed there is a difference,

and how we should think about emotions.

What are they?

They have all these names, happiness, sadness,

depression, anger, rage.

How should we think about them,

and why might states be at least as useful a thing

to think about, if not more useful?

That’s great.

First, the short answer to your question

is that I see emotions as a type of internal state,

in the sense that arousal’s also a type of internal state,

motivation’s a type of internal state,

sleep is a type of internal state.

And the sort of simplest way I think of internal states

is that, as you’ve shown in your own work,

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,

unless it’s a really, really loud noise.

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,

and this gets around all of the definitional problems

that people have with the word emotion,

where 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.

So 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 that’s sort of floating

above the surface of your consciousness.

Not that that isn’t important, it is,

but you have to understand consciousness

if you wanna understand feelings,

and we’re not ready to study that in animals yet.

And so that’s how I think about it.

What are the different components of a state?

You know, you mentioned arousal as a key component.

What are some of the other features of states

that represent this, as you so beautifully put in your book,

that represent below the tip of the iceberg?

Right, right.

So you can break states up into different facets,

or people would call them dimensions,

and so there have been people who have thought of emotions

as having just really two dimensions, an arousal dimension,

how intense is it, and also a valence dimension,

which is, is it positive or negative, good or bad?

Ralph Adolphs 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,

and this is something that distinguishes

state-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 gonna jump in the air,

but your heart is gonna continue to beat,

and your palms sweat,

and your mouth is gonna be dry for a while

after it’s slithered off in the bush,

and you’re gonna be hypervigilant.

If you see something that even remotely looks snake-like,

a stick, you’re gonna stop and jump.

Persistence is an important feature of emotion states.

Not all states have persistence.

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 that may have to do with the arousal dimension

or some other part of it.

And then generalization is an important component

of emotion states that make them,

if they have been triggered in one situation,

they can apply to another situation.

And 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 soothe it.

And if you had a bad day at work,

you might react very differently to it and scream at it.

And so that’s a generalization of the state

that was triggered at work

by something your boss said to you

to a completely different interaction.

And again, that’s something that distinguishes

emotion states from motivation states.

Motivation states are really specific.

Find and eat food, obtain and consume water,

and they’re involved in homeostatic maintenance.

So states are very multifaceted

and just asking questions

about how these components of states are encoded,

like what makes a state persist?

What gives a state a positive or a negative valence?

How do you crank up or crank down the intensity of the state?

It just opens up a whole bunch of questions

that you can ask in the brain

with the kinds of tools we have now.

You mentioned arousal a few times

and you mentioned valence.

Realizing that there are these other aspects of states,

I’d like to just talk about arousal a little bit more

and valence, because at a very basic level,

it seems to me that arousal,

we can be very alert and pissed off,

stressed, worried, you have insomnia.

We can also be very alert and be quite happy.

So the valence flips.

People can be sexually aroused,

people can be aroused in all sorts of ways.

Is there any simple or simple-ish neurochemical signature

that can flip valence?

So for instance, is there any way that we can safely say

that arousal with some additional dopamine release

is going to be of positive valence

and arousal with very low dopamine

is going to be of negative valence?

I would be reluctant to say that it’s a chemical flip.

I would say it’s more likely to be a circuit flip,

different circuits being engaged.

And it might be that a given neurochemical,

even dopamine, is involved

in both positively valenced arousal

and negatively valenced arousal.

That’s why people think about these as different axes.

So I think the interesting question that you touch on

is arousal something that is just completely generic

in the brain, or are there actually different kinds

of arousal that are specific to different behaviors?

And you raised the question,

sexual arousal feels different

from aggressive arousal, for example.

And we actually published a paper on this back in 2009

in Fruit Flies where we found some evidence

for two types of arousal states,

one of which is sleep-wake arousal.

You’re more aroused when you wake up

than when you’re asleep, and flies show that.

And the other is a startle response,

an arousal response to a mechanical stimulus,

a noxious mechanical stimulus.

If you puff air on flies,

kind of like trying to swat the wasp away

from your burger at the picnic table,

they come back more and more and more vigorously.

And we were able to dissect this and show

that although both of those forms

of arousal require dopamine,

they were exerted through completely separable

neural circuits in the fly.

And so that really put, number one,

the emphasis on it’s the circuit

that determines the type of arousal,

but also that arousal isn’t unitary,

that there are behavior-specific forms of arousal.

And I think the jury is still out

as to whether there is such a thing

as completely generalized arousal or not.

I think some people would argue there is,

but I think more attention needs to be paid

to this question of domain-specific

or behavior-specific forms of arousal.

Yeah, it’s a super interesting idea

because I always thought of arousal as along a continuum,

like you need to be in a panic attack

at the one end of the extreme, or you can be in a coma.

And then somewhere in the middle, you’re alert and calm.

But then this issue of valence really,

as you say, presents this opportunity

that really there might be multiple circuits

for arousal or multiple mechanisms

that would include neurochemicals

as well as different neural pathways.

So I’d like to talk a bit about a state,

if it is indeed a state, which is aggression.

Your lab’s worked extensively on this.

And if you would,

could you highlight some of the key findings there,

which brain areas that are involved,

the beautiful work of Dayu Lin and others in your lab,

that point to the idea

that indeed there are kind of switches in the brain,

but that thinking of switches for aggression

might be too simple.

How should we think about aggression?

And I’ll just sort of skew the question a bit more

by saying we see lots of different kinds of aggression.

This terrible school shooting down in Texas recently,

clearly an act that included aggression.

And yet you could imagine

that’s a very different type of aggression

than an all-out rage or a controlled aggression.

There’s a lot of variation there.

So what are your thoughts on aggression,

how it’s generated, the neural circuit mechanisms,

and some of the variation in what we call aggression?

Yeah, this is a great question.

And it’s a large area.

I would say that the, first of all,

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 it could reflect fear,

or it could reflect hunger if it’s predatory aggression.

And so this gets at the issue that you raised

of the different types of aggression that exist.

The work that Dayu did when she was in my lab

that really broke open the field

to the application of modern genetic tools

for studying circuits in mice

is that she found a way to evoke aggression in mice

using optogenetics to activate specific neurons

in a region of the hypothalamus,

the ventromedial hypothalamus, VMH,

which people had been studying and looking at for decades

following first the work of,

in cats, the famous Nobel Prize winning work of Walter Hess

and then followed by work done by Menno Crook

in the Netherlands in rats

where they would stick electrical wires into the brain

and send electric currents into the brain.

And they could trigger a placid cat

to suddenly bear its teeth, hiss,

and almost strike out at the experimenter.

And they could trigger rats to fight with each other.

And even 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 cat has its ears forward

and it’s like batting with its paw at a mouse-like object

like it wants to catch it and eat it.

So he already had at that stage some information

about segregation in the brain

of different forms of aggression.

So fast forward to 2008, 2009,

when Dayu came to the lab

and we had started working on aggression in fruit flies,

and I wanted to bring it into mice

so that we could apply genetic tools.

And we started by having Dayu,

who was an electrophysiologist,

just repeat the electrical stimulation

of the ventromedial hypothalamus in the mouse,

just like people had done in rats, in cats, in hamsters,

even in monkeys.

And she could not get that experiment to work

over 40 different trials.

It just didn’t work.

