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

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.260 | where we discuss science and science-based tools

00:00:04.900 | for everyday life.

00:00:05.740 | [upbeat music]

00:00:08.320 | I'm Andrew Huberman,

00:00:10.340 | and I'm a professor of neurobiology and ophthalmology

00:00:13.240 | at Stanford School of Medicine.

00:00:15.020 | Today, my guest is Dr. David Anderson.

00:00:17.440 | Dr. Anderson is a professor of biology

00:00:19.380 | at the California Institute of Technology,

00:00:21.960 | often commonly referred to as Caltech University.

00:00:25.440 | Dr. Anderson's research focuses on emotions

00:00:28.080 | and states of mind and body.

00:00:30.000 | And indeed, he emphasizes how emotions like happiness,

00:00:32.500 | sadness, anger, and so on are actually subcategories

00:00:36.280 | of what are generally governed by states.

00:00:39.340 | That is, things that are occurring in the nervous system

00:00:42.120 | in our brain and in the connections between brain and body

00:00:45.760 | that dictate whether or not we feel good

00:00:47.480 | about how we are feeling and that drive our behaviors,

00:00:50.660 | that is, bias us to be in action or inaction

00:00:54.520 | and strongly influence the way we interpret our experience

00:00:57.520 | and our surroundings.

00:00:58.700 | Today, Dr. Anderson teaches us, for instance,

00:01:01.160 | why people become aggressive

00:01:02.680 | and why that aggression can sometimes take the form of rage.

00:01:06.900 | I also talk about sexual behavior and the boundaries

00:01:10.200 | and overlap between aggression and sexual behavior.

00:01:13.640 | And that discussion about aggression and sexual behavior

00:01:16.600 | also starts to focus on particular aspects of neural circuits

00:01:19.880 | and states of mind and body that govern things like,

00:01:22.640 | for instance, male-male aggression

00:01:24.800 | versus male-female aggression versus female-female aggression.

00:01:28.760 | So today you will learn a lot about the biological mechanisms

00:01:31.480 | that govern why we feel the way we feel.

00:01:33.880 | Indeed, Dr. Anderson is an author

00:01:35.840 | of a terrific new popular book entitled

00:01:38.320 | "The Nature of the Beast, How Emotions Guide Us."

00:01:41.000 | I've read this book several times now.

00:01:43.200 | I can tell you it contains so many gems

00:01:45.040 | that are firmly grounded in the scientific research.

00:01:47.520 | In fact, a lot of what's in the book

00:01:49.520 | contrasts with many of the common myths

00:01:51.660 | about emotions and biology.

00:01:53.900 | So whether or not you're a therapist or you're a biologist

00:01:56.520 | or you're simply just somebody interested

00:01:58.500 | in why we feel the way we feel

00:02:00.200 | and why we act the way we act,

00:02:02.120 | I cannot recommend the book highly enough.

00:02:03.920 | Again, the title is "The Nature of the Beast,

00:02:05.540 | How Emotions Guide Us."

00:02:07.220 | Today's discussion also ventures into topics

00:02:09.480 | such as mental health and mental illness.

00:02:12.120 | And some of the exciting discoveries

00:02:13.940 | that have been made by Dr. Anderson's laboratory

00:02:15.740 | and other laboratories identifying specific peptides,

00:02:18.600 | that is, small proteins that can govern

00:02:21.200 | whether or not people feel anxious or less anxious,

00:02:23.680 | aggressive or less aggressive.

00:02:25.360 | This is an important area of research

00:02:27.140 | that has direct implications

00:02:28.480 | for much of what we read about in the news,

00:02:30.560 | both unfortunate and fortunate events,

00:02:33.080 | and that will no doubt drive

00:02:35.080 | the future of mental health treatments.

00:02:37.060 | Dr. Anderson is considered one of the most pioneering

00:02:40.620 | and important researchers in neurobiology of our time.

00:02:43.840 | Indeed, he is a member of the National Academy of Sciences

00:02:45.940 | and a Howard Hughes Medical Institute investigator.

