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 Cal Tech University dr. Anderson's research focuses on emotions and states of mind and body.
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 an action or inaction and strongly influence the way we interpret our experience and our surroundings today. Dr. Anderson teaches
Us for instance, why people become aggressive and why that aggression can sometimes take the form of Rage also talked 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
At 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, contrast 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.
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 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, Unfortunate 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. Hm, I guess on this podcast. But for those of you not familiar the Howard Hughes Medical Institute funds, a small number of investigators doing
Hurley 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 there. 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
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And you'll get a free sample pack with your order again. That's drink LMN t.com huberman to get a free sample pack with your order and now, for my discussion with dr. David Anderson, David great to be here and great to finally sit down and chat with
you great to be here to. 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
You 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 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 arousals also, a type of internal state,
Ins at type of internal State, sleep is a type of internal State and the sort of simplest way. I think of internal States is that as you've shown in your own work, they change the input to Output transformation of the brain when you're asleep. You don't hear something that you would hear if you were awake, unless it's a really, really loud noise. So, from that broad perspective, I see emotion as a class of state that controls Behavior.
The reason I think it's useful to think about it as a state is it puts the focus on it as a neurobiological process rather than as a psychological process. And this gets around all of the definitional problems that people have, with the word emotion, where many people equate emotion with feeling, which is a subjective sense that we can only study in humans because
To find out what someone's feeling, you have to ask them and people are the only animals that can talk that we can understand. So that's how I think about emotion. It's the if you think, 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 sort of floating above the surface of your Consciousness. Not that? That is an important it is but you have to understand Consciousness if you want to understand.
Things and we're not ready to study that an animal's yet and so that's how I think about it. What
are the different components of a state? You know, you mentioned arousal as a key component? What are some of the other features of states that represent this as you so beautifully? Put in your book that represent below the tip of the
iceberg, right? Right. So you can break States up into
Different facets or people would call them dimensions. And so there have been people who thought of emotions as having just really two dimensions and arousal Dimension, how intense is it and also available it's Dimension which is, is it positive or negative good or bad? Ralph adolf's. And I have tried to expand that a little bit to think about
opponents 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
Willis on set and a 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 rattle snake 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 slithered off in the bush and you're going to be hyper-vigilant. If you see something that even remotely looks
It's snake like a stick, you're going to stop and jump. So, persistence is an important feature of 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.
Minute 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 and soothe it. 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.
In and consume water and they're 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 negative valence? How do you crank up or crank down the intensity? The
Ate 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 arouse a little bit more and Valence because at a very basic level, it seems to me that arousal we can be very alert and pissed off stressed worried. You have insomnia. We can also be very alert and be quite happy. So the valence flips we can be very 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 valent? So for instance, is there any way that we can safely say that arousal with some additional dopamine release is going to be of positive valence, and arousal with very low dopamine is going to be of negative
valence. I would be reluctant to say that it's a chemical flip. I would say it's more likely to
Be a circuit, flip different circuits being engaged and it might be that a given neurochemical. Even dopamine is involved in both positively valence to arousal and negatively valence to wrassle. That's why people think about these as different axes. So I think the interesting question that that you touch on is is arousal something that is just completely generic in the brain or are there actually different?
What kinds of Rouse 'l that are specific to different behaviors and you raised a question, you know, 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 then when you're asleep and fly, show that and the other
Is a startle response and arousal response to a mechanical stimulus and not just mechanical stimulus. If you puff are on flies kind of like trying to swat the WASP away from your burger 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 they were exerted through completely separate.
Herbal neural circuits in the fly and so that really put number one, the emphasis on its the circuit that determines the type of arousal. But also that arousal isn't unitary that there are Behavior specific forms of arousal, and I think the jury is still out as to whether there is such a thing as completely generalized arousal or not. I think some people would argue there is but I think more attention needs to be paid.
This question of domain-specific or behavior specific forms of
arousal, it's a super interesting idea because I always thought of arousal is along a Continuum of you need to be in a panic attack at the one end of the extreme where you can be in a coma and then somewhere in the middle your alert and calm. But then this issue of valence really. As you, as you say, presents this opportunity that really, there might be multiple circuits for arousal and or multiple mechanisms that would include neurochemicals as well as different neural pathways.
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 dowel in 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
Simple.
How should we think about aggression? And I'll just sort of ask you the question a bit more by saying, we see lots of different kinds of aggression. This
terrible shoe
school shooting down in Texas recently, clearly an act that included aggression and yet you can imagine that's a very different type of aggression than a, you know, an all outraged or controlled aggression, you know, there's a there's a lot of variation there. So, what are your thoughts on aggression? How its generated the neural circuit?
Alms and some of the variation in what we call aggression?
Yeah, this is a great question and it's a, it's a large area, I would say that. The first of all, the word aggression, in my mind, refers more to a description of behavior than it does to an internal State aggression could reflect an internal state that we would call anger in humans or could reflect fear.
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 exists, the work that died. You 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 a
Optogenetics, to activate specific neurons in a region of the hypothalamus, the ventromedial hypothalamus vmh, which people have been studying. And, and looking at for decades following first, the work of in cats, the famous Nobel prize-winning work of Walter Hess and and Then followed by work done by meno Crook in the
Marlins in rats where they would stick electrical wires into the brain, and send electric currents into the brain. And they could trigger a Placid cat to suddenly bear its teeth hiss and almost strike out of 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
X from cats, depending on, where in the hypothalamus, he puts his electrode one of which he calls defensive Rage. That's the ears laid back teeth, bared, and hissing. And the other one is predatory aggression where the the cat has its ears forward and it's like batting with its paw at a 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 died. You came to the lab and we had started working on aggression and fruit flies. And I wanted to bring it into mice, so that we could apply genetic tools and we started by having died. You who was an electrophysiologist just repeat the electrical.