What she got instead was fear behaviors.

She got freezing, cornering, and crouching.

And finally, in desperation,

and we got a lot of input from Menno Crook on this,

he really was mystified.

Why doesn’t it work in mice?

We realized why there had been no paper

on brain-stimulated aggression in mice in 50 years

because the experiment doesn’t work.

And the one bit of credit I can claim there

is I convinced Dayu to try optogenetics

because it just had sort of come into use

deep in the brain from Carl Deisseroth and others’ work.

And I thought maybe because it could be directed

more specifically to a region of the brain

and types of cells than electrical stimulation,

it might work.

And Dayu said, never, never gonna work.

If it doesn’t work with electricity,

why should it work with optogenetics?

And the fact is that it did work,

and we were able to trigger aggression in this region

using optogenetic stimulation of ventromedial hypothalamus.

And in retrospect, I think the reason

that we were seeing all these fear behaviors

is because right at the upper part,

if you think of ventromedial hypothalamus

like a pear sitting on the ground,

the fat part of the pear near the ground

is where the aggression neurons are,

but the upper part of the pear has fear neurons.

And it could be because it’s so small in a mouse,

when you inject electrical current anywhere in the pear,

it flows up through the entire pear

and it activates the fear circuits

and those totally dominate aggression.

And so that’s why we were never able to see

any fighting with electrical stimulation.

Whereas when you use optogenetics,

you confine the stimulation just to the region

where you’ve implanted the channelrhodopsin gene

into those neurons.

And so in fast forward from that,

from a lot of work from Dayu now on her own at NYU

and with her postdoc, Anna Gret Falkner,

there is, as well as work of other people,

there’s evidence that the type of fighting

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.

And in more recent experiments,

if you activate those neurons

and the mouse has a chance to be

in one of two compartments in a box,

they will gravitate towards the compartment

where those neurons are activated.

It has a positive valence.

And when I went into this field and I was thinking,

well, what goes on in my brain and my body

when I’m furious?

It certainly doesn’t feel like a rewarding experience.

It’s not something that I would want to repeat

because it feels good when I’m in that state.

It doesn’t feel good at all when I’m in that state.

And it is still, I think, a mystery

as to where that type of aggression,

which is more defensive aggression,

the kind of aggression you feel if you’re being attacked

or if you’ve been cheated by somebody,

where that is encoded in the brain and how that works

still, I think, is a very important mystery

that we haven’t solved.

And predatory aggression, there has been some progress on.

So mice show predatory aggression.

They use that to catch crickets that they eat,

and that involves different circuits

than the ventromedial hypothalamic circuits.

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.

There’s a paper suggesting that there might be

a final common pathway for all aggression

in a region, which is one of my favorites.

It’s called the substantia innominata,

the substance with no name.

You know, I like these-

Anatomists are so creative.

Or the nucleus ambiguous, you know, or the zona inserta.

These are places that no one can think of what they are.

Anyhow, that might be a final common pathway

for predatory aggression and offensive

and defensive aggression, but it can be really hard to tell

just from looking at a mouse fight,

whether it’s engaged in offensive or defensive aggression.

And we’ve tried to take that apart

using machine learning analysis of behavior.

But in rats, for example, it’s much clearer

when the animal is engaged in offensive

versus defensive aggression.

They direct their bites at different parts

of the opponent’s body.

In particular.

Offensive aggression is flank directed.

Defensive aggression goes for the neck, goes for the throat.

I’ve seen some nature specials where,

in a very barbaric way, at least to me,

it seems like hyenas will try and go after

the reproductive axis.

They’ll go after testicles and penis,

and they basically wanna,

it seems they wanna limit future breeding potential.

Or create pain.

Right, or create pain, or both.

Yeah, I mean, in terms of offensive aggression

and your reflection that it doesn’t feel good,

I mean, I can say I know some people

who really enjoy fighting.

I have a relative who’s a lawyer.

He loves to argue and fight.

I don’t think of him as physically aggressive.

In fact, he’s not, but loves to fight

and loves to prosecute and go after people.

And he’s pretty effective at it.

I have a friend, former military special operations,

and very calm guy.

Had a great career in military special operations.

And he’ll quite plainly say, I love to fight.

It’s one of my great joys.

He really enjoyed his work.

And also respected the other side

because they offered the opportunity to test that

and to experience that joy.

So in a kind of bizarre way to somebody like me

who I’ll certainly defend my stance if I need to,

but I certainly don’t consider myself somebody

who offensively goes after people just to go after them.

There’s no quote unquote dopamine hit here.

Acknowledging that dopamine does many things, of course.

I have a couple of questions

about the way you described the circuitry.

I should say the way the circuitry is arranged.

And of course we don’t know

because we weren’t consulted at the design phase.

But 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 cheek to jowl

with the neurons that generate offensive aggression

of all things.

It’s like putting the neurons that control swallowing

next to the neurons that control vomiting.

It just seems to me that on the one hand,

this is the way that neural circuits are often arranged.

And yet to me, it’s always been perplexing

as to why this would be the case.

Yeah, I think that is a very profound question.

And I’ve wondered about that a lot.

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 to think about

who’s gonna be the alpha male 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 pre-existing cell populations,

that might be the way that those regions wound up

next to each other.

And developmentally, they start out

from a common pool of precursors

that expresses the same gene,

the fear neurons and the aggression neurons.

And then with development,

it gets shut off in the aggression neurons

and maintained in the fear neurons.

Now that view says, oh, it’s just an,

it’s an accident of evolution and development,

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 you think about it, if you think about it,

if offensive aggression is rewarding and pleasurable,

if you start to get really scared,

that tends to take the fun out of it.

And maybe these two regions are close to each other

to facilitate inhibition of aggression by 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, detonates 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.

And how that inhibition would work is not clear

because all these neurons are pretty much excitatory.

They’re almost all glutamatergic.

And so one of the interesting questions for the future

is how exactly does fear dominate over

and shut down offensive aggression in the brain?

How does that work?

Is it all circuitry?

Are there chemicals involved?

What’s the mechanism and when is it called into play?

But I think that’s the way I tend to think about

why these neurons are all mixed up together.

And it’s not just fight and freezing or fight and flight.

There are also metabolic neurons

that are mixed together in VMH as well.

Controlling body-wide metabolism?

Yeah, there are neurons there that respond to glucose.

When glucose goes up in your bloodstream,

they’re activated.

And VMH has a whole history in the field of obesity

because if you destroy it in a rat, you get a fat rat.

So the way most of the world thinks about VMH

is they think about, oh, that’s the thing

that keeps you from getting fat.

It’s the anti-obesity area.

But in the area of social behavior,

we see it as a center for control

of aggression and fear behaviors.

And again, why these neurons and these functions,

I like to call them the four Fs,

feeding, freezing, fighting, and mating,

that they all seem to be closely intermingled

with each other, maybe because crosstalk between them

is very important to help the animal’s brain

decide what behavior to prioritize

and what behavior to shut down at any given moment.

One of the things that we will do

is link to the incredible videos of these mice

that have selective stimulation of neurons in the VMH,

DIU’s and the other studies that you’ve done.

Whenever I teach, I show those videos at some point

with the caveats and warnings that are required

when one is about to see a video of a mouse

trying to mate with another mouse

or mating with another mouse.

