- 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. We 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 are 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. I'm pleased to announce that
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of my desire and effort to bring zero cost to consumer
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with Dr. David Anderson. David, great to be here and great to finally sit
down and chat with you. - Great to be here too, thank you so much. - Yeah, I have a ton of questions, but I want to start with
something fairly basic, but that I'm aware is a
pretty vast landscape, and that's the difference
between emotions and states, if indeed there is a difference, and how we should think about emotions. What are they? They have all these names, happiness, sadness,
depression, anger, rage, how should we think about them and why might states be at least as useful a thing to think about, if not more useful? - That's great. First, the short answer to your question is that I see emotions as
a type of internal state, in the sense that arousal's
also a type of internal state, motivation's a type of internal state, sleep is a type of internal state. And the sort of simplest way I think of internal states is that, as you've shown in your own work, they change the input-to-output
transformation of the brain. When you're asleep, you
don't hear something that you would hear if you were awake, unless it's a really, really loud noise. So from that broad perspective, I see emotion as a class of state that controls behavior. The reason I think it's useful
to think about it as a state is it puts the focus on it
as a neurobiological process rather than as a psychological process. And this gets around all of
the definitional problems that people have with the word emotion, where many people equate
emotion with feeling, which is a subjective sense that we can only study in humans, because to find out
what someone's feeling, you have to ask them, and people are the only
animals that can talk, that we can understand. So that's how I think about emotion, 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 want to 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 mentioned arousal as a key component, what are some of the
other features of states that represent this, as you so
beautifully put in your book, that represent below the tip of the iceberg?
- Right, right. So you can break states
up into different facets, or people would call them dimensions, and so there have been people who have thought of emotions as having just really two dimensions, an arousal dimension, how intense is it? And also a valence dimension, which is, is it positive
or negative, good or bad? Ralph Adolphs and I have tried to expand that a little bit to think about components of emotion, particularly those that
distinguish emotion states from motivational states, because they are very closely related. One of those important
properties is persistence, and this is something that distinguishes state-driven behaviors
from simple reflexes. Reflexes tend to terminate
when the stimulus turns off, like the doctor hitting
your knee with a hammer, it initiates with the stimulus onset and it terminates with
the stimulus offset, emotions tend to outlast, often, the stimulus that evoke them. If you're walking along a trail
here in Southern California, you hear a rattlesnake rattling, you're going to jump in the air, but your heart is going
to continue to beat and your palms sweat and
your mouth is going to be dry for a while after it's
slithered off in the bush, and you're going to be hypervigilant, if you see something that even remotely looks
snake-like, a stick, you're going to stop and jump. So persistence is an important
feature of emotion states, not all states have persistence. So for example, you think about hunger. Once you've eaten, the state is gone, you're not hungry anymore, but if you are 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 sooth 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 valance? 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, we can 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.
- Mm-hmm. - Different circuits being engaged. And it might be that a given
neurochemical, even dopamine, is involved in both
positively valanced arousal and negatively valanced arousal, that's why people think about
these as different axes. So I think the interesting
question that you touch on is, 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 raise 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, and not just mechanical stimulus. If you puff air on flies, kind of like trying to swat the wasp away from your burger at a 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 required 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. And 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, 'cause I always thought of
arousal as along a continuum, like you can either 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. - Yeah.
- Or multiple mechanisms that would include
neurochemicals, as well as different neural pathways.
- Yeah. - So like to talk a bit about a state, if it is indeed a state,
which is aggression, your labs 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, 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 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 Kruk, 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 bare 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 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 Kruk 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, 'cause 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 Karl 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 going to 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 fast forward from that, from a lot of work from
Dayu now on her own at NYU, and with her postdoc, Annegret Falkner, 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 valance. 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, I like. - Anatomists are so creative.
- Yes. [Andrew laughing]
Or the nucleus ambiguous, or the zona incerta, 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. 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. - [Andrew] In particular. - Offensive aggression is flank directed, defensive aggression goes for the neck, goes for the throat.
- Mm, I've seen some nature specials where in a very barbaric way, [laughing] 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 want to,
it seems they want to limit future breeding potential.