Emulation of the ventromedial hypothalamus in the mouse, just like people had done in rats and 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 many.
Crook on this, he really was mystified. Why doesn't it work in mice? We realized why. There had been no paper on brain. Stimulated aggression in mice, in 50 years because the experiment doesn't work. And the, the one bit of credit I can claim their as I convince die you to try optogenetics because it just had sort of come into use deep in the brain from called ice.
Roth and others work. And I thought maybe because it could be directed more specifically to a region of the brain and types of cells and optogenetics stimulate. Then electrical stimulation, it might work and die who said never never going to work. If it doesn't work with electricity, why should it work with optogenetics and fact, is that it did work and we were able to trigger aggression in this region using
Genetic 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 Ventura of ventromedial hypothalamus, like a are sitting on the ground, the fat part of the pair near the ground is where the aggression neurons are. But the upper part of the pair has fear neurons, and it could be because it's so small in
A mouse. When you inject electrical current anywhere in the pair, it flows up through the entire pair and it activates the fear circuits and those totally dominate aggression. And so that's why we were never able to see any fighting with electrical stimulation. Whereas, when you use optogenetics, you confine the stimulation, just to the region where you've implanted, the channelrhodopsin gene into those neurons.
And so, in fast forward from that, from a lot of work from die. You now on her own at NYU, and with her postdoc, and a gret Faulkner, there is as well as work of other people. There's evidence that the type of fighting that we were that we elicit, when we stimulate vmh is offensive aggression. That is actually rewarding to male mice. They like it. They like it male mice will
Press learn to poke their nose, or press a bar, to get the opportunity to beat up a subordinate male Mouse, and in more recent experiments, if you activate those neurons, and the mouse has a chance to be in one of two compartments. In a box, they will gravitate towards the compartment, where those neurons are activated. It has a positive valence and when I went into this field, and I was thinking well, what goes on in my brain
Rain 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 wear 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, my show predatory aggression, they use that to catch crickets that they eat, and that involves different circuits than the ventromedial hypothalamus circuits. So it's become clear that if you want to call it, the state of aggressiveness is
The faceted, it depends on the type of aggression and it involves different sorts of circuits. There is 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 substantial in amanada, the substance with no name. You know,
I like Natomas are so creative
for the nucleus ambiguus, you know, or the Zona insert of 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 offense versus defense,
Offensive aggression they direct their bites at different parts of the opponent's body in particular. This is the offense of aggression is flanked directed defense of aggression. Goes for the neck goes for the
throat. I've seen some nature specials, we're in a very barbaric way at least to me. It seems like hyenas will try and go after the the reproductive axis. They'll go after testicles and penis, and they basically want to. It seems they want to limit
Future breeding, potential
create pain,
they are create, or create pain, or both. Yeah, I mean, in terms of offensive aggression and the your reflection that it doesn't feel good. I mean, I can say, I know some people who really enjoy fighting, have a relative who's a lawyer he loves to argue and fight. I don't think of him as physically aggressive fact, he's not but loves to fight and loves to prosecute and go after people in months and he's pretty
about it, right? I've friend former military Special Operations and very calm guy. Had a great career in the military Special Operations and heal quite plainly. Say I love to fight. It's one of the one of my great Joys. He really enjoyed his work. Yeah. And also respect to the other side because they offer the opportunity to test that that and to experience that Joy. So in a kind of bizarre way to somebody like me, who I'll certainly defend my stance if I need to but I certainly am. Don't consider myself.
Somebody who offensively goes after people just to go after them. There's no quote-unquote. Dopamine, hit here acknowledging. The dopamine does many things, of course. Yeah, I have a couple of questions about the way you describe this, the circuitry, I should say, the way the circuitry is arranged. And of course, we don't know because we weren't consulted that the design phase, but why do you think there would be such a close positioning of neurons that can elicit such Divergent states, and
Saviors, when you're talking about this pear shaped structure where the neurons that generate fear our cheek to jowl with the neurons that generate offense of aggression of all things. It's like putting the neurons that control swallowing next, to the neurons that control vomiting. It just seems to me that. On the one hand, this is the way that neural circuits are often arranged and yet to me it's always been perplexing as to why this would be the
case. Yeah, I think that that is a very profound question.
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 about start to think about who's going to be the alpha male in my group year. And so it could be that if you think that brain regions and cell populations evolved by duplication and modification of pre-existing cell populations that might be the way that those regions wound up next to each other.
And developmentally. They start out from a common pool of precursors that expresses the same gene, the fear neurons and the aggression neurons. And then with development, it gets, shut off. In the aggression neurons and maintained in the fear neurons. Now that view says, oh, it's just an, it's an accident of evolution and development, but I think there must be a functional part as well. So one thing we know about offensive aggression is that strong?
