Essentials: The Biology of Aggression, Mating & Arousal | Dr. David Anderson

Welcome to Huberman Lab Essentials, Welcome to Huberman Lab Essentials, where we revisit past episodes for the where we revisit past episodes for the where we revisit past episodes for the most potent and actionable science-based most potent and actionable science-based most potent and actionable science-based tools for mental health, physical tools for mental health, physical tools for mental health, physical health, and performance. health, and performance. health, and performance. I'm Andrew Huberman and I'm a professor I'm Andrew Huberman and I'm a professor I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at of neurobiology and opthalmology at of neurobiology and opthalmology at Stanford School of Medicine. And now for Stanford School of Medicine. And now for Stanford School of Medicine. And now for my discussion with Dr. David Anderson. my discussion with Dr. David Anderson. my discussion with Dr. David Anderson. David, great to be here and great to David, great to be here and great to David, great to be here and great to finally sit down and chat with you. finally sit down and chat with you. finally sit down and chat with you. >> Great to be here too. Thank you so much. >> Great to be here too. Thank you so much. >> Great to be here too. Thank you so much. I want to start with something fairly I want to start with something fairly I want to start with something fairly basic and that's the difference between basic and that's the difference between basic and that's the difference between emotions and states. How should we think emotions and states. How should we think emotions and states. How should we think about them and why might states be at about them and why might states be at about them and why might states be at least as useful a thing to think about least as useful a thing to think about least as useful a thing to think about if not more useful? if not more useful? if not more useful? >> The short answer to your question is >> The short answer to your question is >> The short answer to your question is that I see emotions as a type of that I see emotions as a type of that I see emotions as a type of internal state in the sense that arousal internal state in the sense that arousal internal state in the sense that arousal is also a type of internal state. is also a type of internal state. is also a type of internal state. Motivation is a type of internal state. Motivation is a type of internal state. Motivation is a type of internal state. Sleep is a type of internal state. They Sleep is a type of internal state. They Sleep is a type of internal state. They change the input to output change the input to output change the input to output transformation of the brain. When you're transformation of the brain. When you're transformation of the brain. When you're asleep, you don't hear something that asleep, you don't hear something that asleep, you don't hear something that you would hear if you were awake. So you would hear if you were awake. So you would hear if you were awake. So from that broad perspective, I see from that broad perspective, I see from that broad perspective, I see emotion as a class of state that emotion as a class of state that emotion as a class of state that controls behavior. The reason I think controls behavior. The reason I think controls behavior. The reason I think it's useful to think about it as a state it's useful to think about it as a state it's useful to think about it as a state is it puts the focus on it as a is it puts the focus on it as a is it puts the focus on it as a neurobiological process rather than as a neurobiological process rather than as a neurobiological process rather than as a psychological process. Many people psychological process. Many people psychological process. Many people equate emotion with feeling which is a equate emotion with feeling which is a equate emotion with feeling which is a subjective sense that we can only study subjective sense that we can only study subjective sense that we can only study in humans because to find out what in humans because to find out what in humans because to find out what someone's feeling you have to ask them someone's feeling you have to ask them someone's feeling you have to ask them and people are the only animals that can and people are the only animals that can and people are the only animals that can talk that we can understand. That's how talk that we can understand. That's how talk that we can understand. That's how I think about emotion. It's the if you I think about emotion. It's the if you I think about emotion. It's the if you think of an iceberg it's the part of the think of an iceberg it's the part of the think of an iceberg it's the part of the iceberg that's below the surface of the iceberg that's below the surface of the iceberg that's below the surface of the water. The feeling part is the tip. What water. The feeling part is the tip. What water. The feeling part is the tip. What are some of the other features of states are some of the other features of states are some of the other features of states that represent below the tip of the that represent below the tip of the that represent below the tip of the iceberg? iceberg? iceberg? >> Right? There have been people who have >> Right? There have been people who have >> Right? There have been people who have thought of emotions as having just thought of emotions as having just thought of emotions as having just really two dimensions, a an arousal really two dimensions, a an arousal really two dimensions, a an arousal dimension and a veilance dimension. dimension and a veilance dimension. dimension and a veilance dimension. Ralph Adolf and I have tried to expand Ralph Adolf and I have tried to expand Ralph Adolf and I have tried to expand that a little bit to think about that a little bit to think about that a little bit to think about components of emotion, particularly components of emotion, particularly components of emotion, particularly those that distinguish emotion states those that distinguish emotion states those that distinguish emotion states from motivational states because they from motivational states because they from motivational states because they are very closely related. One of those are very closely related. One of those are very closely related. One of those important properties is persistence. important properties is persistence. important properties is persistence. This is something that distinguishes This is something that distinguishes This is something that distinguishes stated driven behaviors from simple stated driven behaviors from simple stated driven behaviors from simple reflexes. Reflexes tend to terminate reflexes. Reflexes tend to terminate reflexes. Reflexes tend to terminate when the stimulus turns off, like the when the stimulus turns off, like the when the stimulus turns off, like the doctor hitting your knee with a hammer. doctor hitting your knee with a hammer. doctor hitting your knee with a hammer. It initiates with the stimulus onset and It initiates with the stimulus onset and It initiates with the stimulus onset and it terminates with the stimulus offset. it terminates with the stimulus offset. it terminates with the stimulus offset. Emotions tend to outlast often the Emotions tend to outlast often the Emotions tend to outlast often the stimulus that evoke them. If you're stimulus that evoke them. If you're stimulus that evoke them. If you're walking along a trail here in Southern walking along a trail here in Southern walking along a trail here in Southern California, you hear a rattlesnake California, you hear a rattlesnake California, you hear a rattlesnake rattling, you're going to jump in the rattling, you're going to jump in the rattling, you're going to jump in the air, your heart is going to continue to air, your heart is going to continue to air, your heart is going to continue to beat and your palms sweat for a while beat and your palms sweat for a while beat and your palms sweat for a while after it's slithered off in the bush and after it's slithered off in the bush and after it's slithered off in the bush and you're going to be hypervigilant. If you you're going to be hypervigilant. If you you're going to be hypervigilant. If you see something that even remotely looks see something that even remotely looks see something that even remotely looks snake like a stick, you're going to snake like a stick, you're going to snake like a stick, you're going to stop. Not all states have persistence. stop. Not all states have persistence. stop. Not all states have persistence. So, for example, you think about hunger. So, for example, you think about hunger. So, for example, you think about hunger. Once you've eaten, the state is gone. Once you've eaten, the state is gone. Once you've eaten, the state is gone. You're not hungry anymore. But if you're You're not hungry anymore. But if you're You're not hungry anymore. But if you're really angry and you get into a fight really angry and you get into a fight really angry and you get into a fight with somebody, even after the fight is with somebody, even after the fight is with somebody, even after the fight is over, you may remain riled up for a long over, you may remain riled up for a long over, you may remain riled up for a long time and it takes you a while to calm time and it takes you a while to calm time and it takes you a while to calm down. And then generalization is an down. And then generalization is an down. And then generalization is an important component of emotion states um important component of emotion states um important component of emotion states um that uh make them if they have been uh that uh make them if they have been uh that uh make them if they have been uh triggered in one situation they can triggered in one situation they can triggered in one situation they can apply to another situation. My favorite apply to another situation. My favorite apply to another situation. My favorite example of that is you come home from example of that is you come home from example of that is you come home from work and your kid is screaming. If you work and your kid is screaming. If you work and your kid is screaming. If you had a good day at work you might pick it had a good day at work you might pick it had a good day at work you might pick it up and and soothe it. And if you had a up and and soothe it. And if you had a up and and soothe it. And if you had a bad day at work, you might react very bad day at work, you might react very bad day at work, you might react very differently to it. differently to it. differently to it. >> Like to talk a bit about aggression, the >> Like to talk a bit about aggression, the >> Like to talk a bit about