And they seem both to be quite happy

about the mating experience,

at least as far as we know,

as observers of mice.

And then upon stimulation of those VMH neurons,

one of the mice essentially tries to kill the other mouse.

And then when that stimulation is stopped,

they basically go back to hanging out.

They don’t go right back to mating.

There’s some reconciliation clearly

that needs to happen first, we assume.

But it’s just so striking.

I think equally striking is the video

where the mouse is alone in there with the glove,

the VMH neurons are stimulated,

and the mouse goes into a rage.

It looks like it wants to kill the glove, basically.

So striking.

I encourage people to go watch those

because it really puts a tremendous amount of color

on what we’re describing.

And it’s just the idea that there are switches in the brain

to me really became clear upon seeing that.

One of the concepts, excuse me,

one of the concepts that you’ve raised

in your lectures before,

and that I think was Hess’s idea,

is this idea of a sort of hydraulic pressure,

or maybe it was Conrad, I can’t speak now, excuse me,

Conrad Lorenz, pardon,

who talked about a kind of hydraulic pressure

towards behavior.

I’m fascinated by this idea of hydraulic pressure

because I don’t consider myself a hot-tempered person,

but I am familiar with the fact that when I lose my temper,

it takes quite a while for me to simmer down.

I can’t think about anything else.

I don’t wanna think about anything else.

In fact, trying to think about anything else

becomes aversive to me,

which to me underscores this notion of prioritization

of the different states and potentially conflicting states.

What do you think funnels into this idea

of hydraulic pressure toward a state?

And why is it perhaps that sometimes we can be very angry

and if we succeed in winning an argument,

all of a sudden it will subside?

Because clearly that means that there are

external influences.

It’s a complex space here that we’re creating.

I realize I’m creating a bit of a cloud

and I’m doing it on purpose because to me,

the idea of a hydraulic pressure towards a state,

like sleep, there’s a sleep pressure.

There’s a pressure towards, that all makes sense.

But what’s involved?

Is it too multifactorial to actually separate out

the variables?

But what’s really driving hydraulic pressure

toward a given state?

Yeah, so really important question.

I think 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 need-based 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.

It’s 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.

I don’t think that’s how aggression works.

That is, it’s not that we all go around,

at least subjectively, I don’t go around

with an accumulating need to fight,

which I then look for something to,

an excuse to release it.

Now, maybe there are people that do that

and they go out and look for bar fights to get into.

Or Twitter.

Yeah, or Twitter.

Twitter seems to, I’m sort of half joking

because Twitter seems to draw a reasonably sized crowd

of people that are there for combat of some sort,

even though the total intellectual power

of any of their comments is about that of a cap gun,

they seem to really like to fire off that cap gun.

But I agree.

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Yeah, so 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 driver or pressure to do that.

And the natural way to think about that, at least for me,

is as a gradual increases in neural activity

in a particular region of the brain.

And so for example, in the area 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 that state is actually negatively valence.

So it’s like the animal, quote unquote,

feels increasingly uncomfortable,

just like we feel increasingly uncomfortable

the hungrier we are.

And then when we eat, it taps it down.

But there is this increased activity.

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.

And the interesting thing is that

if there is nothing for the animal to attack,

it doesn’t really do much

when you’re stimulating this region.

It sort of wanders around the cage a little bit more,

but it will not actually show overt attack

unless you put something in front of it.

And the same thing is true for the areas

we’ve described that control mating behavior.

This is what Lindsey is working on.

You can stimulate those areas till you’re blue in the face

and the mouse just sort of wanders around.

But if you put another mouse in, wham,

he will try to mount that mouse.

If you put a kumquat in the cage,

he’ll try to mount the kumquat.

And so it becomes a sort of any port in the storm.

So there is this idea that the drive is building up pressure

that somehow needs to be released

where that pressure is actually being exerted.

If you accept that it’s increased activity

in some circuit or circuits someplace,

what is it pushing up against that needs something else

to sort of unplug it in the Lorentz hydraulic model?

That is, you don’t see the behavior

until you release a valve on this bucket

and let the accumulated pressure flow out.

And that’s one of the things we’re trying to study

in the context of the mating behavior as well.

How does the information that there’s an object

in front of you come together with this drive state

that is generated by stimulating these neurons

in the hypothalamus to say, okay, pull the trigger and go.

It’s time to mate, it’s time to attack.

And we’re just starting to get some insights into that now.

Fascinating.

And I should mention people, Dr. Anderson mentioned Lindsey.

Lindsey is a former graduate student of mine

that’s now a postdoc in David’s lab.

And I haven’t caught up with her recently

to hear about these experiments, but they sound fascinating.

I would love to spend some time on this issue

of why is it that a mouse won’t attack nothing,

but it’ll attack even a glove.

And why, well, it will only try and mate

if there’s another mouse to mate with.

It’s actually, I think fortunately for you,

you’re not spending a lot of time

on Twitter and Instagram or YouTube,

but there’s this whole online community that exists now.

As far as I know, it’s almost exclusively young males

who are obsessed with this idea.

I’ll just say it has a name,

it’s called NoFap of No Masturbation

as a way to maintain their motivation

to go out and actually seek mates

because of the ready availability of online pornography.

There’s probably a much larger population of young males

that are never actually going out and seeking mates

because they’re getting porn addicted, et cetera.

This is actually a serious issue that came up in our episode

with Anna Lemke, who wrote the book,

“‘Dopamine Nation’,”

because the availability of pornography,

there’s a whole social context

that’s being created around this and genuine addiction.

So humans are not like the mice

or mice are not like the humans.

Humans seem to resolve the issue on their own

in ways that might actually impede

seeking and finding of sexual partners

and or long-term mates.

So serious issue there.

I raise it as a serious issue that I hear a lot about

because I get asked hundreds,

if not thousands of questions about this.

Is there any physiological basis for what they call NoFap?

And I never actually reply because there’s no data,

but what you’re raising here

is a very interesting mechanistic scenario

that can, as you mentioned, is being explored.

So what do we know about the internal state of a mouse

whose VMH is being stimulated

or a mouse whose other brain region

that can stimulate the desire to mate?

What do we know about the internal state of that a mouse

if it’s just alone in the cage wandering around?

Is it wandering around really wanting to mate

and really wanting to fight?

We of course don’t know, but is its heart rate up?

Is its blood pressure up?

Is it wishing that there was pornography?

Is it something’s going on presumably

that’s different than prior to that stimulation

and is it arousal?

And what do you think it is about the visual

or olfactory perception of a conspecific

that ungates this tremendous repertoire of behaviors?

Right, that is the central question.

I can say, at least with respect to the fear neurons

that sit on top of the aggression neurons,

we know that when those neurons are activated optogenetically

in the same way we would activate the aggression neurons,

that there’s clearly an arousal process that’s occurring.

You can see the pupils dilate in the animal.

There is an increase in stress hormone release

into the bloodstream.

We’ve shown that heart rate goes up.

So in addition to the drive to actually freeze,

which is what those animals do,

there is autonomic arousal and neuroendocrine activation

of stress responses.

And some of that is probably shared by the aggression neurons

and the mating neurons,

although we haven’t investigated it in as much detail.