Here shuts, it down, whereas defense of aggression, at least in rats is actually enhanced by fear. It's one of the big differences between defense of aggression and offensive aggression. And you think about it, if you think about it, if offensive aggression is rewarding and pleasurable, if you start to get really scared, that tends to take the fun out of it. And maybe these two regions are close to each other to facilitate inhibition of
Shin-bi feet, the fear neurons. We know for a fact that if we deliberately stimulate those fear neurons at the top of the hair, 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 Fries. So at least hierarchical e. It seems like fear is the dominant Behavior over offense of aggression and how that inhibition would work is not clear because all these neurons are pretty much excitatory. They're almost all
Oh, 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 are all mixed up together and it's not just fight and freezing or fight and flight,
Also metabolic neurons that are mixed together in vmh as well.
Controlling body-wide metabolism.
Yeah there's 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 as they think about, oh, that's the thing that keeps
Keeps you from getting fat as 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 these neurons and these functions, I like to call them the four FS feeding freezing fighting and mating that, they all seem to be closely intermingled with each other, maybe because crosstalk between them is very important to Help the Animals. 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 deleuze and the other studies that you've done. One of the, 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, is 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 or some reconciliation clearly that needs to happen. First we assume but it's just so
Striking, I think equally striking is the video where the mouse is alone in there. With the glove, the vmh neurons are stimulated and the mouse goes into a rage. It looks like it wants to kill the glove basically. So striking, I encourage people to go watch those because it really puts a tremendous amount of color on what we're describing. And it's just the idea that there are switches in the brain, to me really became clear upon seeing that one of the concepts. Excuse me, one of the concepts that
That you've raised in your lectures before and and that I think was hess's idea is this idea of a sort of hydraulic pressure or maybe it was called let Karma lad Conrad? I can't speak. Now, excuse me, Konrad Lorenz Martin 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, thick trying to think about anything else. Becomes aversive to me, which to me underscores this notion of prioritization of the different states and potentially conflicting States. What do you think funnels into this idea of hydraulic pressure toward a state? And why is it perhaps that? Sometimes we can be very angry. And if we succeed in winning an argument, all of a sudden, it will
Subside, because clear, that means that there are external influences. It's a complex space here that we're creating. I realize I'm creating a bit of a cloud and I'm doing it on purpose because to me, the idea of a hydraulic pressure towards a state, like, sleep. There's a sleep pressure. There's there's a pressure towards her, that all makes sense. But what's involved is it to multifactorial to actually separate out the variables? But what, what's what's really driving hydraulic pressure toward a given State?
Yeah, so really
Horton 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 as basically the thermostat.
It'll of your brain. You have a set point, and then if the temperature gets too hot, you turn on the AC. And if the temperature gets too cold, you turn on the heater and you put yourself back to the set point. I don't think that's how aggression works that is it's not that we all go around at least subjectively. I don't go around with an accumulating need to fight which I then look for something to an excuse to release it. Now maybe there are people that do that and they go out and look for
Our fights to get into Twitter. Yeah, Twitter Twitter
seems to draw Adams over half. Joking? Because Twitter seems to draw a reasonably sized crowd of people that are there for combat of some sort. Even though the total intellectual power of any of their comments is about, that of a cap gun. They seem to really like to fire off that cap, right? But in, but I agree. Yeah, before we continue with today's discussion, like to just briefly acknowledge our sponsor athletic greens, now called a G1
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offer. So you can think you can think of this accumulated hydraulic pressure either being based on something that you were deprived of creating an accumulating need or something that you want to do. Building up a driver, 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 brain of a hypothalamus that controls feeding Scott Stearns and and others have shown that the hungrier you get the higher, the level of activity in that region in the brain. And then when you eat, Boom, the activity goes right back down again and that state is actually negatively valence. So it's like the
Mille quote-unquote feels increasingly uncomfortable just like we feel increasingly uncomfortable the hungrier we are and then we eat it, Taps it down but there is this increased activity and I think in the case of aggression our data and others show that the more strongly you drive. This region of the brain optogenetic lie, the more of just a hair trigger. You need to set the animal off to get it to fight 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 over to attack if unless you put something in front of it and the same thing is true for the area's, we've described the control mating behavior. This is what Lindsay is working on. You can stimulate those areas till you're blue in the face and
the mouse just sort of wanders around, but if you put another mouse in Wham, he will try to mount that Mouse. If you put a kumquat in the cage, he'll try to mount the kumquat. And so it's, 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 in the Lorenz hydraulic model? That's 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
Checked in front of you, come together with this drive state, that is generated by stimulating. These neurons in the hypothalamus to say, okay, pull the trigger and go, it's time to mate, it's time to attack and we're just starting to get some insights into that
now, fascinating, and I should mention people, dr. Anderson mentioned, 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 where they sound fascinating. I would love to
And some time on this issue of why is it that a mouse won't attack nothing but it'll attack even a glove or and why? Well, it will only try and mate. If there's another mouse to mate with, it's actually, I think fortunately for you, you're not spending a lot of time on Twitter and Instagram, but or YouTube, but there's this whole online community. That is this. Now, as far as I know, it's almost exclusively young males, who are
Are obsessed with this idea. I'll just say it has a name. It's called nofap of no masturbation as a way to maintain their motivation, to go out and actually seek mates because of the ready availability of online pornography. There's anima probably a much larger population of young males that are never actually going out and seeking mates because they're getting porn addicted etcetera. There's actually a serious issue that came up in our episode with on a Lemke. Who wrote the book dopamine nation of because available ability of pornography, there's a whole so
Context that's being created around this in genuine addiction. So, humans are not like the mice or mice or not like the humans. Humans seem to resolve the issue on their own in ways that might actually impede seeking and finding of sexual partners and or long-term mates, right? So, serious issue there. I raised it as a serious issue that I hear a lot about because I get asked hundreds, if not thousands of questions about this. Is there any physiological basis for what they call nofap? And I never actually replied because there's no data. Yeah, but
But what you're raising here is a very interesting mechanistic scenario that that can 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 who's bring other brain region that can stimulate the desire to mate. What do we know about the internal state of that Emmaus? If it's just a loan in the cage, wandering around, is it wandering around really wanting to mate and really wanting to fight? We of course don't know but is its heart rate up is its blood pressure up. Is it wishing that there was pornography? Is it?