aggression, the beautiful work of Da Lin and others in beautiful work of Da Lin and others in beautiful work of Da Lin and others in your lab. What are your thoughts on your lab. What are your thoughts on your lab. What are your thoughts on aggression, how it's generated, the aggression, how it's generated, the aggression, how it's generated, the neural circuit mechanisms, and some of neural circuit mechanisms, and some of neural circuit mechanisms, and some of the variation in what we call the variation in what we call the variation in what we call aggression? First of all, um the word aggression? First of all, um the word aggression? First of all, um the word aggression aggression aggression in my mind refers more to a description in my mind refers more to a description in my mind refers more to a description of behavior than it does to an internal of behavior than it does to an internal of behavior than it does to an internal state. Aggression could reflect an state. Aggression could reflect an state. Aggression could reflect an internal state that we would call anger internal state that we would call anger internal state that we would call anger in humans or could reflect fear or it in humans or could reflect fear or it in humans or could reflect fear or it could reflect hunger if it's predatory could reflect hunger if it's predatory could reflect hunger if it's predatory aggression. The work that Dau did when aggression. The work that Dau did when aggression. The work that Dau did when she was in my lab, she found a way to she was in my lab, she found a way to she was in my lab, she found a way to evoke aggression in mice using evoke aggression in mice using evoke aggression in mice using optogenetics optogenetics optogenetics to activate specific neurons in a region to activate specific neurons in a region to activate specific neurons in a region of the hypothalamus, the ventromedial of the hypothalamus, the ventromedial of the hypothalamus, the ventromedial hypothalamus, VH. Following first the hypothalamus, VH. Following first the hypothalamus, VH. Following first the famous Nobel Prize-winning work uh of famous Nobel Prize-winning work uh of famous Nobel Prize-winning work uh of Walter Hess, in Hess's original Walter Hess, in Hess's original Walter Hess, in Hess's original experiments, he describes two types of experiments, he describes two types of experiments, he describes two types of aggression that he evokes from cats aggression that he evokes from cats aggression that he evokes from cats depending on where in the hypothalamus depending on where in the hypothalamus depending on where in the hypothalamus he puts his electrode. One of which he he puts his electrode. One of which he he puts his electrode. One of which he calls defensive rage. That's the ears calls defensive rage. That's the ears calls defensive rage. That's the ears laid back, teeth bared and hissing. And laid back, teeth bared and hissing. And laid back, teeth bared and hissing. And the other one is predatory aggression the other one is predatory aggression the other one is predatory aggression where the the cat has its ears forward where the the cat has its ears forward where the the cat has its ears forward and it's like batting with its paw at a and it's like batting with its paw at a and it's like batting with its paw at a mouselike object like it wants to catch mouselike object like it wants to catch mouselike object like it wants to catch it and eat it. If you think of it and eat it. If you think of it and eat it. If you think of ventromedial hypothalamus like a pear ventromedial hypothalamus like a pear ventromedial hypothalamus like a pear sitting on the ground, the fat part of sitting on the ground, the fat part of sitting on the ground, the fat part of the pair near the ground is where the the pair near the ground is where the the pair near the ground is where the aggression neurons are, but the upper aggression neurons are, but the upper aggression neurons are, but the upper part of the pair has fear neurons. Fast part of the pair has fear neurons. Fast part of the pair has fear neurons. Fast forward from that from a lot of work forward from that from a lot of work forward from that from a lot of work from Dau now on her own at NYU and with from Dau now on her own at NYU and with from Dau now on her own at NYU and with her postto Anna Gret Falconer there's her postto Anna Gret Falconer there's her postto Anna Gret Falconer there's evidence that the type of fighting that evidence that the type of fighting that evidence that the type of fighting that we were that we elicit when we stimulate we were that we elicit when we stimulate we were that we elicit when we stimulate VMH is offensive aggression that is VMH is offensive aggression that is VMH is offensive aggression that is actually rewarding to male mice. actually rewarding to male mice. actually rewarding to male mice. >> They like it. >> They like it. >> They like it. >> They like it. male mice will learn to >> They like it. male mice will learn to >> They like it. male mice will learn to poke their nose or press a bar to get poke their nose or press a bar to get poke their nose or press a bar to get the opportunity to beat up a subordinate the opportunity to beat up a subordinate the opportunity to beat up a subordinate male mouse. It has a positive veilance. male mouse. It has a positive veilance. male mouse. It has a positive veilance. So it's become clear that if you want to So it's become clear that if you want to So it's become clear that if you want to call it the state of aggressiveness call it the state of aggressiveness call it the state of aggressiveness is multifaceted. It depends on the type is multifaceted. It depends on the type is multifaceted. It depends on the type of aggression and it involves different of aggression and it involves different of aggression and it involves different sorts of circuits. Why do you think sorts of circuits. Why do you think sorts of circuits. Why do you think there would be such a close positioning there would be such a close positioning there would be such a close positioning of neurons that can elicit such of neurons that can elicit such of neurons that can elicit such divergent states and behaviors? I mean, divergent states and behaviors? I mean, divergent states and behaviors? I mean, you're talking about this pear-shaped you're talking about this pear-shaped you're talking about this pear-shaped structure where the neurons that structure where the neurons that structure where the neurons that generate fear are cheekto jowlel with generate fear are cheekto jowlel with generate fear are cheekto jowlel with the neurons that generate offensive the neurons that generate offensive the neurons that generate offensive aggression. If you think from an aggression. If you think from an aggression. If you think from an evolutionary perspective, it might have evolutionary perspective, it might have evolutionary perspective, it might have been the case that defensive behaviors been the case that defensive behaviors been the case that defensive behaviors and fear arose before offensive and fear arose before offensive and fear arose before offensive aggression because animals first and aggression because animals first and aggression because animals first and foremost have to defend themselves from foremost have to defend themselves from foremost have to defend themselves from predation by other animals. And maybe predation by other animals. And maybe predation by other animals. And maybe it's only when they're comfortable with it's only when they're comfortable with it's only when they're comfortable with having warded off predation and made having warded off predation and made having warded off predation and made themselves safe that they can start themselves safe that they can start themselves safe that they can start about start to think about who's going about start to think about who's going about start to think about who's going to be the alpha male in in my group to be the alpha male in in my group to be the alpha male in in my group here. And so it could be that if you here. And so it could be that if you here. And so it could be that if you think that brain regions and cell think that brain regions and cell think that brain regions and cell populations evolved by duplication and populations evolved by duplication and populations evolved by duplication and modification of preexisting modification of preexisting modification of preexisting cell populations. cell populations. cell populations. that might be the way that those regions that might be the way that those regions that might be the way that those regions wound up next to each other. But I think wound up next to each other. But I think wound up next to each other. But I think there must be a functional part as well. there must be a functional part as well. there must be a functional part as well. So one thing we know about offensive So one thing we know about offensive So one thing we know about offensive aggression is that strong fear shuts it aggression is that strong fear shuts it aggression is that strong fear shuts it down. Whereas defensive aggression, at down. Whereas defensive aggression, at down. Whereas defensive aggression, at least in rats, is actually enhanced by least in rats, is actually enhanced by least in rats, is actually enhanced by fear. It's one of the big differences fear. It's one of the big differences fear. It's one of the big differences between defensive aggression and between defensive aggression and between defensive aggression and offensive aggression. And maybe these offensive aggression. And maybe these offensive aggression. And maybe these two regions are close to each other to two regions are close to each other to two regions are close to each other to facilitate inhibition of aggression by facilitate inhibition of aggression by facilitate inhibition of aggression by fe the fear neurons. We know for a fact fe the fear neurons. We know for a fact fe the fear neurons. We know for a fact that if we deliberately stimulate those that if we deliberately stimulate those that if we deliberately stimulate those fear neurons at the top of the pair, fear neurons at the top of the pair, fear neurons at the top of the pair, when two animals are involved in a when two animals are involved in a when two animals are involved in a fight, it just stops the fight, dead in fight, it just stops the fight, dead in fight, it just stops the fight, dead in its tracks, and they go off into the its tracks, and they go off into the its tracks, and they go off into the corner and freeze. So, at least corner and freeze. So, at least corner and freeze. So, at least hierarchically, it seems like fear is hierarchically, it seems like fear is