- Yes, or create pain. [David laughing]
- Right, or create pain, or both.
- Yeah. - 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. - [David] Hmm. - I have a relative who's a lawyer, he loves to argue and fight. - [David] Huh. - 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.
- Hmm. - And he's pretty effective at it. - Right.
- 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." - Mm-hmm.
- "It's one my great joys." He really enjoyed his work. - [David] Yep. - 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. - Yeah.
- 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. - Right.
- Acknowledging that dopamine does many things, of course. - Yeah.
- I have couple of questions about the way you describe the circuitry, I should say, the way the
circuitry is arranged. - [David] Mm-hmm. - And of course, we don't know, because we weren't consulted
at the design phase. [David laughing]
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, [laughing] 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 going to be the alpha
male in my group here?" And so it could be that if
you think that brain regions and cell populations evolve by duplication and modification of
preexisting 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 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 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 pear, when two animals are involved in a fight, it just stops the fight dead in its tracks and they go off into
the corner and freeze. So at least hierarchically,
it seems like fear is the dominant behavior
over offensive aggression, and how that inhibition
would work is not clear, 'cause 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.
- Mm-hmm. Controlling body-wide metabolism? - Yeah. - Very interesting.
- There are neurons there that respond to glucose, when glucose goes up in your
bloodstream, they're activated, and VMH has a whole history
in the field of obesity, because if you destroy it
in a rat, you get a fat rat. So the way most of the
world thinks about VMH is they think about, "Oh, that's the thing that keeps you from getting fat." It's the anti-obesity area, but in the area of social behavior, we see it as a center
for control of aggression and fear behaviors. And again, why these
neurons and these functions, I like to call them the four Fs, feeding, freezing, fighting and mating. - Mm-hmm.
- 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, Dayu'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. - Right.
- There's some reconciliation clearly that needs to
[laughing] happen first, we assume.
- Yes. - But it's just so striking, and 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.
- Yep. - So striking, I encourage
people to go watch those, because it really puts a
tremendous amount of color on what we're describing, and it's just the idea that
there are switches in the brain, to me, really became
clear upon seeing that. One of the, 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. - Mm-hmm.
- Or maybe it was Konrad, I can't speak now. [David laughing]
Excuse me, Konrad Lorenz, pardon.
- Mm-hmm. - Who talked about a kind
of hydraulic pressure towards behavior. I'm fascinated by this
idea of hydraulic pressure, because I don't consider
myself a hot-tempered person, but I am familiar with the fact
that when I lose my temper, it takes quite a while
for me to simmer down. I can't think about anything else, I don't want to 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.
- Mm-hmm. - And potentially conflicting states. What do you think funnels into this idea of hydraulic pressure toward a state? And why is it, perhaps, that
sometimes we can be very angry, and if we succeed in winning an argument, all of a sudden, it will subside? Because clearly that means that there are external influences, it's a complex space
here that we're creating, I realize I'm creating a bit of a cloud.
- Yeah. - 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. - Yeah.
- There is a pressure towards aggression, that all makes sense, but what's involved? Is it too multifactorial to actually separate out the variables, but what's really driving
hydraulic pressure toward a given state? - Yeah, so really important question, I think one way that is
helpful, at least for me, to break this question
apart and think about it is to distinguish homeostatic behaviors, that is, need-based behaviors, where the pressure is
built up because of a need, like, "I'm hungry, I need to eat. I'm thirsty, I need to drink. I'm hot, I need to get to a cold place," it's basically the thermostat
model of your brain. You have a set point, and then if the temperature gets too hot, you turn on the AC, and if the temperature gets too cold, you turn on the heater and you put yourself
back to the set point. I don't think that's how aggression works. That is, it's not that we all go around, at least subjectively, I don't go around with an
accumulating need to fight, which I then look for
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 to. - Or Twitter. - Yeah, [laughing] or Twitter, yeah.
- 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. [David laughing]
They seem to really like to fire off that cap gun.
- Right, right. - But I agree.