Something's going on. Presumably that's different than prior to that stimulation. And is it arousal. And what do you think it is about the visual or olfactory perception of a conspecific that onion Gates? This tremendous, repertoire
behaviors, right? That that, that is the central question, I can say, at least, with respect to the fear neurons that sit on top of the aggression. Neurons, we know that when those neurons
Or activated optogenetics lie 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 too 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 Mal adaptations of fear, but not mental illnesses, that are based on Mal adaptations of aggression if they have pretty similar circuits in the brain. But that's, 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.
It as both an antenna and a broadcasting Center is like a satellite dish that takes in information from different sensory, modalities smell maybe Vision, mechanical mechana sensation, and then it's sort of synthesizes an integrate that into a fairly low dimensional. As the computational, people call it representation of this pressure to attack and that broadcast that all over the brain.
In to trigger, all these systems that have to be brought into play. If the animal is going to engage in aggression, because aggression is a very risky thing for an animal to engage in, It could wind up losing, and It could wind up getting killed. And and so, it's 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 grabbed 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 were 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 exoticness testosterone, it tends to make them more of the way they were before if they were jerk before. They'll become more of a jerk. If they were very altruistic to become more altruistic and then eventually I
It out, you'll aromatize that testosterone and estrogen, and you'll start getting opposite effect. So it's a it's a murky space, it's not straightforward, but if I'm not mistaken, testosterone plays a role in generating aggression. However the specific hormones that are involved in generating aggression via vmh.
Are things other than testosterone. Can you tell us a little bit more about that? Because there's some interesting surprises in there.
Yeah, that's a really important question. So the when we finally identify 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 late.
Old 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, near our Shah at Stanford, who is one of my former PhD students that if you have a straight, a mouse and it loses the ability 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.
Fact people may have most of your listeners may have heard of aromatase because aromatase Inhibitors are widely. Used in female humans, as adjuvant chemotherapy for breast cancer. They are a way of reducing the production of estrogen by preventing testosterone from being converted into estrogen. And in fact there are a lot of animal experiments showing. If you give males, aromatase Inhibitors, they stop fighting as well as all.
So stop being sexually active. And so that's one of the counterintuitive ideas and Nero 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
A very important role in controlling aggression in male mice and then presumably in male humans as well. Fascinating, so
estrogen is doing many more things than I think. Most people believe in testosterone is doing may be different and fewer things in some cases and More in others.
I've known some aggressive females over time, I've been alive. What's involved in female aggression? That's Unique from the pathways that generate male aggression.
Great, great question. So we and other labs have studied this in both mice and also in fruit flies. So, one thing in mice, that is distinguishes aggression. And females from males, is that male mice are pretty much ready to fight at the drop of a hat, female mice.
Only fight when they are nurturing and nursing their pups after they've delivered a litter. And there is a window there where they become hyper aggressive and then after their pups are weaned, that aggressiveness goes away. So this is pretty remarkable that you take a virgin, female Mouse, and expose it to a male and her response is to become sexually receptive and to mate with him and now you letter
Her have her pups and you put the same mail 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 among you leave you
Within vmh and 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 subset in a virgin, you can get the Virgin to attack which is something that we were never 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
Pop's. The activation ability of those neurons goes way up and the mating neuron 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, in the nursing mother there's more activity or more activation in the, in the other way, around the fighting neurons in the main did I say fighting and making the first mating neurons dominate fighting?
In the Virgin fighting neurons dominate mating in 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, the the, this gets into the whole issue of neurons that are present in females but not in males. So, we've known for the field is 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 activate.
It's the female specific fighting neurons and in males activates the male-specific fighting neuron. So it's kind of a hierarchy with this commoner on top and in mice, we discovered that there are male specific neurons in vmh and those neurons are activated during male aggression. Now, that neurons that are active in females when females fight in vmh are not sex-specific. So they are also found
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
Mayors
I'm fixated on this transition from the Virgin female Mouse to the maternal female Mouse. I have a couple questions about whether or not for instance, the transition is governed by the presence of pop. So, for instance, you take a virgin female, she'll mate with a male 1. She's had pops Shoal try and fight that mail or presumably another Intruder female, right?
Equally towards females and male
Intruders. Does that require the presence of her pups? Meaning, if you were to take those pups and give them to another?
Mother. It does she revert to the more virgin like behavior? Is it related to? Is it triggered by lactation or could it actually be triggered by the mating behavior itself? Because 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. 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 females 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
Us to meet 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 due 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 must the lids are, there must lid and they, they're mating behavior. I guess I didn't say. Wow, I was watching this doesn't matter.
It simply doesn't matter, but if one observes The Mating behaviors of different animals, we know that there's a tremendous range of mating behaviors in humans. There can be no aggressive component. That could be aggressive component. Humans have all sorts of Kingston, fetishes, and behaviors and most of which probably has never been documented. Because most of this happens in private. And here, I always say on this podcast. Any time we're talking about sexual behavior in humans, were always making the presumption that it's consensual age, appropriate context, appropriate and species-appropriate.
