A (4:03)

I'd like to talk a bit about aggression, the beautiful work of Dayu Lin and others in your lab. What are your thoughts on aggression, how it's generated, the neural circuit mechanisms, and some of the variation in what we call aggression?

C (4:14)

First of all, the word aggression in my mind refers more to a description of behavior than it does to an internal state. Aggression could reflect an internal state that we would call anger in humans or, or could reflect fear, or it could reflect hunger if it's predatory aggression. The work that Dayu did when she was in my lab, 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. Following first the famous Nobel prize winning work of Walter Hess. 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. If you think of ventromedial hypothalamus like a pear sitting on the ground, the fat part of the pear near the ground is where the aggression neurons are. But the upper part of the pair has fear neurons. Fast forward from that from a lot of work from Dayu now on her own at NYU and and with her postdoc Anna Gret Faulkner. There's evidence that the type of fighting that we elicit when we stimulate VMH is offensive aggression that is actually rewarding to male mice.

A (6:10)

They like it.

C (6:11)

They like it. Male mice will learn to poke their nose or press a bar to get the opportunity to beat up a subordinate male mouse. It has a positive valence. 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.

B (6:39)

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A (7:42)

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.

C (7:58)

If you think from an evolutionary perspective, it might have been the case that defensive behaviors and fear arose before offensive behavior aggression because animals first and foremost have to defend themselves from predation by other animals. And maybe it's only when they're comfortable with having warded off predation and made themselves safe that they can start to think about who's going to be the alpha male in my group here. And so it could be that if you think that brain regions and cell populations evolved by duplication and modification of pre existing cell populations, that might be the way that those regions wound up next to each other. 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. By fear. It's one of the big differences between defensive aggression and offensive aggression. And maybe these two regions are close to each other to facilitate inhibition of aggression by the fear neurons. We know for a fact that if we deliberately stimulate those fear neurons at the top of the pair, when two animals are involved in a fight, it just stops the fight dead in its tracks and. And they go off into the corner and freeze. So at least hierarchically, it seems like fear is the dominant behavior over offensive aggression. I think that's the way I tend to think about why these neurons are all mixed up together. And it's not just fight and flight. There are also metabolic neurons that are mixed together in VMH as well.

A (9:56)

One of the concepts that you've raised in your lectures before is this idea

B (10:00)

of a sort of hydraulic pressure, or

A (10:02)

maybe it was conlabs. Conrad, I can't speak now. Excuse me. Conrad Lorenz Martin, who talked about a kind of hydraulic pressure towards behavior. What's really driving hydraulic pressure toward a given state?

C (10:14)

One way that is helpful, at least for me to break this question apart and think about it, is to distinguish homeostatic behaviors, I.e. need based behaviors, where the pressure is built up to because of a need. Like I'm hungry, I need to eat, I'm thirsty, I need to drink, I'm hot, I need to get to a cold place. It's basically the thermostat model of your brain. You have a set point and then if the temperature gets too hot, you turn on the ac, and if the temperature gets too cold, you turn on the heater and you put yourself back to the set point. You can think of this accumulated hydraulic pressure either being based on something that you were deprived of, creating an accumulating need, or something that you want to do, building up a drive or a pressure to do that. And the natural way to think about that, at least for me, is as gradual increases in neural activity in a particular region of the brain. So for example, in the area of the hypothalamus that controls feeding, Scott Sternson and others have shown that the hungrier you get, the higher the level of activity in that region in the brain. And then when you eat, boom, the activity goes right back down again. And 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. You need to set the animal off to get it to fight. VMH projects to about 30 different regions in the brain, and it gets input from about 30 different regions. So I kind of see it as both an antenna and a broadcasting center. It's like a satellite dish that takes in information from different sensory modalities. Smell, maybe vision, mechanosensation. And then it sort of synthesizes and integrates that into a fairly low dimensional, as the computational people call it, representation of this pressure to attack. And it broadcasts that all over the brain to trigger all these systems that have to be brought into play if the animal is 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 so its brain constantly has to make a cost benefit analysis of whether to continue on that path or to back off.