00:02:49.120 | I've mentioned the HHMI once or twice before

00:02:51.440 | when we've had other HHMI guests on this podcast,

00:02:54.440 | but for those of you that are not familiar,

00:02:55.880 | the Howard Hughes Medical Institute

00:02:57.200 | funds a small number of investigators

00:02:59.380 | doing particularly high-risk, high-benefit work,

00:03:02.800 | and it is an extremely competitive process

00:03:05.580 | to identify those Howard Hughes investigators.

00:03:08.800 | They're essentially appointed, and then every five years,

00:03:11.540 | they have to compete against one another

00:03:13.720 | and against a new incoming flock

00:03:16.080 | of would-be HHMI investigators

00:03:18.680 | to get another five years of funding.

00:03:19.920 | They are literally given a grade every five years

00:03:22.100 | as to whether or not they can continue, not continue,

00:03:24.580 | or whether or not they should worry about being funded

00:03:27.120 | for an extended period of time.

00:03:28.540 | Dr. Anderson has been an investigator

00:03:30.300 | with the Howard Hughes Medical Institute since 1989.

00:03:33.860 | I'm pleased to announce that the Huberman Lab Podcast

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00:03:38.080 | We partnered with Momentus for several important reasons.

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00:04:27.860 | Before we begin, I'd like to emphasize that this podcast

00:04:30.340 | is separate from my teaching and research roles at Stanford.

00:04:33.000 | It is, however, part of my desire and effort

00:04:35.220 | to bring zero cost to consumer information about science

00:04:37.700 | and science-related tools to the general public.

00:04:40.260 | In keeping with that theme,

00:04:41.340 | I'd like to thank the sponsors of today's podcast.

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00:08:07.400 | And now for my discussion with Dr. David Anderson.

00:08:10.760 | David, great to be here

00:08:11.860 | and great to finally sit down and chat with you.

00:08:14.120 | - Great to be here too, thank you so much.

00:08:16.020 | - Yeah, I have a ton of questions,

00:08:17.420 | but I want to start with something fairly basic,

00:08:20.260 | but that I'm aware is a pretty vast landscape.

00:08:23.620 | And that's the difference between emotions and states,

00:08:27.680 | if indeed there is a difference,

00:08:28.940 | and how we should think about emotions.

00:08:31.900 | What are they?

00:08:33.540 | They have all these names, happiness, sadness, depression,

00:08:37.200 | anger, rage.

00:08:38.740 | How should we think about them?

00:08:39.980 | And why might states be at least as useful

00:08:44.540 | a thing to think about, if not more useful?

00:08:46.940 | - That's great.

00:08:48.380 | First, the short answer to your question

00:08:50.380 | is that I see emotions as a type of internal state,

00:08:55.380 | in the sense that arousal is also a type of internal state,

00:08:59.180 | motivation's a type of internal state,

00:09:01.300 | sleep is a type of internal state.

00:09:04.240 | And the sort of simplest way I think of internal states

00:09:08.540 | is that as you've shown in your own work,

00:09:10.540 | they change the input to output transformation of the brain.

00:09:15.380 | When you're asleep, you don't hear something

00:09:18.260 | that you would hear if you were awake,

00:09:20.180 | unless it's a really, really loud noise.

00:09:22.300 | So from that broad perspective,

00:09:25.080 | I see emotion as a class of state that controls behavior.

00:09:30.080 | The reason I think it's useful to think about it as a state

00:09:33.840 | is it puts the focus on it as a neurobiological process,

00:09:38.840 | rather than as a psychological process.

00:09:42.620 | And this gets around all of the definitional problems

00:09:46.500 | that people have with the word emotion,

00:09:49.580 | where many people equate emotion with feeling,

00:09:53.460 | which is a subjective sense that we can only study in humans

00:09:58.460 | because to find out what someone's feeling,

00:10:01.760 | you have to ask them, and people are the only animals

00:10:04.900 | that can talk that we can understand.

00:10:07.260 | So that's how I think about emotion.

00:10:10.540 | It's the, if you think of an iceberg,

00:10:13.420 | it's the heart of the iceberg

00:10:15.580 | that's below the surface of the water.

00:10:18.100 | The feeling part is the tip that's sort of floating

00:10:21.320 | above the surface of your consciousness.

00:10:23.700 | Not that that isn't important, it is,

00:10:25.780 | but you have to understand consciousness

00:10:28.300 | if you wanna understand feelings,

00:10:30.420 | and we're not ready to study that in animals yet.

