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

1. 0:00 – 3:33

   Dr. David Anderson, Emotions & Aggression

   1. AHAndrew Huberman0:00

      (Music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is Dr. David Anderson. Dr. Anderson is a professor of biology at the California Institute of Technology, often commonly referred to as Caltech University. Dr. Anderson's research focuses on emotions and states of mind and body, and indeed, he emphasizes how emotions like happiness, sadness, anger, and so on are actually subcategories of what are generally governed by states. That is, things that are occurring in the nervous system, in our brain, and in the connections between brain and body, that dictate whether or not we feel good about how we are feeling and that drive our behaviors. That is, bias us to be an action or inaction and strongly influence the way we interpret our experience and our surroundings. Today, Dr. Anderson teaches us, for instance, why people become aggressive and why that aggression can sometimes take the form of rage. We'll also talk about sexual behavior and the boundaries and overlap between aggression and sexual behavior. And that discussion about aggression and sexual behavior also starts to focus on particular aspects of neural circuits and states of mind and body that govern things like, for instance, male-male aggression versus male-female aggression versus female-female aggression. So today, you will learn a lot about the biological mechanisms that govern why we feel the way we feel. Indeed, Dr. Anderson is an author of a terrific new popular book entitled The Nature of the Beast: How Emotions Guide Us. I've read this book several times now. I can tell you it contains so many gems that are firmly grounded in the scientific research. In fact, a lot of what's in the book contrasts with many of the common myths about emotions and biology. So whether or not you're a therapist or you're a biologist or you're simply just somebody interested in why we feel the way we feel and why we act the way we act, I cannot recommend the book highly enough. Again, the title is The Nature of the Beast: How Emotions Guide Us. Today's discussion also ventures into topics such as mental health and mental illness and some of the exciting discoveries that have been made by Dr. Anderson's laboratory and other laboratories identifying specific peptides, that is, small proteins that can govern whether or not people feel anxious or less anxious, aggressive or less aggressive. This is an important area of research that has direct implications for much of what we read about in the news, both unfortunate and fortunate events, and that will no doubt drive the future of mental health treatments. Dr. Anderson is considered one of the most pioneering and important researchers in neurobiology of our time. Indeed, he is a member of the National Academy of Sciences and a Howard Hughes Medical Institute investigator. I've mentioned the HHMI once or twice before when we've had other HHMI guests on this podcast, but for those of you that are not familiar, the Howard Hughes Medical Institute funds a small number of investigators doing particularly high-risk, high-benefit work, and it is an extremely competitive process to identify those Howard Hughes investigators. They're essentially appointed, and then every five years, they have to compete against one another and against a new incoming flock of would-be HHMI investigators to get another five years of funding. They are literally given a grade every five years as to whether or not they can continue, not continue, or whether or not they should worry about being funded for an extended period of time. Dr. Anderson has been an investigator with the Howard Hughes Medical Institute since 1989.

2. 3:33 – 4:27

   Momentous Supplements

   1. AHAndrew Huberman3:33

      I'm pleased to announce that the Huberman Lab Podcast is now partnered with Momentous supplements. We partnered with Momentous for several important reasons. First of all, they ship internationally, because, uh, we know that many of you are located outside of the United States. Second of all, and perhaps most important, the quality of their supplements is second to none, both in terms of purity and precision of the amounts of the ingredients. Third, we've really emphasized supplements that are single ingredient supplements and that are supplied in dosages that allow you to build a supplementation protocol that's optimized for cost, that's optimized for effectiveness, and that you can add things and remove things from your protocol in a way that's really systematic and scientific. If you'd like to see the supplements that we partner with Momentous on, you can go to livemomentous.com/huberman. There, you'll see those supplements, and just keep in mind that we are constantly expanding the library of supplements available through Momentous on a regular basis. Again, that's livemomentous.com/huberman.

3. 4:27 – 8:10

   Levels, Helix Sleep, LMNT

   1. AHAndrew Huberman4:27

      Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Levels. Levels is a program that lets you see how different foods affect your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors governing our immediate and long-term health, and indeed our ability to think and focus clearly, is our blood glucose levels, also referred to as blood sugar. To maintain healthy energy and focus throughout the day, you want to keep your blood glucose levels steady and avoid peaks and crashes. I first started using Levels about a year ago as a way to better understand how specific foods, food combinations, exercise, and supplements impact my blood glucose levels, and it's been tremendously informative. In fact, it's changed and shaped the way that I organize my entire day. Levels even provides a simple score after you eat a meal, so you can see how different foods affect you and develop a personalized nutrition program that's ideal for you. So if you're interested in learning more about Levels and trying a continuous glucose monitor yourself, you can go to levels.link/huberman. That's levels.link/huberman. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are of the absolute highest quality. They also have some really unique features, because they are customized to your unique sleep needs. I've talked over and over again on this podcast and on other podcasts about the fact that sleep is the foundation of mental health, physical health, and performance. There's just simply no other substitute for a quality night's sleep on a regular basis. I've been sleeping on a Helix mattress for well over a year now, and it's the best sleep that I've ever had, and that's in large part because the mattress was designed for me. What you need to know, however, is what's the ideal mattress for you, and you can do that by going to Helix site. You can take their brief quiz, which will ask you, "Do you sleep on your side, your back, your stomach, or maybe you don't know, or maybe all three? Do you tend to run hot or cold in the night? Maybe you know, maybe you don't."At the end of that short quiz, they will match you to the ideal mattress for you. I matched to the Dusk, the D-U-S-K, mattress, but again, that's what I need, that's not necessarily what you need in order to get your best night's sleep. But if you're interested in upgrading your mattress, go to helixsleep.com/huberman, take their two-minute sleep quiz, and they'll match you to a customized mattress for you, and you'll get up to $200 off any mattress order and two free pillows, they have terrific pillows. And you get to try out that mattress for 100 nights risk-free, they'll even pick it up for you if you don't love it, but I'm certain you will. Again, if you're interested and you go to helixsleep.com/huberman for up to $200 off your mattress order and two free pillows. Today's episode is also brought to us by LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't, meaning no sugar, but it has sodium, magnesium, and potassium in the proper ratios. Sodium, magnesium, and potassium are critical for the functioning of all your cells, but of your neurons, your nerve cells, in particular. Many people out there, believe it or not, need to ingest more sodium and more potassium, and magnesium in the proper ratios to sodium and potassium. For those of you that are prehypertensive or hypertensive, you definitely don't want to crank up your sodium intake, but many people out there, especially people following low-carb diets or eating exceptionally clean very well may need more sodium, and by drinking LMNT mixed with water, which is what I do once or twice a day, and certainly also during workouts and after workouts, you can optimize mental functioning and physical performance by increasing your electrolyte balance in the proper ratios. If you'd like to try LMNT, you can go to DrinkLMNT, that's L-M-N-T.com/huberman, and you'll get a free sample pack with your order. Again, that's DrinkL-M-N-T.com/huberman to get a free sample pack with your order. And now for my discussion with Dr. David Anderson.

4. 8:10 – 10:36

   Emotions vs. States

   1. AHAndrew Huberman8:10

      David, great to be here and great to finally sit down and chat with you.

   2. DADavid Anderson8:14

      Great to be here too. Thank you so much.

   3. AHAndrew Huberman8:16

      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 emotion. What are they? They have all these names, happiness, sadness, depression, uh, 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?

   4. DADavid Anderson8:47

      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 arousal's also a type of internal state, motivation's a type of internal state, sleep is a type of internal state. And the sort of simplest way I think of internal states is that, as you've shown in your own work, they change the input to output transformation of the brain. When you're asleep, you don't hear something that you would hear if you were awake, unless it's a really, really loud noise. So from that broad perspective, I see emotion as a class of state that controls behavior. The reason I think it's useful to think about it as a state is it puts the focus on it as a neurobiological process rather than as a psychological process, and this gets around all of the definitional problems that people have with the word emotion, where many people equate emotion with feeling, which is a subjective sense that we can only study in humans, because to find out what someone's feeling, you have to ask them, and people are the only animals that can talk that we can understand. So that's how I think about emotion. It's the, if you think, if you think of an iceberg, it's the part of the iceberg that's below the surface of the water. The feeling part is the tip that's sort of floating above the surface of your consciousness. Not that that isn't important, it is, but you have to understand consciousness if you want to understand feelings, and we're not ready to study that in animals yet. And so that's how I think about it.

5. 10:36 – 14:38

   Dimensions of States: Persistence, Intensity & Generalization

   1. DADavid Anderson10:36

   2. AHAndrew Huberman10:36

      What are the different components of a state? Um, you know, you mentioned arousal as a key component. Um, what are some of the other features of states that, uh, represent this, as you, um, so beautifully put in your book, that represent below the tip of the iceberg?

