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.
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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?
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?
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.
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,
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.
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
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
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
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.
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.
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,
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.
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,
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.
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.
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,
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.
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 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
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.
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.
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?
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 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.
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.
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?
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.
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.
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.
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?
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.
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.
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
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.
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.
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.
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?
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.
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.
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.
I second that.
Well, thank you.
It’s been a delight.
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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