A (12:58)

As we're talking about aggression and mating behavior, I think hormones, 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. The specific hormones that are involved in generating aggression via VMH are things other than testosterone. Can you tell us a little bit more about that? Cause there's some interesting surprises in there.

C (13:31)

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. Other labs have shown that the estrogen receptor in adult male mice is necessary for aggression. If you knock out the gene in vmh, they don't fight. And it's been shown, and a lot of this is work from your colleague Nirao Shah at Stanford, who is one of my former PhD students, that if you castrate a mouse and, and it loses the ability to fight, not only can you rescue fighting with a testosterone implant, but you can rescue it with an estrogen implant. So you can bypass completely the requirement for testosterone to restore aggressiveness to the mice. And as you say, it's because many of the effects of testosterone, although not all, many of them, are mediated by its conversion to, 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 because aromatase inhibitors are widely used in female humans as adjuvant chemotherapy for breast cancer.

A (14:51)

What's involved in female aggression that's unique from the pathways that generate male aggression?

C (14:57)

So we and other labs have studied this in, in both mice and also in fruit flies. One thing in mice that distinguishes aggression in females from males is that male mice are pretty much ready to fight at the drop of a hat. Female mice only fight when they are nurturing and nursing their pups after they've delivered a litter. And there is a window there where they become hyper aggressive. After their pups are weaned, that aggressiveness goes away. So this is pretty remarkable that you take a virgin female mouse and expose it to a male, and her response is to become sexually receptive and to mate with him. And now you 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. We recently showed in a paper, this is work from one of my students, Meng Yu 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. This gets into the whole issue of neurons that are present in females, males, but not 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.

B (16:49)

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A (18:13)

If one observes the mating behaviors of different animals, we know that there's a tremendous range of mating behaviors in humans. There can be no aggressive component. There could be aggressive component. Humans have all sorts of kinks and fetishes and behaviors, and most of which probably has never been documented because most of this, this happens in private. With that said, when you look at mating behavior of various animals, you see an aggressive component sometimes, but not always. Is it species specific? Is it context specific? And more generally, do you think that there is crosstalk between these different neuronal populations and the animal itself might be kind of confused about what's going on?

C (18:50)

I can't really speak to the issue of whether this is species specific because I'm not a naturalist or a zoologist. I've seen, like you have in the wild, for example, lions, when they mate, I've seen them in Africa, there's often a biting component of that as well. One of the things that surprised us when we identified neurons in VMH VL 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. There's some evidence that those female selective neurons in VMH are part of the mating behavior. If you shut them down, the animals don't mate as effectively as they otherwise would. What happens when you stimulate them? We don't yet know because we don't have a way to specifically do that without activating the male aggression neurons. But I think they must be there for a reason because VMH is not traditionally the brain region to which male sexual behavior has been assigned. That's another area called the medial preoptic area. And there we have Shown that there are neurons that definitely stimulate mating behavior. In fact, if we activate those mating neurons in a male while it's in the middle of attacking a male, another male, it will stop fighting, start singing to that male, and start to try to mount that male until we shut those neurons off. So those are the make love, not war neurons and VMH are the make war, not love neurons. And there are dense interconnections between these two nuclei, which are very close to each other in the brain. But it's also possible that that there are some cooperative interactions between those structures as well as antagonistic interactions. And the balance of whether it's the cooperative or antagonistic interactions that are firing at any given moment in a mating encounter, as you suggest, may determine whether a moment of coital bliss among two lions may suddenly turn into a snap or a growl and a bearing of fangs. We don't know that, but certainly the substrate, the wiring, is there for that to happen. When we made that discovery initially, it raised the question in my mind whether some people that are serial rapists, for example, and engage in sexual violence might at some level have their wires crossed in some way that these states that are supposed to be pretty much separated and mutually antagonistic are not and are actually more rewarding and reinforcing.

A (21:48)

I'd love to talk about this structure because it seems to be involved in everything, which is the pag, the periaqueductal gray. It's been studied in the context of pain. It's been studied in the context of the so called lordosis response, the receptivity or arching of the back of the female to receive in TR and mating from the male in particular. I want to know is there some mechanism of pain modulation and control during fighting and or mating? And the reason I ask is that while I'm not a combat sports person, years ago I did a little bit of martial arts and it always was impressive to me how little it hurt to get punched during a fight and how much it hurt afterwards.