   3. DADavid Anderson10:52

      Right. Right. So, uh, you can break states up, uh, into different facets, or people would call them dimensions, and so, uh, there have been people who have thought of emotions as having just really two dimensions, a, an arousal dimension, uh, uh, how intense is it, um, and also a valence dimension, um, which is, is it positive or negative, good or bad? Um, Ralph Adolphs and I have tried to expand that a little bit to think about components of emotion, particularly those that distinguish emotion states from motivational states, because they are very closely related. Um, one of those important properties is persistence, um, and this is something that distinguishes state-driven behaviors from simple reflexes. Reflexes tend to terminate when the stimulus turns off, like the doctor hitting your knee with a hammer. It initiates with the stimulus onset and it terminates with the stimulus offset. Emotions tend to outlast, often, the stimulus that evoke them. If you're walking along a, a trail here in Southern California, you hear a rattlesnake rattling, you're going to jump in the air, but your heart is going to continue to beat and your palms sweat and your mouth is going to be dry for a while after it's slithered off in the bush, and you're going to be hypervigilant if you see something that even remotely looks snake-like, a stick, you're going to stop and jump. So persistence is an important feature, uh, of, of emotion states. Not all states have persistence. So for example, you think about hunger. Once you've eaten, the state is gone....you're not hungry anymore. But if you are really angry and you get into a fight with somebody, even after the fight is over, you may remain riled up for a long time and it takes you a while to calm down, and that may have to do with the arousal dimension or some other part of it. 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 soothe it, and if you had a bad day at work, you might react very differently to it and scream at it. And so that's a generalization of the state that was triggered at work by something your boss said to you, to a completely different interaction.

   4. AHAndrew Huberman13:48

      Mm-hmm.

   5. DADavid Anderson13:48

      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 they're, they're involved in homeostatic maintenance. So s- states are very multifaceted, and just asking questions about how these components of states are encoded, like what makes a state persist? What gives a state a positive or a negative valence? How do you crank up or crank down the intensity of the state? It just opens up a whole bunch of questions that you can ask in the brain with the kinds of tools we have now.

6. 14:38 – 18:11

   Arousal & Valence

   1. AHAndrew Huberman14:38

      You mentioned arousal a few times, and you mentioned valence. Realizing that there are these other aspects of states, I'd like to just talk about arousal a little bit more, and valence, because at a very basic level, it seems to me that arousal, we can be very alert and kind of pissed off, uh, stressed, worried, could have insomnia. We can also be very alert and be quite happy, so the v- the valence flips. Uh, we could be very, you know, people can be sexually aroused, people can be aroused in all sorts of ways. Is there any simple or simple-ish neurochemical signature that can flip valence? So for instance, is there any way that we can safely say that arousal with some additional dopamine release is going to be of positive valence, and arousal with, um, very low dopamine is going to be of negative valence?

   2. DADavid Anderson15:34

      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.

   3. AHAndrew Huberman15:42

      Mm-hmm.

   4. DADavid Anderson15:43

      Different circuits being engaged, and it might be that a given neurochemical, even dopamine, is involved in both positively valenced arousal and negatively valenced arousal, that's why people think about these as different axes. So w- 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 arousal that are specific to different behaviors? And you raise the question, you know, sexual arousal feels different from aggressive arousal, for example. And we actually published a paper on this back in 2009 in fruit flies, where we found some evidence for two types of arousal states, one of which is sleep/wake arousal, you're more aroused when you wake up than when you're asleep, and flies show that. And the other is a, a startle response, an arousal response to a mechanical stimulus, a noxious mechanical stimulus. If you puff air on flies, kind of like trying to swat the wasp away from your burger at the picnic table, they come back more and more and more vigorously. And we were able to dissect this and show that although both of those forms of arousal require dopamine, they were, they were exerted through completely separable neural circuits in the fly. And so that really put, number one, the emphasis on it's the circuit that determines the type of arousal, but also that arousal isn't unitary, that there are behavior-specific forms of arousal. And I think the jury is still out as to whether there is such a thing as completely generalized arousal or not. I, I think some people would argue there is, but I think more attention needs to be paid to this question of domain-specific or behavior-specific forms of arousal.

   5. AHAndrew Huberman17:46

      Yeah, it's a super interesting idea, 'cause I always thought of arousal as along a continuum, like you can either be in a panic attack at the one end of the extreme or you can be in a coma, and then somewhere in the middle you're alert and calm. But then this issue of valence really, as you, as you say, uh, presents this opportunity that really there might be multiple circuits for arousal or-

   6. DADavid Anderson18:05

      Yeah.

   7. AHAndrew Huberman18:05

      ...multiple mechanisms that would include neurochemicals as well as different neural pathways.

7. 18:11 – 24:42

   Aggression, Optogenetics & Stimulating Aggression in Mice, VMH

   1. AHAndrew Huberman18:11

   2. DADavid Anderson18:11

      Yeah.

   3. AHAndrew Huberman18:11

      So like to talk a bit about a state, um, if, if it is indeed a state, uh, which is aggression. Your lab's worked extensively on this. And if you would, could you highlight some of the, the key findings there? Um, which brain areas are involved? Um, the beautiful work of Dayu Lin and others in your lab, um, 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, uh, skew the question a bit more by saying we see lots of different kinds of aggression.Um, this terrible s- shoo- school shooting down in Texas recently, clearly an act that included aggression-

   4. DADavid Anderson18:58

      Mm-hmm.

   5. AHAndrew Huberman18:58

      ... and yet you could imagine that's a very different type of aggression than a, you know, an all-out rage or a controlled aggression, you know, there's a, 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?

   6. DADavid Anderson19:13

      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 it 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 it's predatory aggression, and so this gets at the issue that you raised of the different types of aggression that exist. Um, the work that Dayu did when she was in my lab, uh, that really broke open the field to the application of modern genetic tools for studying circuits in mice, is that she found a way to evoke aggression in mice using optogenetics to activate specific neurons in a region of the hypothalamus, the ventromedial hypothalamus, VMH, which people had been studying and, and looking at for decades, following first the work of, uh, um, in, in cats, the famous Nobel Prize winning work, uh, of Walter Hess, and, and then followed by work done by Menno Kruk in the Netherlands in rats, where they would stick electrical wires into the brain and send electric currents into the brain, and they could trigger a placid cat to suddenly s- bare its teeth, hiss, and almost strike out at the experimenter, um, and they could trigger, uh, uh, rats to fight with each other. And even in Hess's original experiments, he describes two types of aggression that he evokes from cats depending on where in the hypothalamus he puts his electrode, one of which he calls defensive rage, that's the ears laid back, teeth bared, and hissing, and the other one is predatory aggression, where the, the cat has its ears forward and it's, like, batting with its paw at a mouse-like object like it wants to catch it and eat it. So he already had, at that stage, some information about segregation in the brain of different forms of aggression. So fast-forward to, uh, um, 2008, 2009, um, when Dayu came to the lab, and we had started working on aggression in fruit flies, and I wanted to bring it into mice so that we could apply genetic tools. And we started by having Dayu, who was an electrophysiologist, just repeat the electrical stimulation of the ventromedial hypothalamus in the mouse, just like people had done in rats, in cats, in hamsters, even in monkeys, and she could not get that experiment to work over 40 different trials. It just didn't work. What she got instead was fear behaviors, she got freezing, cornering, and crouching. And finally, in desperation, and we got a lot of input from Menno Kruk on this, he really was mystified, "Why doesn't it work in mice?" We realized why there had been no paper on brain-stimulated aggression in mice in 50 years, 'cause the experiment doesn't work. And the, the, the one bit of credit I can claim there is I convinced Dayu to try optogenetics, because, uh, it just had sort of come into use deep in the brain from Karl Deisseroth 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 than optogenetics stimula- than electrical stimulation, it might work. And Dayu said, "Never. Never going to work. If it doesn't work with electricity, why should it work with, uh, optogenetics?" And the fact is that it did work, and we were able to, uh, uh, trigger aggression in this region using optogenetic stimulation of ventromedial hypothalamus, and in retrospect, I think the reason that we were seeing all these fear behaviors is because right at the upper part, if you think of ventro- of ventromedial hypothalamus like a pear sitting on the ground, the fat part of the pear, uh, near the ground is where the aggression neurons are, but the upper part of the pear has fear neurons. And it could be because it's so small in a mouse, when you inject electrical current anywhere in the pear, it flows up through the entire pear and it activates the fear circuits, and those totally dominate aggression.

   7. AHAndrew Huberman24:22

      Mm-hmm.

   8. DADavid Anderson24:22

      And so that's why we were never able to see any fighting with electrical stimulation, whereas when you use optogenetics, you confine the stimulation just to the region where you've implanted the channelrhodopsin gene into those neurons. Um, and so in...

8. 24:42 – 29:20

   Aggression Types: Offensive, Defensive & Predatory

   1. DADavid Anderson24:42

      Fast-forward from that, from a lot of work from Dayu now on her own at NYU, and with her post-doc, Annegret Falkner, uh, there is, uh, as well as work of other people, there's evidence that the type of fighting...... that we were, that we elicit when we stimulate VMH is offensive aggression that is actually rewarding to male mice.

   2. AHAndrew Huberman25:07

      They like it.

   3. DADavid Anderson25:08

      They like it. Male mice will press, learn to poke their nose or press a bar to get the opportunity to beat up a subordinate male mouse. And in more recent experiments, if you activate those neurons and the mouse has a chance to be in one of two compartments in a box, they will gravitate towards the compartment where those neurons are activated. It has a positive valence. And when I went into this field and I was thinking, "Well, what goes on in my brain and my body when I'm furious?" It certainly doesn't feel like a rewarding experience. It's not something that I would want to repeat because it feels good when I'm in that state. It doesn't feel good at all when I'm in that state. And it is still, I think, a mystery as to where that type of aggression, which is more defensive aggression, the kind of aggression you feel if you're being attacked or if you've been cheated by somebody, where that is encoded in the brain and how that works still, I think, is a, a very important mystery that we haven't solved. And predatory aggression, there has been some progress on. So mice show predatory aggression, they use that to catch crickets that they eat, and that involves different circuits than the ventromedial hypothalamic circuits. So it's become clear that, if you want to call it the state of aggressiveness, is multifaceted, it depends on the type of aggression, and it involves different sorts of circuits. There is, there's a paper suggesting that there might be a final common pathway for all aggression in a region which is one of my favorites, it's called the substantia innominata, the substance with no name. You know, I- I like these names.