hierarchically, it seems like fear is the dominant behavior over offensive the dominant behavior over offensive the dominant behavior over offensive aggression. I think that's the way I aggression. I think that's the way I aggression. I think that's the way I tend to think about why these neurons tend to think about why these neurons tend to think about why these neurons are are all mixed up together. And it's are are all mixed up together. And it's are are all mixed up together. And it's not just fight and flight. There are not just fight and flight. There are not just fight and flight. There are also metabolic neurons that are mixed also metabolic neurons that are mixed also metabolic neurons that are mixed together in VMH as well. One of the together in VMH as well. One of the together in VMH as well. One of the concepts that you've raised in your concepts that you've raised in your concepts that you've raised in your lectures before is this idea of a sort lectures before is this idea of a sort lectures before is this idea of a sort of hydraulic pressure or maybe it was of hydraulic pressure or maybe it was of hydraulic pressure or maybe it was Conrad Conrad I can't speak now excuse Conrad Conrad I can't speak now excuse Conrad Conrad I can't speak now excuse me Conrad Lauren Barton who talked about me Conrad Lauren Barton who talked about me Conrad Lauren Barton who talked about a kind of hydraulic pressure towards a kind of hydraulic pressure towards a kind of hydraulic pressure towards behavior. What's really driving behavior. What's really driving behavior. What's really driving hydraulic pressure toward a given state? hydraulic pressure toward a given state? hydraulic pressure toward a given state? >> One way that is helpful, at least for >> One way that is helpful, at least for >> One way that is helpful, at least for me, to break this question apart and me, to break this question apart and me, to break this question apart and think about it is to distinguish think about it is to distinguish think about it is to distinguish homeostatic homeostatic homeostatic behaviors that is needbased behaviors behaviors that is needbased behaviors behaviors that is needbased behaviors where the pressure is built up because where the pressure is built up because where the pressure is built up because of a need like I'm hungry, I need to of a need like I'm hungry, I need to of a need like I'm hungry, I need to eat, I'm thirsty, I need to drink, I'm eat, I'm thirsty, I need to drink, I'm eat, I'm thirsty, I need to drink, I'm hot, I need to get to a cold place. is hot, I need to get to a cold place. is hot, I need to get to a cold place. is basically the thermostat model of your basically the thermostat model of your basically the thermostat model of your brain. You have a set point and then if brain. You have a set point and then if brain. You have a set point and then if the temperature gets too hot, you turn the temperature gets too hot, you turn the temperature gets too hot, you turn on the AC and if the temperature gets on the AC and if the temperature gets on the AC and if the temperature gets too cold, you turn on the heater and you too cold, you turn on the heater and you too cold, you turn on the heater and you put yourself back to the set point. You put yourself back to the set point. You put yourself back to the set point. You can think of this accumulated hydraulic can think of this accumulated hydraulic can think of this accumulated hydraulic pressure either being based on something pressure either being based on something pressure either being based on something that you were deprived of creating an that you were deprived of creating an that you were deprived of creating an accumulating need or something that you accumulating need or something that you accumulating need or something that you want to do building up a uh a drive or a want to do building up a uh a drive or a want to do building up a uh a drive or a pressure to do that. And the natural way pressure to do that. And the natural way pressure to do that. And the natural way to think about that at least for me is to think about that at least for me is to think about that at least for me is as gradual increases in neural activity as gradual increases in neural activity as gradual increases in neural activity in a particular region of the brain. So in a particular region of the brain. So in a particular region of the brain. So for example in the area of the brain of for example in the area of the brain of for example in the area of the brain of the hypothalamus that controls feeding the hypothalamus that controls feeding the hypothalamus that controls feeding Scott Sternson and others have shown Scott Sternson and others have shown Scott Sternson and others have shown that the hungrier you get the higher the that the hungrier you get the higher the that the hungrier you get the higher the level of activity in that region in the level of activity in that region in the level of activity in that region in the brain and then when you eat boom the brain and then when you eat boom the brain and then when you eat boom the activity goes right back down again. And activity goes right back down again. And activity goes right back down again. And I think in the case of aggression, our I think in the case of aggression, our I think in the case of aggression, our data and others show that the more data and others show that the more data and others show that the more strongly you drive this region of the strongly you drive this region of the strongly you drive this region of the brain optogenetically, brain optogenetically, brain optogenetically, the more of just a hair trigger you need the more of just a hair trigger you need the more of just a hair trigger you need to set the animal off to get it to to set the animal off to get it to to set the animal off to get it to fight. VMH projects to about 30 fight. VMH projects to about 30 fight. VMH projects to about 30 different regions in the brain and it different regions in the brain and it different regions in the brain and it gets input from about 30 different gets input from about 30 different gets input from about 30 different regions. So I kind of see it as both an regions. So I kind of see it as both an regions. So I kind of see it as both an antenna and a broadcasting center. It's antenna and a broadcasting center. It's antenna and a broadcasting center. It's like a satellite dish that takes in like a satellite dish that takes in like a satellite dish that takes in information from different sensory information from different sensory information from different sensory modalities, smell, maybe vision, modalities, smell, maybe vision, modalities, smell, maybe vision, mechanical uh mechano sensation and then mechanical uh mechano sensation and then mechanical uh mechano sensation and then it sort of synthesizes and integrates it sort of synthesizes and integrates it sort of synthesizes and integrates that into a fairly lowdimensional as the that into a fairly lowdimensional as the that into a fairly lowdimensional as the computational people call it uh computational people call it uh computational people call it uh representation of this pressure to representation of this pressure to representation of this pressure to attack. And it broadcasts that all over attack. And it broadcasts that all over attack. And it broadcasts that all over the brain to trigger all these systems the brain to trigger all these systems the brain to trigger all these systems that have to be brought into play. If that have to be brought into play. If that have to be brought into play. If the animal is going to engage in the animal is going to engage in the animal is going to engage in aggression because aggression is a very aggression because aggression is a very aggression because aggression is a very risky thing for an animal to engage in. risky thing for an animal to engage in. risky thing for an animal to engage in. It could wind up losing and it could It could wind up losing and it could It could wind up losing and it could wind up getting killed and and so its wind up getting killed and and so its wind up getting killed and and so its brain constantly has to make a brain constantly has to make a brain constantly has to make a costbenefit analysis of whether to costbenefit analysis of whether to costbenefit analysis of whether to continue on that path or to back off. As continue on that path or to back off. As continue on that path or to back off. As we're talking about aggression and we're talking about aggression and we're talking about aggression and mating behavior, I think hormones. One mating behavior, I think hormones. One mating behavior, I think hormones. One of the common myths that's out there and of the common myths that's out there and of the common myths that's out there and I think that persists is that I think that persists is that I think that persists is that testosterone makes animals and humans testosterone makes animals and humans testosterone makes animals and humans aggressive and estrogen makes animals aggressive and estrogen makes animals aggressive and estrogen makes animals placid and kind or emotional. And as we placid and kind or emotional. And as we placid and kind or emotional. And as we both know, nothing could be further from both know, nothing could be further from both know, nothing could be further from the truth. The specific hormones that the truth. The specific hormones that the truth. The specific hormones that are involved in generating aggression are involved in generating aggression are involved in generating aggression via VMH via VMH via VMH are things other than testosterone. are things other than testosterone. are things other than testosterone. Could you tell us a little bit more Could you tell us a little bit more Could you tell us a little bit more about that because there's some about that because there's some about that because there's some interesting surprises in there. interesting surprises in there. interesting surprises in there. >> When we finally identified the neurons >> When we finally identified the neurons >> When we finally identified the neurons in VMH that control aggression with a in VMH that control aggression with a in VMH that control aggression with a molecular marker, we found out that that molecular marker, we found out that that molecular marker, we found out that that marker was the estrogen receptor. Other marker was the estrogen receptor. Other marker was the estrogen receptor. Other labs have shown that the estrogen labs have shown that the estrogen labs have shown that the estrogen receptor in adult male mice is necessary receptor in adult male mice is necessary receptor in adult male mice is necessary for aggression. If you knock out