Dr. David Anderson: The Biology of Aggression, Mating, & Arousal
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I manager huberman and am a professor of neurobiology optio logy at stanford school of medicine today. My guest is doctor David Anderson. Doctor Anderson is a professor biology at the california institute technology, often commonly referred to as cal tech university. Doctor inner son's research focuses on emotions and states of mind and body, and in dt emphasizes how emotions like happiness, sadness, anger and so on, are actually sub categories 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. The dict, whether 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 influenced the way we interpret our experience and our surroundings.

Today, doctor inertion teachers us, for instance, why people become aggressive, and why that aggressive can sometimes take the form of rage, also talk about sexual behavior and the boundaries and overlap between aggression and sexual behavior, and that discussion about aggression and sexual behavior also starts to focus on particular aspects of neural circuits and states of mind and body. The govern things like, for instance, male, male aggression versus male, female aggression versus female, female aggression. So today you will learn a lot about the biological mechanisms that govern why we feel the way we feel.

Indeed, dr. Renison 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 to contain 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 myth about emotions and biology.

So whether not you're a therapist or your a biologist or you're simply just somebody interested in why we feel the way we feel and why we act the way we act, I cannot recommend the both highly enough. Again, the title is the nature of the beast, how emotions guide us. Today's discussion also ventures into topics such as mental health and mental illness, and some of the exciting discoveries that have been made by doctor Anderson's laboratories and other laboratories identifying specific peptides, that is, small proteins that can govern whether not people feel anxious or less anxious, aggressive or less aggressive.

This is an import 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. Doctor Anderson is considered one of the most pioneering, an important researchers in neurology of our time, indeed, is remember the national academy of sciences and Howard, huge medical institute investigator.

I've mentioned the hh of mi wants to twice before when we've had other hh of my guests on this podcast. But for those who you are not familiar, the how are you use medical institute funds a small number of investigation, doing particularly high risk, high benefit work. And IT is an extremely competitive process to identify those how he he's investigators.

They are essentially appointed in every five years. They have to compete against one another and against a new incoming flock of would be A J R mi investigators to get another five years of funding. They are literally given a grade every five years as to whether not they continue, not continue, or whether not they should worry about being funded for an extended period time after r.

Anderson has been investigated with the Harry he's medical institute since nineteen eighty nine. Before I begin, i'd like to emphasize that this podcast is separate from my teaching and researchers at stanford. IT is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public.

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Today's episode is also brought to us by waking up, waking up as a meditation APP that includes hundreds of meditation programs, mindfulness trainings, yoga eja, recessions and n sdr non sleep depressed protocols. I started using the waking up up a few years ago because even though i've been doing regular meditation since my teens, and I started doing yoga ea about a decade ago, my dad mentioned to me that he had found an APP turned out to be the waking up APP, which could teach you meditations of different durations. And they had a lot of different types of meditations to place, to bring your body into different states, and that he liked IT very much.

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And now for my discussion with doctor 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 we should think about emotions, what are they they have all these names, happiness, sadness, depression, anger, rage. How should we think about them and why might states be at least as useful a thing to think about, if not more useful?

That's great. Um first, the short answer to your question is that I see emotions as a type of internal state in the sense that arouses also a type of internal state motivations, the 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 classic state that controlled behavior. The reason I think is 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 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 at 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 isn't important, IT is but you have to understand consciousness if you want to understand feelings and we're not ready to study that in animals yeah and so that's how I think about IT.

What are the different components of a state? Um you know you mentioned a raw sal as a key component. What are some of the other features of states that represent this as you so beautiful ly put in your book that represent below the tip of the eyes.

right so um you can break states up uh into different facets or people would call them dimensions. And so uh there been people who thought of emotions as having just really two dimensions a an arousal dimension uh uh how intense IT um and also a violent dimension um which is is a positive or negative, good or bad. Rw, fat off.

And I have tried to expand that a little bit to think about components of emotion, particularly those that distinguish emotional states from motivation states because they are very closely related. Um one of those important properties is persistence um and this is something that distinguishes state driven behaviors from simple reflex. It's reflexes tend to terminate when the stimulus turns off, like the doctor hitting your knee with a hammer initiates with the stimulus onset and a terminate 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 gonna jump in the air, but your heart is gone to continue to beat, and your palms sweat, and your mouth is going to be dry for a while after IT slivered off in the bush, and you're going na be hyper visual. And if you see something that even remotely looks snake like a stick, you're going to a stop and jump so persistently important feature uh of of emotion states not all states have persistence.

So for example, you think about hunger. Once you've eaten, the state has gone. You're not hungry anymore. But if you are really angry and you get into a fight with somebody, even after the fight is over, you may remain riled up for a long time, and that takes you a while to calm down. And that may have to do with the arousal.

Dimension or some other part of IT um and then uh generalization is an important component of emotion states um that uh make them if they have been uh triggered in one situation, they can apply to another situation. 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 sue that if you had a bad day at work, you might react very differently to IT and scream at IT. And so that's the generalization of the state that was triggered at work by something your boss said to you to completely different interaction.

And again, that's something that distinguishes emotion states from motivation states. Motivation states are really specific, find and eat food, obtain and consume water, uh, and there they're involved in homeostatic maintenance. So states are very multivu.

And just asking questions about how these components of states are encoded, like what makes a state persist? What gives a state a positive or a negative violence? How do you crank up or crank down the intensity? The state IT just opens up a whole bunch of questions that you can ask in the brain with the kinds of tools we have now.

You mentioned the rosal a few times, and you mentioned violence. Realizing that there are these other aspects of states, i'd like to just talk about a rose a little bit more unveiling, because at a very basic level, that seems to me that although 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, the, the illness 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 lish neurochemical signature that can flip violent? So rena, is there any way that we can safely rely, say, that arouse with some additional dopamine in release is going to be of positive violence and although with very low doping is going to be of negative violence.

uh, I 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 that might be that a given neurochemical leaving dopamine is involved in both positive ly violently ed rosal and negatively violence to rusal.

That's why people think about these as different as 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 kinds of rosal that are specific to different behaviors? And you raise a question of sexual arousal feels different from aggressive arousal, for example.

And we actually published a paper on this back in two thousand nine in fruit flies, where we found some evidence for two types of arousal states, one of which is sleep wake. Zl, you're more rose when you wake up, and when you are sleep and fly, show that. And the other is A A startle response and a razer response to a mechanical stimulus.

And not just mechanical stimulus, if you puff air on flies, kind like trying to swap the wasp away from your burger picnicked 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 our sal required dopamine, they were, they were exerted through completely separate neural circuits in the fly.

And so that really put number one, the emphasis on is the circuit that determines the type of arousal, but also that arousal l isn't unitary, that there are behavior specific forms of arousal. And I think the jury is still out as to whether there is such a thing as completely generalized arousal or not. I think some people would argue there is, but I think more attention needs to be paid to this question of domain specific or behavior .

specific forms of ousel. It's a super interesting idea because I always thought of arouse as along as continue to bring a panic attack at the one end of the extreme origin in a coma and then somewhere in the medal you're alert, calm but then this issue of the illness really as as you say um presents this opportunity that really there might be multiple circuits for use or multiple mechanisms that would include new chemicals as well as different neural pathworks. So like to talk a bit about a state um if if this is indeed a state which is aggression. Your labs worked extensively on this.