Viet let's say we're talking about a lot of different species with that said just to set context as 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 an anthropomorphize I'd say it's not really clear. They both want to be there. It, you would just one would make that assumption. And of course, we don't know. We have no idea. This is could be the ritual. It seems to me that there is some crossover of
Aggression and mating behavior circuitry during the act of 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 in, you can imagine that states overlapping, your four different states, the the motivational drive to mate, the motivational drive to get away from this experience, the motivational drive to
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 and 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 cross talk between these different neuronal populations? And the animal itself might be kind of confused about what's going
on, right great, great questions. I can't really,
Speak to the issue of whether this is species-specific, as 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 VM, H, VL, that control aggression in males, is that within that population, there is a subset of neurons that is active.
Dated by females during male female mating encounters. Now, you don't generally think of mouse sex as rough sex, but they're there is a lot of what superficially looks like violent Behavior sometimes, especially if the female rejects the mail and runs away, and there's some evidence that those female selective neurons in vmh our part.
Of the mating behavior. If you shut them down, the animals, don't mate. As effectively as they otherwise would what happens when you stimulate them? We don't yet know because we don't have a way to specifically do that without activating the male aggression neurons. But I think they must be there for a reason because vmh is not traditionally the brain region to which male sexual behavior has.
Been assigned. That's another area called the medial preoptic area, and there we have shown that there are neurons that definitely stimulate mating behavior. In fact, if we activate those mating neurons in a mail, while it's in the middle of attacking another male, it will stop fighting. Start singing to that mail and start to try to mount that mail until we shut those neurons off. So those are the Make Love Not War, neurons and vmh.
Are the make war not love neurons. And there are dense interconnections between these two nuclei which are very close to each other into the in the brain. And we 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 some an animal. It's supposed to be attacking but it's also possible that there are some
operative 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.
Bearing of fangs, we don't know that but certainly the substrate the wiring is there for that to happen,
I'm sure people's. I mines are running wild with all this. I'll just use this as an opportunity to raise a something. I've wondered about for far too long which is I have a friend who's a psychiatrist who works on the treatment of fetishes. This is not a psychiatrist that I was treated by. I'll just point that out but they mentioned something very interesting to me long ago which
Is that when you look at true fetishes and what meets the criteria for fetish that there does seem to be some what one would think? Would be competing circuitry that suddenly becomes aligned. For instance, avoidance of feces dead, bodies feet things that are very infectious, typically those States and of discussed are antagonistic to states of desire. As when wood
Hope it's the present during sexual behavior. Fetish is often involve exactly those things that are aversive feet dead, body's disgusting things to most people and true fetishes in the pathologic sense exists. When people have a basically a requirement for thinking about or even the presence of those ordinarily, disgusting things in order to become sexually aroused as if the
Circuitry has crossed over and there the statement the wrong in my mind was people don't develop fetishes to mailboxes or to the color red or two random objects and things, they develop fetishes to things that are highly infectious and counter reproductive appetitive States. So I 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.
This area of the brain that so highly conserved the hypothalamus, which you have these dense populations intermixed. And that the addition of a forebrain is especially in humans that can think and make decisions could in some ways facilitate these, 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 neurobiological standpoint is that they represent a kind of
Headed of conditioning wear, something that is natively, aversive or disgusting by being repeatedly paired with a rewarding experience changes. Its valence it's sign. So that now it somehow produces the anticipation of reward the next time a person sees it. Now I don't know how, I don't know that literature in animals, so I don't know.
Know, if you could condition a mouse to eat feces. For example, although there are animals that are naturally coprophagic, that is and maybe mice. Do that occasionally? I'm not sure. But that is one way to think about it. And that could certainly involve in humans. The more recently of all parts of the brain, the cortex that is sort of orchestrating, both what behaviors are happening and whether reward States.
Turning on in association with those behaviors that are happening. And that's the, that's the part that I think is difficult and challenging to study in a mouse. But certainly, 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 it, when we made that Discovery initially, it raised the question in my mind, whether some people that are are serial rapists, for example, and engage in sexual violence, might in some level have their wires crossed in some way that that these states that are supposed to be pretty much separated and mutually antagonistic. Are not in are actually more rewarding and reinforcing. I think it's
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 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
Certainly the menstrual and or estrous cycle and females is related to changes in body temperature. In fact, measuring body temperature is one way that women can fairly reliably predict, ovulation, Etc. Although additional, this is not a show about contraception please. Rely on multiple methods as necessary. Don't use this discussion as your guide for contraception based on temperature, but if you stimulate certain neurons in the medial preoptic area, you can trigger dramatic changes in body.
Temperature and or mating behavior. What's the relationship? If any between temperature and mating or do we simply not
know, I don't know what the relationship is between temperature and mating neurons in the preoptic area. I suspect that they are different populations of neurons because it's become pretty clear that the preoptic area has many different subsets of neurons.
Bonds that are specifically active during different behaviors, even different phases of mating behavior. So there are mounting neurons there intromission thrusting, neurons and ejaculation neurons and sniffing
neurons. Wait, so I think I've heard this before, but I just want to make sure that people get this. I want to make sure I get this. So you're telling me within media myth, in medial, preoptic area, there, specific neurons that if you stimulate them will make males thrust as if they're mating.