the for aggression. If you knock out the for aggression. If you knock out the gene in VMH, they don't fight. And it's gene in VMH, they don't fight. And it's gene in VMH, they don't fight. And it's been shown and a lot of this is work been shown and a lot of this is work been shown and a lot of this is work from your colleague Ner Sha at Stanford from your colleague Ner Sha at Stanford from your colleague Ner Sha at Stanford who is one of my former PhD students who is one of my former PhD students who is one of my former PhD students that if you castrate a mouse uh and it that if you castrate a mouse uh and it that if you castrate a mouse uh and it loses the abil ability to fight, not loses the abil ability to fight, not loses the abil ability to fight, not only can you rescue fighting with a only can you rescue fighting with a only can you rescue fighting with a testosterone implant, but you can rescue testosterone implant, but you can rescue testosterone implant, but you can rescue it with an estrogen implant. So you can it with an estrogen implant. So you can it with an estrogen implant. So you can bypass completely the requirement for bypass completely the requirement for bypass completely the requirement for testosterone to restore aggressiveness testosterone to restore aggressiveness testosterone to restore aggressiveness to the mice. And as you say, it's to the mice. And as you say, it's to the mice. And as you say, it's because many of the effects of because many of the effects of because many of the effects of testosterone, although not all, many of testosterone, although not all, many of testosterone, although not all, many of them are mediated by its conversion to them are mediated by its conversion to them are mediated by its conversion to estrogen by a process called estrogen by a process called estrogen by a process called aromatization. aromatization. aromatization. It's carried out by an enzyme called It's carried out by an enzyme called It's carried out by an enzyme called aromatase. In fact, people may have most aromatase. In fact, people may have most aromatase. In fact, people may have most of your listeners may have heard of of your listeners may have heard of of your listeners may have heard of aromatase because aromatase inhibitors aromatase because aromatase inhibitors aromatase because aromatase inhibitors are widely used in female humans as are widely used in female humans as are widely used in female humans as adgivant chemotherapy for breast cancer. adgivant chemotherapy for breast cancer. adgivant chemotherapy for breast cancer. what's involved in female aggression what's involved in female aggression what's involved in female aggression that's unique from the pathways that that's unique from the pathways that that's unique from the pathways that generate male aggression. generate male aggression. generate male aggression. >> So, uh we and other labs have studied >> So, uh we and other labs have studied >> So, uh we and other labs have studied this in both mice and also in fruit this in both mice and also in fruit this in both mice and also in fruit flies. One thing in mice that is flies. One thing in mice that is flies. One thing in mice that is distinguishes aggression and females distinguishes aggression and females distinguishes aggression and females from males is that male mice are pretty from males is that male mice are pretty from males is that male mice are pretty much ready to fight at the drop of a much ready to fight at the drop of a much ready to fight at the drop of a hat. Female mice only fight when they hat. Female mice only fight when they hat. Female mice only fight when they are nurturing and nursing their pups are nurturing and nursing their pups are nurturing and nursing their pups after they've delivered a litter. And after they've delivered a litter. And after they've delivered a litter. And there is a window there where they there is a window there where they there is a window there where they become hyperaggressive. become hyperaggressive. become hyperaggressive. After their pups are weaned, that After their pups are weaned, that After their pups are weaned, that aggressiveness goes away. So this is aggressiveness goes away. So this is aggressiveness goes away. So this is pretty remarkable that you take a virgin pretty remarkable that you take a virgin pretty remarkable that you take a virgin female mouse and expose it to a male and female mouse and expose it to a male and female mouse and expose it to a male and her response is to become sexually her response is to become sexually her response is to become sexually receptive and to mate with him. And now receptive and to mate with him. And now receptive and to mate with him. And now you let her have her pups and you put you let her have her pups and you put you let her have her pups and you put the same male or another male mouse in the same male or another male mouse in the same male or another male mouse in the cage with her and instead of trying the cage with her and instead of trying the cage with her and instead of trying to mate with him, she attacks him. We to mate with him, she attacks him. We to mate with him, she attacks him. We recently showed in a paper, this is work recently showed in a paper, this is work recently showed in a paper, this is work from one of my students, Mongu Leu, that from one of my students, Mongu Leu, that from one of my students, Mongu Leu, that within VMH in females, there are two within VMH in females, there are two within VMH in females, there are two clearly divisible subsets of estrogen clearly divisible subsets of estrogen clearly divisible subsets of estrogen receptor neurons. and she showed that receptor neurons. and she showed that receptor neurons. and she showed that one of those subsets controls fighting one of those subsets controls fighting one of those subsets controls fighting and the other one controls mating. This and the other one controls mating. This and the other one controls mating. This gets into the whole issue of neurons gets into the whole issue of neurons gets into the whole issue of neurons that are present in females but not in that are present in females but not in that are present in females but not in males. So this is already showing you males. So this is already showing you males. So this is already showing you some complexity. The male mouse VMH has some complexity. The male mouse VMH has some complexity. The male mouse VMH has both male specific aggression neurons both male specific aggression neurons both male specific aggression neurons and generic aggression neurons. And then and generic aggression neurons. And then and generic aggression neurons. And then the female VMH, the mating cells are the female VMH, the mating cells are the female VMH, the mating cells are only found in females. they are female only found in females. they are female only found in females. they are female specific and not found in the male specific and not found in the male specific and not found in the male brain. And so we're trying to find out brain. And so we're trying to find out brain. And so we're trying to find out what these sex specific populations of what these sex specific populations of what these sex specific populations of neurons are doing. But that indicates neurons are doing. But that indicates neurons are doing. But that indicates that that is some of the mechanism by that that is some of the mechanism by that that is some of the mechanism by which different sexes show different which different sexes show different which different sexes show different behaviors. If one observes the mating behaviors. If one observes the mating behaviors. If one observes the mating behaviors of different animals, we know behaviors of different animals, we know behaviors of different animals, we know that there's a tremendous range of that there's a tremendous range of that there's a tremendous range of mating behaviors in humans. Um there can mating behaviors in humans. Um there can mating behaviors in humans. Um there can be no aggressive component, there could be no aggressive component, there could be no aggressive component, there could be aggressive component. Humans have all be aggressive component. Humans have all be aggressive component. Humans have all sorts of kinks and fetishes and sorts of kinks and fetishes and sorts of kinks and fetishes and behaviors and most of which probably has behaviors and most of which probably has behaviors and most of which probably has never been documented because most of never been documented because most of never been documented because most of this happens in private. With that said, this happens in private. With that said, this happens in private. With that said, when you look at mating behavior of when you look at mating behavior of when you look at mating behavior of various animals, you see an aggressive various animals, you see an aggressive various animals, you see an aggressive component sometimes but not always. Is component sometimes but not always. Is component sometimes but not always. Is it species specific? Is it context it species specific? Is it context it species specific? Is it context specific? And more generally, do you specific? And more generally, do you specific? And more generally, do you think that there um is cross talk think that there um is cross talk think that there um is cross talk between these different neuro neuronal between these different neuro neuronal between these different neuro neuronal populations and the animal itself might populations and the animal itself might populations and the animal itself might be kind of confused about what's going be kind of confused about what's going be kind of confused about what's going on? I can't really speak to the issue of on? I can't really speak to the issue of on? I can't really speak to the issue of whether this is species specific because whether this is species specific because whether this is species specific because I'm not a naturalist or a zoologologist. I'm not a naturalist or a zoologologist. I'm not a naturalist or a zoologologist. Uh I've seen like you have in the wild Uh I've seen like you have in the wild Uh I've seen like you have in the wild for example lions when they mate I've for example lions when they mate I've for example lions when they mate I've seen them in Africa. There's often a seen them in Africa. There's often a seen them in Africa. There's often a biting component of that as well. One of biting component of that as well. One of biting component of that as well. One of the things that surprised us when we the things that surprised us when we the things that surprised us when we identified neurons in VMHVL that control identified neurons in VMHVL that control identified neurons in VMHVL