   4. AHAndrew Huberman27:04

      Anatomists are so creative. (laughs)

   5. DADavid Anderson27:06

      Yes. Or the nucleus ambiguus, you know, or the zona incerta. These are places that no one can think of what they are. Anyhow, that might be a final common pathway for predatory aggression and offensive and defensive aggression, but it can be really hard to tell just from looking at a mouse fight whether it's engaged in offensive or defensive aggression. We've tried to take that apart using machine learning analysis of behavior, but in rats, for example, it's much clearer when the animal is engaged in offensive versus defensive aggression. They direct their bites at different parts of the opponent's body.

   6. AHAndrew Huberman27:46

      In particular-

   7. DADavid Anderson27:46

      Neck versus... Uh, uh, offensive aggression is flank-directed, defensive aggression goes for the neck-

   8. AHAndrew Huberman27:53

      Mm-hmm.

   9. DADavid Anderson27:53

      ... goes for the throat.

   10. AHAndrew Huberman27:55

       I've seen some nature specials where f- in a very, um, barbaric way, at least to me, it-

   11. DADavid Anderson27:59

       (laughs)

   12. AHAndrew Huberman27:59

       ... seems, uh, like hyenas will try and go after the, the reproductive, uh, axis, they'll go after testicles and penis, and they basically want to, uh, it seems they want to limit, uh, future breeding potential.

   13. DADavid Anderson28:12

       Yes.

   14. AHAndrew Huberman28:12

       But i-

   15. DADavid Anderson28:12

       Or create pain. (laughs)

   16. AHAndrew Huberman28:13

       Right, or create, or create pain or both.

   17. DADavid Anderson28:15

       Yeah.

   18. AHAndrew Huberman28:15

       Yeah. I mean, in terms of, um, offensive aggression and, and the, your, uh, reflection that it doesn't feel good, I, I mean, I can say I know some people who really enjoy fighting.

   19. DADavid Anderson28:27

       Hmm.

   20. AHAndrew Huberman28:27

       Um, I have a relative who's a lawyer. He loves to argue and fight.

   21. DADavid Anderson28:31

       Huh.

   22. AHAndrew Huberman28:31

       It, um, I don't think of him as physically aggressive. In fact, he's not, but loves to fight and loves to prosecute and go after people-

   23. DADavid Anderson28:39

       Mm-hmm.

   24. AHAndrew Huberman28:39

       ... and that's, and he's pretty effective at it.

   25. DADavid Anderson28:41

       Right.

   26. AHAndrew Huberman28:41

       I have a friend, former, uh, military special operations, and very calm guy, had a great career in, in the, um, in military special operations, and he'd, he'll quite, you know, plainly say, "I love to fight."

   27. DADavid Anderson28:52

       Mm-hmm.

   28. AHAndrew Huberman28:52

       "It's one of the, one of my great joys." He really enjoyed his work.

   29. DADavid Anderson28:55

       Yep.

   30. AHAndrew Huberman28:56

       Um, and, and also respected 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, um, defend my stance if I need to-
9. 29:20 – 35:38

   Evolution & Development of Defensive vs. Offensive Behaviors, Fear

   1. AHAndrew Huberman29:20

      have a c- a couple of questions about the way you described the c- the circuitry. I should say the way the circuitry is arranged.

   2. DADavid Anderson29:25

      Mm-hmm.

   3. AHAndrew Huberman29:26

      And of course, we don't know because, uh, we weren't consulted at the design phase.

   4. DADavid Anderson29:31

      (laughs)

   5. AHAndrew Huberman29:31

      But why do you think there would be such a close positioning of neurons that can elicit such divergent states and behaviors? I mean, you're talking about this pear-shaped structure where the neurons that generate fear are cheek to jowl with the neurons that generate offensive aggression, of all things. It's like, um, putting the neurons that c- control, um, swallowing next to the neurons that control vomiting. It just 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 perplexing as to why this would be the case.

   6. DADavid Anderson30:06

      Yeah, I think that, that is a very profound question, and, um, I've, 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 have to defend themselves from predation by other animals. And maybe it's only when they're comfortable with having warded off predation and made themselves safe that they can start about, start to think about, "Who's going to be the alpha male in, 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 neurons and the aggression neurons, and then with development, it gets shut off in the aggression neurons and maintained in the fear neurons. Now, that, that view says, "Oh, it's just an, it's an accident of evolution and development," but I think there must be a functional part as well. So one thing we know about offensive aggression is that strong fear shuts it down, whereas defensive aggression, at least in rats, is actually enhanced by fear. It's one of the big differences between defensive aggression and offensive aggression. And you think about it, if you think about it, if offensive aggression is rewarding and pleasurable, if you start to get really scared, that tends to take the fun out of it, and maybe these two regions are close to each other to facilitate inhibition of aggression by fe- the fear neurons. We know for a fact that if we deliberately stimulate those fear neurons at the top of the pair, when two animals are involved in a fight, it just stops the fight dead in its tracks and they go off into the corner and freeze. So at least hierarchically, it seems like fear is the dominant behavior over offensive aggression. And how that inhibition would work is not clear 'cause all these neurons are pretty much excitatory, they're almost all glutamatergic. And so one of the interesting questions for the future is, how exactly does fear dominate over and shut down offensive aggression in the brain? How does that work? Is it all circuitry? Are there chemicals involved? What's the mechanism and when is it called into play? 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 flight, there are also metabolic neurons that are mixed together-

   7. AHAndrew Huberman33:14

      Mm-hmm.

   8. DADavid Anderson33:15

      ... in VMH as well.

   9. AHAndrew Huberman33:16

      Controlling, uh, body-wide metabolism?

   10. DADavid Anderson33:18

       Yeah. There are-

   11. AHAndrew Huberman33:19

       Interesting.

   12. DADavid Anderson33:19

       ... neurons there that respond to glucose. When glucose goes up in, in your bloodstream, they're activated. And VMH has a whole history in the field of obesity because if you destroy it in a rat, you get a fat rat. So the way most of the world thinks about VMH is they think about, "Oh, that's the thing that keeps you from getting fat," it's the anti-obesity area, but in the area of social behavior, um, we see it as a center for control of aggression and fear behaviors. And again, why these, these neurons and these functions, I, I like to call them the four Fs, feeding, freezing, fighting, and mating-

   13. AHAndrew Huberman34:00

       Mm-hmm.

   14. DADavid Anderson34:01

       ... that they all seem to be closely intermingled with each other maybe because crosstalk between them is very important to help the animal's brain decide what behavior to prioritize and what behavior to shut down at any given moment.

   15. AHAndrew Huberman34:17

       One of the things that we will do is link to the incredible videos of these mice that have, uh, selective stimulation of neurons in the VMH, Dayu's, and the other studies that you've done. One of the, uh, uh, whenever I teach, uh, I show those videos at some point, um, with the caveats and warnings that are required when one is about to see a video of a mouse trying to mate with another mouse, or mating with another mouse, and they seem both to be quite happy about the, the mating experience, at least as far as we know as observers of mice. And then upon stimulation of those s- VMH neurons, one of the mice essentially tries to kill the other mouse, and then when that stimulation is stopped, they basically go back to hanging out. They don't go right back to mating.

   16. DADavid Anderson35:06

       Right.

   17. AHAndrew Huberman35:06

       There's some reconciliation, clearly, that needs to happen first- (laughs)

   18. DADavid Anderson35:08

       Yes.

   19. AHAndrew Huberman35:09

       ... we assume. But it's just so striking. I think equally striking is the video where the mouse is alone in there with the glove, the VMH neurons are stimulated, and the mouse goes into a rage, it looks like it wants to kill the glove-

   20. DADavid Anderson35:21

       Yep.

   21. AHAndrew Huberman35:21

       ... basically. Um, so striking. I encourage people to go watch those because it really puts, um, a, a tremendous amount of color on what we're describing, and it's just th- the idea that there are switches in the brain, uh, to me, really became clear upon seeing that. Uh, one of the concepts,

10. 35:38 – 38:33

    Hydraulic Pressures for States & Homeostasis

    1. AHAndrew Huberman35:38

       excuse me, one of the concepts that, um, y- you've raised in your lectures before, and, and that I think was Hess's idea, is this idea of a sort of hydraulic pressure-

    2. DADavid Anderson35:47

       Mm-hmm.

    3. AHAndrew Huberman35:47

       ... or maybe it was Conlad, Conlad, Conrad, I can't speak now, excuse me, Conrad Lorenz-

    4. DADavid Anderson35:53

       Mm-hmm.

    5. AHAndrew Huberman35:53

       ... pardon, who talked about a kind of hydraulic pressure towards behavior. I'm fascinated by this idea of hydraulic pressure, um, because I don't consider myself a hot-tempered person, but I am familiar with the fact that when I lose my temper, it takes quite a while for me to simmer down. I can't think about anything else, I don't want to think about anything else. In fact, th- trying to think about anything else becomes aversive to me, which, to me, underscores this notion of prioritization-

    6. DADavid Anderson36:21

       Mm-hmm.

    7. AHAndrew Huberman36:21

       ... of the different, uh, states, and potentially conflicting states. Wh- what do you think funnels into this idea of hydraulic pressure toward a state? And why is it, perhaps, that sometimes we can be very angry and-... if we succeed in winning an argument, all of a sudden it will subside. Um, because clearly that means that there are external influences. It's a complex space here that we're, we're creating. I realize I'm creating a bit of-

    8. DADavid Anderson36:47

       Yeah.