00:10:33.840 | And so that's how I think about it.

00:10:36.480 | What are the different components of a state?

00:10:39.120 | You know, you mentioned arousal as a key component.

00:10:43.620 | What are some of the other features of states

00:10:45.840 | that represent this, as you so beautifully put in your book,

00:10:50.300 | that represent below the tip of the iceberg?

00:10:52.320 | Right, right.

00:10:53.280 | So you can break states up

00:10:58.820 | into different facets, or people would call them dimensions.

00:11:03.820 | And so there have been people who've thought of emotions

00:11:08.300 | as having just really two dimensions,

00:11:11.100 | an arousal dimension, how intense is it,

00:11:16.100 | and also a valence dimension,

00:11:19.960 | which is, is it positive or negative, good or bad?

00:11:24.180 | Ralph Adolphs and I have tried to expand that a little bit

00:11:28.380 | to think about components of emotion,

00:11:31.080 | particularly those that distinguish emotion states

00:11:34.160 | from motivational states,

00:11:36.160 | because they are very closely related.

00:11:38.660 | One of those important properties is persistence.

00:11:43.620 | And this is something that distinguishes

00:11:46.580 | state-driven behaviors from simple reflexes.

00:11:50.380 | Reflexes tend to terminate when the stimulus turns off,

00:11:55.820 | like the doctor hitting your knee with a hammer.

00:11:58.500 | It initiates with the stimulus onset,

00:12:00.920 | and it terminates with the stimulus offset.

00:12:03.700 | Emotions tend to outlast often the stimulus that evoke them.

00:12:08.380 | If you're walking along a trail here in Southern California,

00:12:12.540 | you hear a rattlesnake rattling,

00:12:15.200 | you're gonna jump in the air,

00:12:16.940 | but your heart is gonna continue to beat,

00:12:19.300 | and your palms sweat, and your mouth is gonna be dry

00:12:22.540 | for a while after it slithered off in the bush,

00:12:25.500 | and you're gonna be hypervigilant.

00:12:27.220 | If you see something that even remotely looks snake-like,

00:12:31.180 | a stick, you're gonna stop and jump.

00:12:33.540 | So persistence is an important feature of emotion states.

00:12:38.540 | Not all states have persistence.

00:12:42.460 | So for example, you think about hunger.

00:12:45.420 | Once you've eaten, the state is gone.

00:12:48.500 | You're not hungry anymore.

00:12:50.120 | But if you're really angry

00:12:52.380 | and you get into a fight with somebody,

00:12:54.260 | even after the fight is over,

00:12:56.100 | you may remain riled up for a long time,

00:13:00.060 | and it takes you a while to calm down.

00:13:02.460 | And that may have to do with the arousal dimension

00:13:05.340 | or some other part of it.

00:13:06.660 | And then generalization is an important component

00:13:11.920 | of emotion states that make them,

00:13:16.920 | if they have been triggered in one situation,

00:13:21.380 | they can apply to another situation.

00:13:24.400 | And my favorite example of that

00:13:26.140 | is you come home from work and your kid is screaming.

00:13:30.020 | If you had a good day at work,

00:13:31.580 | you might pick it up and soothe it.

00:13:34.020 | And if you had a bad day at work,

00:13:35.960 | you might react very differently to it and scream at it.

00:13:39.260 | And so that's a generalization of the state

00:13:42.260 | that was triggered at work by something your boss said to you

00:13:46.060 | to a completely different interaction.

00:13:48.900 | And again, that's something that distinguishes

00:13:51.480 | emotion states from motivation states.

00:13:54.460 | Motivation states are really specific.

00:13:57.220 | Find and eat food, obtain and consume water.

00:14:02.220 | And they're involved in homeostatic maintenance.

00:14:06.940 | So states are very multifaceted

00:14:11.940 | and just asking questions

00:14:15.940 | about how these components of states are encoded.

00:14:19.740 | Like what makes a state persist?

00:14:22.660 | What gives a state a positive or a negative valence?

00:14:26.340 | How do you crank up or crank down the intensity of the state?

00:14:30.280 | It just opens up a whole bunch of questions

00:14:32.900 | that you can ask in the brain

00:14:35.160 | with the kinds of tools we have now.