that control aggression in males is that within that aggression in males is that within that aggression in males is that within that population there is a subset of neurons population there is a subset of neurons population there is a subset of neurons that is activated by females during male that is activated by females during male that is activated by females during male female mating encounters. There's some female mating encounters. There's some female mating encounters. There's some evidence that those female selective evidence that those female selective evidence that those female selective neurons in VMH are part of the mating neurons in VMH are part of the mating neurons in VMH are part of the mating behavior. If you shut them down, the behavior. If you shut them down, the behavior. If you shut them down, the animals don't mate as effectively as animals don't mate as effectively as animals don't mate as effectively as they otherwise would. U what happens they otherwise would. U what happens they otherwise would. U what happens when you stimulate them, we don't yet when you stimulate them, we don't yet when you stimulate them, we don't yet know because we don't have a way to know because we don't have a way to know because we don't have a way to specifically do that without activating specifically do that without activating specifically do that without activating the male aggression neurons. But I think the male aggression neurons. But I think the male aggression neurons. But I think they must be there for a reason because they must be there for a reason because they must be there for a reason because VMH is not traditionally the brain VMH is not traditionally the brain VMH is not traditionally the brain region to which male sexual behavior has region to which male sexual behavior has region to which male sexual behavior has been assigned. That's another area been assigned. That's another area been assigned. That's another area called the medial preoptic area. And called the medial preoptic area. And called the medial preoptic area. And there we have shown that there are there we have shown that there are there we have shown that there are neurons that definitely stimulate mating neurons that definitely stimulate mating neurons that definitely stimulate mating behavior. In fact, if we activate those behavior. In fact, if we activate those behavior. In fact, if we activate those mating neurons in a male while it's in mating neurons in a male while it's in mating neurons in a male while it's in the middle of attacking another male, it the middle of attacking another male, it the middle of attacking another male, it will stop fighting, start singing to will stop fighting, start singing to will stop fighting, start singing to that male, and start to try to mount that male, and start to try to mount that male, and start to try to mount that male until we shut those neurons that male until we shut those neurons that male until we shut those neurons off. So those are the make, love, not off. So those are the make, love, not off. So those are the make, love, not war neurons. And VMH are the make, war, war neurons. And VMH are the make, war, war neurons. And VMH are the make, war, not love neurons. And there are dense not love neurons. And there are dense not love neurons. And there are dense interconnections interconnections interconnections between these two nuclei which are very between these two nuclei which are very between these two nuclei which are very close to each other into the in the close to each other into the in the close to each other into the in the brain. But it's also possible that there brain. But it's also possible that there brain. But it's also possible that there are some cooperative interactions are some cooperative interactions are some cooperative interactions between those structures as well as uh between those structures as well as uh between those structures as well as uh antagonistic interactions. And the antagonistic interactions. And the antagonistic interactions. And the balance of whether it's the cooperative balance of whether it's the cooperative balance of whether it's the cooperative or antagonistic interactions that are or antagonistic interactions that are or antagonistic interactions that are firing at any given moment in a mating firing at any given moment in a mating firing at any given moment in a mating encounter, as you suggest, may determine encounter, as you suggest, may determine encounter, as you suggest, may determine whether a a moment of of uh of uh quital whether a a moment of of uh of uh quital whether a a moment of of uh of uh quital bliss among two lions may suddenly turn bliss among two lions may suddenly turn bliss among two lions may suddenly turn into a snap or a growl and a bearing of into a snap or a growl and a bearing of into a snap or a growl and a bearing of fangs. We don't know that but certainly fangs. We don't know that but certainly fangs. We don't know that but certainly the substrate the wiring is there for the substrate the wiring is there for the substrate the wiring is there for that to happen. When we made that that to happen. When we made that that to happen. When we made that discovery initially, it it raised the discovery initially, it it raised the discovery initially, it it raised the question in my mind whether uh some question in my mind whether uh some question in my mind whether uh some people that are serial rapists, for people that are serial rapists, for people that are serial rapists, for example, uh and engage in sexual example, uh and engage in sexual example, uh and engage in sexual violence might in some level have their violence might in some level have their violence might in some level have their wires crossed in some way that that wires crossed in some way that that wires crossed in some way that that these states that are supposed to be these states that are supposed to be these states that are supposed to be pretty much separated and mutually pretty much separated and mutually pretty much separated and mutually antagonistic are not and are actually antagonistic are not and are actually antagonistic are not and are actually more rewarding and reinforcing. I'd love more rewarding and reinforcing. I'd love more rewarding and reinforcing. I'd love to talk about this structure because it to talk about this structure because it to talk about this structure because it seems to be involved in everything which seems to be involved in everything which seems to be involved in everything which is the P A the perryqueductal gray. It's is the P A the perryqueductal gray. It's is the P A the perryqueductal gray. It's been studied in the context of pain. been studied in the context of pain. been studied in the context of pain. It's been studied in the context of the It's been studied in the context of the It's been studied in the context of the so-called lordosis response the the so-called lordosis response the the so-called lordosis response the the receptivity or arching of the back of receptivity or arching of the back of receptivity or arching of the back of the female to receive intrammission and the female to receive intrammission and the female to receive intrammission and mating from the male. In particular, I mating from the male. In particular, I mating from the male. In particular, I want to know is there some mechanism of want to know is there some mechanism of want to know is there some mechanism of pain modulation and control during pain modulation and control during pain modulation and control during fighting and or mating? And the reason I fighting and or mating? And the reason I fighting and or mating? And the reason I ask is that um while I'm not a combat ask is that um while I'm not a combat ask is that um while I'm not a combat sports person, years ago, I did did a sports person, years ago, I did did a sports person, years ago, I did did a little bit of martial arts and it always little bit of martial arts and it always little bit of martial arts and it always was um impressive to me how little it was um impressive to me how little it was um impressive to me how little it hurt to get punched during a fight and hurt to get punched during a fight and hurt to get punched during a fight and how much it hurt afterwards, right? So how much it hurt afterwards, right? So how much it hurt afterwards, right? So there clearly is some indogenous pain there clearly is some indogenous pain there clearly is some indogenous pain control control control >> um that then wears off and then you feel >> um that then wears off and then you feel >> um that then wears off and then you feel beat up. beat up. beat up. >> Y >> Y >> Y >> what's P A doing visav pain and what's >> what's P A doing visav pain and what's >> what's P A doing visav pain and what's pain doing visav these other behaviors? pain doing visav these other behaviors? pain doing visav these other behaviors? So, I think of P A like a old-fashioned So, I think of P A like a old-fashioned So, I think of P A like a old-fashioned telephone switchboard. There are calls telephone switchboard. There are calls telephone switchboard. There are calls coming in and then the cables have to be coming in and then the cables have to be coming in and then the cables have to be punched into the right hole to get the punched into the right hole to get the punched into the right hole to get the information to be routed to the right information to be routed to the right information to be routed to the right recipient on the other end of it. recipient on the other end of it. recipient on the other end of it. Because pretty much every type of innate Because pretty much every type of innate Because pretty much every type of innate behavior you can think of has had the behavior you can think of has had the behavior you can think of has had the pag implicated. In cross-section, the pag implicated. In cross-section, the pag implicated. In cross-section, the pag kind of looks like the water in a pag kind of looks like the water in a pag kind of looks like the water in a toilet when you're standing over an open toilet when you're standing over an open toilet when you're standing over an open toilet bowl. And if you imagine a clock toilet bowl. And if you imagine a clock toilet bowl. And if you imagine a clock face projected onto that, it's like the face projected onto that, it's like the face projected onto that, it's like the pag has sectors from 1 to 12, maybe even pag has sectors from 1 to 12, maybe even pag has sectors from 1 to 12, maybe even more of them. And in each of those more of them. And in each of those more of them. And in each of those sectors, you find different neurons from sectors, you find different neurons from sectors, you find different neurons from the