- Yeah. - Before we continue
with today's discussion, I'd like to just briefly acknowledge our sponsor, Athletic
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athleticgreens.com/huberman to claim that special offer. - 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 drive or
a pressure to do that, and the natural way to think
about that, at least for me, is as gradual increases in neural activity in a particular region of the brain. 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 valenced, 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 tamps 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. Now, 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 Lindsay is working on, you can stimulate those areas
'til 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. [Andrew laughing]
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 Lorenz hydraulic model? That is, you don't see the behavior until you release a valve on this bucket and let the accumulated pressure flow out. And that's one of the
things we're trying to study in the context of the
mating behavior as well, how does the information that there's an object in front of you come together with this drive state that is generated by stimulating these neurons in the hypothalamus to say, "Okay, pull the trigger and go, it's time to mate, it's time to attack?" And we're just starting to get
some insights into that now. - Fascinating, and I
should mention to people, Dr. Anderson mentioned Lindsay, Lindsay 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 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, 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. - Huh.
- 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. There's actually a serious issue that came up in our episode with Anna Lembke, who wrote the book "Dopamine Nation".
- Hmm. - Because of 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. - Yeah.
- In ways that might actually impede seeking and
finding of sexual partners and/or long-term mates. - Right.
- So serious issue there, I raise it as a serious issue. - Yep.
- That I hear a lot about, 'cause 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
'cause there's no data. - [David] Yep. - But what you're raising here is a very interesting mechanistic scenario that can, and 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 mouse if it's just alone in the
cage wandering around? iI 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? [David and Andrew laughing] 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 factory
perception of a conspecific that ungates this tremendous
repertoire of behaviors? - Right, that is a 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, 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 going
to engage in aggression. Because aggression is a very risky thing for an animal to engage in, it could wind up losing and it could wind up getting killed, and 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 want to 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 into 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? 'Cause 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,
Nirao Shah, at Stanford, who is 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, most of your listeners may have heard of aromatase 'cause aromatase inhibitors are
widely used in female humans as adjuvant chemotherapy
for breast cancer. They are a way of reducing
the production of estrogen by preventing testosterone from being converted into estrogen. And in fact, there are a
lot of animal experiments showing if you give males
aromatase inhibitors, they stop fighting, as well as also stop
being sexually active. And so that's one of the
counterintuitive ideas, and Nirao has shown that progesterone also seems to play a role in aggression, because these aggression neurons also express the progesterone receptor. So here are two hormones that
are classically thought of as female reproductive hormones, this is what goes up and goes
down during the estrous cycle, estrogen and progesterone, and yet, they're playing
a very important role in controlling aggression in male mice, and presumably in male humans as well. - Fascinating, so estrogen
is doing many more things than I think most people believe. - Yep.
- And 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 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 weened, that aggressiveness goes away. So this is pretty remarkable that you take a virgin female mouse and expose it to a male, and her response is to
become sexually receptive and to mate with him. And now you let her have her pups, and you put the same male or another male mouse
in the cage with her, and instead of trying to mate
with him, she attacks him. So there is some presumably hormonal and also neuronal switch
that's occurring in the brain that switches the response of the female from sex to aggression when she goes from virginity to maternity. And we recently showed in a paper, this is work from one of
my students, Mengyu Liu, that within VMH in females, there are two clearly divisible subsets of estrogen receptor neurons, and she showed that one of
those subsets controls fighting and the other one controls mating. And in fact, if you stimulate the fighting-specific subset in a virgin, you can get the virgin to attack, which is something that we
were never able to do before, and if you stimulate the
mating one, you enhance mating. The reason we could
never get these results when we stimulated the whole population of estrogen receptor neurons is that these effects are
opposite and they cancel out. And so it turns out that
if you measure the activity of the fighting and the mating neurons going from a virgin to a maternal female, the aggression neurons are
very low in their activity in the virgin, but once the female has pups, the activation ability of
those neurons goes way up and the mating neurons stay the same. So if you think of the balance
between them like a seesaw, in the virgin, there is more activity in the mating neurons than
in the fighting neurons, whereas in the nursing mother, there's more activity or more activation the other way around, the fighting neurons in the mating. - Mm-hmm.
- 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 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, and 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?