B (22:29)

Right.

A (22:30)

So there clearly is some endogenous pain control that then wears off and then you feel beat up. What's PAG doing vis a vis pain and what's pain doing vis a vis these other behaviors?

C (22:41)

So I think of PAG like a old fashioned telephone switchboard. There are calls coming in and then the cables have to be punched into the right hole to get the information to be routed to the right recipient on the other end of it. Because pretty much every type of innate behavior you can think of has had the PAG implicated in cross section. The PAG kind of looks like the water in a toilet when you're standing over an open toilet bowl. And if you imagine a clock face projected onto that, it's like the PAG has sectors from 1 to 12, maybe even more of them. And in each of those sectors you find different neurons from the hypothalamus or are projecting. So it could turn out that there is a topographic arrangement along the dorsal ventral axis of the PAG and the medial lateral axis of the PAG that determines the type of behavior that will be emitted when neurons in that region are stimulated. And I think sort of all of the evidence is pointing in that direction, but by no means has it been mapped out. Now, the thing that you mentioned about it not hurting when you got beat up during martial arts, there is a well known phenomenon called fear induced analgesia, where when an animal is in a high state of fear, like if it's trying to defend itself, there is a suppression of pain responses. And I'm not sure completely about the mechanisms and how well that's understood. But for example, the adrenal gland has a peptide in it that is released from the adrenal medulla which controls the fight or flight responses. And that peptide has analgesic activities.

B (24:40)

That's what that peptide is.

C (24:41)

It's called bovine adrenal medullary peptide of 22amino acid residues. And I only know about it because it activates a receptor that we discovered many years ago that that's involved in pain. And we thought it promoted pain, but it turns out that this actually inhibits pain. It's like an endogenous analgesic. Whether this is happening, this type of analgesia is happening when an animal is engaged in offensive aggression or in mating behavior, I don't know. But it certainly is possible. And I don't know whether the these analgesic mechanisms are happening in the pag. They could also be happening a little further down in the spinal cord. The PAG is really continuous with the spinal cord. If you just follow it down towards the tail of an animal, you will wind up in the spinal cord. And so it could be that there are influences acting at many levels on pain in the PAG and in the spinal cord as well. And it may well be known. I just don't know it. I want to distinguish clearly between things that are not known, that I know are unknown, which is in a fairly small area where I have expertise from things that may be known, but I'm ignorant of them because I just don't have a broad enough knowledge base to know that.

B (26:03)

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A (27:14)

Tell us about Tachykinin I've talked about this a couple times on different podcast episodes because of its relationship to social isolation. My understanding is that tachykinin is present in flies and mice and in humans and may do similar things in those species.

C (27:32)

So tachykinin is refers to a family of related neuropeptides. So these are brain chemicals. They're different from dopamine and serotonin in that they're not small organic molecules. They're actually short pieces of protein that are directly encoded by genes that are active in specific neurons and not in others. And when those neurons are active, those neuropeptides are released together with with classical transmitters like glutamate, whatever. Tachykinins have been famously implicated in pain, particularly tachykinin 1, which is called substance P, one of the original pain modulating. This is something that promotes inflammatory pain. And so we did a screen, unbiased screen of peptides, and found indeed that one of the tachykinins, Drosophila tachykinin, those neurons, when you activate them, strongly promote aggression and it depends on the release of tachykinin. Now the interesting thing is that in flies, just like in people, and practically any other social animal that Shows aggression. Social isolation increases aggressiveness. So putting a violent prisoner in solitary conflict is absolutely the worst, most counterproductive thing you could do to them. And indeed, we found in flies that social isolation increases the level of tachykinin in the brain. And if we shut that gene down, it prevents the isolation from increasing aggression. So since my lab also works on mice, it was natural to see whether tachykinins might be upregulated in social isolation and whether they play a role in aggression. And this is work done by a former postdoc, Muriel Zelikovsky, 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 because there's so much of this stuff released. And she went on to show that that increase in tachykinin is responsible for the effect of social isolation to increase aggressiveness and to increase fear and to increase anxiety. And, in fact, there are drugs that block the receptor for tachykinin, which were tested in humans and abandoned because they had no efficacy in the tests that they were analyzed for. If you give those drugs to a socially isolated mouse, it blocks all of the effects of social isolation. It blocks the aggression. It blocks the increased fear and the increased anxiety. And Moriel described it, the mice just 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 Osanoton, that blocks tachykinin, too, 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. Or bereavement stress. But it's just very difficult for economic reasons, to find a way to get somebody to test that.