And if you would, could you highlight some of the the key findings there, which brain areas are involved, the beautiful work of du 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 too simple um how should we think about aggression? And i'll just sort of screw the question a bit more by saying we see lots of different kinds of aggression.

This terrible school shooting down in texas recently, clearly an act that included aggression. And yet you can imagine that a very different type of aggression, and you know IT all outrage or controlled aggression. There's there's a lot of variation there. So uh, what are your thoughts on aggression, how it's generated, the neural circuit mechanisms and some of the variation in what we call aggression?

Yeah this is a great question and it's a it's a large area. I would say that the first of all um the word aggression in my mind refers more to a description of behavior than that does to an internal state um aggression could reflect an internal state that we would call anger in humans or could reflect fear or IT could reflect hunger if its predatory aggression and so this gets at the issue that you raised of the different types of aggression that exist on the work that die did when he was in my lab. Uh, that really broke. Open the field to the application of modern genetic tools for studying circuits and mice is that SHE found a way to evoke aggression in mice, using up the genetics to activate specific neurons in a region of the hypotheses.

The venture media hypothetic V M H, which people have been studying and and looking at for decades following first the work of uh um in in hats, the famous nobel prize winning work of water hess and and then followed by work done by meno crook in the netherlands in rats where they would stick electrical wires into the brain and send electric current into the brain and they could trigger a plastic cat to suddenly spare its team, his and almost strike out of the experimenter um and they could trigger uh uh rats to fight with each other and even in houses. Original experiments, he describes two types of aggression that he evokes from cats, depending on where in the hypothenuse he puts his electrode, one of which he calls defensive rage, that's the years 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 one to hatch 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 um um two thousand eight two thousand nine um when that 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 die you who was an electrical hesiod gist, just repeat the electrical stimulation of the venture media hyper Thomas 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 forty different trials.

IT just didn't work. What he got instead was fear behaviors. SHE got freezing, corny and crowd in. And finally, in desperation, and we got a lot of input from mental crook on this, he really was missed. Fied, why doesn't IT work in mice? We realize why there had been no paper on brain stimulated aggression in mice in fifty years, because experiment doesn't work.

And the one bit of credit I can claim there is, I convinced, die to try up the genetics because, uh, I just had sort of come into use deep in the brain from a cal dice raw and others work um and I thought maybe because IT could be directed more specifically to a region of the brain and types of cells and up the genetic stimulation, electrical stimulation, IT might work. And dial said, never never gonna work. If IT doesn't work with electricity, why should IT work with othe genetics and fact is that I did work and we were able to uh uh trigger aggression in this region using up the genetic stimulation, eventual medial hypothalamic.

And in retrospect, CT. I think the reason that we were seeing all these fear behaviors is because right at the upper part, if you think of the of the media hypothesis, like a pair sitting on the ground, the fat part of the pair, I knew 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 feeder circuits. And those totally dominate aggression. And so that's why we were never able to see any fighting with electrical stimulation.

As when you use up up the genetics, you confine the stimulation just to the region where you've implanted the channel, adopts and gene into those neurons. And so in fast ford from that from a lot of work from die now on her own N Y U. And with her post stock and a gtd falker, uh, there's a as well as work of other people.

There's evidence that the type of fighting that we were that we illicit when we stimulate vm h 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 gravity towards the compartment where those neurons are activated. IT has a positive violence. And when I went into this field and I was thinking, well, what goes on in my brain and my body when i'm furious, IT certainly doesn't feel like a rewarding experience.

It's not something that I would want to repeat because IT feels good when i'm in that state. IT doesn't feel good at all when i'm in that state. And IT is still, I think, a mystery as to wear that type of aggression, which is more defensive ve aggression, the kind of aggression you feel if you're being attacked or if you been cheated by somebody where that is encoded in the brain and how that works still I think, is, uh, a very important mystery that we hadn'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 venture medial hypothalamic c circuits.

So it's become clear that if you want to call IT, the state of aggressiveness is multifaceted, 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 favorite sits called the substantial in amona.

The substance with no name I like that are so the nucleus ambience, you know, or the zona inserted, these places that no one can think of what they are any how that might be a final common pathway for predatory aggression and offensive and defensive aggression. But I 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 clear when the animals engaged offensive versus defensive aggression, they direct their bites at different parts of the opponents body. In the a offensive aggression is fank directed. Defensive aggression goes for the neck, goes for the throat.

I've seen some nature specials were in a very barbering way, least to me. IT seems like highly us will trying go after the the reproductive access. They'll go after testicles and penis and they busy IT seems they want to limit future breeding potential but create pain or a or create pain or both yeah yeah.

I mean, in terms of offensive aggression, that your a reflection that IT doesn't feel good. I I mean, I can say I know some people who really enjoy fighting. Every relative who is a lawyer, he loves to argue and fight. I don't think a woman is physically aggressive fact.

He's a not but loves to fight and loves to prosecute and go after people not and he's pretty effective at IT of a friend, former military special Operations and very calm guy, had a great career in the in military special Operations, and he held quite, you plainly say, I love to fight. It's one of one of my great joys. He really enjoyed his work um and and also respect to the other side because they offered 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 don't deserve myself somebody who offensively goes after you'll just to go after them. There's no quote and quote dopa mine hit here acknowledged that dopamine does many things, of course. Yeah, I have a couple of questions about the way you described this, the circuit tree, I should say the way the circuitry is arrange.

And of course, we don't know because we weren't consulted the design phase. But why do you think there would be such a close positioning of neurons that can illicit such divergent states and behaviors? I think you're talking about this pair shape structure where the neurons that generate fear are cheek to jaw with the neurons that generate offensive aggression of all things. It's like um putting the neurons that control um swallowing next to the neurons that control vomitings IT seems to me that um on the one hand this is the way that neural circuits are often arranged and yet to me it's always been prolixity as to why this would be the case.

Yeah I think that that is a very profound question and um I i've wondered about that a lot. Um if you think from an evolutionary perspective, uh IT might have been the case that defensive behaviors and fear arose before offensive aggression um because animals first and foremost s 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 and safe that they can start about start to think about who's gonna the alpha male in in my group here.

And so IT could be that if you think that brain regions and cell populations evolved by duplication and modification of preexisting cell populations, that might be the way that those regions wound up next to each other um and developmentally they start out from a common pool of precursors that expresses the same gene, the fear neuron 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 or is just an it's an accident of evolution and development, but I think there must be a functional part as well. So one thing we know about offensive aggression is that strong fear shut IT down.