- Yes, 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, does she revert to the
more virgin-like behavior? Is it triggered by lactation or could it actually be triggered by the mating behavior itself? 'Cause it's possible for the
virgin to become a non-virgin, but not actually have a litter of pups. - Right, those are all great questions, and we don't know the
answer to most of them. What I can say is that a nursing mother doesn't have to have her
pups with her in the cage in order to attack an intruder male or an intruder female, she is just in a state of brain that makes her aggressive to any intruder. And those aggression neurons
in that female's brain are activated by both male
and female intruders equally, whereas in male mice,
the aggression neurons are only ever activated
by males, not by females, because males are never
supposed to attack females, they're only supposed to mate with them. So that's another difference in how those neurons are tuned to signals from different conspecifics. Does it require lactation? I don't know the answer to that, I think there are some experiments where people have tried
to, classical experiments, people have tried to reproduce
the changes in hormones that occur during pregnancy in female rats to see if it can make them aggressive. And some of those manipulations
do, to some extent, but there's a whole biology there that remains to be explored about how much of this is hormones, how much of this is
circuitry and electricity, and how much of it is other factors that we haven't identified yet? - I don't want to anthropomorphize, but, well, I'll just ask the question. So the other day, I was
watching ferrets mate, right? They're mustelids, and
they're mating behavior, I guess I didn't say
why I was watching this, doesn't matter.
[David laughing] 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 an aggressive component in humans that have all sorts of kinks and fetishes and behaviors, and most of which probably
has never been documented 'cause most of this happens in private. And here, I always say on this podcast, any time 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. Well, today, 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 going to project
and anthropomorphize, I'd say it's not really clear
they both want to be there, 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 questions. I can't really speak to the issue of whether this is species specific, 'cause 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 'em 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 baring 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, [laughing] 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.
[David laughing] 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 the 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. - Hmm.
- As if the circuitry has crossed over, and the
statement that wrung 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. - Hmm.
- 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 concerned
with the hypothalamus, in which you have these
dense populations intermixed, and that the addition of a
forebrain, especially in humans, that can think and make decisions could in some ways facilitate the expression of these
primitive behaviors, but could also complicate the expression of primitive behaviors. - Right, I would agree. I think one way of looking at fetishes from a neurobiological standpoint is that they represent a kind
of appetitive conditioning where something that is
natively aversive or disgusting, by being repeatedly paired
with a rewarding experience, changes its valence, its sign so that now it somehow produces
the anticipation of reward the next time a person sees it. Now, I don't know that
literature in animals, so I don't know if you could condition a mouse to eat feces, for example, although there are animals
that are naturally coprophagic, 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
arts of the brain, the cortex that is sort of orchestrating both what behaviors are happening and whether reward states are turning on in association with those
behaviors that are happening. And that's the part that
I think is difficult and challenging to study in a mouse, but certainly bears thinking about, because it's a really interesting, again, sort of counterintuitive aspect. Again, like rough sex, people that want to have fighting, or violence, or aggressiveness in order to be sexually
aroused, and fetishes. And in fact, when we made
that discovery initially, it raised the question in my mind whether some people that are
serial rapists, for example, and engage in sexual violence might, in some level, have
their wires crossed in some way, that these states that are supposed to be pretty much separated and
mutually antagonistic are not, and are actually more
rewarding and reinforcing. I think it's going to be a long time before we have figured it out, but when you think about it, there is no treatment that we have for a violent sexual offender that eliminates the violence, but not the sexual desire and sexual urge, whether it's physical castration
or chemical castration, it eliminates both. - Definitely an area that I think, well, human neuroscience in general needs a lot of tools, right? In terms of how to probe and
manipulate neural circuitry. I'd love to turn to this
area that you mentioned, the medial preoptic area. I'm fascinated by it, because
just as within the VMH, you have these neurons for mating and fighting, or aggression, my understanding is medial preoptic area contains neurons for mating, but also for temperature regulation. And perhaps I'm making
too much of a leap here, but I've always wondered
about this phrase, "In heat," as certainly the menstrual and
or estrous cycle in females is related to changes in body temperature. In fact, measuring body temperature is one way that women can fairly reliably predict ovulation, et cetera. Although this is not a
show about contraception, please rely on multiple methods
[laughing] 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 intromission thrusting neurons, and ejaculation neurons
and sniffing neurons. - Wait, wait, so I think
I've heard this before, but I just want to make
sure that people get this and I want to make sure I get this. So you're telling me within
medial preoptic area, there are specific neurons
that if you stimulate them, will make males thrust
as if they're mating? - No, so this is not based
on stimulation experiments. - Mm.