    9. AHAndrew Huberman36:47

       ... a cloud, and I'm doing it on purpose because, to me, the idea of a hydraulic pressure towards a state, like sleep, there's a sleep pressure-

    10. DADavid Anderson36:53

        Yeah.

    11. AHAndrew Huberman36:53

        ... there's a, there's a pressure towards (​sigh)   that all makes sense. But what's involved? Is it too multifactorial to, to actually, um, separate out the variables? But what, what, what's, what's really driving hydraulic pressure toward a given state?

    12. DADavid Anderson37:08

        Yeah. So, uh, really important question, uh, I think one way that is helpful, at least for me, to break this question apart and think about it, is to distinguish homeostatic behaviors, that is need-based behaviors where the pressure is built up because of a need, like, "I'm hungry, I need to eat. I'm thirsty, I need to drink. I'm hot, I need to get to a cold place." It's basically the thermostat model of your brain. You have a setpoint, and then if the temperature gets too hot, you turn on the AC, and if the temperature gets too cold, you turn on the heater and you put yourself back to the setpoint. 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, to-

    13. AHAndrew Huberman38:12

        Or Twitter.

    14. DADavid Anderson38:13

        Yeah, (laughs) or Twitter, yeah.

    15. AHAndrew Huberman38:14

        Twitter seems to dr- I'm sort of half-joking, because Twitter seems to draw a reasonably sized crowd of people that are there for combat of some sort, um, even though the total intellectual power of any of their comments is about that of a cap gun.

    16. DADavid Anderson38:28

        (laughs)

    17. AHAndrew Huberman38:28

        They seem to really like to fire-

    18. DADavid Anderson38:30

        Right.

    19. AHAndrew Huberman38:30

        ... off that cap gun.

    20. DADavid Anderson38:30

        Right.

    21. AHAndrew Huberman38:31

        But i- in, but I agree.

11. 38:33 – 39:46

    AG1 (Athletic Greens)

    1. AHAndrew Huberman38:33

    2. DADavid Anderson38:33

       Yeah.

    3. AHAndrew Huberman38:33

       Before we continue with today's discussion, I'd like to just briefly acknowledge our sponsor, Athletic Greens, now called AG1. Athletic Greens, AKA AG1, is an all-in-one vitamin mineral probiotic drink that also has adaptogens and digestive enzymes. I've been taking Athletic Greens since way back in 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens, and the reason I still drink Athletic Greens twice a day, is that it supplies total foundational coverage of my vitamin mineral needs, and it supplies important nutrients that I need to support my gut microbiome. The gut microbiome, as many of you know, supports the immune system, it also supports the so-called gut-brain axis, which is vital for mood, for energy levels, for regulating focus, and many other features of our mental health and physical health that impact our daily performance and high performance in any endeavors we might be involved in. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman and claim a special offer. They're giving away five free travel packs, plus a year's supply of vitamin D3+K2 with every order. And of course, vitamin D3+K2 are vital for all sorts of things like hormone health and metabolic health, and K2 for cardiovascular health and calcium regulation. Again, you can go to athleticgreens.com/huberman to claim that

12. 39:46 – 44:50

    Hydraulic Pressure & Aggression

    1. AHAndrew Huberman39:46

       special offer.

    2. DADavid Anderson39:46

       So, you can think, you can think of this accumulated hydraulic pressure either being based on something that you were deprived of, creating an accumulating need, or something that you want to do building up a, uh, a drive or a pressure to do that. And the natural way to think about that, at least for me, is as gradual increases in neural activity in a particular region of the brain. And so for example, in the area of the brai- of the hypothalamus that controls feeding, Scott Sternson and others have shown that the hungrier you get, the higher the level of activity in that region in the brain, and then when you eat, boom, the activity goes right back down again. And, uh, that state is actually negatively valenced, so it's like the animal, quote-unquote, "feels" increasingly uncomfortable, just like we feel increasingly uncomfortable the hungrier we are, and then when we eat, it tamps it down. But there is this increased activity, and I think in the case of aggression, our data and others show that the more strongly you drive this region of the brain, optogenetically, the more of just a hair trigger you need to set the animal off to get it to fight. Now, the interesting thing is that if there is nothing for the animal to attack, it doesn't really do much when you're stimulating this region. It sort of wanders around the cage a little bit more, but it will not actually show overt attack if, unless you put something in front of it. And the same thing is true for the areas we've described that control mating behavior. This is what Lindsay is working on. You can stimulate those areas 'til you're blue in the face and the mouse just sort of wanders around, but if you put another mouse in, wham, he will try to mount that mouse. If you put a kumquat in the cage, he'll-

    3. AHAndrew Huberman41:49

       (laughs)

    4. DADavid Anderson41:49

       ... try to mount the kumquat. And so it's, it becomes a sort of any port in the storm. So there is this idea that the drive is building up pressure that somehow needs to be released. Where that pressure is actually being exerted, if you accept that it's increased activity in some circuit or circuits someplace, what is it pushing up against that needs something else to sort of unplug it in the, in the Lorenz hydraulic model? That is, you don't see the behavior until you release a valve on this bucket and let the accumulated pressure flow out, and that's one of the things we're trying to study in the context of the mating behavior as well. How does the information that there's an object in front of you come together with this drive state that is generated by stimulating these neurons in the hypothalamus to say, "Okay, pull the trigger and go. It's time to mate, it's time to attack"? And we're just starting to get some insights into that now.

    5. AHAndrew Huberman42:56

       Fascinating. And I should mention to people, um...Uh, Dr. Anderson mentioned Lindsay. Lindsay is a former graduate student of mine that's now a postdoc in David's lab, and, uh, I haven't caught up with her recently to hear about these experiments, but they sound fascinating. I, I'm, would love to spend some time on this issue of why is it that, uh, a mouse won't attack nothing, but it'll attack even a glove, um, or, and why it, um, will only try and mate if there's another, uh, mouse to mate with. It's actually, um, I think fortunately, um, for you, you're not spending a lot of time on Twitter and Instagram but, or YouTube, um, but there's 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, I'll just say it, it has a name, it's called NoFap, of no masturbation, as a way to maintain their motivation to go out and actually seek mates. Because of the, uh, ready availability of online pornography-

    6. DADavid Anderson43:54

       Huh.

    7. AHAndrew Huberman43:54

       ... there's an in- probably a much larger population of young males that are never actually going out and seeking mates because they're getting porn-addicted, etc. There's actually a serious issue that came up in our episode with Anna Lembke, who wrote the book Dopamine Nation-

    8. DADavid Anderson44:07

       Mm.

    9. AHAndrew Huberman44:07

       ... uh, because the availabil- ability of pornography, there's a whole social context that's, that's being created around this, and genuine addiction. Um, so humans, uh, are not like the mice, or mice are not like the humans. Um, humans, um, seem to resolve the issue on their own-

    10. DADavid Anderson44:21

        Yeah.

    11. AHAndrew Huberman44:21

        ... in ways that might actually impede, um, seeking and finding of sexual partners and/or long-term mates.

    12. DADavid Anderson44:26

        Right.

    13. AHAndrew Huberman44:26

        So a serious issue there. Um, I raise it as a serious issue-

    14. DADavid Anderson44:29

        Yep.

    15. AHAndrew Huberman44:29

        ... that, that I hear a lot about 'cause I get asked hundreds, if not thousands, of questions about this, "Is there any physiological basis for what they call NoFap?" And I never actually reply 'cause there's no data.

    16. DADavid Anderson44:39

        Yep.

    17. AHAndrew Huberman44:39

        But, um, but what you're raising here is a very interesting, uh, mechanistic, uh, scenario that, uh, that can, can, and as you mentioned, is being explored. So

13. 44:50 – 48:31

    Balancing Fear & Aggression

    1. AHAndrew Huberman44:51

       what do we know about the internal state of a mouse whose VMH is being stimulated, or a mouse whose, um, bra- other brain region that can stimulate the desire to mate, what do we know about the internal state of that mouse if it's just alone in the cage wandering around? Is it wandering around really wanting to mate and really wanting to fight? We, 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? (laughs)

    2. DADavid Anderson45:19

       (laughs)

    3. AHAndrew Huberman45:19

       Uh, is it, um, uh, c- something's going on, presumably, that's different, um, than prior to that stimulation, and is it arousal? Um, and what do you think it is about the visual or olfactory perception of a conspecific that ungates this tremendous repertoire of behaviors?

    4. DADavid Anderson45:40

       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 optogenetically, in the same way we would activate the aggression neurons, that there's clearly an arousal process that's occurring. You can see the pupils dilate in the animal. There is an increase in stress hormone release into the bloodstream. We've shown that. Um, heart rate goes up. So in addition to the drive to actually freeze, which is what those animals do, there is autonomic arousal and neuroendocrine activation of stress responses. And some of that is probably shared by the aggression neurons and the mating neurons, although we haven't investigated it in as much detail. But I wouldn't be surprised because they project to many of the same regions that the, uh, fear neurons project to, which is a interesting issue in the context, to discuss later maybe, in the context of why we're comfortable with mental illnesses that are based on maladaptations of fear, but not mental illnesses that are based on maladaptations of aggression if they have pretty similar circuits in the brain.

    5. AHAndrew Huberman47:02

       Mm-hmm.