00:14:37.200 | You mentioned arousal a few times

00:14:40.140 | and you mentioned valence.

00:14:41.500 | Realizing that there are these other aspects of states,

00:14:45.700 | I'd like to just talk about arousal a little bit more

00:14:47.860 | and valence, because at a very basic level,

00:14:50.280 | it seems to me that arousal, we can be very alert

00:14:54.020 | and pissed off, stressed, worried.

00:14:58.740 | You have insomnia.

00:15:01.180 | We can also be very alert and be quite happy.

00:15:03.500 | So the valence flips.

00:15:05.980 | We can be very, people can be sexually aroused.

00:15:08.340 | People can be aroused in all sorts of ways.

00:15:11.220 | Is there any simple or simple-ish neurochemical signature

00:15:16.220 | that can flip valence?

00:15:17.980 | So for instance, is there any way that we can safely say

00:15:20.840 | that arousal with some additional dopamine release

00:15:25.700 | is going to be of positive valence

00:15:28.240 | and arousal with very low dopamine

00:15:31.660 | is going to be of negative valence?

00:15:33.860 | I would be reluctant to say that it's a chemical flip.

00:15:39.340 | I would say it's more likely to be a circuit flip,

00:15:43.260 | different circuits being engaged.

00:15:45.060 | And it might be that a given neurochemical,

00:15:48.100 | even dopamine is involved in both positively valenced arousal

00:15:52.660 | and negatively valenced arousal.

00:15:55.060 | That's why people think about these as different axes.

00:15:59.300 | So I think the interesting question that you touch on

00:16:04.300 | is, is arousal something that is just completely generic

00:16:08.000 | in the brain, or are there actually different kinds

00:16:11.500 | of arousal that are specific to different behaviors?

00:16:15.340 | And you raise the question, sexual arousal feels different

00:16:18.720 | from aggressive arousal, for example.

00:16:21.540 | And we actually published a paper on this back in 2009

00:16:26.100 | in Fruit Flies, where we found some evidence

00:16:29.980 | for two types of arousal states,

00:16:32.860 | one of which is sleep-wake arousal.

00:16:35.680 | You're more aroused when you wake up

00:16:37.400 | and when you're asleep, and flies show that.

00:16:39.900 | And the other is a startle response, an arousal response

00:16:44.900 | to a mechanical stimulus, a noxious mechanical stimulus.

00:16:48.820 | If you puff air on flies, kind of like trying to swat

00:16:52.620 | the wasp away from your burger at the picnic table,

00:16:55.640 | they come back more and more and more vigorously.

00:16:58.700 | And we were able to dissect this and show

00:17:01.820 | that although both of those forms of arousal

00:17:05.240 | require dopamine, they were exerted

00:17:09.320 | through completely separable neural circuits in the fly.

00:17:13.500 | And so that really put, number one, the emphasis on,

00:17:17.220 | it's the circuit that determines the type of arousal,

00:17:20.660 | but also that arousal isn't unitary,

00:17:24.140 | that there are behavior-specific forms of arousal.

00:17:27.420 | And I think the jury is still out as to whether

00:17:30.380 | there is such a thing as completely generalized arousal or not.

00:17:35.380 | I think some people would argue there is,

00:17:38.440 | but I think more attention needs to be paid

00:17:40.920 | to this question of domain-specific

00:17:43.820 | or behavior-specific forms of arousal.

00:17:46.640 | Yeah, it's a super interesting idea,

00:17:48.220 | 'cause I always thought of arousal as along a continuum,

00:17:50.240 | like you can either be in a panic attack

00:17:52.060 | at the one end of the extreme, or you can be in a coma.

00:17:54.320 | And then somewhere in the middle, you're alert and calm.

00:17:56.720 | But then this issue of valence really, as you say,

00:18:00.600 | presents this opportunity that really there might be

00:18:03.000 | multiple circuits for arousal or multiple mechanisms

00:18:07.100 | that would include neurochemicals

00:18:08.940 | as well as different neural pathways.

00:18:11.260 | So I'd like to talk a bit about a state,

00:18:15.160 | if it is indeed a state, which is aggression.

00:18:18.080 | Your lab's worked extensively on this.