Where as defensive aggression, at least in rats, is actually enhanced by fear, is one of the big differences between defensive aggression and offence of aggression. And you think about IT, if you think about IT, if offence of aggression is rewarding and pleasurable, if you start to get really scared, that tends to take the fun out of IT. And maybe these two regions are close to each other to facilitate inhibition of aggression.

Bit the fear neurons. We know for a fact that if we deliberately stimulate those fear neurons at top of the air, when two animals are involved in a fight, IT just stops the fight that in its tracks, and they go off into the corner and freeze. So at least hierarchically IT seems like fear is the dominant behavior over offence of aggression.

And how that inhibition would work is not clear, because all these neurons are pretty much excited, tory there, almost all glue material. And so one of the interesting questions for the future is, how exactly does fear dominate over and shut down offensive aggression, the brain? How does that work? Is at all circuitry of their chemicals involved.

What's the mechanism and when is IT called into play? Um 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 fight. There are also met a BOC neurons that are mixed together in vm h as well .

controlling the body wide .

metabolising ah there on there that respond to glue cos. When glue cos goes up in in your bloodstream, they're activated. And vm h as 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 the V M H is they think about, oh, that's the thing that keeps you from getting fat is the anti obesity area. But in the area of social behavior, um we see IT as a center for control of aggression and fewer behaviors. And again, why these these neurons and these functions, I i'd like to call them before f feeding, freezing, fighting and mating that they all seem to be closely and intermingled with each other maybe because cross talk 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 linked to the incredible videos of these mice that have a selective stimulation of neurons in the V H die use and the other studies that you've done.

One of I teach I show those videos at some point um with the covey's and warnings that are required when one is about to see a video of a mouse trying to mate with another mouths were made with another mouse and they seem both to be quite happy about the meeting experiences, as far as we know as the observers of mice and then upon stimulation of those via a neons, one of the mice SHE 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 make 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 vm irons are stimulated and the mouse goes into a rage. IT looks like he wants to kill a glove basically. Um so striking and encourage people to go watch those because IT really puts um a tremendous ounce of color on what we're describing.

And it's just the the idea that there are switches in the brain uh to me really became clear upon seeing that a one of the concept, excuse me, one of the concepts that um you raised in your lectures before and and that I think was has his idea is this idea of a sort of hydraulics sure or maybe he was lad kon rad. I can speak down, excuse me, con red law rends and who talked about a kind of hydraulic pressure towards behavior i'm fascinated by this idea of hydrology pressure because I don't consider myself a hot temper person, but I am familiar with the fact that when I lose my temper, IT takes quite a while for me to simmered down. I can't think about anything else.

I don't want to think about anything else. In fact, think trying to think about anything else becomes aversive to me, which to me underscores this notion of prioritization of the different states and potential conflicting states. What do you think falls into this idea of hydraulic c pressure towards state? And why is IT perhaps that sometimes we can be very angry, and if we succeed in winning an argument of a senate will um because clearly that means that there are external influences.

It's a complex space here that where we're creating I realized 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 the state, like sleep, there's a sleep pressure there. There is a pressure towards her that all makes sense. But what's involved is IT too multi factorial to actually um separate out the variables. But what what's really driving hydraulic pressure toward a given state?

Yeah so uh really important question. Uh, I think one way that is helpful, least for me to break this question apart and think about IT, is to distinguish homeostatic behaviors, that is, need base behaviors where the pressure is built up because of a need like, i'm hungry, I need to eat, i'm thirsty, I need to drink, i'm hot, I need to get to a cold place, is basically the thermostat model of your brain.

You have a set point, and then if the temperature gets too hot, you turn on the ac, and if the temperature gets too cold, you turn on the heater and put yourself back to the set point. I don't think that's how aggression works. That is it's not that we all go around, at least subjectively, I don't go around with an accumulating need to fight, which I then look for something to an excuse to release IT. Now maybe there are people that do that and they go out and look for bar fights to get into or twitter yeah twitter twitter .

seems to do ads over half chicken because twitter seems to draw a reasonably sized crowd of people that are there for combat of some sort um 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 but I agree. I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens.

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Yeah so you can think you can think of this accumulated hydroid pressure either being based on something that you are deprived of creating an accumulating need, or something that you want to do, building up A A driver 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 brand of the hypothesis that controlled feeding, Scott stern son and others have shown that the hungry you get, the hire, the level of activity in that region, in the brain, and then when you eat, boom, the activity goes right back down again. And um that state is actually negatively violence. So it's like the animal coron quote, feels increasingly uncomfortable, just like we feel increasingly uncomfortable, the hungry where we are and then when we eat IT tamps IT down.

But there is this increased activity. And I think in the case of aggression, our data and other show that the more strongly you drive this region of the brain, of the genetically, the more of just a hair trigger you need to set the animal off to get IT to fight. And the interesting thing is that if there is nothing for the animal to attack, IT doesn't really do much.

When you're stimulating this region, IT sort of wonders around the cage a little bit more. But IT will not actually show over attack if unless you put something in front of IT. And the same thing is true of the areas we've described, the control mating behavior.

This is what linsey is working on. You can stimulate those areas till you're blue in the face and the mouse just sort of wonders around. But if you put another mouse in one, he will try to a mount that mouse.

If you put a come quite in the cage, he'll try to a mount the come. And so IT becomes the 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 is increased activity in some circuit or circuit some place, what is IT pushing up against that needs something else to sort of unplugged in the in the lower hydraulic model that you don't see the behavior until you release a valve on this bucket and let the accumulated pressure flow out. And that's one of the things we're trying to study in the context of the mating behavior as well. How does the information that there's an object in front of you come together with this drive state that is generated by stimulating these neurons in the hypothenuse 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 mentioned people, doctor son mentioned linsey linzie as a former graduate student of mine that's now a postdoc and David slab and um I haven't caught up with her recently to hear about these experiments, but they sound fascinating. I I would love to spend some time on this issue of. Why is IT that a mouse won't attack nothing but it'll attack even a glove? Um or and why um will only try me if there's another a mouse to mate with.

Actually I think fortunately um for you, you're not spending a lot of time on twitter and instagram but or youtube, but there is this whole online community that exists now as far as I know, it's um almost exclusively Young males who are obsessed with this idea um to say that has a name it's called no fab of no mastering as a way to maintain their motivation to go out and actually seek mates because of the uh ready availability of online pornography. There's an probably a much larger population of Young males that are never actually going out in seeking mates because they're getting porn addicted at that. There is actually a serious issue that came up in our episode with analysts y who wrote the book dopamine of a because available build a pornography.

There's a whole social contacts that's that's being created around this and genuine addiction. Um so humans are are not like the mice or mice are not like the humans. Humans um seem to resolve the issue on their own ways that might actually impede seeking in finding of sexual partners and our long term mates.

So serious issue there um I raised IT as a serious issue that 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 no fab and I never actually replied because there's no data yeah but but what you're raising here is a very interesting mechanistic uh, scenario that that can can in as you mentioned, is being explored. So what do we know about the internal state of a mouse whose vm h is being stimulated or a mouse whose um other brain region that can stimulate the desire to mate?