But I wouldn’t be surprised because they project

to many of the same regions that the fear neurons project to,

which is a interesting issue in the context

to discuss later maybe in the context

of why we’re comfortable with mental illnesses

that are based on maladaptations of fear,

but not mental illnesses that are based

on maladaptations of aggression

if they have pretty similar circuits in the brain.

But that’s how I would imagine

there is an arousal dimension, as you say.

There are stress hormones that are activated.

These regions, 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, mechanosensation,

and then it sort of synthesizes and integrates that

into a fairly low dimensional,

as the computational people call it,

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 gonna 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 so its brain constantly has

to make a cost-benefit analysis

of whether to continue on that path

or to back off as well.

And I think that part of this broadcasting function

of this region is engaging all these other brain domains

that play a role in this kind of cost-benefit analysis.

I wanna talk more about mating behavior,

but as a segue to that,

as we’re talking about aggression and mating behavior,

I think hormones.

And whenever there’s an opportunity on this podcast

to shatter a common myth, I grab it.

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,

although there’s some truth to the idea

that these hormones are all involved.

Robert Sapolsky supplied some information to me

when he came on this podcast

that if you give people exogenous testosterone,

it tends to make them more of the way they were before.

If they were a jerk before, they’ll become more of a jerk.

If they were very altruistic, they’ll become more altruistic.

And then eventually I pointed out,

you’ll aromatize that testosterone and estrogen

and you’ll start getting opposite effects.

So it’s a murky space.

It’s not straightforward.

But if I’m not mistaken,

testosterone plays a role in generating aggression.

However, the specific hormones that are involved

in generating aggression via VMH

are things other than testosterone.

Can you tell us a little bit more about that?

Because there’s some interesting surprises in there.

Yeah, that’s a really important question.

So 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.

So that might strike you as a little strange.

Why should aggression-promoting neurons in male mice

be labeled with 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,

Nirav Shah at Stanford,

who was one of my former PhD students,

that if you castrate a mouse

and it loses the 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 adjuvant chemotherapy for breast cancer.

They are a way of reducing the production of estrogen

by preventing testosterone

from being converted into estrogen.

And in fact, there are a lot of animal experiments

showing if you give males aromatase inhibitors,

they stop fighting

as well as also stop being sexually active.

And so that’s one of the counterintuitive ideas.

And Nirao has shown that progesterone

also seems to play a role in aggression

because these aggression neurons

also express the progesterone receptor.

So here are two hormones that are classically thought of

as female reproductive hormones.

This is what goes up and goes down during the estrous cycle,

estrogen and progesterone.

And yet they’re playing a very important role

in controlling aggression in male mice

and presumably in male humans as well.

Fascinating.

So estrogen is doing many more things

than I think most people believe in.

Testosterone is doing maybe different

and fewer things in some cases and more in others.

I’ve known some aggressive females

over the time I’ve been alive.

What’s involved in female aggression

that’s unique from the pathways

that generate male aggression?

Great, great question.

So we and other labs have studied this

in both mice and also in fruit flies.

So one thing in mice

that distinguishes aggression in 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 hyper aggressive.

And then 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.

So there is some presumably hormonal

and also neuronal switch that’s occurring in the brain

that switches the response of the female

from sex to aggression

when she goes from virginity to maternity.

And we recently showed in a paper,

this is work from one of my students,

Mengyu Liu,

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.

And in fact,

if you stimulate the fighting specific subset in a virgin,

you can get the virgin to attack,

which is something that we were never able to do before.

And if you stimulate the mating one,

you enhance mating.

The reason we could never get these results

when we stimulated the whole population

of estrogen receptor neurons

is that these effects are opposite and they cancel out.

And so it turns out that if you measure the activity

of the fighting and the mating neurons

going from a virgin to a maternal female,

the aggression neurons are very low

in their activity in the virgin.

But once the female has pups,

the activation ability of those neurons goes way up

and the mating neurons stay the same.

So if you think of the balance between them like a seesaw,

in the virgin,

there is more activity in the mating neurons

than in the fighting neurons.

Whereas in the nursing mother,

there’s more activity or more activation

in the other way around,

the fighting neurons and the mating.

Did I say fighting and mating the first?

Mating neurons dominate fighting.

In the virgin, fighting neurons dominate mating

in the mother.

So that’s a really cool observation

and it’s not something that happens in males.

And we don’t know what causes that or controls that.

Interestingly, this gets into the whole issue

of neurons that are present in females, but not in males.

So we’ve known for, the field has known for a long time

that male and female fruit flies have sex specific neurons.

And most of the neurons that we’ve identified

in fruit flies that control fighting in males

are male specific.

They’re not found in the female brain,

but recently we discovered a set of female specific

fighting neurons in the female brain,

together with a couple of other laboratories.

Now they do share one common population of neurons

in both male and female flies that in females activates

the female specific fighting neurons

and in males activates the male specific fighting neurons.

So it’s kind of a hierarchy with this common neuron on top.

And in mice, we discovered that there are

male specific neurons in VMH

and those neurons are activated during male aggression.

Now the neurons that are active in females,

when females fight in VMH are not sex specific.

So they are also found 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.

I’m fixated on this transition from the virgin female mouse

to the maternal female mouse.

I have a couple of questions about whether or not,

for instance, the transition is governed

by the presence of pups.

So for instance, if you take a virgin female,

she’ll mate with a male.

Once she’s had pups, she’ll try and fight that male

or presumably another intruder female, right?

Equally towards females and male intruders.

Does that require the presence of her pups?

Meaning if you were to take those pups

and give them to another mother,

it does she revert to the more virgin like behavior?

Is it related to, is it triggered by lactation

or could it actually be triggered

by the mating behavior itself?

Cause it’s possible for the virgin to become a non-virgin,

but not actually have a litter of pups.

Right.

Those are all great questions.

And we don’t know the answer to most of them.

What I can say is that a nursing mother

doesn’t have to have her pups with her in the cage

in order to attack an intruder male or an intruder female.

She is just in a state of brain

that makes her aggressive to any intruder.

And those aggression neurons in that female’s brain

are activated by both male and female intruders equally.

Whereas in male mice,

the aggression neurons are only ever activated by males,

not by females,

because males are never supposed to attack females.

They’re only supposed to mate with them.

So that’s another difference in how those neurons

are tuned to signals from different conspecifics.

Does it require lactation?

I don’t know the answer to that.

I think there are some experiments

where people have tried to, classical experiments,

people have tried to reproduce the changes in hormones

that occur during pregnancy in female rats

to see if it can make them aggressive.

And some of those manipulations do to some extent,

but there’s a whole biology there

that remains to be explored

about how much of this is hormones,

how much of this is circuitry and electricity,

and how much of it is other factors

that we haven’t identified yet.

I don’t want to anthropomorphize,

but well, I’ll just ask the question.

So the other day I was watching ferrets mate, right?

The mustelids, they’re mustelids and they’re mating behavior.

I guess I didn’t say why I was watching this.

Doesn’t matter.

It simply doesn’t matter.

But if one observes the mating behaviors

of different animals,

we know that there’s a tremendous range

of mating behaviors in humans.

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.

And here I always say on this podcast,

anytime we’re talking about sexual behavior in humans,

we’re always making the presumption

that it’s consensual, age appropriate,

context appropriate, and species appropriate.