No. So this is
Not based on on stimulation experiments. It's based on Imaging, ice experiments right now that we see when we look in the preoptic area at what neurons are active during different phases of aggression. We see that there are different neurons that are active during sniffing mounting thrusting and ejaculation and they become repeatedly activated each time. The animal goes through that site during mating during The Mating Season.
Cool. There are also some neurons there that are active during aggression which are distinct. And we don't know whether those neurons are there to promote aggression or to inhibit mating when animals are fighting. We have some evidence that suggests, it may be the latter, but we don't know for sure. Yet the thermo sensitive neurons are really interesting because you mentioned the phrase in heat. And then in the context of aggression you talk about hot-blooded people or
Hot Headz. 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 V zones, that control these basic survival behaviors, like mating, and aggression and Predator defense. And I would imagine that the thermoregulation is tight.
Be connected to energy expenditure. And 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? Seems hard to believe because we're homeo thermic. And we pretty much stay around 98.6 Fahrenheit. Could be other social reasons why that happens, people are outside out on the street, bumping into each other, but I think there could well be something that ties.
Relation to aggressiveness as well as two mating behavior.
Fascinating? Gal I asked in the hopes that in maybe in the years to come, your lab will parse some of the temperature relationships it. And I realized it could be also regulated by hormones in general. So it's tapping into two systems for completely different reasons. But anyway, an area that intrigues me because of this notion of hotheadedness I'm cool calm and collected and also
The fact that I probably should have asked about this earlier that arousal itself is Tethered to the whole mating and reproductive process. I mean, without a sort of see-sawing back between the sympathetic and parasympathetic, you know, arousal, relaxed states. There is no meaning to that will take place. So it's a 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 another context, actually be related to we presume dominance. And I think that my friends who practice
It's ooh, we'll say they when I talk about that result. They say of course you know, mounting the other person and dominating them. It's there's nothing sexual about it. It's about overtaking them physically literally being on their next side, as opposed to on their own lying on their own back, just fascinating very primitive. And yet I think speaks to this idea that mounting Behavior might be one of the most fundamental ways in which animals and perhaps even humans Express dominance and
Or sexual
interactions. Yep, that's a fascinating question and it was harder to figure out than you might have fought. So, we've just been this debate for a long time in the field. When you see two male mace met 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,
Wish 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 and 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, we found out is they don't sing at all when they're mounting a male, so you can easily distinguish whether mounting
Mayor by a male Mouse is reproductive or agonistic aggressive according to whether it's accompanied by ultrasonic vocalizations or not. And it turns out that different brain regions are maximally active during these different types of mounting. So vmh, the aggression, Locus is actually active during dominance mounting and you can stimulate mounting if you
Dominus mounting if you weekly activate the EMH, whereas mpo, a is most strongly activated during sexual mounting and that's always accompanied by the ultrasonic vocalizations. So this shows how difficult and dangerous, it can be to try to infer an animal 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 nose, a even more. So with when that animal, is it, human or has multiple humans?
That's right. And there are many examples, you know, 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 etc, etc. And one thing I can tell you is that female dogs will Mount and thrust. We had a female pit bull. Mix, very sweet dog, but in observing her, it could it convinced me that one can never assume that male dogs are more aggressive than female dogs. There's a it turns out and talking to. People were quite skilled at dog, genetics and dog. Breeding
That there is a dominance hierarchy within a litter, and it crosses over male-female delineations. So you can get a female in the litter. That's very dominant a male. That's very subordinate, and no one really knows what relates to. This is also, why little dogs sometimes we'll get right up in the face of a big Doberman Pinscher and just start barking, which is an idiotic thing for it to do. But they can be, they can be dominant over a much larger, dog. Very strange to me. Anyway,
Female female mounting Do You. Observe it in mice? Are there known circuits and what evokes female female mounting or female to male mounting if it
occurs? Good. Yes, there is female. There are clear examples of females, displaying male-type mounting Behavior towards other females. We see this most commonly in the lab, where we are housing, females with their sisters, say three or four and A
Age. 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. 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 mount, the neurons that control mounting in males in the medial
Optic 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 males on top and she's underneath and we stimulate those, that region of mpo, a, in the female and she crawls out from underneath, the male, who is 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. Don't ask me how I know that. Okay, but it's a pretty yeah. It's a it's a term that that you hear you also hear that the the term topping from the bottom, which it sounds like that is a literal topping for my son. 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, at some point, right? It, we, I attempt in my mind to superimpose observations from the the online communities that I'm told about and asked about to this, but I should point out it's always dangerous and and in fact inappropriate to make a one-to-one, the link, you know, humans are they maintain all the same neural circuitry and Pathways that were talking about today in mice, but that for brain does allow for
Context Etc. Yep. So what the function is of of female mounting, I don't know. It could be a type of dominance display. It's hard to measure that because people haven't worked on female dominance hierarchies to the same extent that they've worked on male dominance hierarchies. But it indicates that the circuits for male type mounting are there in females as early work from Catherine, duloc suggested.
Some years ago, fascinating
fascinating, I love that paper because as you point out for Chase, you know, the four mounting Behavior, you know, we see it. And we think one thing specifically, and after hearing this was all, actually, I'm not a big fan of fight Sports. I walked them occasionally because friends are into them, but I 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 thrust.
On the back of the other person before they get off almost like I dominated you and I'm, you know, so mimicking, sexual, like Behavior. But there's no reason to think that it's sexual but they're sending a message of dominance is what it implies.