What do we know about the internal state of that a mouse, if it's just alone in the cage wandering around, is IT wandering around really wanting to mate and really wanting to fight? Of course don't know. Um but is its heart rate up? Is its blood pressure up?

Um is IT wishing that there was pornography? Is IT some things going on personably that's different than prior to that stimulation? And is IT arousal? And what do you think IT is about the visual al factory perception of a on specific that engage this tremendous repetitive 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 are activated up the genetically in the same way we would activate the aggression irons, that there is clearly an arousal process that's occurring. You can see the pupils, Dylan, 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 automated ic arousal and neural indecent activation of stress responses. And some of that is probably shared by the aggression neurons and the main neurons, although we haven't investigated in as much detail.

But I wouldn't be surprised because they project to many of the same regions that the uh fear neurons project to, which is an interesting issue in the context to discuss later, maybe in the context of and why we're comfortable with mental illness nesses that are based on mal adaptations of fear, but not mental illnesses that are based on maladaptive tient of aggression if they have pretty similar circuits in the brain. But um that's that's how I would imagine there is an arousal dimension, as you say, their stress harmons that are activated. These regions V M H projects to about thirty different regions in the brain, and IT gets input from about thirty different region.

So I kind of see IT as both an antenna and a broadcasting center is like a satellite dish that takes in information from different sensory aliis smell, maybe vision, the mechanical sensation and then it's sort of synthesizes and integrates that into a fairly low dimensional, as the computational people call IT, uh, representation of this pressure to attack and a broadcast that all over the brain to trigger all these systems that have to be brought into play. If the animal is going na engage in aggression, because aggression is a very risky thing for an animal to engage, IT could wind up losing and IT could wind up getting killed. And and so its brain constantly has to make a cost benefit analysis of whether to continue on that path or to back off as well. And I think that part of this broadcasting function of this region is engaging all these other brain domains that play a role in this kind of cost benefit analysis.

I want to talk more about mating behavior. But as a segway to that, as were talking about aggression and mating behavior, I think cormon's. And whenever there's an opportunity on this podcast to shatter a common myth, I I grab IT. One of the common myths that's out there, and I think that persist, is that testosterone makes animals and humans aggressive, and estrogen makes animals plastic and kind or emotional. And as we both know, nothing could be further from the truth.

Although there is some truth to the idea that these four mones are all involved, Robert super ski a supplied some information to me when he came on this podcast that if you give people exogenous testoon IT tends to make them more of the way they were um before if they were jerk before, they become more of a jerk, if they were very altruisti C2Become mor e alt ruistic. And then eventually I pointed out, you'll realize that testosterone and air gen and you'll start getting opposite effects. So it's it's a monkey space.

It's not straight forward. But if i'm not mistaken, testosterone plays a role in generating aggression. However, the specific hormones that are involved in generating aggression via vm h are things other than test aston on. Could you tell us a little bit more about the access? Is some interesting surprises in there?

Yeah, that's a really important question. So the, when we finally identified the neurons in V M H that control aggression with a molecular marker, we found out that that marker was the s region recept. So that might strike you as a little strange.

Why should a aggression promoting neurons in male mice be labeled with the s rogen recept? Other labs have shown that the estrogen receptor in adult mail mice is necessary for aggression. If you knocked out the gene in vm h, they don't fight. And it's been shown.

And a lot of this is work from your colleague, nearby shaw at stanford, who is one of my former PHD students, that if you castrate a mouse, uh, and IT loses the ability to fight, not only can you rescue fighting with a testosterone in plant, but you can rescue with an s regen in plant, 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 them, are mediated by its conversion to extradition by a process called a ommatidia. It's Carried out by an ensign called aromatase.

In fact, people may have most of your listeners may have heard of a roma e because a romas inhibits are widely used in female humans as adjuvant chemotherapy for breast cancer. They are a way of reducing the production of echogen by preventing testosterone from being converted into a trigen. And in fact, there a lot of animal experiment showing if you give males aromatic inhibitors, they stop fighting as well as also a stop being sexually active um and so that's one of the counter intuitive ideas and neuro has shown that progestins one also seems to play a role in aggression because these aggression irons also expressed the progesterone recept.

So here are two hormones that are classically thought of as female reproductive hormones. This is what goes up and goes down during the extra cycle, estrogen and protesters one. And yet they're playing a very important role in controlling aggression in and IT, presumably in male humans as well.

fascinating. So asteroid is doing many more things than I think most people believe. And just to strong is doing maybe different and fewer things in some cases, and more and others. I've some aggressive females over the time I been alive. What's involved in female aggression that's unique from the pathways that generate male aggression?

Great, great question. So uh, we and other lambs have studied ed this in both mice and also in fruit flies. So uh 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 weed, that aggressiveness goes away.

So this is pretty remarkable that you take a virgin female mouse and expose IT to a mail and her responses to become sexually receptive and to mate with him. And now you let her have pups, and you put the same male or another male mouse in the cage with her. And instead of trying to mate with him, SHE attacks him.

So there is some resume bly hormonal and also neuronal switch that's occurring in the brain that switches the response of the female from sex to aggression, uh, when he goes from virginity to maternity. And we recently shown in a paper, this is work for one of my students among you leave that with in via and females, there are too clearly divisible subsets of estrogen receptor neurons. And he showed that one of those subsets controlled fighting, and the other one controls made in.

In fact, if you stimulate the fighting specific subset in a virgin, you can get the virgin to attack, which is something that we were never, never able to do before. And if you stimulate the meeting one, you enhance mating. The reason we could never get these results when we stimulated the whole population of estrogen reception irons is that these effects are opposite, and they cancell out.

And so IT turns out that if you measure the activity of the fighting in the mating neurons going from a virgin to a maternal female, the aggression around are very low in their activity in the virgin. But once the female has pops, 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 sea saw in the virgin, there is more activity in the mating neurons and in the fighting neurons, where, as in the in the nursing mother, there is more activity or more activation in the, in the other way around the fighting irons, in the main.

Did I say finding in making the first made neurons dominate fighting in the virgin fighting neurons dominate made in in the mother so that's a really cool uh uh observation and it's not something that happens in males and we don't know what causes that or controls that. Uh interestingly, 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 neuron. 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 human population of neurons in both male and female flies, that in females activates the specific fighting neurons and in males activates the male specific fighting neurons. So it's kind of a higher archy with this common neuron on top.

And in mice, we discovered that there are male specific neurons in vm h, and those neurons are activated during male aggression. Now that neurons that are active in females when females fight in vm h are not sex specific, so they are also found in males. So this is already showing you some complexity.

The male mouse V H has both male specific aggression neurons and generic aggression neurons. And then the female vm h, 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 population tions of neurons are doing. But that indicates that that is some of the mechanism by which different sexes is show different behaviors.

I'm fixated on this, a 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 solferino. We take a virgin female, she'll met with the mail when she's had pops. Shall trying to fight that male, or presuming another intruder female, right?

Equally towards females and males.