    6. DADavid Anderson47:02

       But, um, that's, that's how I would imagine. There is a, an arousal dimension, as you say. There are stress hormones that are activated. These regions, VMH projects to about 30 different regions in the brain, and it gets input from about 30 different regions. So I kind of see it as both an antenna and a broadcasting center. It's like a satellite dish that takes in information from different sensory modalities, smell, maybe vision, mechanical, uh, mechanosensation, and then it 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 it broadcasts that all over the brain to trigger all these systems that have to be brought into play if the animal is gonna engage in aggression. Because aggression is a very risky thing for an animal to engage in. It could wind up losing, and it could wind up getting killed, and, 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.

    7. AHAndrew Huberman48:29

       I want to talk more about mating behavior,

14. 48:31 – 52:33

    Aggression & Hormones: Estrogen, Progesterone & Testosterone

    1. AHAndrew Huberman48:31

       but as a segue to that, um, as we're talking about aggression and mating behavior, I think hormones. And whenever there's an opportunity on this podcast to shatter a common myth, I, I grab it. One of the common myths that's out there, and I think that persists, is that testosterone makes animals and humans aggressive, and estrogen makes animals placid and kind or emotional. And as we both know, nothing could be further from the truth, although there's some truth to the idea that these hormones are all involved.... uh, Robert Sapolsky, uh, supplied some information to me when, uh, he came on this podcast, that, uh, if you give people exogenous testosterone, it tends to make them more of the way they were, um, before. If they were a jerk before, they'll become more of a jerk. If they were very altruistic, they'll become more altruistic. And then eventually, I pointed out, you'll aromatize that testosterone into estrogen and you'll start getting opposite effects. So it's a, it's a murky space, it's not straightforward. But if I'm not mistaken, testosterone plays a role in generating aggression, however, the specific hormones that are involved in generating aggression via VMH are things other than testosterone. Could you tell us a little bit more about that? 'Cause there's some interesting surprises in there.

    2. DADavid Anderson49:47

       Yeah. That's a really important question. So the, when we finally identified the neurons in VMH that control aggression with a molecular marker, we found out that that marker was the estrogen receptor. So that might strike you as a little strange. Why should aggression-promoting neurons in male mice be labeled with the estrogen receptor? Uh, other labs have shown that the estrogen receptor in adult male mice is necessary for aggression, if you knock out the gene in VMH, they don't fight. And it's been shown, and a lot of this is work from your colleague, Nirav Shah, at Stanford, who was one of my former PhD students, that if you castrate a mouse, uh, and it loses the abil- ability to fight, not only can you rescue fighting with a testosterone implant, but you can rescue it with an estrogen implant. So you can bypass completely the requirement for testosterone to restore aggressiveness to the mice. And as you say, it's because many of the effects of testosterone, although not all, many of them are mediated by its conversion to estrogen by a process called aromatization. It's carried out by an enzyme called aromatase. In fact, people may have, most of your listeners may have heard of aromatase, 'cause aromatase inhibitors are widely used in female humans as adjuvant chemotherapy for breast cancer. They are a way of reducing the production of estrogen by preventing testosterone from being converted into estrogen. And in fact, there are a lot of animal experiments showing if you give males aromatase inhibitors, they stop fighting, as well as also, uh, stop being sexually active.

    3. AHAndrew Huberman51:43

       Mm-hmm.

    4. DADavid Anderson51:44

       Um, and so that's one of the counterintuitive ideas. And Nirav has shown that progesterone also seems to play a role in aggression, because these aggression neurons also ex- express the progesterone receptor. So here are two hormones that are classically thought of as female reproductive hormones, this is what goes up and goes down during the estrus cycle, estrogen and progesterone, and yet they're playing a very important role in controlling aggression in male mice, and then presumably in male humans as well.

    5. AHAndrew Huberman52:20

       Fascinating. So estrogen is doing many more things than, uh, I think most people believe-

    6. DADavid Anderson52:26

       Yeah.

    7. AHAndrew Huberman52:26

       ... and testosterone is doing maybe different and fewer things in some cases, and more in others.

15. 52:33 – 59:48

    Female Aggression, Motherhood

    1. AHAndrew Huberman52:33

       I've known some aggressive females over the time I've been alive. What's involved in female aggression that's unique from the pathways that generate male aggression?

    2. DADavid Anderson52:44

       Great, great question. So, uh, we and other labs have studied this in both mice and also in fruit flies. So, uh, one thing in mice that is, distinguishes aggression in females from males is that male mice are pretty much ready to fight at the drop of a hat. Female mice only fight when they are nurturing and nursing their pups after they've delivered a litter, and there is a window there where they become hyperaggressive. And then after their pups are weaned, that aggressiveness goes away. So this is, it's pretty remarkable, that you take a virgin female mouse and expose it to a male, and her response is to become sexually receptive and to mate with him, and now you let her have her pups and you put the same male or another male mouse in the cage with her, and instead of trying to mate with him, she attacks him. So there is some presumably hormonal and also neuronal switch that's occurring in the brain that switches the response of the female from sex to aggression, uh, when she goes from virginity to maternity. And we recently showed in a paper, this is work from one of my students, uh, Mengyu Liu, that within VMH in females, there are two clearly divisible subsets of estrogen receptor neurons, and she showed that one of those subsets controls fighting and the other one controls mating. And in fact, if you stimulate the fighting-specific subset, subset in a virgin, you can get the virgin to attack, which is something that we were never, never able to do before. Uh, and if you stimulate the mating one, you enhance mating. The reason we could never get these results when we stimulated the whole population of estrogen receptor neurons is that these effects are opposite and they cancel out. And so it turns out that if you measure the activity of the fighting and the mating neurons going from a virgin to a maternal female-... the aggression neurons are very low in their activity in the virgin, but once the female has pups, the activation ability of those neurons goes way up and the mating neurons stay the same. So if you think of the balance between them like a seesaw, in the virgin, there is more activity in the mating neurons than in the fighting neurons. Whereas in the, in the nursing mother, there's more activity or more activation in the, in the other way around, the fighting neurons than the mating. Did I say-

    3. AHAndrew Huberman55:29

       Mm-hmm.

    4. DADavid Anderson55:29

       ... fighting and mating the first? Mating neurons dominate fighting in the virgin, fighting neurons dominate mating 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, 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 has known for a long time that male and female fruit flies have sex-specific neurons, and most of the neurons that we've identified in fruit flies that control fighting in males are male-specific, they're not found in the female brain. But recently, we discovered a set of female-specific fighting neurons in the female brain, uh, together with, uh, a couple of other laboratories. Now, they do share one common population of neurons in both male and female flies that, in females, activates the female-specific fighting neurons, and in males, activates the male-specific fighting neurons. So it's kind of a hierarchy with this common neuron on top. And in mice, we discovered that there are male-specific neurons in VMH, and those neurons are activated during male aggression. Now, the neurons that are active in females when females fight in VMH are not sex specific, so they are also found in males. So this is already showing you some complexity, the male mouse VMH has both male-specific aggression neurons and generic aggression neurons, and then the female VMH, the mating cells are only found in females, they are female-specific and not found in the male brain. And so we're trying to find out what these sex-specific populations of neurons are doing, but that indicates that that is some of the mechanism by which different sexes show different behaviors.

    5. AHAndrew Huberman57:34

       I'm fixated on this, uh, transition from the virgin female mouse to the maternal female mouse, and I have a couple questions about whether or not, for instance, the transition is governed by the presence of pups. So for instance, if you take a virgin female, she'll mate with a male, um, once she's had pups, she'll try and fight that male, or presumably another intruder female-

    6. DADavid Anderson57:56

       Yes.

    7. AHAndrew Huberman57:56

       ... right?

    8. DADavid Anderson57:56

       Equally towards-

    9. AHAndrew Huberman57:57

       F-

    10. DADavid Anderson57:57

        ... females and male intruders.

    11. AHAndrew Huberman57:59

        Does that require the presence of her pups? Meaning if you were to take those pups and give them to another mother, does she revert to the more virgin-like behavior? Is it related to, is it triggered by lactation, or could it actually be triggered by the mating behavior itself? 'Cause it's possible for the virgin to become a non-virgin, but not actually have a litter of pups.

    12. DADavid Anderson58:18

        Right. Those are all great questions, and we don't know the answer to 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, she is just in a state of brain that makes her aggressive to any intruder, and those aggression neurons in that female's brain are activated by both male and female intruders equally. Whereas in male mice, the aggression neurons are only ever activated by males, not by females, because males are never supposed to attack females, they're only supposed to mate with them. So that's another difference in how those neurons are tuned to signals from different conspecifics. Does it require lactation? I don't know the answer to that. I think there are some experiments where people have tried to, classical experiments, people have tried to reproduce the changes in hormones that occur during pregnancy in female rats to see if it can make them aggressive, and some of those manipulations do to some extent, but there's a whole biology there that remains to be explored about how much of this is hormones, how much of this is circuitry and electricity, and how much of it is other factors that we haven't identified yet.