- It's based on imaging experiments right now.
- I see, I see. - That we see when we
look in the preoptic area at what neurons are active during different phases of aggression, we see that there are different neurons that are active during sniffing, mounting, thrusting and ejaculation, and they become repeatedly activated each time the animal
goes through that cycle. - During mating, yeah.
- 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
suggest 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 hotblooded
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 thermal regulation 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. It could be other social
reasons why that happens, people are outside, out on the street, bumping into each other, but I think there could well be something that ties thermoregulation
to aggressiveness, as well as to mating behavior. - Fascinating, yeah. I ask in the hopes that
maybe in the years to come your lab will parse some of
the temperature relationships. And I realize 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 intrigues me, because of this notion of hotheadedness. - Right.
- Or cool, calm and collected. And also the fact that, and I probably should've
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, 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 neck side, as opposed to lying on their own back. - [David] Hmm. - Just fascinating, very primitive.
- Hmm. - 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, and 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, dominance mounting, if you weakly activate VMH, whereas MPOA is most strongly activated during sexual mounting, and that's always accompanied by the ultrasonic vocalization. So this shows how difficult
and dangerous it can be to try to infer an animal's
state, or intent, or emotion, from the behavior that it's exhibiting because the same behavior can
mean very different things depending on the context of the
interaction with the animal. - And I would say, even more so with when that animal is a
human or is multiple humans. - That's right, and
there are many examples, animals show chasing to obtain food, a prey animal that they're
going to kill and eat, and they show chasing to obtain a mate that they're going to 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 and 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.
- Mm. - And just start barking, which is an idiotic thing for it to do, but they can be dominant
over a much larger dog. - Hmm.
- Very strange, to me anyway. Female-female mounting,
do you observe it in mice? Are there known circuits, and what evokes female-female mounting, or female-to-male mounting if it occurs? - Good, yes, there 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. [Andrew laughing]
- Is that right? [laughing] - [Andrew] Don't ask me how I know that. - Okay. - But it's a pretty, yeah,
it's a term that you hear. You also hear the term
topping from the bottom, which it sounds like
that is a literal topping from the bottom.
- I see. - That's a 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. And at some point, right? I attempt, in my mind, to
superimpose observations from the online communities. - Yeah.
- 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.
- Yes. - Humans, they maintain all
the same neural circuitry and pathways that we're
talking about today in mice, but that forebrain does
allow for context, et cetera. - Yep.
- Yeah. - 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
Dulac suggested some years ago. - Fascinating, fascinating. I love that paper because,
as you pointed out for chase, for mounting behavior, we see it and we think one thing specifically, and after hearing this result, actually, I'm not a big
fan of fight sports. I watch them occasionally
'cause 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.
- Really? - Almost like, "I dominated you, and I'm," so mimicking sexual-like behavior, but there's no reason to
think that it's sexual, but they're sending a message.
- Yeah. - Of dominance is what it 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, 'cause 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 want to 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, [laughing] right? So there clearly is some
endogenous pain control. - Yep.
- That then wears off, and then you feel beat up. - [David] Yep. - Or at least, in my case, I felt beat up. What's PAG doing vis-a-vis pain, and what's pain doing vis-a-vis
these other behaviors? - Good, good. So I think of PAG like a old-fashioned
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. - Mm-hmm.
- 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.
- May I ask what that peptide is?