Let’s say we’re talking about a lot of different species.

With that said, just to set context,

I was watching this video of ferrets mating,

and it’s quite violent, actually.

There’s a lot of neck biting.

There’s a lot of squealing.

If I were gonna project an anthropomorphize,

I’d say it’s not really clear they both want to be there.

You would just, one would make that assumption.

And of course we don’t know.

We have no idea.

This could be the ritual.

It seems to me that there is some crossover

of aggression and mating behavior circuitry

during the act of the mating.

And do you think that reflects this sort of

stew of competing neurons

that are prioritizing in real time?

Because of course, as states, they have persistence,

as you point out, and you can imagine

that states overlapping, four different states,

the motivational drive to mate,

the motivational drive to get away from this experience,

the motivational drive to eat at some point,

to defecate at some point,

all of these things are competing.

And what we’re really seeing is a bias in probabilities.

But 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 is crosstalk

between these different neuronal populations

and the animal itself might be kind of confused

about what’s going on?

Right, great, great questions.

I can’t really speak to the issue

of whether this is species specific

because I’m not a naturalist or a zoologist.

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.

Now, you don’t generally think of mouse sex as rough sex,

but there is a lot of what superficially looks

like violent behavior sometimes,

especially if the female rejects the male and runs away.

And 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.

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 in the brain.

And we’ve shown that some of those connections

are mutually inhibitory to prevent the animal

from attacking a mate that it’s supposed to be mating with

or to prevent it from mating

with an animal it’s supposed to be attacking.

But it’s also possible

that there are some cooperative interactions

between those structures

as well as 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 moment

of coital 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.

I’m sure people’s minds are running wild with all this.

I’ll just use this as an opportunity

to raise something I’ve wondered about for far too long,

which is I have a friend who’s a psychiatrist

who works on the treatment of fetishes.

This is not a psychiatrist that I was treated by.

I’ll just point that out.

But they mentioned something very interesting to me long ago

which is that when you look at true fetishes

and what meets the criteria for fetish,

that there does seem to be some,

what one would think would be competing circuitry

that suddenly becomes aligned.

For instance, avoidance of feces, dead bodies, feet,

things that are very infectious.

Typically, those states of disgust

are antagonistic to states of desire

as one would hope is present during sexual behavior.

Fetishes often involve exactly those things

that are aversive, feet, dead bodies,

disgusting things to most people.

And true fetishes in the pathologic sense

exist when people have basically a requirement

for thinking about or even the presence

of those ordinarily disgusting things

in order to become sexually aroused.

As if the circuitry has crossed over.

And the statement that rung in my mind

was people don’t develop fetishes to mailboxes

or to the color red or to random objects and things.

They develop fetishes to things that are highly infectious

and counter reproductive appetitive states.

So I find that interesting.

I don’t know if you have any reflections on that

as to why that might be.

I’m tempted to ask whether or not you’ve ever observed

fetish-like behavior in mice,

but I find it fascinating that you have this area

of the brain that’s so highly conserved,

the hypothalamus,

which you have these dense populations intermixed

and that the addition of a forebrain,

especially in humans that can think and make decisions

could in some ways facilitate

the expression of these primitive behaviors,

but could also complicate

the expression of primitive behaviors.

Right.

I would agree.

I think one way of looking at fetishes

from a neurobiological standpoint

is that they represent a kind of appetitive conditioning

where something that is natively aversive or disgusting

by being repeatedly paired with a rewarding experience

changes its valence, its sign,

so that now it somehow produces the anticipation of reward

the next time a person sees it.

Now, I don’t know that literature in animals,

so I don’t know if you could condition a mouse

to eat feces, for example,

although there are animals that are naturally coprophagic.

That is, and maybe mice do that occasionally.

I’m not sure, but that is one way to think about it.

And that could certainly involve in humans,

the more recently evolved parts of the brain,

the cortex that is sort of orchestrating

both what behaviors are happening

and whether reward states are turning on

in association with those behaviors that are happening.

And that’s the part that I think is difficult

and challenging to study in a mouse,

but certainly bears thinking about

because it’s a really interesting,

again, sort of counterintuitive aspect,

again, like rough sex,

people that want to have fighting or violence

or aggressiveness in order to be sexually aroused

and fetishes.

And in fact, when we made that discovery initially,

it raised the question in my mind

whether some people that are serial rapists, for example,

and engage in sexual violence

might in some level have their wires crossed in some way

that these states that are supposed to be

pretty much separated and mutually antagonistic are not

and are actually more rewarding and reinforcing.

I think it’s gonna be a long time

before we have figured it out.

But when you think about it,

there is no treatment that we have

for a violent sexual offender that eliminates the violence,

but not the sexual desire and sexual urge.

Whether it’s physical castration or chemical castration,

it eliminates both.

Definitely an area that I think,

well, human neuroscience in general

needs a lot of tools, right?

In terms of how to probe and manipulate neural circuitry.

I’d love to turn to this area that you mentioned,

the medial preoptic area.

I’m fascinated by it because just as within the VMH,

you have these neurons for mating and fighting

or aggression.

My understanding is medial preoptic area

contains neurons for mating,

but also for temperature regulation.

And perhaps I’m making too much of a leap here,

but I’ve always wondered about this phrase in heat.

As certainly the menstrual and,

or estrous cycle in females

is related to changes in body temperature.

In fact, measuring body temperature is one way

that women can fairly reliably predict ovulation, et cetera.

Although additional,

this is not a show about contraception.

Please rely on multiple methods as necessary.

Don’t use this discussion

as your guide for contraception based on temperature.

But if you stimulate certain neurons

in the medial preoptic area,

you can trigger dramatic changes in body temperature

and or mating behavior.

What’s the relationship, if any,

between temperature and mating,

or do we simply not know?

I don’t know what the relationship is

between temperature and mating neurons

in the preoptic area.

I suspect that they are different populations of neurons

because it’s become pretty clear

that the preoptic area has many different subsets

of neurons that are specifically active

during different behaviors,

even different phases of mating behavior.

So there are mounting neurons,

there are intermission thrusting neurons

and ejaculation neurons and sniffing neurons.

Wait, wait.

So I think I’ve heard this before,

but I just want to make sure that people get this.

I want to make sure I get this.

So you’re telling me within medial preoptic area,

there are specific neurons that if you stimulate them

will make males thrust as if they’re mating?

No.

So this is not based on stimulation experiments.

It’s based on imaging experiments right now

that we see when we look in the preoptic area

at what neurons are active

during different phases of aggression.

We see that there are different neurons

that are active during sniffing,

mounting, thrusting, and ejaculation,

and they become repeatedly activated

each time the animal goes through that cycle.

During mating.

During the mating cycle.

There are also some neurons there

that are active during aggression, which are distinct.

And we don’t know whether those neurons are there

to promote aggression or to inhibit mating

when animals are fighting.

We have some evidence that suggests it may be the latter,

but we don’t know for sure yet.

The thermosensitive neurons are really interesting

because you mentioned the phrase in heat,

and then in the context of aggression,

you talk about hot-blooded people or hotheads.

There’s just recently a paper showing

there are thermoregulatory neurons in VMH as well.

So all of these homeostatic systems for metabolic control

and temperature control are intermingled in these nuclei,

these zones that control these basic survival behaviors

like mating and aggression and predator defense.