16. 59:48 – 1:05:10

    Mating & Aggressive Behaviors

    1. DADavid Anderson59:48

    2. AHAndrew Huberman59:48

       I don't want to anthropomorphize, but, um, well, I'll just ask the question. So the other day, I was watching, uh, ferrets mate, right? They're mustelids, or, they're mustelids, and they, their mating behavior, I guess I didn't say why I was watching this-

    3. DADavid Anderson1:00:02

       (laughs)

    4. AHAndrew Huberman1:00:02

       Doesn't matter, um, uh, it- it simply doesn't matter. But if one w- 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, there could be aggressive component in humans that have all sorts of kinks and fetishes and behaviors, and most of which probably has never been documented 'cause most of this happens in private. And here, I always say on this podcast, anytime we're talking about sexual behavior in humans, we're always making the presumption that it's, uh, consensual, age-appropriate, context-appropriate, and species-appropriate. Let's say we're talking about a lot of different species. With that said, just to set context, I was watching this video of ferrets mating, and it's quite violent, actually. There's a lot of neck-biting, there's a lot of squealing. If I were going to project and anthropomorphize, I'd say, "It's not really clear they both want to be there." It, you would just, one would make that assumption. And of course, we don't know, we have no idea, this is, could be the ritual. Um-It seems to me that there is some crossover of aggression and mating behavior circuitry during the act of mating. And do you think that reflects this sort of, um, uh, stew of competing neurons that are dr- prioritizing in real time? Because, of course, as s- states, they have persistence, as you point out, and you can imagine that states overlapping, you know, four different states, the, the motivational drive to mate, 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 y- what we're really seeing is a bias improbabilities. But when you look at mating behavior of various animals, you see an aggressive component sometimes, but not always. Is it species specific? Is it context specific? And more generally, do you think that there, um, is crosstalk between these different neuro- neuronal populations and the animal itself might be kind of confused about what's going on?

    5. DADavid Anderson1:02:00

       Right. Great, great questions. I can't really speak to the issue of whether this is species specific 'cause I'm not a naturalist or a zoologist. Uh, I've seen, like you have, in the wild, for example, lions when they mate, I've seen them in Africa, there's often a biting component of that as well. One of the things that surprised us when we identified neurons in VMHVL that control aggression in males is that within that population, there is a subset of neurons that is activated by females during male female mating encounters. Now, you don't generally think of mouse sex as rough sex, but there, there is a lot of what superficially looks like violent behavior sometimes, especially if the female rejects the male and runs away, and there's some evidence that those female selective neurons in VMH are part of the mating, uh, behavior. If you shut 'em down, the animals don't mate as effectively as they otherwise would. Um, 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 VMH is not traditionally the brain region to which male sexual behavior has been assigned. That's another area called the medial preoptic area and there we have shown that there are neurons that definitely stimulate mating behavior. In fact, if we activate those mating neurons in a male while it's in the middle of attacking another male, it will stop fighting, start singing to that male, and start to try to mount that male until we shut those neurons off. So those are the make love, not war neurons and VMH are the make war, not love neurons, and there are dense interconnections between these two nuclei, which are very close to each other into the br- in the brain, and we've shown that some of those connections are mutually inhibitory to prevent the animal from attacking a, a, a mate that it's supposed to be mating with or to prevent it from mating with some, uh, uh, an animal it's supposed to be attacking, but it's also possible that there are some cooperative interactions between those structures as well as, uh, antagonistic interactions and the balance of whether it's the cooperative or antagonistic interactions that are firing at any given moment in a mating encounter, as you suggest, may determine whether at a moment of, of, uh, of, uh, coital bliss among two lions may suddenly turn into a snap or a growl and a baring of fangs. We don't know that, but certainly the substrate, the wiring is there for that to happen.

17. 1:05:10 – 1:10:06

    Neurobiology of Sexual Fetishes

    1. DADavid Anderson1:05:10

    2. AHAndrew Huberman1:05:10

       I'm sure people's ide- uh, minds are running wild with all this. I'll just use this as an opportunity to raise, uh, something I've wondered about for far too long (laughs) , which is, um, I have a friend who's a psychiatrist who works on the treatment of fetishes. This is not a psychiatrist that I was treated by, I'll just point that out. But, um, they mentioned something very interesting to me long ago, which is that when you look at true fetishes, um, and what meets the criteria for fetish, that there does seem to be some, uh, what one would think would be competing circuitry that suddenly becomes, uh, aligned. For instance, um, avoidance of, uh, feces, dead bodies, feet, things that are very infectious, typically those states and, of disgust, are antagonistic to states of desire as one would hope is present, uh, during sexual behavior. Fetishes often involve exactly those things that are aversive, feet, uh, dead bodies, um, disgusting things to most people and true fetishes in the pathologic sense, um, exist when people have a, a basically a requirement for thinking about or even the presence of those, um, ordinarily disgusting things in order to become sexually aroused-

    3. DADavid Anderson1:06:31

       Yeah.

    4. AHAndrew Huberman1:06:31

       ... as if the circuitry has crossed over and their, the statement that rung in my mind was people don't develop fetishes to mailboxes or to the color red or to random objects and things, they develop fetishes to things that are highly infectious and counter reproductive appetitive states. So I, I find that interesting. I don't know if you have any reflections on that as to why that might be. Um, I'm tempted to ask whether or not you've ever observed, uh, fetish like behavior in mice, but, um, I find it fascinating that you have this area of the brain that's so highly conserved, the hypothalamus, which you have these dense populations intermixed and that-... the addition of a forebrain, e- 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.

    5. DADavid Anderson1:07:20

       Right. Uh, I, I would agree. I think one way of looking at fetishes from a neurobiological standpoint is that they represent a kind of appetitive conditioning, where something that is natively aversive or disgusting, by being repeatedly paired with a rewarding experience, changes its valence, its sign, so that now it somehow produces the anticipation of reward the next time a person sees it. Now, I don't know how f- I don't know that literature in animals, so I don't know if you could condition a mouse to eat feces, for example, although there are animals that are naturally coprophagic. That is, uh, and maybe mice 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.

    6. AHAndrew Huberman1:08:37

       Mm-hmm.

    7. DADavid Anderson1:08:37

       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, sort of counterintuitive aspect, again, like rough sex, people that want to have fighting or violence or aggressiveness in order to be sexually aroused, and, uh, uh, fetishes. And in fact, it, when we made that discovery initially, it, 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 s- some level, have their wires crossed in some way, that, that these states that are supposed to be pretty much separated and mutually antagonistic are not, and are actually more rewarding and reinforcing. Um, I think it's going to be a long time before we have figured it out. But when you think about it, there is no treatment that we have for a violent sexual offender that eliminates the violence, but not the sexual desire and sexual urge. Whether it's physical castration or chemical castration, it eliminates both.

    8. AHAndrew Huberman1:09:57

       Definitely an area that I think, well, human neuroscience in general needs a lot of, uh, tools, right? Um, in terms of how to probe and, and manipulate neural circuitry.

18. 1:10:06 – 1:15:25

    Temperature, Mating Behavior & Aggression

    1. AHAndrew Huberman1:10:06

       I'd love to turn to this area that you mentioned, the medial preoptic area. Um, I'm fascinated by it because just as within the VMH, you have these neurons for mating and fighting, or aggression, uh, my understanding is medial preoptic area, uh, contains neurons for mating, but also for temperature regulation. And perhaps I'm making too much of a leap here, but I've always wondered about this phrase, "in heat." (laughs) Um, as certainly the, uh, menstrual and, uh, or estrous cycle in females is related to changes in body temperature. In fact, measuring body temperature is one way that women can fairly reliably predict ovulation, et cetera. Although additional me- this is not a show about contraception. Please rely on multiple methods as necessary. (laughs) Don't use this discussion as your, uh, guide for contraception based on temperature. But if you stimulate certain neurons in the medial preoptic area, you can trigger dramatic changes in body temperature and/or mating behavior. What's the relationship, if any, between temperature and mating? Or do we simply not know?

    2. DADavid Anderson1:11:11

       Uh, I don't know what the relationship is between temperature and mating 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, there are intromission, thrusting neurons and ejaculation neurons and sniffing neurons.

    3. AHAndrew Huberman1:11:46

       Wait, wait. So I, I, I think I've heard this before, but I just want to make sure that people get this, and I want to make sure I get this. So you're telling me within medial, uh, m- within medial preoptic area, there are specific neurons that, if you stimulate them, will make males thrust as if they're mating. This-

    4. DADavid Anderson1:12:00

       No. So, so this is not based, um, on, on stimulation experiments.

    5. AHAndrew Huberman1:12:05

       Hmm.

    6. DADavid Anderson1:12:05

       It's based on imaging-

    7. AHAndrew Huberman1:12:07

       I see.

    8. DADavid Anderson1:12:07

       ... experiments right now-

    9. AHAndrew Huberman1:12:08

       I see.

    10. DADavid Anderson1:12:08

        ... that we see, when we look in the preoptic area at what neurons are active during different phases of aggression, we see that there are different neurons that are active during sniffing, mounting, thrusting, and ejaculation, and they become repeatedly activated each time the animal goes through that cycle.

    11. AHAndrew Huberman1:12:30

        During mating.

    12. DADavid Anderson1:12:31

        During-

    13. AHAndrew Huberman1:12:31

        Yeah.

    14. DADavid Anderson1:12:31

        ... the mating cycle. Um, there are also some neurons there that are active during aggression, which are distinct, and we don't know whether those neurons are there to promote aggression or to inhibit mating when animals are fighting. We have some evidence that suggest it may be the latter, but we don't know for sure yet. The, the thermosensitive neurons are really interesting because you mentioned, uh, uh, the phrase, "in heat," and then in the context of aggression, you talk about hot-blooded people or hotheads. There's just recently a paper showing there are thermoregulatory neurons in VMH as well. So all of these homeostatic systems for metabolic control and temperature control are intermingled in these nuclei, these zones that control these basic survival behaviors, like mating and aggression and predator defense. And I would imagine that the thermoregulation is tightly connected to energy expenditure, 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 particular behavior or that behavior. I mean, I've always been fascinated by the question, why is it that, uh, violence goes up in the summertime when the temperatures are high? Does it really have something to do with the idea that increased temperature increases violence? It seems hard to believe because we're homeothermic and we pretty much stay around 98.6 Fahrenheit. Uh, it could be other social reasons why that happens, people are outside, out on the street bumping into each other, but, uh, I think there could well be something that ties thermoregulation to aggressiveness, as well as to, uh, mating behavior.