hypothalamus are projecting. So it the hypothalamus are projecting. So it the hypothalamus are projecting. So it could turn out that there is a could turn out that there is a could turn out that there is a topographic arrangement along the dorsal topographic arrangement along the dorsal topographic arrangement along the dorsal vententral axis of the PAG and the vententral axis of the PAG and the vententral axis of the PAG and the medial axis of the PAG that determines medial axis of the PAG that determines medial axis of the PAG that determines the type of behavior that will be the type of behavior that will be the type of behavior that will be emitted when neurons in that region are emitted when neurons in that region are emitted when neurons in that region are stimulated. And I think sort of all of stimulated. And I think sort of all of stimulated. And I think sort of all of the evidence is pointing in that the evidence is pointing in that the evidence is pointing in that direction but by no means has it been direction but by no means has it been direction but by no means has it been mapped out. Now the thing that you mapped out. Now the thing that you mapped out. Now the thing that you mentioned about it not hurting when you mentioned about it not hurting when you mentioned about it not hurting when you got beat up during martial arts. There got beat up during martial arts. There got beat up during martial arts. There is a well-known phenomenon called is a well-known phenomenon called is a well-known phenomenon called fearinduced fearinduced fearinduced uh analesia uh analesia uh analesia where when an animal is in a high state where when an animal is in a high state where when an animal is in a high state of fear like if it's trying to defend of fear like if it's trying to defend of fear like if it's trying to defend itself there is a suppression of pain itself there is a suppression of pain itself there is a suppression of pain responses and I'm not sure completely responses and I'm not sure completely responses and I'm not sure completely about the mechanisms and how well that's about the mechanisms and how well that's about the mechanisms and how well that's understood but for example the adrenal understood but for example the adrenal understood but for example the adrenal gland has a peptide in it that is gland has a peptide in it that is gland has a peptide in it that is released from the adrenal medela which released from the adrenal medela which released from the adrenal medela which controls the fightor-flight responses controls the fightor-flight responses controls the fightor-flight responses and that peptide has analesic and that peptide has analesic and that peptide has analesic activities. activities. activities. what is what is what is >> it's called boine adrenal medularary >> it's called boine adrenal medularary >> it's called boine adrenal medularary peptide of 22 amino acid residues and I peptide of 22 amino acid residues and I peptide of 22 amino acid residues and I only know about it because it activates only know about it because it activates only know about it because it activates a receptor that we discovered many years a receptor that we discovered many years a receptor that we discovered many years ago that's involved in pain and we ago that's involved in pain and we ago that's involved in pain and we thought it promoted pain but it turns thought it promoted pain but it turns thought it promoted pain but it turns out that this actually inhibits pain. out that this actually inhibits pain. out that this actually inhibits pain. It's like an endogenous analesic. It's like an endogenous analesic. It's like an endogenous analesic. Whether this is happening, this type of Whether this is happening, this type of Whether this is happening, this type of analesia is happening when an animal is analesia is happening when an animal is analesia is happening when an animal is engaged in offensive aggression or in engaged in offensive aggression or in engaged in offensive aggression or in mating behavior. I don't know, but it mating behavior. I don't know, but it mating behavior. I don't know, but it certainly is possible. And I don't know certainly is possible. And I don't know certainly is possible. And I don't know whether these uh analesic mechanisms are whether these uh analesic mechanisms are whether these uh analesic mechanisms are happening in the PAG. They could also be happening in the PAG. They could also be happening in the PAG. They could also be happening a little further down in the happening a little further down in the happening a little further down in the spinal cord. The PAG is really spinal cord. The PAG is really spinal cord. The PAG is really continuous with the spinal cord. If you continuous with the spinal cord. If you continuous with the spinal cord. If you just follow it down towards the tail of just follow it down towards the tail of just follow it down towards the tail of an animal, you will wind up in the an animal, you will wind up in the an animal, you will wind up in the spinal cord. And so it could be that spinal cord. And so it could be that spinal cord. And so it could be that there are influences acting at many there are influences acting at many there are influences acting at many levels on pain in the pag and in the levels on pain in the pag and in the levels on pain in the pag and in the spinal cord as well. And it may well be spinal cord as well. And it may well be spinal cord as well. And it may well be known. I just don't know it. I want to known. I just don't know it. I want to known. I just don't know it. I want to distinguish clearly between things that distinguish clearly between things that distinguish clearly between things that are not known that I know are unknown are not known that I know are unknown are not known that I know are unknown which is in a fairly small area where I which is in a fairly small area where I which is in a fairly small area where I have expertise from things that may be have expertise from things that may be have expertise from things that may be known but I'm ignorant of them because I known but I'm ignorant of them because I known but I'm ignorant of them because I just don't have a broad enough knowledge just don't have a broad enough knowledge just don't have a broad enough knowledge base to know that. Tell us about base to know that. Tell us about base to know that. Tell us about tachikinan. tachikinan. tachikinan. I've talked about this a couple times on I've talked about this a couple times on I've talked about this a couple times on different podcast episodes because of different podcast episodes because of different podcast episodes because of its relationship to social isolation. My its relationship to social isolation. My its relationship to social isolation. My understanding is that tachikinanine is understanding is that tachikinanine is understanding is that tachikinanine is present in flies and mice and in humans present in flies and mice and in humans present in flies and mice and in humans and may do similar things in those and may do similar things in those and may do similar things in those species. So tachyin is uh refers to a species. So tachyin is uh refers to a species. So tachyin is uh refers to a family of related neuropeptides. So family of related neuropeptides. So family of related neuropeptides. So these are brain chemicals. They're these are brain chemicals. They're these are brain chemicals. They're different from dopamine and serotonin in different from dopamine and serotonin in different from dopamine and serotonin in that they're not small organic that they're not small organic that they're not small organic molecules. They're actually short pieces molecules. They're actually short pieces molecules. They're actually short pieces of protein that are directly encoded by of protein that are directly encoded by of protein that are directly encoded by genes that are active in specific genes that are active in specific genes that are active in specific neurons and not in others. And when neurons and not in others. And when neurons and not in others. And when those neurons are active, those those neurons are active, those those neurons are active, those neuropeptides are released together with neuropeptides are released together with neuropeptides are released together with classical transmitters like glutamate. classical transmitters like glutamate. classical transmitters like glutamate. Whatever tackyins have been famously Whatever tackyins have been famously Whatever tackyins have been famously implicated in pain, particularly implicated in pain, particularly implicated in pain, particularly tachikin 1, which is called substance P, tachikin 1, which is called substance P, tachikin 1, which is called substance P, one of the original pain modulating. one of the original pain modulating. one of the original pain modulating. This is something that promotes This is something that promotes This is something that promotes inflammatory pain. And so we did a a inflammatory pain. And so we did a a inflammatory pain. And so we did a a screen unbiased screen of peptides and screen unbiased screen of peptides and screen unbiased screen of peptides and found indeed that one of the tachikinins found indeed that one of the tachikinins found indeed that one of the tachikinins Drosopha tachiinan those neurons when Drosopha tachiinan those neurons when Drosopha tachiinan those neurons when you activate them strongly promote you activate them strongly promote you activate them strongly promote aggression and it depends on the release aggression and it depends on the release aggression and it depends on the release of tachikinanine. Now the interesting of tachikinanine. Now the interesting of tachikinanine. Now the interesting thing is that in flies just like in thing is that in flies just like in thing is that in flies just like in people and practically any other social people and practically any other social people and practically any other social animal that shows aggression, social animal that shows aggression, social animal that shows aggression, social isolation increases aggressiveness. So isolation increases aggressiveness. So isolation increases aggressiveness. So putting a violent prisoner in solitary putting a violent prisoner in solitary putting a violent prisoner in solitary confinement is absolutely the worst most confinement is absolutely the worst most confinement is absolutely the worst most counterproductive thing you could do to counterproductive thing you could do to counterproductive thing you could do to them. And indeed we found in flies that them. And indeed we found in flies that them. And indeed we found in flies that social isolation increases the level of social isolation