I'd love to talk about something slightly off from this circuitry, but I think thats 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 it, cuz seems to be involved in everything, which is the P AG, the periaqueductal gray, which a little bit further, back in the brain for people 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 to the receptivity or arching of the back of the female tourist.
Intermission and mating from the mail.
How should we think about PA G, clearly? It can't be involved in it 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 PA G 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 Combat Sports person years ago. I did did a little bit of
Larson. It always was impressive to me how little it hurt to get punched during a fight and how much it hurt afterwards, right? So, they're clearly as some endogenous pain control that then wears off and then you feel beat up. Yeah. At least in my case, I felt beat up. What's P AG doing, vis-à-vis, pain and vis-à-vis and what Spain doing vis-à-vis? These other behaviors.
Good. Good. So so I think of PA G like a old fashioned telephone switchboard.
Where there are, 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 and the other end of it because pretty much every type of innate behavior, you can think of has had the pag implicated. If 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.
Behavior running away. The ventral pag is involved in freezing Behavior, both the mpo A and vmh, send projections to the pag to different regions of the pack. So in cross-section, I hate to say this but in cross-section the pag kind of looks like the water in a toilet when you're standing over an open toilet bowl. And if you imagine a clock face projected,
On to that it's like the pag has sectors from 1 to 12 maybe even more of them and in each of those sectors you find different neurons from the hypothalamus are projecting so 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
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
a of pain responses and I'm not sure completely about the mechanisms and how well that's understood. But, for example, the 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 with that peptide is 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 offense of aggression, or in mating behavior. I don't know.
No, but it certainly is possible and I don't know whether these analgesic mechanisms are happening in the pack. They could also be happening a little further down in the spinal cord and the pack 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 and so, it could be that there are influences acting at many levels on pain in the pag.
In the spinal cord as well and it may well be known. I just don't know what 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
we appreciate those delineations. Thank you. Pack is I think this description of is it old fashioned telephone switchboard
And now, every time I look into the toilet, I'll think about the periaqueductal gray and every time I see an image of periaqueductal gray, I think about
a toilet, that is an excellent
description because I, in fact, I drew a circle with a little thing at the bottom and well, I'll put a post, a link to a picture of phe, and you'll understand why, why David? And I are chuckling here because indeed, it looks like a toilet when staring into a toilet.
Tell us about tacky kynan. 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 tacky kynan 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 tacky
One is 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 class
Circle transmitters like glutamate, whatever tacky Keenan's have been famously, implicated in pain, protect particularly tacky kind in one which is called substance P. One of the original Haines modulating. This is something that promotes inflammatory pain but there are other tacky Heinen 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 town
Chi, chi nen's 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 and 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 can
Troll aggression in flies in a people. And so we did a screen unbiased screen of peptides and found indeed that one of the tacky Keenan's drosophila tacky kainan those neurons when you activate them strongly promote aggression and it depends on the release of tacky kynan. Now the interesting thing is that in flies just like in people and practically any other social animal that shows aggression, social isolation.
Elation 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 tacky kynan 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
a key Keenan's might be upregulated in Social isolation and whether they play a role in aggression. And this is work done by a former postdoc morial zoellick offski. 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 tacky kainan to in their brain. In fact, if you tag the peptide with a green fluorescent protein,
Protein from a jellyfish genetically. The brain looks green. When the mice are socially isolated, because there's so much of this stuff released and she went on to show that that increase in tacky. Kainan 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 tacky kinda
In which were tested in humans and abandoned because they had no efficacy in the test that they were analyzed for. If you give those drugs to a socially isolated Mouse, it blocks all of the effects of social isolation. It blocks the aggression, it blocks The increased fear and the increased anxiety, and that Memorial 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 over night. But if you give it this drug, which is called a sonnet on that Black Blocks tacky kinda into 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.
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 be Reeve meant stress and this is one of the areas where I learned an eye-opening lesson as a basic
Dentist 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. And schizophrenia, I have no idea why there's very little preclinical data to suggest that not surprisingly, they failed.
When a, when a drug fails in clinical trials, in Phase 3, it costs a hundred million dollars to the company. That 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 test 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 an
Amal 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 a board.
Line personality disorder. There is a strong correlation between their self-reported level of aggressiveness and serum levels of attack ich einen. In this case, tacky kind in one as detected by radio immunoassay, this is work of Emma and Wilco Caro, 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
Well company that was testing these drugs actually for treatment of hot flashes in females, in humans, where there is actually good animal data to think that it might be useful. But I realized that this clinical trial was going on during the covid pandemic. And I approached him and said look nature may have actually done for you. The experiment that I want you to do because some of the people who are getting drug or placebo
We 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 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 and then it is to try to find out more information that could lead to another clinical indication.
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. Yet
a true shame that these companies won't do this and especially given the fact that many of these drugs exist. And their safety profiles, are established because that's always a
serious consideration, when embarking on a clinical trial. Perhaps in hearing this discussion someone out, there will understand that the key importance of this and will reach out to us, will provide ways to do that, to get such a study going in humans. Because I think if enough Laboratories ran small scale, clinical trials, farmer, certainly would perk up their ears, right? I mean, they're, they're so strategic sometimes to their
own. I mean, I would just, I would like to say also, I'd
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 pain to another and now they're home alone, 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 were
Work on animals and we ultimately want to understand humans. We care about how are our results apply to the welfare of animals as well and particularly domestic pets which is a billion multibillion-dollar industry in this country. So if there is ways that they can be made to feel better when they're separated from their 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.