- It's called bovine adrenal medullary peptide
of 22 amino acid residues. And I only know about it because it activates a receptor that we discovered many years ago that's involved in pain, and we thought it promoted pain, but it turns out that this
actually inhibits pain, it's like an endogenous analgesic. Whether this is happening,
this type of analgesia is happening when an animal is engaged in offensive aggression or in mating behavior, I don't know, but it certainly is possible. And I don't know whether
these analgesic mechanisms are happening in the PAG, they could also be happening
a little further down in the spinal cord. The PAG is really continuous
with the spinal cord, if you just follow it down
towards the tail of an animal, you will wind up in the spinal cord. And so it could be that
there are influences acting at many levels on pain in the PAG and in the spinal cord as well. And it may well be known,
I just don't know it, I want to distinguish
clearly between things that are not known,
that I know are unknown, which is in a fairly small
area where I have expertise, from things that may be known, but I'm ignorant of them, because I just don't have a broad enough knowledge base to know that. - Sure, we appreciate those delineations. Thank you, PAG, I think
this description of it as an old-fashioned telephone switchboard, and now every time I look into
the toilet, I'll think about the periaqueductal gray.
- [laughing] That's right. - [Andrew] And every time I see an image of periaqueductal gray, I'll think about a toilet.
- That's right. [laughing] - That is an excellent description, because, in fact, I drew a circle with a little thing at the bottom. And 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 times on different podcast episodes because of its relationship
to social isolation, and in part, because
the podcast was launched during a time when there
was more social isolation. My understanding is that tachykinin, and you'll tell us what it is in a moment, is present in flies
and mice and in humans, and may do similar
things in those species. - That's right, so
tachykinin refers to a family of related neuropeptides. So these are brain chemicals, they're different from
dopamine and serotonin in that they're not
small, organic molecules, they're actually short pieces of protein that are directly encoded by genes that are active in specific neurons and not in others. And when those neurons are active, those neuropeptides are released together with classical transmitters, like glutamate, whatever. Tachykinins have been
famously implicated in pain, particularly Tachykinin-I, 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, Moriel Zelikowsky, now at University of
Salt Lake City in Utah, and she found, remarkably, that when mice are socially
isolated for two weeks, there is this massive upregulation of Tachykinin-II 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 'cause 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 Moriel 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 osanetant,
that blocks Tachykinin-II, 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 going to be falling all
over themselves to try it. And they are 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 3, 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-I, 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, 'cause some of the people who are getting drug or placebo are going to 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, 'cause that's always a serious consideration.
- Yep. - 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, we'll 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. - Yep.
- 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, yeah.
- Okay? And if this thing works in mice, there's certainly a higher chance it's going to work in dogs or in cats than it is going to 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 want
to 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 is ways that they
can be made to feel better when they're separated from their owners, that would certainly be a good thing. - Absolutely, we will put out the call, we are putting out the call, and I know for sure
there will be a response. 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 that committed that, and every single time, the person who commits those acts is socially isolated, as far as I know.
- Yeah, yeah. - There might be some exceptions there. And sometimes this crosses over with other mental health issues, but sometimes no, no apparent
mental health issues. So social isolation clearly drives powerful neurochemical and
neuro biological changes, I really hope that Tachykinin-I and II, those are the main ones in humans?
- Yeah, yeah. - Will be explored in more detail. Also, I didn't know that
Tachykinin-I is Substance P. - Yes.
- And Substance P is Tachykinin-I.
- Yes. Tachykinin-I is the gene name, and Tachykinin-II, in humans,
is called Neurokinin B, that's the name of the protein. I just refer to it by the gene name 'cause 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 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. [laughing] - Wonderful, as long as
we're talking about humans, I'd love to get your thoughts about human studies of emotion. I know you wrote this
book with Ralph Adolphs, you have this new book, which
we'll provide a link to, which I've read front to
back twice, it's phenomenal. - Thank you.
- 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.
- Thank you. - 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. - [David] Yep. - And I'm not coming to this as a Northern California, mind-body. - Yeah.
- I've been to Esalen once. [David laughing]
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. - Yes.
- Because the nervous system extends through out of the cranial vault and into the spinal cord.