And I would imagine that the thermoregulation

is tightly connected to energy expenditure,

and that, again, these neurons are mixed together

to facilitate integration of all these signals by the brain

in some way that we don’t understand

to maintain the proper balance between energy conservation

and energy consumption during this particular behavior

or that behavior.

I mean, I’ve always been fascinated by the question,

why is it that violence goes up in the summertime

when the temperatures are high?

Does it really have something to do with the idea

that increased temperature increases violence?

It seems hard to believe because we’re homeothermic

and we pretty much stay around 98.6 Fahrenheit.

Could be other social reasons why that happens.

People are outside out on the street

bumping into each other.

But I think there could well be something

that ties thermoregulation to aggressiveness

as well as to mating behavior.

Fascinating, yeah.

I asked in the hopes that maybe in the years to come,

your lab will parse some of the temperature relationships.

And I realized it could be also regulated by hormones

in general, so it’s tapping into two systems

for completely different reasons.

But anyway, an area that intrigued me

because of this notion of hotheadedness

or cool, calm, and collected.

And also the fact that,

I probably should have asked about this earlier,

that arousal itself is tethered

to the whole mating and reproductive process.

I mean, without a sort of seesawing back

between the sympathetic and parasympathetic,

arousal relaxed states,

there is no mating that will take place.

So it’s fascinating the way these different

competing forces and seesaws operate.

Several times during the discussion so far,

we’ve hit on this idea that the same behavior

can reflect different states

and different states can converge

on multiple behaviors as well.

You had a paper not long ago about mounting behavior,

which I found fascinating.

Maybe you could tell us about that result.

Because to me, it really speaks to the fact

that mounting behavior can, in one context, be sexual,

and in another context actually be related

to, we presume, dominance.

And I think that my friends who practice jujitsu

will say, when I talk about that result,

they say, of course,

mounting the other person and dominating them,

there’s nothing sexual about it.

It’s about overtaking them physically,

literally being on their next side

as opposed to lying on their own back.

It’s fascinating, very primitive,

and yet I think speaks to this idea

that mounting behavior might be one

of the most fundamental ways in which animals

and perhaps even humans express dominance

and or sexual interactions.

Yep, that’s a fascinating question.

And it was harder to figure out than you might’ve thought.

So there’s been this debate for a long time

in the field when you see two male mice

mounting each other, is this homosexual behavior?

Is this a case of mistaken sexual identification?

Or is this dominance behavior?

And if you train an AI algorithm

to try to distinguish male-male mounting

from male-female mounting, it does not do a very good job

because motorically, those behaviors look so similar.

And so how did we wind up figuring out

that most male-male mounting is dominance mounting?

There are two important clues.

One is the context.

And so male-male mounting tends to be more prominent

among mice when they haven’t had a lot

of fighting experience.

And then as they become more experienced in fighting,

they will show relatively less mounting

towards the other male and more attack.

And they’ll transition quickly from mounting to attack.

And so the mounting is always seen in this context

of an overall aggressive interaction.

And then the second thing, which believe it or not

was suggested by a computational theoretical person

in my lab, Ann Kennedy,

who now has her own lab at Northwestern.

She said, well, males are known to sing

when they mount females, ultrasonic vocalizations.

Why don’t you see what kinds of songs they’re singing

when they’re mounting males?

Maybe it’s a different kind of song.

Well, what we found out is they don’t sing at all

when they’re mounting a male.

So you can easily distinguish whether mounting behavior

by a male mouse is reproductive or agonistic,

aggressive, according to whether it’s accompanied

by ultrasonic vocalizations or not.

And it turns out that different brain regions

are maximally active

during these different types of mounting.

So VMH, the aggression locus,

is actually active during dominance mounting,

and you can stimulate mounting if you,

dominance mounting, if you weakly activate VMH.

Whereas MPOA is most strongly activated

during sexual mounting,

and that’s always accompanied

by the ultrasonic vocalization.

So this shows how difficult and dangerous it can be

to try to infer an animal’s state or intent or emotion

from the behavior that it’s exhibiting,

because the same behavior can mean very different things,

depending on the context

of the interaction with the animal.

And I would say even more so with when that animal

is a human or is multiple humans.

That’s right.

And there are many examples.

Animals show chasing to obtain food,

a prey animal that they’re gonna kill and eat,

and they show chasing to obtain a mate

that they’re gonna have sex with.

And so the intent of the chasing is completely different.

And we don’t know in all these cases

whether there are separate circuits

or common circuits that are being activated.

I’m obsessed with dogs and dog breeds and et cetera, et cetera.

And one thing I can tell you

is that female dogs will mount and thrust.

We had a female pit bull mix, a very sweet dog,

but in observing her, it convinced me

that one can never assume that male dogs

are more aggressive than female dogs.

It turns out in talking to people

who are quite skilled at dog genetics and dog breeding,

that there’s a dominance hierarchy within a litter,

and it crosses over male-female delineations.

So you can get a female in the litter

that’s very dominant, a male that’s very subordinate,

and no one really knows what relates to.

This is also why little dogs sometimes

will get right up in the face of a big Doberman Pinscher

and just start barking,

which is an idiotic thing for it to do,

but they can be dominant over a much larger dog.

Very strange to me anyway.

Female-female mounting, do you observe it in mice?

Are there known circuits?

And what evokes female-female mounting,

or female-to-male mounting, if it occurs?

Good.

Yes, there is female.

There are clear examples of females

displaying male-type mounting behavior

towards other females.

We see this most commonly in the lab

where we are housing females with their sisters,

say three or four in a cage.

We take one out and we have her mate with a male

where the male’s doing the mounting.

Now we take that female and we put her back in the cage

with her litter mates and she starts mounting them.

Now what the function of that is,

if it has any function, or what it means,

what’s driving it, we don’t know.

But we do know that if we stimulate

the neurons that control mounting in males

in the medial preoptic area,

if we stimulate that same population in females,

it evokes male-type mounting

towards either a male or a female target.

In fact, we have a movie where we have a female

that has just been mounted by a male,

so the male’s on top and she’s underneath,

and we stimulate that region of MPOA in the female,

and she crawls out from underneath the male

who has just mounted her, circles around behind him,

and climbs up on top of him,

and starts to try to mount him and thrust at him.

That has a name online, it’s called a switch.

Is that right?

Don’t ask me how I know that.

Okay.

But it’s a pretty, yeah, it’s a term that you hear.

You also hear the term topping from the bottom,

which it sounds like that is a literal topping

from the bottom. I see.

That’s more of a psychological phrase from what I hear.

I have friends that are educating me in this language,

mostly because I find this kind

of neurobiological discussion fascinating.

At some point, right, I attempt in my mind

to superimpose observations from the online communities

that I’m told about and asked about to this,

but I should point out it’s always dangerous,

and in fact, inappropriate to make a one-to-one link.

Humans are, they maintain all the same neural circuitry

and pathways that we’re talking about today in mice,

but that forebrain does allow for context, et cetera.

Yep.

So what the function is of female mounting, I don’t know.

It could be a type of dominance display.

It’s hard to measure that because people haven’t worked

on female dominance hierarchies to the same extent

that they’ve worked on male dominance hierarchies,

but it indicates that the circuits

for male type mounting are there in females

as early work from Catherine Duloc suggested some years ago.