Tudes does that require the present suffered? Pops, meaning, if you were to take those pops and give them to another mother IT does SHE revert to the more virgin like behavior is IT relate to? Is that trigger 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 pops?

right? Those are all great questions and we don't know the answer most of them. What I can say is that A 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 um uh he 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 intruder equally. Or as in male mice, the aggression neurons are only ever activated by males, not by females, because males are never supposed to attack females. They're only supposed to make with them.

So that's another difference in how those neurons are tuned to signals from different on specifics does IT require action? 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 I can make them aggressive. And some of those manipulations do to some extent. But there's a whole biology there that remains to be explored about how much of this is hormones, how much of this is circuitry and electricity and how much of IT is other factors that we haven't identified yet.

I don't want to answer propertied, but um well, just asked the question. So the other day I was watching a ferrets mate right the muscles, the muslims and they they're made in behavior I guess I didn't say why was watching this doesn't matter um 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.

Um there can be no aggressive component that can be aggressive component. Humans at all sorts of kinks and fetish and behaviors and most of which probably has never been documented because most of this happens in private. And here always say on this podcast anytime we're talking about sexual behavior and humans were always making the presumption that it's consensual, age appropriate, context appropriate and species appropriate as they we're talking about a lot of different species.

With that said, just a set context as watching this video of ferrets meeting. And it's quite violent actually. There's a lot of neck biting.

There's a lot of squaring. If I were going to project in into more fies, 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 meeting.

And do you think that reflects this sort of two of competing neurons that are prioritizing in real time? Because, of course, as states, they have persistently, as you point out, and you can imagine that states over lapping in four different states, the the motivational drive to make, the motivational drive to get away from this experience, the motivational drive to um to eat at some point um to defecate at some point, all of these things are competing and what we're really seeing as a biased probabilities. But when you look at mating behavior of various animals, you see an aggressive components sometimes, but not always, is IT species specific is a context specific. And more generally, do you think that there um is cross talk between these different real 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 natural as or zuo logic i've seen like you have in the wild, for example, lions when they made 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 real that control aggression in males is that within that population there is a subset of neurons that is activated by females during male female meeting encounters. Now you don't generally think of male sex as rough sex, but there there is a lot of what superficially looks like violent behavior sometimes, especially if the female rejects the male and runs away. And there are some evidence that those female selective neurons in vm h are part of the main uh, behavior.

If you shut them down, the animals don't mate as effectively as they otherwise would. Uh, 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 I think they must be there for a reason, because V M H 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 made in neurons in a male, while it's in the middle of attacking another mail, 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 vm are the make war, not love neurons. And there are dense interconnections between these two nuclear ye, 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 uh, uh, a mate that is supposed to be made with or to prevent IT from meeting with some uh, uh, an animal is supposed to be attacking. But it's also possible that there are some co Operative interactions between those structures as well as uh and tagish interactions and the baLance of whether it's the CoOperative or and tagish interactions that are firing at any given moment in a mating encounter, as you suggest, may determine whether at a moment of of of coal bliss among two lions may suddenly turn into a snap or a ground and the bearing of fans. We don't know that, but certainly the substrate, the wiring is there for that to happen.

I'm sure people that minds are running wild with all this. I'll just use this as an opportunity to raise IT something i've wondered about for far too long which is um I have a friend with a psychiatrist who works on the treatment of fetish. It's not a psychiatrist that I was treated by.

I would just point that out but um they mention something very interesting to me long ago which is that when you look at true fetishes and what means 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 a faces, dead bodies, feet. Things are very infectious. Typically those states of disgust are tagish to the states of desire, as one would hope is the present during sexual behavior.

Fetish is often involve exactly those things that are aversive feet, a dead bodies um disgusting things to most people. And true fertility in the pathologic sense um exist when people have A A basically requirement for thinking about even the presence of those um ordinary disgusting things in order to become sexually aroused as if the circuitry has crossed over and their the state that wrong in my mind was people don't develop fetish to mailboxes or to the color red or two random objects and things. They develop fetishes to things that are highly infectious encounter reproductive competitive states so I find that interesting. I don't know if you have any reflections on that as to why there might be um I tempted to ask with that you've ever observed fetish like behavioral in mice, but um I find IT fascinating that you have this area of the brain that so highly conserve the athamas, which you have these dense populations intermixed, and that the addition of a four brain, 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 I, I would agree. I think one way of looking at finishes from a neurobiological standpoint is that they represent a kind of competitive conditioning where something that is natively aversive or disgusting by being repeatedly pared with a rewarding experience changes its violence is sign so that now IT somehow produces the anticipation of reward the next time a person season.

I don't have I don't know that literature in animals, so I don't know if you could condition a mouse to eat feces, for example, although there are animals that are naturally cup rapa gic that is uh, and maybe might do that occasionally, i'm not sure. But uh, that is one way to think about IT and that could certainly involve in humans the more recently evolved parts of the brain, the cortex that is sort of orchestrating both what behaviors are happening and whether reward states are turning on in association with those behaviors that are happening. And that's the that's the part that I think is difficult and chAllenging to study.

In a mouse but uh certainly certainly bears thinking about because it's a really interesting again in sort of counter intuitive aspect again like rough sex people that want to have fighting or violence or aggressiveness in order to be sexually aroused and uh of fetishes and infected. When we made that discovery initially, IT raised the question in my mind whether uh some people that uh uh are are serial rapists, for example uh and engage in sexual violence might in some level have their wires cross in some way that that these states that are supposed to be pretty much separated and mutually antagonistic not and are actually more rewarding and reinforcing. Um I think it's gonna a long time before we have figured this 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 definition .

area that I think human neuroscience in general needs a lot of tools, right, in terms of how to probe and and manipulate neurosis. Citrix, i'd love to turn to this area that you mention, the media preoptic area. I'm fascinated by IT because just as within the vm h, you have these neurons for meeting and fighting or gresson.

My understanding is media preoptic era contains neurons for mating, but also for temperature regulation. And perhaps i'm making too much of a lee here but i've always wondered about this phrase in heat um as certainly the menstrual and or extra cycle in females is related to changes in body temperature. In fact, measuring body temperature one way that women can barely reliably predict violation eeta, although additional, this is not a show about contraction tion.

Please rely on multiple methods as necessary. Don't use this discussion as your a guide for contraction tion based on temperature, but if you stimulate certain neurons in the media preoptic area, you can trigger dramatic changes in body temperature and or mating behavior. What's the relationship of any in between temperature and mating, or do we simply not .

know I don't know what the relationship is between temperature and made neurons in the preoptic area. Um I suspect that they are different populations of neurons because it's become pretty clear that the preoptic area has many different subsets of neurons that are specifically active during different behaviors, even different phases of mating behavior. So there are mounting neurons, their information thrusting neurons and event lation neurons and sniffing neurons.

wait. So I I I think i've had this before, but I just want to make sure that people get this. I want to make sure I get this. So you're told me within media, media preoptic, are there specific neons that if you simulate them will make males thrust as if they're made?

no. So so this is not based on on stimulation experiment, is based on imaging experiments right now that we see when we look in the preoptic area at what neurons are active during different phases of aggression, we see that there are different norms that are active during sniffing, mounting, thrusting and event lation. And they become repeatedly activated each time the animal goes through that cycle.