- Yeah. - And body and back and forth, okay. How should we think about
the body, in terms of states? And at some point, I'd
love for you to comment on that heat map experiment, because it does seem that
there's some regularity as to where people experience emotions. When people are in a rage, for instance, they seem to feel it both in
their gut and in their head, it seems, on average. And people love to
extrapolate to gut intuition or that the chakras or
anger is in the stomach, and this goes to Eastern
medicine, et cetera. How should we think about mind-body in the context of states, and think about it as scientists, maybe even as neuroscientists
or geneticists? - Good, so for the answer
to the first question about the heat maps and people associating
certain parts of their body with certain emotional feelings, this goes back to something called the somatic marker hypothesis, that was proposed by Antonio Damasio, who is a neurologist at USC, the idea that our subjective feeling of a particular emotion is, in part, associated with a sensation of something happening in a
particular part of our body, the gut, the heart, I don't see the liver invoked very much in
emotional characterization, but.
- But gall and the gallbladder.
- Yes. - Somebody having a lot of gall. - That's right.
- I don't know why I make a fist when I say that. - Right.
- But I'm guessing the gall bladder is shaped like a fist. [Andrew laughing]
- That's right, and if there is a physiology
underlying these heat maps, it could reflect increased blood flow to these different structures. And that, in turn, reflects
what you were talking about, that is, emotion definitely involves communication between
the brain and the body, and it's bidirectional communication, and it's mediated by the
peripheral nervous system, the sympathetic and the
parasympathetic nervous system, which control heart rate, for example, blood vessel, blood pressure. And those neurons receive
input from the hypothalamus and other 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
into your heart, your gut, all sorts of visceral organs. 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 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 going
to be developing tools that will allow us to turn on or turn off specific subsets of fibers
within the vagus nerve and ask how that affects
particular emotional behaviors. So you're absolutely right, this brain-body connection is critical, not just for the gut, but for the heart, for the lungs, for all kinds
of other 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 our subjective feelings of an emotion. - Incredible, well, 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. [David laughing]
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 going to 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 when I say thank you for taking time out of your important schedule to share with us what you've learned. My last question is a simple one, which is, will you come back and talk to us again in the future about the additional
work that's sure to come? - I would be happy to do that, and I really have
appreciated your questions, they've all been right on the money, you've hit all of the
critical, important issues in this field. And you've uncovered what is known, the little bit is known, and how much is not known, and I think it's important to
emphasize the unknown things, because that's what the next
generation of neuroscientists has to solve. And so I hope this will help to attract young people into this field, because it's so important, particularly for our
understanding of mental illness and mental health and psychiatry, we've got to figure
out how emotion systems are controlled in a causal way if we ever want to improve on the psychiatric
treatments that we have now, and that's going to require the next generation of
people coming into the field. - Absolutely, I second that. Well, thank you, it's been a delight. - Thank you, great, really appreciate it. - Thank you for joining me today for my discussion with Dr. David Anderson. Please also be sure to
check out his new book, "The Nature of the Beast:
How Emotions Guide Us". It's a truly masterful exploration of the biology and psychology behind what we call emotions and states of mind and body. If you're learning from
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up for the newsletter, you go to hubermanlab.com, click on the menu, go to Newsletter. You supply your email, but we do not share
your email with anybody, we have a very clear and
rigorous privacy policy, which is we do not share
your email with anybody. And the newsletter comes out once a month, and it is completely zero cost. Again, just go to hubermanlab.com and go to the Neural Network Newsletter. I'd also like to point out that the Huberman Lab
Podcast has a clips channel. So these are brief clips, anywhere from three to 10 minutes, that encompass single concepts
and actionable protocols, related to sleep, to focus, interviews with various guests, we talk about things like caffeine, when to drink caffeine relative to sleep, alcohol, when and how and
if anyone should ingest it relative to sleep, dopamine, serotonin, mental
health, physical health, and on and on, all the things that relate to the topics most of interest to you. You can find that easily
by going to YouTube, look for, "Huberman Lab
Clips," in the search area, and it will take you there, subscribe. And we are constantly
updating those with new clips. This is especially useful, I believe, for people that have missed
some of the earlier episodes or you're still working through the back catalog of Huberman Lab podcasts, which admittedly can be rather long. And last but certainly not least, thank you for your interest in science.