00:18:20.520 | And if you would, could you highlight

00:18:22.920 | some of the key findings there?

00:18:25.040 | Which brain areas are involved?

00:18:27.560 | The beautiful work of Dai-Yu Lin and others in your lab

00:18:30.120 | that point to the idea that indeed

00:18:34.440 | there are kind of switches in the brain,

00:18:37.140 | but that thinking of switches for aggression

00:18:40.240 | might be too simple.

00:18:41.720 | How should we think about aggression?

00:18:44.360 | And I'll just sort of skew the question a bit more

00:18:47.960 | by saying we see lots of different kinds of aggression.

00:18:51.680 | This terrible school shooting down in Texas recently,

00:18:56.360 | clearly an act that included aggression.

00:18:58.320 | And yet you could imagine

00:19:00.200 | that's a very different type of aggression than a,

00:19:02.480 | you know, an all outrage or a controlled aggression.

00:19:04.920 | You know, there's a lot of variation there.

00:19:06.680 | So what are your thoughts on aggression,

00:19:09.040 | how it's generated the neural circuit mechanisms

00:19:11.000 | and some of the variation in what we call aggression?

00:19:13.840 | Yeah, this is a great question.

00:19:15.360 | And it's a large area.

00:19:17.680 | I would say that the, first of all, the word aggression

00:19:22.680 | in my mind refers more to a description of behavior

00:19:28.360 | than it does to an internal state.

00:19:31.300 | Aggression could reflect an internal state

00:19:35.320 | that we would call anger in humans or could reflect fear,

00:19:40.320 | or it could reflect hunger if it's predatory aggression.

00:19:45.120 | And so this gets at the issue that you raised

00:19:47.720 | of the different types of aggression that exist.

00:19:51.440 | The work that Dayu did when she was in my lab

00:19:55.760 | that really broke open the field

00:19:58.760 | to the application of modern genetic tools

00:20:01.800 | for studying circuits in mice

00:20:04.040 | is that she found a way to evoke aggression in mice

00:20:09.040 | using optogenetics to activate specific neurons

00:20:15.480 | in a region of the hypothalamus,

00:20:18.360 | the ventromedial hypothalamus, VMH,

00:20:21.360 | which people had been studying and looking at for decades,

00:20:26.360 | following first the work of, in "Cats,"

00:20:32.400 | the famous Nobel Prize winning work of Walter Hess,

00:20:36.500 | and then followed by work done by Meno Crook

00:20:40.080 | in the Netherlands, in "Rats,"

00:20:42.620 | where they would stick electrical wires into the brain

00:20:46.980 | and send electric currents into the brain,

00:20:49.780 | and they could trigger a placid cat

00:20:52.860 | to suddenly bare its teeth, hiss,

00:20:56.080 | and almost strike out at the experimenter,

00:20:58.520 | and they could trigger rats to fight with each other.

00:21:03.500 | And even in Hess's original experiments,

00:21:07.220 | he describes two types of aggression

00:21:10.020 | that he evokes from cats depending on where

00:21:13.360 | in the hypothalamus he puts his electrode,

00:21:16.720 | one of which he calls defensive rage,

00:21:20.040 | that's the ears laid back, teeth bared and hissing,

00:21:24.360 | and the other one is predatory aggression,

00:21:27.560 | where the cat has its ears forward

00:21:30.660 | and it's like batting with its paw at a mouse-like object

00:21:34.440 | like it wants to catch it and eat it.

00:21:36.800 | So he already had at that stage some information

00:21:40.740 | about segregation in the brain

00:21:42.820 | of different forms of aggression.

00:21:44.780 | So fast forward to 2008, 2009,

00:21:48.260 | when Dayu came to the lab,

00:21:54.780 | and we had started working on aggression in fruit flies,

00:21:58.180 | and I wanted to bring it into mice

00:22:00.860 | so that we could apply genetic tools.

00:22:03.260 | And we started by having Dayu, who was an electrophysiologist,

00:22:08.180 | just repeat the electrical stimulation

00:22:11.780 | of the ventromedial hypothalamus in the mouse,

00:22:15.240 | just like people had done in rats, in cats, in hamsters,

00:22:19.340 | even in monkeys, and she could not get that experiment

00:22:22.760 | to work over 40 different trials.