    15. AHAndrew Huberman1:14:38

        Fascinating. Yeah. I, I asked, um, in the hopes that in, maybe in the years to come your lab will parse some of the temperature relationships, it, and I realize it could be, also, uh, regulated by hormones in general, so it's tapping into two systems for completely different reasons. But, um, anyway, a- an area that, that in- intrigues me, because of this notion of hot-headedness-

    16. DADavid Anderson1:14:58

        Right.

    17. AHAndrew Huberman1:14:58

        ... or cool, calm and collected. And also, um, the fact that, and I probably should have asked about this earlier, that arousal itself is tethered to the whole mating and reproductive process. I mean, th- without a sort of see-sawing back between the sympathetic and parasympathetic, you know, arousal relaxed states, uh, there is no mating t- that will take place. Um, so it's fascinating the way these different competing forces and see-saws, uh, operate.

19. 1:15:25 – 1:20:59

    Mounting: Sexual Behavior or Dominance?

    1. AHAndrew Huberman1:15:25

       Several times during the discussion so far we've, uh, hit on this idea that the same behavior can reflect different states and different states can converge on, um, multiple behaviors as well. You had a paper not long ago about mounting behavior, uh, which I found fascinating. Uh, maybe you could tell us about that result.

    2. DADavid Anderson1:15:47

       Mm-hmm.

    3. AHAndrew Huberman1:15:47

       Um, because to me, it really speaks to the fact that mounting behavior can, in one context be sexual, and in another context actually be related to, we presume, dominance. And I think that, um, my friends, uh, who practice jujitsu, um, will say, they, when I talk about that result, they say, "Of course, you know, mounting the other person and, and dominating them, it's, there's nothing sexual about it. It's about overtaking them physically, literally being on their neck side, as opposed to on their own, lying on their own back."

    4. DADavid Anderson1:16:17

       Hmm.

    5. AHAndrew Huberman1:16:17

       Um, uh, just fascinating, very primitive, and yet, um, I think speaks to this idea that mounting behavior might be one of the most fundamental ways in which animals, and perhaps even humans, express dominance and/or sexual interactions.

    6. DADavid Anderson1:16:34

       Yep. Uh, that's a fascinating question, and it was harder to figure out than you might have thought. So we've, there's been this debate for a long time in the field, when you see two male mace, me- mice mounting each other, is this homosexual behavior? Is this a case of mistaken sexual identification? Or is this dominance behavior? And if you train an AI algorithm to try to distinguish, 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, uh, h- how did we wind up figuring out that most male-male mounting is dominance mounting? There are two important clues. One is the context. And so male-male mounting tends to be more prominent among mice when they haven't had a lot of fighting experience, and then as they become more experienced in fighting, they will show relatively less mounting towards the other male and more attack, and they'll transition quickly from mounting to attack. And so the mounting is always seen in this context of an overall aggressive interaction. And then the second thing, which believe it or not was suggested by a computational theoretical person in my lab, Anne Kennedy, uh, who now has her own lab at Northwestern. She said, "Well, males are known to sing when they mount females, ultrasonic vocalizations. Why don't you see what kinds of songs they're singing when they're mounting males? Maybe it's a different kind of song." Well, what we found out is they don't sing at all when they're mounting a male. So you can easily distinguish whether mounting behavior by a male mouse is reproductive or agonistic aggressive according to whether it's accompanied by ultrasonic vocalizations or not. And it turns out that different brain regions are maximally active during these different types of mounting. So VMH, the aggression locus, is actually active during dominance mounting, and you can stimulate mounting if you, dominance mounting, if you weakly activate VMH. Whereas mPOA is most strongly activated during sexual mounting, and that's always accompanied by the ultrasonic vocalization. So this shows how difficult and dangerous it can be to try to infer an animal's state or intent or emotion from the behavior that it's exhibiting, because the same behavior can mean very different things depending on the context or the interaction with the animal.

    7. AHAndrew Huberman1:19:32

       And I would say, uh, even more so with when that animal is a, a human or, or is multiple humans.

    8. DADavid Anderson1:19:37

       That's right. And there are many examples, you know, animals show chasing to obtain...... food, a, a prey animal that they're gonna kill and eat, and they show chasing to obtain a mate that they're gonna have sex with. And so the intent of the chasing is completely different, and we don't know in all these cases whether there are separate circuits or common circuits that are being activated.

    9. AHAndrew Huberman1:20:02

       I'm obsessed with dogs and dog breeds and et cetera, et cetera, and, um, 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, um, but in observing her, it con- it convinced me that i- one can never assume that male dogs are more aggressive than female dogs. There's a... It turns out, in talking to people who are s- quite skilled at dog genetics and dog breeding, that there's a dominance hierarchy within a litter and it crosses over male/female, um, delineations. So you can get a female in the litter that's very dominant and a male that's very subordinate, and it... No one really knows what, what relates to. This is also why little dogs sometimes will, will get right up in the face of a big Doberman pinscher-

    10. DADavid Anderson1:20:50

        Mm-hmm.

    11. AHAndrew Huberman1:20:50

        ... and just start barking, which is an idiotic thing for it to do, but they can be, they can be dominant over a much larger dog.

    12. DADavid Anderson1:20:56

        Hmm.

    13. AHAndrew Huberman1:20:56

        Very strange, um, to me anyway.

20. 1:20:59 – 1:24:40

    Females & Male-Type Mounting Behavior

    1. AHAndrew Huberman1:20:59

       (smacks lips) Female/female mounting, do you observe it in mice? Uh, are there known circuits? And, uh, what evokes female/female mounting or female-to-male mounting if it, if it occurs?

    2. DADavid Anderson1:21:10

       Good. Yes, there is female... There are clear examples of females displaying male-type mounting behavior towards other females. We see this most commonly in the lab where we are housing females-

    3. AHAndrew Huberman1:21:26

       Hm.

    4. DADavid Anderson1:21:26

       ... with their sisters, say three or four in a cage. We take one out and we have her mate with a male, where the male's doing the mounting. Now we take that female and we put her back in the cage with her litter mates and she starts mounting them. Now, what the function of that is, if it has any function, or what it means, what's driving it, we don't know. But we do know that if we stimulate the mount- the neurons that control mounting in males in the medial preoptic area, if we stimulate that same population in females, it evokes male-type mounting towards either a male or a female target. In fact, we have a movie where we have a female that has just been mounted by a male, so the male's on top and she's underneath, and we stimulate those, that region of mPOA in the female, and she crawls out from underneath the male who has just mounted her, circles around behind him, and climbs up on top of him, and starts to try to mount him, and thrust at him. It-

    5. AHAndrew Huberman1:22:36

       That has a name online. It's called a switch. (laughs)

    6. DADavid Anderson1:22:39

       Is that right? (laughs)

    7. AHAndrew Huberman1:22:40

       Don't ask me how I know that.

    8. DADavid Anderson1:22:41

       Okay.

    9. AHAndrew Huberman1:22:42

       The, uh... But it- it's a pretty... Yeah. It's, um, it's a term that, that you hear. Um, you also hear the, the, the term topping from the bottom, which it sounds like that is a literal topping from the bottom.

    10. DADavid Anderson1:22:53

        I see.

    11. AHAndrew Huberman1:22:53

        That's a more of a psychological phrase from what I hear. I have friends that are, are educating me in this, uh, language, mostly because I find this kind of neurobiological discussion fascinating. At some point, right, it, we, I attempt in my mind to superimpose observations from the, the online communities-

    12. DADavid Anderson1:23:11

        Yeah.

    13. AHAndrew Huberman1:23:11

        ... that I'm told about and asked about, um, to this. But, uh, I- I should point out, it's always dangerous and f- and in fact inappropriate to make a one-to-one l-

    14. DADavid Anderson1:23:19

        Yes.

    15. AHAndrew Huberman1:23:19

        ... uh, link. You know? Uh, humans are... They maintain all the same neural circuitry and pathways that we're talking about today in mice, but, um, that forebrain does, uh, allow for context, et cetera.

    16. DADavid Anderson1:23:30

        Yup.

    17. AHAndrew Huberman1:23:30

        Yeah.

    18. DADavid Anderson1:23:30

        So what the function is of, uh, of, uh, female mounting, I don't know. It could be a type of dominance display. It's hard to measure that because people haven't worked on female dominance hierarchies to the same extent that they've worked on male dominance hierarchies. But it indicates that the circuits for male-type mounting are there in females, as, uh, early work from Catherine Dulac suggested some years ago.

    19. AHAndrew Huberman1:24:00

        Fascinating. Fascinating. I love that paper because I, as you, uh, pointed out for chase, you know, the, um, for mounting behavior, you know, we see it and we think one thing specifically, um, and w- after hearing this result, actually, I, I'm not a big fan of, of fight sports. I watch them occasionally 'cause friends are into them, but I, I've seen boxing matches, um, MMA matches, where at the end of a round if someone felt that they dominated, they will do the unsportsmanlike thing of, uh, th- thrusting on the back of the other person before they get off-

    20. DADavid Anderson1:24:30

        Really?

    21. AHAndrew Huberman1:24:30

        ... almost like a, "I dominated you and I..." You know, so mimicking sexual-like behavior, but there's no reason to think that it's sexual.