In made during the mating cycle. There are also some neurons there that are active during aggression, which are distinct. And we don't know whether those neurons are there to promote aggression or to inhibit when animals are fighting.

We have some evidence that suggests that may be the latter, but we don't know for sure yet. The the thermal sensitive neurons are really interesting because you mention uh uh the phrase in heat and then in the context of aggression, you talk about hot blooded people or hot heads. There's just recently a paper showing there are thermoregulatory neurons in V M H as well.

So all of these homeostatic systems for meta lic control and temperature control are intermingled in these nuclei, these zones that control these basic survival behaviors like mating and aggression and predator defense. And I would imagine that the thermal regulation is tightly connected to energy expenditure, uh, 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 particularly behavior or that behavior. I mean, i've always been fascinated by the question, why is IT that of violence goes up in the summer time when the temperatures are high? Does that really have something to do with the idea that increase temperature increases violence? That seems hard to believe because we're homeowner ic and we pretty much stay around ninety eight point six fn height.

Uh 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 thermal regulation to aggressive as well as to a mating .

behavior. I I asked um in the hopes that in maybe in the years to come, your level will part some of the temperature relationships and I realize that could be also regulated by hormones in general. So it's tapping into two systems for completely different reasons. But um anyway an area that that intrigued to me because of this notion of hot headiness are cool, common, collected and also um the fact that I probably should have asked about this earlier that arousal itself is tethered to the whole meeting and reproductive process I mean without a sort of sea saying back between the sympathetic and are sympathetic you know alisal relaxed states there is no meeting that will take place so it's fascinating the way these different competing forces and see saw 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 um which I found fascinating um maybe you could tell us about that result um 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 um my friends who practice judo um will say they when I talk about the result, they say of course you know mounting the other person and and dominating them 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 um just fascinating, very primitive and yet um I think piece this idea that mounting behavior might be one of the most fundamental ways in which animals and proactive and humans express dominance and or sexual interaction yep and that's .

uh fascinating question and IT was harder to figure out than you might have fought so we've there's been this debate for a long time in the field when you see two male, my my mounting each other.

Is this homosexual behavior? Is this a case of mistaken sexual identification? Or is this dominance? And if you train an A I algorithm to try to distinguish, uh, male, male mounting from male female mounting, IT does not do a very good job because motorically those behaviors look so similar.

And so ah 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 to towards the other mail and more attack. And yl 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 believed or not, was suggested by a computational theoretical person in my lab and Kennedy, who now is their own lab, bit northwestern SHE, said, well, males are known to sing when they mount females ultra sonic 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, or we found out is they don't sing at all when they're mounting a sale.

So you can easily distinguish whether mounting behavior by a mere mouse is reproductive or agonistes aggressive according to whether it's accompany ed by ultrasonic vocalizations or not. And IT turns out that different brain regions are maximum active during these different types of mounting. So vm h, the aggression locus, is actually active during dominance mounting.

And you can stimulate mounting if you dominance morning, if you weakly activate V M H, where S M P O A is most strongly activated during sexual mounting. And that's always accompanied by the ultra sonic vocalization. So this shows how difficult and dangerous that can be to try to infer an animal state or intent or emotion from the behavior that is exhibiting, because the same behavior can mean very different things depending on the context of the interaction .

with the animal. Say even more when that animal is a human or or is multiple humans.

It's right. And there are many examples. You know, animals show chasing to obtain food of, uh, uh, pray animals that they're gonna kill and eat, and they showed chasing to obtain a mate that they are 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 are being activated.

I'm obsess with dogs and dog breeds and at, at, at, at. And one thing I can tell you is that female dogs will mount and thrust. We had a female pit bull mix, a very sweet dog, but in observing her IT, IT convinced me that one can never assume that male dogs are more aggressive than female dogs.

There is IT turns out, in talking to people quite skill, dog genetics and dog breeding, that there is a dominant hier key within a litter and IT crosses over male, female gillinson so you can get a female in the letter that's a very dominant a mail that's very suborned and no one really knows what what relates to this is also why little dog sometimes will will get right up in the face of a big doberman in pincher and just start barking, which is an idiotic thing for you 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 feemale mounting or female to male mounting?

If if IT occurs? good. Yes, there is females. There are clear examples of females displaying male type mounting be behavior towards other females.

We see this most commonly in the lab where we are housing females with their sisters, say, three or four gna cage. We take one out, and we have her mate with a male, where the males doing the mountain. 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 news of control mounting in males in the media preoptic area, if we stimulate that same population.

In females, IT evokes male type mounting who is 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 M P O A in the female and SHE crows out from underneath the male who is just mounted her circles around behind him and climbs up on top of them and to try to mount him and rust at him.

That has a name online. It's called a switch. Don't ask me how I know that, okay, but it's pretty yeah it's a terminal that that yeah here um you also hear the the the term topping from the bottom, which that sounds like that is a literal topping from the bottom.

That's a bore of a psychological phrase from what I hear. My friends that are are educating me in this a language mostly because I find this kind of new biological discussion fascinating at some point, right? IT. We I attempt to my mind to superimpose observations from the the online communities that i'm told about and asked about this. But I I should point out it's always dangerous and in in fact inappropriate to make a one to one a link you know humans are they maintained all the same mineral circuitry in pathways that we're talking about today and mice but um that forebrain does a allow for context at sea.

yes. So what the function is of a of a 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 we've worked on male dominance hierarchies. But IT indicates that the circuits for male type mounting are there in females as a early work from caffeine do locks suggested some years ago.

Fascinating, fascinating. I love that paper because as you point out for chase, you know the um for mounting behavior and we see IT and we think one thing specifically um and after hearing this result, actually i'm not a big fan of fight sports. I watched them occasionally because friends are into them.

But I i've seen boxing matches. MMA matches were at the end of around. If someone felt that they dominated, they will do the unsportsmanlike thing of thrusting on the back of the other person. They get off almost like I I dominated you and know so mimmy's sexual like behavior. But there's no reason to think that it's sexual.

But they're sending a message of dominance is what implies i'd love to talk about something um slightly off from the circuit, but I think that's related to the circuitry at least in some way, which is is structure that i've always been faster by and I can figure out what the helps for IT could seem to be involved in everything, which is the P. A G. The paradox of gray, which is 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 lords' response, the receptivity or arching of the back of the female to receive information and meeting from the mail. How should we think about P A G? Um clearly, I can be involved in at 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 pg play into this in particular? I want to know is there are some mechanism of pain modulation in control during fighting and or made.

And the reason I ask is that, well, i'm not combat sports person. Years ago I did did a little bit of march large and I always was um 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 indulgin ous pain control um that then wears off and then you feel beat up. At least in my case, I will beat up what's pig doing visit pain and via v and what's pain doing visit these other behaviors.