W.
just underscoring what we've been talking about, even more every time we hear about a school shooting like in Texas recently or I happen to be in New York during the time, when there was a Subway shooting for whatever reason, I listen to the the book about Columbine that when into a very detailed way about the origin of those boys, and that committed that and every single time
There's the person who commits those acts as socially isolated. As far as I know, there might be some exceptions there and sometimes this crosses over with other mental health issues, but sometimes no, no, apparent mental health issues. So social social isolation, clearly drives. Powerful neurochemical neurobiological changes, really hope that tacky kind in 1 and 2. Those are the main ones that humans will be explored in more detail. Also I didn't know that tacky kind and one is substance p and C is tacky
condoms.
He kind of one is the gene name and tacky kind and to in humans is called neuro kainan be, that's the name of the protein. I just refer to it by the gene name because it makes it easier. And I don't have to keep remembering two names for each thing
and I if I'm not mistaken, you see her you, you put yourself in the company of geneticists, because of your original training, was in genetics, immunology, and areas of, it
wasn't into the 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 came out of the closet as a geneticist as it were wonderful.
As long as we're talking about humans, I'd love to get your thoughts about human studies of emotion. I know you wrote this book with Ralph a doll so you have this new book which will provide a link to which I've read front to back twice. It's phenomenal, I've mentioned it before on the podcast, it's really there are books that are worth reading and then there are books that
Important. And I think this book is truly important for the general population to read and understand and neuroscientist should read and understand the contents because we, as a, as a culture are way off in terms of how we think about emotions and states and behaviors. So we'll put a link to that. It's really worth the time and energy to read it and it's written beautifully. I should say very accessible. Even for non-scientists, there's a heat map diagram in that book that I think about this is,
A heat map diagram of subjective reports that people gave of where they experience an emotion, or a feeling somatic feeling in their body, or in their head, or both when they are angry sad. Calm lonely, etc, etc. And I wouldn't want people to think that those heat Maps were generated by any physiological measurement because they were not. And yet,
I don't think we can have a discussion about emotions and states and the sorts of behaviors that were talking about today without thinking about the body also. Yep. And I'm not coming to this as a northern California mind-body. I've been to asselin once I didn't go in the baths. I went there, I gave a talk and I left it is very beautiful if anyone wants to know what it looks like, I think that final scene of Mad Men is shot at esalen. It's a very beautiful place and yet, mine body is a nurse to me as a neurobiological construct because the nervous system extending
Through the out of the cranial Vault and into the spinal cord and body and back and forth. Okay, how should we think about the body and in terms of states? And at some point, I'd love for you to comment on that heatmap 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, you know, the chakras or anger, is in the stomach and this goes to Eastern medicine, Etc. How should we think about Mind Body, in the context of states? And think about it as scientist? Maybe even as neuroscientists are 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, 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 heart. I don't see the liver invoked
Very much in in emotional
characterization, but goal and the gallbladder. Somebody having a lot of gall. I know. I make a fist when I say that, but I'm guessing the gallbladder shaped like a fist. That's right.
And and you know, if there is a physiology, underlying, these heat maps, that could reflect increase blood flow to these different structures. And that in turn reflects, what you were talking about? That is emotion, is definitely involves communication.
Between the brain and the body and it's bi-directional communication and it's mediated by the peripheral nervous system the sympathetic and the parasympathetic nervous system which control heart rate, for example, blood vessel blood pressure. And those neurons receive input from the hypothalamus and other blood brain region, Central brain regions that control their activity and when the brain
Rain 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 on to the brain through the sensory system. And a large part of this bi-directional communication is also mediated through the vagus nerve which many of your listeners and viewers may have heard about
Has become a topic of intense activity. Now, people have known for a long time. So the vagus nerve is a bundle of nerve fibers that comes out basically of your skull out of the central nervous system and then sends fibers in to your heart, your gut, all sorts of visceral organs. So when you have a and that information is both use
use the words earlier in our discussion afferent and efferent. So the the vagal fibers sense things that are happening in the body. So when you're the reason, you feel your stomach tied up in knots, if you're tense is that those vagal fibers are sensing the contraction of the gut muscles, and they're also afferents, which means that information coming out of the brain can influence.
It's 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, controlled 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.
In 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 recognize that as well. And I think it's it's a central feature of emotion State. And I think what underlies, our subjective, feelings of an emotion credible,
David. I have to say, as a true fan of the work that your lab has been doing over so many decades. And first of all, I was delighted when you stopped working on stem cells, not because you weren't doing incredible work there. But because I saw a talk where you showed a movie of an octopus spitting out, or not spitting, but squirting out a bunch of ink and escaping and you said you were going to work on things of the sort that were talking about today. Fear, aggression, mating behavior, social behaviors. It's been incredible to see the work that your lab
Don. And I know I speak on behalf of a tremendous of. 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 sure to come.
I would be happy to do that and I really have appreciated your questions there all they've all been right on the money. You've hit all of the critical important issues in this.
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, and
Tree. 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?
Yes, 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 and are enjoying this podcast, please subscribe to our YouTube channel. That's a simple, zero cost way to support us. Please also, subscribe to the podcast on Spotify and apple and on both Spotify and apple, you have the opportunity to leave us up to a five star review. If you have questions or comments, or suggestions about topics, you'd like us to cover, guess you'd like us to interview on The huberman Lab podcast, please.
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