00:22:26.420 | It just didn't work.

00:22:27.540 | What she got instead was fear behaviors.

00:22:31.120 | She got freezing, cornering, and crouching.

00:22:35.800 | And finally, in desperation,

00:22:39.100 | and we got a lot of input from Meno Crook on this,

00:22:41.800 | he really was mystified, why doesn't it work in mice?

00:22:44.840 | We realized why there had been no paper

00:22:47.720 | on brain-stimulated aggression in mice in 50 years,

00:22:52.480 | 'cause the experiment doesn't work.

00:22:54.900 | And the one bit of credit I can claim there

00:22:59.200 | is I convinced Dayu to try optogenetics,

00:23:03.300 | because it just had sort of come into use

00:23:08.300 | deep in the brain from Carl Deiss-Roth and others' work.

00:23:12.120 | And I thought maybe because it could be directed

00:23:16.180 | more specifically to a region of the brain

00:23:19.400 | and types of cells and optogenetic stimulation,

00:23:22.580 | then electrical stimulation, it might work.

00:23:25.540 | And Dayu said, "Never, never gonna work.

00:23:27.780 | "If it doesn't work with electricity,

00:23:29.520 | "why should it work with optogenetics?"

00:23:32.700 | And the fact is that it did work,

00:23:35.480 | and we were able to trigger aggression in this region

00:23:40.140 | using optogenetic stimulation of ventromedial hypothalamus.

00:23:44.040 | And in retrospect, I think the reason

00:23:46.620 | that we were seeing all these fear behaviors

00:23:50.320 | is because right at the upper part,

00:23:53.780 | if you think of ventromedial hypothalamus like a pear

00:23:57.860 | sitting on the ground, the fat part of the pear

00:24:01.220 | near the ground is where the aggression neurons are,

00:24:03.880 | but the upper part of the pear has fear neurons.

00:24:07.520 | And it could be because it's so small in a mouse,

00:24:11.120 | when you inject electrical current anywhere in the pear,

00:24:15.160 | it flows up through the entire pear

00:24:17.680 | and it activates the fear circuits,

00:24:19.780 | and those totally dominate aggression.

00:24:22.800 | And so that's why we were never able to see

00:24:25.540 | any fighting with electrical stimulation,

00:24:28.020 | whereas when you use optogenetics,

00:24:29.740 | you confine the stimulation just to the region

00:24:34.100 | where you've implanted the channelrhodopsin gene

00:24:38.500 | into those neurons.

00:24:39.960 | And so fast forward from that, from a lot of work

00:24:44.640 | from Dayu now on her own at NYU,

00:24:47.820 | and with her postdoc, Anna-Gret Faulkner,

00:24:51.020 | there's, as well as work of other people,

00:24:53.560 | there's evidence that the type of fighting

00:24:57.380 | that we elicit when we stimulate VMH

00:25:01.820 | is offensive aggression that is actually rewarding

00:25:06.820 | to male mice. They like it.

00:25:08.380 | They like it.

00:25:09.320 | Male mice will press, learn to poke their nose

00:25:13.240 | or press a bar to get the opportunity

00:25:16.380 | to beat up a subordinate male mouse.

00:25:20.020 | And in more recent experiments,

00:25:22.260 | if you activate those neurons and the mouse has a chance

00:25:25.940 | to be in one of two compartments in a box,

00:25:29.100 | they will gravitate towards the compartment

00:25:31.260 | where those neurons are activated.

00:25:33.460 | It has a positive valence.

00:25:35.980 | And when I went into this field and I was thinking,

00:25:38.460 | well, what goes on in my brain and my body when I'm furious?

00:25:43.460 | It certainly doesn't feel like a rewarding experience.

00:25:47.500 | It's not something that I would want to repeat

00:25:50.180 | because it feels good when I'm in that state.

00:25:52.640 | It doesn't feel good at all when I'm in that state.

00:25:55.580 | And it is still, I think, a mystery

00:25:59.300 | as to where that type of aggression,

00:26:01.300 | which is more defensive aggression,

00:26:03.840 | the kind of aggression you feel if you're being attacked

00:26:07.100 | or if you've been cheated by somebody,

00:26:10.020 | where that is encoded in the brain and how that works still,

00:26:14.780 | I think is a very important mystery that we haven't solved.