So I think of P A G like a old fashion telephones 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 ant and the other end of IT. Because pretty much every type of in eight behavior you can think of has had the pg implicated. There's a whole literature uh showing the involved of the pg in fear. Different regions of the pg the dorsal pack is involved in panic like behavior running away.

The venture al pg is involved in freezing behavior are the both the M P A and V M H send projections to the pg to different regions of the pg so um uh in cross section I hate to say this, but in cross section the pg hunt looks like the water in a toilet when you're standing over an open toilet ball and if you imagine a clock face projected onto that, it's like the pig has sectors from one to twelve, maybe even more of them. And in each of those sectors you find different neurons from the hypothenuse are projecting. So could turn out that there is a topographic arrangement along the dorso venturo access of the bag and the media literal access of the pg, that determines the type of behavior that will be emitted when neurons in that region are stimulated.

And I think sort of all of the evidence is pointing in that direction, but by no means has IT been mapped out. Now, the thing that you mentioned about, uh, is not hurting when you ve 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 A suppression of pain responses.

And i'm not sure completely about the mechanisms and how well that understood. But for example, uh the the adrenal gland has a peptide in IT that is released from the adrenal medulla which controls the fighter flight responses. And that peptide has analgesic activities.

Now, whether that pet, it's called bovine, a real megory peptide of twenty two 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 uh, of analgesia is happening when an animal is engaged in offensive aggression or in mating behavior, I don't know, but it's certainly as possible. And I don't know whether these, uh analgesic mechanisms are happening in the pg. They could also be happening a little further down in the spinal court. The pg is really continuous with the spinal court. If you just follow IT down towards the tale of an animal, you will wind up in the spinal cord and uh and so IT could be that there are influences acting at many levels on pain in the pg and in the spinal court as well, and 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 .

based to know that appreciate um those delineations um thank you my pages out I think the description of is at old fashion telephone switchboard. And now every time I look into the toilet, i'll think about the great. And every time I see an image of parietal dal 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 up, post a link to a picture of pg, and you'll understand why, why David and I chocolate here, because indeed, IT looks like a toilet when staring into a toilet. Tell us about tacky kin. 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 socialize. Lation, my shame is that tacky kin, 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 kino is a refers to a family of related neuropathy. Des, so these are brain chemicals. Um they're different from those pine 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 neuropace tides are released together with classical transmittals like glutamate. Whatever tacky kinds have been famously implicated in pain, particularly tacky kind, in one which is called substance p, one of the original pain modulating.

This is something that promotes in flaming pain. But there are other tacky kind. And genes in my, there are two.

In humans, I think there are three. And, uh, in the sofa, there is one. And the way we got into tacky kindness is from studying aggression in flies.

We thought since europeans, tides have this remarkable parallel evolutionary conservation of structure and function like neuropace tiy 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 control aggression in flies and in people.

And so we did a screen and by a screen of petites, and found, indeed, that one of the tacky kinds to sofa tacky kin, those neurons, when you activate them, strongly promote aggression and IT depends on the release of tacky. Now, the interesting thing is that in flies, just like in people and practically any other social animal that shows aggression, social isolation increases aggressively. So putting A A violent prisoner in solitary confinement is absolutely worst, most counterproductive thing you could do to them.

And indeed, we found in flies that social isolation increases the level of tacky, kinda, the brain. And if we shut that gene down, IT prevents the isolation from increasing aggression. So since my lab all also works on mice, IT was natural to see whether tacky kinds might be up regulated in social isolation, and whether they play a role in aggression.

And this has worked done by a former postdoc, mario alico. Sky, now at university, solid city in utah. And SHE found, remarkably, that when mice are socially isolated for two weeks, there is this massive up regulation of tacky kind and two in their brain.

In fact, if you tag the peptide with a Green flu resent 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 he went on to show that that increase in taxi kyn is responsible for the effective 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 kinds, which were tested in humans and abandoned because they had no efficacy in the test that they were a 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 that morial described, that the mice just look chill. It's not a sentiment which is really important, is not at the mice are going to sleep.

Most remarkably, is once you socially isolate a mouse and IT becomes aggressive, you can never put IT back in its cage with its brothers from its litter, because IT will kill them all overnight. But if you give IT this drug, which is called osana, on that black blocks, tacky kind 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 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 the isolation stress or bereavement stress. And this is one of the areas where I learned an eye opening lesson as a basic scientists who naively thought that if you make a discovery and IT has translational applications to humans, that pharm circle companies are going to be falling all over themselves to try IT. And they're not interested.

Because once burned, twice shy, these drugs were tested for efficency and schizophrenia. I have no idea why there's very little preclinical that IT to suggest that not surprisingly, they failed when a when a drug fails and clinical trials and face three IT costs hundred million dollars to the company that uh um that Carried out that clinically trial. So there's a huge slag heap of discarded pharmaceuticals, many of them inhibitors of neuropace tide action that uh could be useful in other indications such as the one we discovered.

But there is 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 two thousand tens and before that, is that the reason they failed is because animal experiments with drugs don't predict how humans will respond to the drugs. And therefore, we shouldn't try to extrapolate from any other data that we get from animal experiments, mouse experiments to humans, because they lead us down the wrong track. And I think that that is probably wrong.

In some cases, that may be right, but in other cases, there's good reason to think, because these brain regions and molecules are so evolutionary conserved that they ought to be playing a similar role in humans. In fact, there is A A paper um showing that in humans that have uh a borderline personality disorder there is a strong correlation between their self reported level of aggressiveness and syrian levels of attacked y kind in in this case tacky kind in one as detected by radio immune sa this is work of amo karo, who was a clinical psychiatrist of the university of chicago. So there is a smoking gun in the case of humans as well.

And uh, I was actually trying to interest a pharmaceutical company that was testing these drugs actually for treatment of hot flashes in females in humans, where there is actually good animal data, to think that I might be useful. But I realized that this clinical trial was going on during the COVID pandemic. And I approached 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 gonna have been socially isolated, and some of them will have not.

Why don't you get them to fill out questionaire and see whether the ones who are 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 are 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 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 wasn't clinical transform. So is Better not to ask and not to know. And h then IT is to try to find out more information that could lead to another clinical indication. So I remain convinced that this family of drugs could have very powerful uses and treating some forms of stress induced anxiety or aggressiveness and humans, but this is very difficult, for economic reasons, to find a way to get somebody to test that.

Yeah, a true shame that these companies won't do this and is especially given the fact that many these drugs exist and their safety profiles are established because that's always a serious consideration when embarking on a clinical trial. Perhaps in hearing this discussion, someone out there will understand the key importance of this and um will reach out to us will provide ways to do that uh to get such a study going in humans because I think of enough laboratories ran small scale clinical trials, farmer certainly would perk up their years right? I'm there there are so um strategic um um sometimes to their own.