Fascinating, fascinating.

I love that paper because as you pointed out for chase,

for mounting behavior, we see it

and we think one thing specifically.

And after hearing this result,

actually, I’m not a big fan of fight sports.

I watch them occasionally because friends are into them,

but I’ve seen boxing matches, MMA matches,

where at the end of a round,

if someone felt that they dominated,

they will do the unsportsmanlike thing of thrusting

on the back of the other person before they get off,

almost like I dominated you.

And so mimicking sexual-like behavior,

but there’s no reason to think that it’s sexual,

but they’re sending a message of dominance is what implies.

I’d love to talk about something slightly off

from this circuitry, but I think that’s related

to the circuitry, at least in some way,

which is this structure that I’ve always been fascinated by

and I can’t figure out what the hell it’s for

because it seems to be involved in everything,

which is the PAG, the periaqueductal gray,

which is a little bit further back in the brain

for people that don’t know.

It’s been studied in the context of pain.

It’s been studied in the context

of the so-called lordosis response,

the receptivity or arching of the back of the female

to receive intromission and mating from the male.

How should we think about PAG?

Clearly it can’t be involved in everything.

I’m guessing it’s at least as complex

as some of these other regions that we’ve been talking about,

different types of neurons controlling different things,

but how does PAG play into this?

In particular, I wanna know,

is there some mechanism of pain modulation and control

during fighting and or mating?

And the reason I ask is that,

while I’m not a combat sports person,

years ago I did a little bit of martial arts

and it always was 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 endogenous pain control

that then wears off and then you feel beat up.

At least in my case, I felt beat up.

What’s PAG doing vis-a-vis pain

and what’s pain doing vis-a-vis these other behaviors?

Good, good.

So I think of PAG like a old-fashioned term

telephone switchboard, where 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.

And there’s a whole literature showing the involvement

of the PAG in fear, different regions of the PAG,

the dorsal PAG is involved in panic-like behavior,

running away, the ventral PAG is involved

in freezing behavior.

Both the MPOA and VMH send projections to the PAG

to different regions of the PAG.

So in cross-section, I hate to say this,

but 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 one to 12,

maybe even more of them.

And in each of those sectors, you find different neurons

from the hypothalamus are projecting.

So could turn out that there is a topographic arrangement

along the dorsal ventral axis of the PAG

and the medial lateral 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 fear-induced analgesia,

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 medulla,

which controls the fight or flight responses,

and that peptide has analgesic activities.

Now, whether- Ask what that peptide is.

It’s called bovine adrenal medullary 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 analgesic.

Whether this is happening,

this type of analgesia 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 analgesic 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.

Sure, we appreciate those delineations.

Thank you.

A PAG, I think this description of it

is an old-fashioned telephone switchboard.

And now every time I look into the toilet,

I’ll think about the periaqueductal gray.

And every time I see an image of periaqueductal gray,

I think about a toilet.

That is an excellent description

because in fact, I drew a circle

with a little thing at the bottom.

Well, I’ll put a post or link to a picture of PAG

and you’ll understand why David and I are chuckling here

because indeed it looks like a toilet

when staring into a toilet.

Tell us about tachykinin.

I’ve talked about this a couple of times

on different podcast episodes

because of its relationship to social isolation.

And in part, because the podcast was launched

during a time when there was more social isolation.

My understanding is that tachykinin,

and you’ll tell us what it is in a moment,

is present in flies and mice and in humans

and may do similar things in those species.

That’s right.

So tachykinin 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.

Tachykinins have been famously implicated in pain,

particularly tachykinin-1, which is called substance P,

one of the original pain modulating.

This is something that promotes inflammatory pain,

but there are other tachykinin genes.

In mice, there are two.

In humans, I think there are three.

And in Drosophila, there’s one.

And the way we got into tachykinins

is from studying aggression in flies.

We thought since neuropeptides have this remarkable

parallel evolutionary conservation of structure

and function, like neuropeptide Y controls feeding

in worms, in flies, and mice, and in people.

Oxytocin-like peptides control reproduction

in worms and mice and in people.

We thought we might find peptides that control aggression

in flies and in people.

And so we did a screen, unbiased screen of peptides

and found indeed that one of the tachykinins,

Drosophila tachykinin, those neurons,

when you activate them, strongly promote aggression.

And it depends on the release of tachykinin.

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 tachykinin 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 tachykinins

might be upregulated in social isolation

and whether they play a role in aggression.

And this is work done by a former postdoc,

Muriel Zelikowski, 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 tachykinin-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 tachykinin

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 tachykinin, 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 Muriel described it, the mice just look chill.

It’s not a sedative, 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 Osanatant

that blocks tachykinin 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.

And this is one of the areas where I learned

an eye-opening lesson as a basic scientist

who naively thought that if you make a discovery

and it has translational applications to humans

that pharmaceutical companies

are gonna be falling all over themselves to try it.

And they’re not interested because once burned, twice shy.

These drugs were tested for efficacy in schizophrenia.

I have no idea why.

There’s very little preclinical data to suggest that.

Not surprisingly, they failed.

When a drug fails in clinical trials in phase three,

it costs $100 million to the company

that carried out that clinical trial.

So there’s a huge slag heap of discarded pharmaceuticals,

many of them inhibitors of neuropeptide action

that could be useful in other indications

such as the one we discovered,

but there’s a huge economic disincentive

for pharmaceutical companies to test them again

because the conclusion that they drew

from all these failed tests,

particularly in the 2010s and before that,

is that the reason they failed

is because animal experiments with drugs

don’t predict how humans will respond to the drugs.

And therefore, we shouldn’t try to extrapolate

from any other data that we get from animal experiments,

mouse or rat experiments to humans

because they’ll lead us down the wrong track.

And I think that that is probably wrong.

In some cases, it may be right,

but in other cases, there’s good reason to think

because these brain regions and molecules

are so evolutionarily conserved

that they ought to be playing a similar role in humans.

In fact, there is a paper showing

that in humans that have borderline personality disorder,

there’s a strong correlation

between their self-reported level of aggressiveness

and serum levels of a tachykinin,

in this case, tachykinin-1,

as detected by radioimmunoassay.

This is work of Emil Coccaro,

who’s a clinical psychiatrist at the University of Chicago.

So there is a smoking gun in the case of humans as well.

And I was actually trying to interest

a pharmaceutical company that was testing these drugs,

actually, for treatment of hot flashes in females,

in humans, where there is actually good animal data

to think that it might be useful.

But I realized that this clinical trial

was going on during the COVID pandemic.

And I approached him and said,

look, nature may have actually done for you

the experiment that I want you to do

because some of the people who are getting drug or placebo

are gonna have been socially isolated,

and some of them will have not.

Why don’t you get them to fill out questionnaires

and see whether the ones who were given the drug

and socially isolated felt less stressed and less anxious

than the ones who were not socially isolated,

and they would not touch it

because they’re in the middle of a clinical trial

for a different indication for this drug,

and they have to report any observation

that they make about that drug in their patient population.

So if they were to ask these questions

and get an unfavorable answer,

oh my God, I felt even worse when I took this drug

and I was isolated,

they would be obliged to report that to the FDA,

and that could torpedo the chances

for the drug being approved

in the thing that it was in clinical trials for.