    22. DADavid Anderson1:24:37

        Right.

    23. AHAndrew Huberman1:24:37

        But they're sending a message of dominance, is what, what it implies.

21. 1:24:40 – 1:30:38

    PAG (Periaqueductal Gray) Brain Region: Pain Modulation & Fear

    1. AHAndrew Huberman1:24:41

       I'd love to talk about, uh, something, um, slightly off from this circuitry, but I think that's related to this circuitry, at least in some way, which is this (laughs) structure that I've always been fascinated by, and I can't figure out what the hell it's for, e- 'cause it seems to be involved in everything, which is the PAG, the periaqueductal gray, which is a little bit further back in the brain, for people th- that don't know. It's been studied in the context of pain, it's been studied in the context of the so-called lordosis response, the, the receptivity or arching of the back of the female to receive intromission and mating from the male. How should we think about PAG? Um, i- clearly it can't be involved in e- everything. I'm guessing it's at least as complex as some of these other regions that we've been talking about, different types of neurons controlling different things. But how does PAG play into this? In particular, I want to know, is there some mechanism of pain modulation and control during fighting and/or mating? And the reason I ask is that, um, while I'm not a combat sports person, years ago I did, did a little bit of martial arts, and it always was, um, impressive to me how little it hurt to get punched during a fight and how much it hurt afterwards, (laughs) right? So there clearly-

    2. DADavid Anderson1:25:52

       Hmm.

    3. AHAndrew Huberman1:25:52

       ... is some endogenous pain control.... um, that then wears off and then you feel beat up.

    4. DADavid Anderson1:25:58

       Yep.

    5. AHAndrew Huberman1:25:58

       Um, or at least in my case, I felt beat up. What's PAG doing vis-à-vis pain and vis-à-vis... And what's pain doing vis-à-vis these other behaviors?

    6. DADavid Anderson1:26:06

       Good, good. So, so I think of PAG like a old-fashioned telephone switchboard, where there are, there are calls coming in and then the cables have to be punched into the right hole to get the information to be routed to the right recipient-

    7. AHAndrew Huberman1:26:24

       Mm-hmm.

    8. DADavid Anderson1:26:24

       ... on the other end of it. Uh, because pretty much every type of innate behavior you can think of has had the PAG implicated. And there's a whole literature, uh, showing the involvement of the PAG in fear, different regions of the PAG, the dorsal PAG is involved in panic-like behavior, running away, the ventral PAG is involved in freezing behavior. Uh, the, both the MPOA and VMH send projections to the PAG, to different regions of the PAG. So, uh, uh, in cross-section, I hate to say this, but in cross-section, the PAG kind of looks like the water in a toilet when you're standing over an open toilet bowl.

    9. AHAndrew Huberman1:27:09

       Mm-hmm.

    10. DADavid Anderson1:27:10

        And if you imagine a clock face projected onto that, it's like the PAG has sectors from one to 12, maybe even more of them, and in each of those sectors, you find different neurons from the hypothalamus are projecting. So could turn out that there is a topographic arrangement along the dorsal-ventral axis of the PAG and the mediolateral axis of the PAG that determines the type of behavior that will be emitted when neurons in that region are stimulated. And I think sort of all of the evidence is pointing in that direction, but by no means has it been mapped out. Now, the thing that you mentioned about, uh, it not hurting when you got beat up during martial arts, there is a well-known phenomenon called fear-induced, uh, analgesia, where when an animal is in a high state of fear, like if it's trying to defend itself, there is a, uh, suppression of pain responses. And I'm not sure completely about the mechanisms and how well that's understood, but, for example, uh, the, the adrenal gland has a peptide in it that is released from the adrenal medulla, which controls the fight-or-flight responses, and that peptide has analgesic activities. Now, whether-

    11. AHAndrew Huberman1:28:39

        May I ask what that peptide is?

    12. DADavid Anderson1:28:40

        It's called bovine adrenal medullary peptide of 22 amino acid residues. And I only know about it because it activates a receptor that we discovered many years ago that's involved in pain, and we thought it promoted pain, but it turns out that it, 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 certainly is possible. And I don't know whether these, uh, analgesic mechanisms are happening in the PAG. They could also be happening a little further down in the spinal cord. The PAG is really continuous with the spinal cord. If you just follow it down towards the tail of an animal, you will wind up in the spinal cord. And, uh, um, and so it could be that there are influences acting at many levels on pain in the PAG and in the spinal cord as well. And it may well be known, I just don't know it. I want to distinguish clearly-

    13. AHAndrew Huberman1:29:50

        (clicking tongue)

    14. DADavid Anderson1:29:50

        ... between things that are not known, that I know are unknown, which is in a fairly small area where I have expertise, from things that may be known but I'm ignorant of them because I just don't have a broad enough knowledge base to know that.

    15. AHAndrew Huberman1:30:04

        Sure. We appreciate, um, those delineations. Um, thank you. Uh, PAG is o- I think this description of it is an old-fashioned teleph- uh, phone switchboard, and, um, and now every time I look into the toilet, I'll think about the periaqueductal gray.

    16. DADavid Anderson1:30:18

        (laughs) That's right.

    17. AHAndrew Huberman1:30:18

        And every time I see an image of periaqueductal gray, I'll think about a toilet.

    18. DADavid Anderson1:30:21

        (laughs) That's right. (laughs)

    19. AHAndrew Huberman1:30:21

        That is an excellent description, uh, because I, and in fact, I drew a circle with a little thing at the bottom and, uh, um... Well, I'll put a post, uh, link to a picture of PAG and you'll understand why, why David and I are chuckling here, because indeed, it looks like a toilet, uh, when staring into a toilet.

22. 1:30:38 – 1:43:49

    Tachykinins & Social Isolation: Anxiety, Fear & Aggression

    1. AHAndrew Huberman1:30:38

       Tell us about tachykinin. I've talked about this a couple times on different podcast episodes because of its relationship to social isolation, and, uh, in part because the podcast was launched during a time when there was more social isolation. Um, my understanding is that tachykinin, and you'll tell us what it is in a moment, um, is present in flies, in mice and in humans, and may do similar things in those species.

    2. DADavid Anderson1:31:05

       That's right. So (clears throat) tachykinin is, uh, refers to a family of related neuropeptides, so these are brain chemicals. Um, they're different from dopamine and serotonin in that they're not small organic molecules, they're actually short pieces of protein that are directly encoded by genes that are active in specific neurons and not in others. And when those neurons are active, those neuropeptides are released together with classical transmitters, like glutamate, whatever. Tachykinins have been famously implicated in pain, prota- particularly tachykinin 1, which is called substance P, one of the original pain modulating, this is something that promotes-... inflammatory pain. But there are other tachykinin genes, in mice, there are two, in humans, I think there are three, and, uh, in Drosophila, there is one. And the way we got into tachykinins is from studying aggression in flies. We thought since neuropeptides have this remarkable parallel evolutionary conservation of structure and function, like neuropeptide Y controls feeding in worms, in flies, and mice, and in people, oxytocin-like peptides control reproduction in worms and mice, and in people, we thought we might find peptides that control aggression in flies and in people. And so we did a, a screen, unbiased screen of peptides, and found indeed that one of the tachykinins, Drosophilin tachykinin, those neurons, when you activate them, strongly promote aggression, and it depends on the release of tachykinin. Now, the interesting thing is that, in flies, just like in people and practically any other social animal that shows aggression, social isolation increases aggressiveness. So putting a, a, a violent prisoner in solitary confinement is absolutely the worst, most counterproductive thing you could do to them. And indeed, we found in flies that social isolation increases the level of tachykinin in the brain, and if we shut that gene down, it prevents the isolation from increasing aggression. So since my lab also works on mice, it was natural to see whether tachykinins might be upregulated in social isolation and whether they play a role in aggression. And this is work done by a former post-doc, Moriel Zelikovski, now at University of Salt Lake City in Utah, and she found, remarkably, that when mice are socially isolated for two weeks, there is this massive upregulation of tachykinin-2 in their brain. In fact, if you tag the peptide with a green fluorescent protein from a jellyfish genetically, the brain looks green when the mice are socially isolated 'cause there's so much of this stuff released. And she went on to show that that increase in tachykinin is responsible for the effect of social isolation to increase aggressiveness and to increase fear and to increase anxiety. And in fact, there are drugs that block the receptor for tachykinin, which were tested in humans and abandoned because they had no efficacy in the tests that they were, uh, analyzed for. If you give those drugs to a socially isolated mouse, it blocks all of the effects of social isolation, it blocks the aggression, it blocks the increased fear and the increased anxiety. And Moriel described it, "The mice just looked chill." It's not a sedative, which is really important, it's not that the mice are going to sleep. Most remarkably is once you socially isolate a mouse and it becomes aggressive, you can never put it back in its cage with its brothers from its litter because it will kill them all overnight. But if you give it this drug, which is called osunatide, that black- blocks tachykinin-2, that mouse can be returned to the cage with its brothers and will not attack them, and seems to be happy about that for the rest of the time. So this is an incredibly powerful effect of this drug, and I've been really interested in trying to get pharmaceutical companies to test this drug, which has a really good safety profile in humans, in testing it in people who are subjected to social isolation stress or bereavement stress. And this is one of the areas where I learned an eye-opening lesson as a basic scientist who naively thought that if you make a discovery and it has translational applications to humans, that pharmaceutical companies are going to be falling all over themselves to try it. And they're not interested because once burned, twice shy. These drugs were tested for efficacy in schizophrenia, I have no idea why.

Episode duration: 1:55:34