increases the level of social isolation increases the level of tachikinan in the brain. And if we shut tachikinan in the brain. And if we shut tachikinan in the brain. And if we shut that gene down, it prevents the that gene down, it prevents the that gene down, it prevents the isolation from increasing aggression. So isolation from increasing aggression. So isolation from increasing aggression. So since my lab also works on mice, it was since my lab also works on mice, it was since my lab also works on mice, it was natural to see whether tachie kinins natural to see whether tachie kinins natural to see whether tachie kinins might be upregulated in social isolation might be upregulated in social isolation might be upregulated in social isolation and whether they play a role in and whether they play a role in and whether they play a role in aggression. And this is work done by a aggression. And this is work done by a aggression. And this is work done by a former postoc Moriel Zelikovsky now at former postoc Moriel Zelikovsky now at former postoc Moriel Zelikovsky now at University of Salt Lake City in Utah. University of Salt Lake City in Utah. University of Salt Lake City in Utah. And she found remarkably that when mice And she found remarkably that when mice And she found remarkably that when mice are socially isolated for two weeks, are socially isolated for two weeks, are socially isolated for two weeks, there is this massive upregulation of there is this massive upregulation of there is this massive upregulation of tachikinan 2 in their brain. In fact, if tachikinan 2 in their brain. In fact, if tachikinan 2 in their brain. In fact, if you tag the peptide with a green you tag the peptide with a green you tag the peptide with a green fluorescent protein from a jellyfish, fluorescent protein from a jellyfish, fluorescent protein from a jellyfish, genetically the brain looks green when genetically the brain looks green when genetically the brain looks green when the mice are socially isolated because the mice are socially isolated because the mice are socially isolated because there's so much of this stuff released. there's so much of this stuff released. there's so much of this stuff released. And she went on to show that that And she went on to show that that And she went on to show that that increase in tachi kynanin is responsible increase in tachi kynanin is responsible increase in tachi kynanin is responsible for the effect of social isolation to for the effect of social isolation to for the effect of social isolation to increase aggressiveness and to increase increase aggressiveness and to increase increase aggressiveness and to increase fear and to increase anxiety. And in fear and to increase anxiety. And in fear and to increase anxiety. And in fact there are drugs that block the fact there are drugs that block the fact there are drugs that block the receptor for tachiein which were tested receptor for tachiein which were tested receptor for tachiein which were tested in humans and abandoned because they had in humans and abandoned because they had in humans and abandoned because they had no efficacy in the tests that they were no efficacy in the tests that they were no efficacy in the tests that they were analyzed for. If you give those drugs to analyzed for. If you give those drugs to analyzed for. If you give those drugs to a socially isolated mouse, it blocks all a socially isolated mouse, it blocks all a socially isolated mouse, it blocks all of the effects of social isolation. It of the effects of social isolation. It of the effects of social isolation. It blocks the aggression. It blocks the blocks the aggression. It blocks the blocks the aggression. It blocks the increased fear and the increased increased fear and the increased increased fear and the increased anxiety. And that Moriel described it. anxiety. And that Moriel described it. anxiety. And that Moriel described it. The mice just look chill. It's not a The mice just look chill. It's not a The mice just look chill. It's not a seditive, which is really important. seditive, which is really important. seditive, which is really important. It's not that the mice are going to It's not that the mice are going to It's not that the mice are going to sleep. Most remarkably is once you sleep. Most remarkably is once you sleep. Most remarkably is once you socially isolate a mouse and it becomes socially isolate a mouse and it becomes socially isolate a mouse and it becomes aggressive, you can never put it back in aggressive, you can never put it back in aggressive, you can never put it back in its cage with its brothers from its its cage with its brothers from its its cage with its brothers from its litter because it will kill them all litter because it will kill them all litter because it will kill them all overnight. But if you give it this drug overnight. But if you give it this drug overnight. But if you give it this drug which is called osanotonant that black which is called osanotonant that black which is called osanotonant that black blocks tachikinanine too that mouse can blocks tachikinanine too that mouse can blocks tachikinanine too that mouse can be returned to the cage with its be returned to the cage with its be returned to the cage with its brothers and will not attack them and brothers and will not attack them and brothers and will not attack them and seems to be happy about that for the seems to be happy about that for the seems to be happy about that for the rest of the time. So, this is an rest of the time. So, this is an rest of the time. So, this is an incredibly powerful effect of this drug. incredibly powerful effect of this drug. incredibly powerful effect of this drug. And I've been really interested in And I've been really interested in And I've been really interested in trying to get pharmaceutical companies trying to get pharmaceutical companies trying to get pharmaceutical companies to test this drug, which has a really to test this drug, which has a really to test this drug, which has a really good safety profile in humans, in good safety profile in humans, in good safety profile in humans, in testing it in people who are subjected testing it in people who are subjected testing it in people who are subjected to social isolation stress or to social isolation stress or to social isolation stress or bereavement stress. But it's just very bereavement stress. But it's just very bereavement stress. But it's just very difficult for economic reasons to find a difficult for economic reasons to find a difficult for economic reasons to find a way to get somebody to test that. As way to get somebody to test that. As way to get somebody to test that. As long as we're talking about humans, I'd long as we're talking about humans, I'd long as we're talking about humans, I'd love to get your thoughts about human love to get your thoughts about human love to get your thoughts about human studies of emotion. I know you wrote studies of emotion. I know you wrote studies of emotion. I know you wrote this book with Ralph Adolf. You have this book with Ralph Adolf. You have this book with Ralph Adolf. You have this new book. There are books that are this new book. There are books that are this new book. There are books that are worth reading and then there are books worth reading and then there are books worth reading and then there are books that are important and I think this book that are important and I think this book that are important and I think this book is truly important for the general is truly important for the general is truly important for the general population to read and understand. population to read and understand. population to read and understand. There's a heat map diagram in that book There's a heat map diagram in that book There's a heat map diagram in that book of subjective reports that people gave of subjective reports that people gave of subjective reports that people gave of where they experience an emotion or a of where they experience an emotion or a of where they experience an emotion or a feeling sematic feeling in their body or feeling sematic feeling in their body or feeling sematic feeling in their body or in their head or both when they are in their head or both when they are in their head or both when they are angry sad calm lonely etc etc and I angry sad calm lonely etc etc and I angry sad calm lonely etc etc and I wouldn't want people to think that those wouldn't want people to think that those wouldn't want people to think that those heat maps were generated by any heat maps were generated by any heat maps were generated by any physiological measurement because they physiological measurement because they physiological measurement because they were not. How should we think about the were not. How should we think about the were not. How should we think about the body in terms of states? And at some body in terms of states? And at some body in terms of states? And at some point, I'd love for you to comment on point, I'd love for you to comment on point, I'd love for you to comment on that heat map experiment. Uh this goes that heat map experiment. Uh this goes that heat map experiment. Uh this goes back to uh something called the somatic back to uh something called the somatic back to uh something called the somatic marker hypothesis that was proposed by marker hypothesis that was proposed by marker hypothesis that was proposed by Antonio Damasio who is a neurologist at Antonio Damasio who is a neurologist at Antonio Damasio who is a neurologist at USC. The idea that our subjective USC. The idea that our subjective USC. The idea that our subjective feeling of a particular emotion is in feeling of a particular emotion is in feeling of a particular emotion is in part associated with a sensation of part associated with a sensation of part associated with a sensation of something happening in a particular part something happening in a particular part something happening in a particular part of our body, the gut, the heart. If of our body, the gut, the heart. If of our body, the gut, the heart. If there is a physiology underlying these there is a physiology underlying these there is a physiology underlying these heat maps, it could reflect increased heat maps, it could reflect increased heat maps, it could reflect increased blood flow to these different structures blood flow to these different structures blood flow to these different structures and that in turn reflects communication and that in turn reflects communication and that in turn reflects communication between the brain and the body and it's between the brain and the body and it's between the brain and the body and it's birectional communication and it's birectional communication and it's birectional communication and it's mediated