I mean I would I would like to say also, i'd like to see this tested on pets. I mean, there's a huge number of pets right now that are suffering separation anxiety because humans bought them to keep them company during the covet pen and home alone OK. And if this thing works in mice is certainly a higher chance is gone to work in dogs or in cats, then IT is gonna in humans.

And if I did, that would be even more encouragement to continue along those line. People sometimes forget that although we work on animals and we ultimately want to understand humans, we care about how our our results applied to the welfare of animals as well, and particularly domestic pets, which is a billion multibillion dollar industry in this country. So there is ways that that they can be made to feel Better when they're separated from their of their owners. That would certainly be a good thing.

absolutely. We will put out the call. We are putting out the call. And I I know for sure there will be a response .

just underscoring what .

we've been talking about even more. Every time we hear about a school shooting. I can text us recently or I happen to be in new york during the time when there was a subway shooting um for whatever reason I listen to the the book um about columbine that went into a very detailed way about the origin of those boys and that committed dad and every single time there's the person who commits those acts socially isolated.

As far as I know, there might be some exceptions there. And sometimes this crosses is over with other mental health issues, but sometimes no, no apparent mental health issues. So social isolation clearly drives powerful neurochemical and neurobiological changes. I really hope that um ti kind in one and two those the main ones of humans will be explored um in more detail. Also I didn't know that tackier one is substance p and sub is tai tacchi .

kind of one is the gene name and tacky kind of two in humans is called neuro kind and b that's the name of the protein. I just referred to IT by the gene, because IT makes IT easier. And I don't have to keep remembering two names for each thing.

And I found that mistake. And you see you you you put yourself in the company of geneticists because of your original training was in genetics. Mino logy in areas will .

need to sell biology. And I didn't actually have formal training in genetics as a graduate student, but I think i'm a geneticist at heart. That's just the way I like to think about things. And when I started working on flies, that sort of, I came out of the closet as a geneticist, as IT were wonderful.

As long we're talking about humans, i'd love to get your thoughts about human studies of emotion. I know you wrote this book with ralf ads. You have this new book I, which will provide a link to which i've read front to back twice.

It's phenomenal. I mentioned the people on the podcast. It's really there are books that are worth reading and then their books that are important. And I think this book is truly important for the general population to read and understand.

And neuroscientists should read and understand the contents because we as a 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 to read IT.

And it's written beautifully, I should say, very accessible even for non scientists. There is 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 of an emotion or a feeling, dramatics, feeling in their body or in their head, or both when they are angry, sad, come lonely at at sada.

And I wouldn't want people to think that those heat maps were generated by any physiological measurement because they were not. And yet, I don't think we can have a discussion about emotions and states and the sorts of behaviors that we're talking about today without thinking about the body. Also, you and i'm not coming to this as a northern california of my body in asylum.

Once I didn't go in the baths, I went there, I give a talk and I left. IT is very beautiful. If anyone wants to know what he looks like, I think that final scene of mad men is shot at assault.

A very beautiful place. And yet mind body is a, to me, as a neurobiological construct, because the nervous system extends through the out of the crane involved in into the spinal court and body and back and forth. Okay, how should we think about the body? And in terms of states? And at some point, I love you to comment on that heat map experiment, because IT does seem that there some regularity as to where people experience emotions.

When people are in arrange, for instance, they seem to feel IT both in their gut and in their head. IT seems on average, and people love to extra gut tuition, or that the, you know, the chokers are angin the stomach. And this goes to eastern medicine at sea. How should we think about mind body in the context of state, and think about IT, a scientist, maybe even in as neo scientists or geneticists?

good. So for the answer, the first question about the heat maps and people associate certain parts of their body with certain emotional feelings of this goes back to, uh, something called the thomaz marker hypothesis that was proposed by antonio demos o who is a neurologist uh u sc. The the idea that are subjective feeling of a particular emotion is in part associated with a sensation of something happening in a particular part of our body, the gut, the heart. I don't see the liver invoke very much in uh in in emotional uh characterization .

but the goal and the goal, somebody having a lot of away make a fist when I say that but i'm getting the goal bal outer shape like a fist that's right.

And and if there is a physiology underlying these heat maps that could reflect increased 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 by directional communication. And it's mediated by the preferable nervous system, the sympathetic and the parasympathetic nervous system, which control heart rate, for example, blood vessel, blood pressure, uh, and those neurons receive input from the hypothalamic, us and other blood, a brain region, central brain regions that control their activity.

And when the brain is put in a particular state, IT activates sympathetic and power, sympathetic neurons, which have effects on the heart and on blood pressure and these in turn feedback onto the brain through the sensory system and uh a large part of this by directional communication is also mediately through the veggies nerve which uh many of your uh uh listeners and viewers may have heard about because it's become a topic of intense activity now people have known for a long time. So the vegas nerve is A 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 us, and that information is both used, the were earlier in our discussion, difference and inference.

So the the vegal fibers sense things that are happening in the body. So when you the reason you feel your stomach hide up in knots, if your tense, is that those vehicle fibers are sensing the contraction of the gut muscles and there are also affects, which means that information coming out of the brain can influence those peripheral organs as well. And there's work from a number of labs just in the last six months or so where people are starting to deep hold the components of the different fibers in the veggies nerve.

And it's amazing how much specificity is. There are specific vehicle nerves that go to the lawn, that control breathing response, that go to the gut, that go to other organs. Uh, it's almost like a set of color coded lines, uh, uh, labeled lines for those things.

And now how those vehicle affect play a role in the playing out of emotion states is a fascinating question that people are just beginning to scrape the surface of. But I think what's exciting now is that people are going to be developing tools that will allow us to turn on or turn off specific subsets of fibers within the vegas nerve and ask how that affects particular emotional behaviors. So you're absolutely right.

This brain body connection is critical not just for the gut, but for the heart, for the lungs, for all kinds of other parts of your body. And Darwin recognized that as well. And I think it's, uh, it's a central feature of emotional state. And I think what underlies our objective feelings of an emotion.

incredible David. I have to say as a true fan of the work that your lab has been doing over so many decades and um first of all, I was delighted when he stopped working on stem cells 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 scoring out a bunch of incan escaping and he said you're going to work on things that the sort they were talking about today, fear, aggression, mating behaviors, social behaviors.

It's been incredible to see the work that your lab is done in. I know I become behalf of time of I know I become 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, 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. They're all you've all been right on the money. You've hit all of the critical important issues in this field.

And you've you've uncovered what is known, the little bit is known and how much is not known. And I think it's important to emphasize the unknown things because that's what the next generation of neuroscientists has to solve. And so I hope this will help to attract Young people into this field because it's so important, particularly for our understanding of mental illness and mental health and and a and psychiatry. We've got to figure out how emotion systems are controlled in a causeway ah if we ever want to improve on the psychiatric treatments that we have now. And that's gona require the next generation of people coming into the field.

absolutely. I second that well, thank you. It's been a delight.

Thank you. Really.

really appreciate you. Thank you for john to me today for my discussion with doctor David Anderson. Please also be sure to check out his new book, the nature of the beast.

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