A (31:45)

As long as we're talking about humans, I'd love to get your thoughts about human studies of emotion. I know you wrote this book With Ralph Adolfs, you have this new book. There are books that are worth reading, and then there are books that are important. And I think this book is truly important for the general population to read and understand. There's a heat map diagram in that book of subjective reports that people gave of where they experience an emotion or a feeling, a somatic feeling, in their body or in their head, or both, when they are angry, sad, calm, lonely, et cetera, et cetera. And I wouldn't want people to think that those heat maps were generated by any physiological measurement, because they were not. How should we think about the body in terms of states? And at some point, I'd love for you to comment on that heat map experiment.

C (32:34)

This goes back to something called the somatic marker hypothesis that was proposed by Antonio Damasio, who is a neurologist at usc. The idea that our subjective feeling of a particular emotion is in part associated with a sensation of something happening in a particular part of our body, the gut, the heart. If there is a physiology underlying these heat maps, it could reflect increased blood flow to these different structures. And that, in turn reflects communication between the brain and the body and its bidirectional communication. And it's mediated by the peripheral nervous system, the sympathetic and the parasympathetic nervous system, which control heart rate, for example, blood vessel, blood pressure. And those neurons receive input from the hypothalamus and other blood brain regions, central brain regions that control their activity. And when the brain is put in a particular state, it activates sympathetic and parasympathetic neurons, which have effects on. On the heart and on blood pressure. These, in turn, feed back onto the brain through the sensory system. And a large part of this bidirectional communication is also mediated through the vagus nerve, which many of your listeners and viewers may have heard about because it's become a topic of intense activity. Now, the vagus nerve is a bundle of nerve fibers that comes out basically of your skull, out of the central nervous system, and then sends fibers into your heart, your gut, all sorts of visceral organs. That information is both afferent and efferent. The vagal fibers sense things that are happening in the body. So when you're. The reason you feel your stomach tied up in knots, if you're tense, is that those vagal fibers are sensing the contraction of the gut muscles. They're also afferents, which means that information coming out of the brain can influence those peripheral organs as well. And there's work from a number of labs just in the last six months or so where people are starting to decode the components of the different fibers in the vagus nerve. And it's amazing how much specificity is there are specific vagal nerves that go to the lung, that control breathing, responses that go to the gut, that go to other organs. It's almost like a set of color coded lines labeled lines for those things. And now how those vagal afferents play a role in the playing out of emotion states is a fascinating question that people are just beginning to scrape the surface of. But I think what's exciting now is that people are going to be developing tools that will allow us to turn on or turn off specific subsets of fibers within the vagus nerve and ask how that affects particular emotional behaviors. So you're absolutely right. This brain body connection is critical not just for the gut, but for the heart, for the lungs, for all kinds of other parts of your body. And Darwin recognized that as well. And I think it's a central feature of emotion state and I think what underlies our subjective feelings of an emotion.

A (36:27)

David, I have to say, as a true fan of the work that your lab has been doing over so many decades, I know I speak on behalf of a tremendous number of people and I say thank you for taking time out of your important schedule to share with us what you've learned.

C (36:40)

I really have appreciated your questions. They've all been right on the money. You've hit all of the critical, important issues in this field and you've uncovered what is known, the little bit is known, and how much is not known. And I think it's important to emphasize the unknown things because that's what the next generation of neuroscientists has to solve. And so I hope this will help to attract young people into this field because it's so important, particularly for our understanding of mental illness and mental health and psychiatry. We've got to figure out how to. How emotion systems are controlled in a causal way if we ever want to improve on the psychiatric treatments that we have now. And that's going to require the next generation of people coming into the field.

A (37:35)

Absolutely. I second that. Well, thank you. It's been a delight.

C (37:38)

Thank you. Great. Really appreciate it.