by the peripheral nervous mediated by the peripheral nervous mediated by the peripheral nervous system, the sympathetic and the system, the sympathetic and the system, the sympathetic and the parasympathetic nervous system which parasympathetic nervous system which parasympathetic nervous system which control heart rate for example, blood control heart rate for example, blood control heart rate for example, blood vessel blood pressure and those nerves vessel blood pressure and those nerves vessel blood pressure and those nerves Neurons receive input from the Neurons receive input from the Neurons receive input from the hypothalamus and other blood uh brain hypothalamus and other blood uh brain hypothalamus and other blood uh brain regions, central brain regions that regions, central brain regions that regions, central brain regions that control their activity. And when the control their activity. And when the control their activity. And when the brain is put in a particular state, it brain is put in a particular state, it brain is put in a particular state, it activates sympathetic and activates sympathetic and activates sympathetic and parasympathetic neurons which have parasympathetic neurons which have parasympathetic neurons which have effects on the heart and on blood effects on the heart and on blood effects on the heart and on blood pressure. These in turn feed back onto pressure. These in turn feed back onto pressure. These in turn feed back onto the brain through the sensory system. the brain through the sensory system. the brain through the sensory system. And uh a large part of this birectional And uh a large part of this birectional And uh a large part of this birectional communication is also mediated through communication is also mediated through communication is also mediated through the vagus nerve which many of your the vagus nerve which many of your the vagus nerve which many of your listeners and viewers may have heard listeners and viewers may have heard listeners and viewers may have heard about because it's become a topic of about because it's become a topic of about because it's become a topic of intense activity. Now the vagus nerve is intense activity. Now the vagus nerve is intense activity. Now the vagus nerve is a bundle of nerve fibers that comes out a bundle of nerve fibers that comes out a bundle of nerve fibers that comes out basically of your skull, out of the basically of your skull, out of the basically of your skull, out of the central nervous system and then sends central nervous system and then sends central nervous system and then sends fibers in to your heart, your gut, all fibers in to your heart, your gut, all fibers in to your heart, your gut, all sorts of visceral organs. That sorts of visceral organs. That sorts of visceral organs. That information is both apherrant and information is both apherrant and information is both apherrant and epherent. The veagal fibers sense things epherent. The veagal fibers sense things epherent. The veagal fibers sense things that are happening in the body. So when that are happening in the body. So when that are happening in the body. So when you're the reason you feel your stomach you're the reason you feel your stomach you're the reason you feel your stomach tied up in knots if you're tense is that tied up in knots if you're tense is that tied up in knots if you're tense is that those veagal fibers are sensing the those veagal fibers are sensing the those veagal fibers are sensing the contraction of the gut muscles. They're contraction of the gut muscles. They're contraction of the gut muscles. They're also aference which means that also aference which means that also aference which means that information coming out of the brain can information coming out of the brain can information coming out of the brain can influence those peripheral organs as influence those peripheral organs as influence those peripheral organs as well. And there's work from a number of well. And there's work from a number of well. And there's work from a number of labs just in the last 6 months or so labs just in the last 6 months or so labs just in the last 6 months or so where people are starting to decode the where people are starting to decode the where people are starting to decode the components of the different fibers in components of the different fibers in components of the different fibers in the vagus nerve. And it's amazing how the vagus nerve. And it's amazing how the vagus nerve. And it's amazing how much specificity is. There are specific much specificity is. There are specific much specificity is. There are specific veagal nerves that go to the lung that veagal nerves that go to the lung that veagal nerves that go to the lung that control breathing responses that go to control breathing responses that go to control breathing responses that go to the gut that go to other organs. uh it's the gut that go to other organs. uh it's the gut that go to other organs. uh it's almost like a set of color-coded lines almost like a set of color-coded lines almost like a set of color-coded lines uh uh labeled lines for those things. uh uh labeled lines for those things. uh uh labeled lines for those things. And now how those vagal aference play a And now how those vagal aference play a And now how those vagal aference play a role in the playing out of emotion role in the playing out of emotion role in the playing out of emotion states is a fascinating question that states is a fascinating question that states is a fascinating question that people are just beginning to scrape the people are just beginning to scrape the people are just beginning to scrape the surface of. But I think what's exciting surface of. But I think what's exciting surface of. But I think what's exciting now is that people are going to be now is that people are going to be now is that people are going to be developing tools that will allow us to developing tools that will allow us to developing tools that will allow us to turn on or turn off specific subsets of turn on or turn off specific subsets of turn on or turn off specific subsets of fibers within the vagus nerve and ask fibers within the vagus nerve and ask fibers within the vagus nerve and ask how that affects particular emotional how that affects particular emotional how that affects particular emotional behaviors. So you're absolutely right. behaviors. So you're absolutely right. behaviors. So you're absolutely right. This brain body connection is critical This brain body connection is critical This brain body connection is critical not just for the gut but for the heart, not just for the gut but for the heart, not just for the gut but for the heart, for the lungs, for all kinds of other uh for the lungs, for all kinds of other uh for the lungs, for all kinds of other uh parts of your body. And Darwin parts of your body. And Darwin parts of your body. And Darwin recognized that as well. And I think recognized that as well. And I think recognized that as well. And I think it's uh it's a central feature of it's uh it's a central feature of it's uh it's a central feature of emotion state and I think what underlies emotion state and I think what underlies emotion state and I think what underlies our subjective feelings of an emotion. our subjective feelings of an emotion. our subjective feelings of an emotion. David, I have to say as a true fan of David, I have to say as a true fan of David, I have to say as a true fan of the work that your lab has been doing the work that your lab has been doing the work that your lab has been doing over so many decades. I know I speak on over so many decades. I know I speak on over so many decades. I know I speak on behalf of a tremendous number of people behalf of a tremendous number of people behalf of a tremendous number of people and I say thank you for taking time out and I say thank you for taking time out and I say thank you for taking time out of your important schedule to share with of your important schedule to share with of your important schedule to share with us what you've learned. us what you've learned. us what you've learned. >> I really have appreciated your >> I really have appreciated your >> I really have appreciated your questions. They're all they've all been questions. They're all they've all been questions. They're all they've all been right on the money. You've hit all of right on the money. You've hit all of right on the money. You've hit all of the critical important issues in this the critical important issues in this the critical important issues in this field and you've you've uncovered what field and you've you've uncovered what field and you've you've uncovered what is known, the little bit is known and is known, the little bit is known and is known, the little bit is known and how much is not known. And I think it's how much is not known. And I think it's how much is not known. And I think it's important to emphasize the unknown important to emphasize the unknown important to emphasize the unknown things because that's what the next things because that's what the next things because that's what the next generation of neuroscientists has to generation of neuroscientists has to generation of neuroscientists has to solve. And so I hope this will help to solve. And so I hope this will help to solve. And so I hope this will help to attract young people into this field attract young people into this field attract young people into this field because it's so important particularly because it's so important particularly because it's so important particularly for our understanding of mental illness for our understanding of mental illness for our understanding of mental illness and mental health and and uh uh and and mental health and and uh uh and and mental health and and uh uh and psychiatry. We've got to figure out how psychiatry. We've got to figure out how psychiatry. We've got to figure out how emotion systems are controlled in a emotion systems are controlled in a emotion systems are controlled in a causal way uh if we ever want to improve causal way uh if we ever want to improve causal way uh if we ever want to improve on the psychiatric treatments that we on the psychiatric treatments that we on the psychiatric treatments that we have now. And that's going to require have now. And that's going to require have now. And that's going to require the next generation of people coming the next generation of people coming the next generation of people coming into the field. into the field. into the field. >> Absolutely. I second that. Well, thank >> Absolutely. I second that. Well, thank >> Absolutely. I second that. Well, thank you. It's been a delight. you. It's been a delight. you. It's been a delight. >> Thank you. Great. Really appreciate it.