So it’s better not to ask and not to know

than it is to try to find out more information

that could lead to another clinical indication.

So I remain convinced that this family of drugs

could have very powerful uses in treating some forms

of stress-induced anxiety or aggressiveness in humans,

but it’s just very difficult for economic reasons

to find a way to get somebody to test that.

Yeah, a true shame that these companies won’t do this,

and especially given the fact

that many of these drugs exist

and their safety profiles are established,

because that’s always a serious consideration

when embarking on a clinical trial.

Perhaps in hearing this discussion,

someone out there will understand

the key importance of this and will reach out to us,

will provide ways to do that

to get such a study going in humans.

Because I think if enough laboratories

ran small-scale clinical trials,

pharma certainly would perk up their ears, right?

I mean, they’re so strategic sometimes to their own.

I mean, I would like to say also,

I’d like to see this tested on pets.

I mean, there’s a huge number of pets right now

that are suffering separation anxiety

because humans bought them to keep them company

during the COVID pandemic.

And now they’re home alone.

And now they’re home alone, okay?

And if this thing works in mice,

there’s certainly a higher chance

it’s gonna work in dogs or in cats

than it is gonna work in humans.

And if it did, that would be even more encouragement

to continue along those lines.

People sometimes forget that although we work on animals

and we ultimately wanna understand humans,

we care about how our results apply

to the welfare of animals as well,

and particularly domestic pets,

which is a multi-billion dollar industry in this country.

So if there’s ways that they can be made to feel better

when they’re separated from their owners,

that would certainly be a good thing.

Absolutely.

We will put out the call.

We are putting out the call.

And I know for sure there will be a response.

And just underscoring what we’ve been talking about

even more, every time we hear about a school shooting,

like in Texas recently,

or I happened to be in New York

during the time when there was a subway shooting,

for whatever reason, I listened to the book about Columbine

that went into a very detailed way

about the origin of those boys and that committed that.

And every single time there’s the person

who commits those acts is socially isolated.

As far as I know, there might be some exceptions there.

And sometimes this crosses over

with other mental health issues,

but sometimes no apparent mental health issues.

So social isolation clearly drives powerful neurochemical

and neurobiological changes.

I really hope that tachykinin 1 and 2,

those are the main ones in humans,

will be explored in more detail.

Also, I didn’t know that tachykinin 1 is substance P

and substance P is tachykinin 1.

Tachykinin 1 is the gene name,

and tachykinin 2 in humans is called neurokinin B.

That’s the name of the protein.

I just refer to it by the gene name

because it makes it easier,

and I don’t have to keep remembering

two names for each thing.

And if I’m not mistaken,

you put yourself in the company of geneticists

because of your original training

was in genetics, immunology, and areas related to that.

It was in cell biology,

and I didn’t actually have formal training in genetics

as a graduate student,

but I think I’m a geneticist at heart.

That’s just the way I like to think about things.

And when I started working on flies,

that sort of, I came out of the closet

as a geneticist, as it were.

Wonderful.

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 Adolphs.

You have this new book, which we’ll provide a link to,

which I’ve read front to back twice.

It’s phenomenal.

I’ve mentioned it before on the podcast.

It’s really, 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,

and neuroscientists should read and understand the contents

because we, as a culture, are way off

in terms of how we think about emotions

and states and behaviors.

So we’ll put a link to that.

It’s really worth the time and energy to read it.

And it’s written beautifully, I should say.

Very accessible, even for non-scientists.

There’s a heat map diagram in that book

that I think about.

This is a heat map diagram of subjective reports

that people gave of where they experience an emotion

or a feeling, a somatic feeling in their body

or in their head, or both, when they are angry, sad,

calm, lonely, et cetera, et cetera.

And I wouldn’t want people to think

that those heat maps were generated

by any physiological measurement because they were not.

And yet, I don’t think we can have a discussion

about emotions and states and the sorts of behaviors

that we’re talking about today

without thinking about the body also.

And I’m not coming to this

as a Northern California mind-body.

I’ve been to Esalen once.

I didn’t go in the baths.

I went there, I gave a talk, and I left.

It is very beautiful.

If anyone wants to know what it looks like,

I think that final scene of Mad Men is shot at Esalen.

It’s a very beautiful place.

And yet, mind-body to me is a neurobiological construct

because the nervous system extends

out of the cranial vault and into the spinal cord

and body and back and forth.

Okay, 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,

because it does seem that there’s some regularity

as to where people experience emotions.

When people are in a rage, for instance,

they seem to feel it both in their gut and in their head,

it seems, on average.

And people love to extrapolate to gut intuition

or that the chakras or anger is in the stomach,

and this goes to Eastern medicine, et cetera.

How should we think about mind-body in the context of states

and think about it as scientists,

maybe even as neuroscientists or geneticists?

Good.

So for the answer to the first question about the heat maps

and people associating certain parts of their body

with certain emotional feelings,

this goes back to 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.

I don’t see the liver invoked very much

in emotional characterization.

But gall and the gallbladder. Yes.

Somebody having a lot of gall.

I don’t know why I make a fist when I say that,

but I’m guessing the gallbladder is shaped like a fist.

That’s right.

And if there is a physiology underlying these heat maps,

it could reflect increased blood flow

to these different structures.

And that in turn reflects what you were talking about,

that is emotion definitely involves communication

between the brain and the body,

and it’s bidirectional 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 neurons receive input

from the hypothalamus and other blood 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.

And these in turn feed back onto the brain

through the sensory system.

And a large part of this bidirectional 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.

People have known for a long time.

So 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.

So when you have a,

and that information is both,

you used the words earlier in our discussion,

afferent and efferent.

So the vagal 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 vagal fibers

are sensing the contraction of the gut muscles.

And they’re also afferents,

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 six 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 vagal nerves that go to the lung,

that control breathing responses,

that go to the gut,

that go to other organs.

It’s almost like a set of color-coded lines,

labeled lines for those things.

And now how those vagal afferents 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 gonna 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 parts of your body.

And Darwin recognized that as well.

And I think it’s a central feature of emotion state.

And I think what underlies

are subjective feelings of an emotion.

Incredible.

David, I have to say as a true fan of the work

that your lab has been doing over so many decades.

And first of all,

I was delighted when you stopped working on stem cells,

not because you weren’t doing incredible work there,

but because I saw a talk

where you showed a movie of an octopus spitting out,

or not spitting,

but squirting out a bunch of ink and escaping.

And you said you were gonna work on

things of the sort that we’re talking about today,

fear, aggression, mating behaviors, social behaviors.

It’s been incredible to see the work that your lab has done.

And 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.

My last question is a simple one,

which is, will you come back and talk to us again

in the future about the additional work that’s sure to come?

I would be happy to do that.

And I really have appreciated your questions.

They’ve all been right on the money.

You’ve hit all of the critical,

important issues in this field.

And 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 psychiatry.

We’ve got to figure out how emotion systems

are controlled in a causal way

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.

Thank you for joining me today

for my discussion with Dr. David Anderson.

Please also be sure to check out his new book,

The Nature of the Beast, How Emotions Guide Us.

It’s a truly masterful exploration

of the biology and psychology

behind what we call emotions and states of mind and body.

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