00:26:18.980 | And predatory aggression there has been some progress on.

00:26:22.260 | So mice show predatory aggression.

00:26:24.540 | They use that to catch crickets that they eat,

00:26:27.260 | and that involves different circuits

00:26:29.780 | than the ventromedial hypothalamic circuits.

00:26:32.780 | So it's become clear that if you want to call it

00:26:36.700 | the state of aggressiveness is multifaceted.

00:26:41.700 | It depends on the type of aggression

00:26:44.580 | and it involves different sorts of circuits.

00:26:47.820 | There's a paper suggesting that there might be

00:26:52.140 | a final common pathway for all aggression in a region,

00:26:57.140 | which is one of my favorites.

00:26:59.220 | It's called the substantia in naminata,

00:27:01.800 | the substance with no name.

00:27:03.940 | I like-

00:27:04.780 | The anatomists are so creative.

00:27:06.340 | Or the nucleus ambiguous, or the zona inserta.

00:27:10.260 | These are places that no one can think of what they are.

00:27:13.140 | Anyhow, that might be a final common pathway

00:27:16.080 | for predatory aggression and offensive

00:27:18.820 | and defensive aggression.

00:27:20.460 | But it can be really hard to tell

00:27:22.620 | just from looking at a mouse fight,

00:27:25.500 | whether it's engaged in offensive or defensive aggression.

00:27:29.660 | We've tried to take that apart

00:27:31.480 | using machine learning analysis of behavior.

00:27:34.620 | But in rats, for example, it's much clearer

00:27:37.940 | when the animal is engaged in offensive

00:27:40.100 | versus defensive aggression.

00:27:41.860 | They direct their bites at different parts

00:27:44.660 | of the opponent's body.

00:27:46.080 | In particular-

00:27:46.920 | Neck versus offensive aggression is flank directed.

00:27:51.240 | Defensive aggression goes for the neck,

00:27:53.880 | goes for the throat.

00:27:55.200 | I've seen some nature specials

00:27:56.500 | where in a very barbaric way, at least to me,

00:27:59.860 | it seems like hyenas will try and go after

00:28:02.700 | the reproductive axis.

00:28:05.180 | They'll go after testicles and penis.

00:28:07.420 | And they basically want to,

00:28:08.860 | it seems they want to limit future breeding potential.

00:28:12.540 | - Or create pain.

00:28:13.740 | - Or create pain or both.

00:28:15.720 | Yeah, I mean, in terms of offensive aggression

00:28:18.820 | and your reflection that it doesn't feel good.

00:28:23.220 | I mean, I can say,

00:28:24.500 | I know some people who really enjoy fighting.

00:28:27.080 | I have a relative who is a lawyer.

00:28:29.460 | He loves to argue and fight.

00:28:32.160 | I don't think of him as physically aggressive.

00:28:34.740 | In fact, he's not,

00:28:35.580 | but loves to fight and loves to prosecute

00:28:38.580 | and go after people and he's pretty effective at it.

00:28:41.380 | I have a friend, former military special operations

00:28:44.500 | and very calm guy,

00:28:46.260 | had a great career in military special operations.

00:28:49.780 | And he'll quite plainly say, I love to fight.

00:28:52.700 | It's one of my great joys.

00:28:54.380 | He really enjoyed his work.

00:28:55.860 | And also respected the other side

00:28:58.840 | because they offered the opportunity to test that

00:29:01.820 | and to experience that joy.

00:29:03.060 | So in a kind of bizarre way to somebody like me

00:29:04.980 | who I'll certainly defend my stance if I need to,

00:29:08.780 | but I certainly don't consider myself

00:29:10.860 | somebody who offensively goes after people

00:29:12.980 | just to go after them.

00:29:13.820 | There's no quote unquote dopamine hit here,

00:29:17.260 | acknowledging that dopamine does many things, of course.

00:29:19.900 | I have a couple of questions

00:29:21.340 | about the way you describe the circuitry.

00:29:24.060 | I should say the way the circuitry is arranged.

00:29:26.900 | And of course we don't know

00:29:28.060 | because we weren't consulted at the design phase,

00:29:31.620 | but why do you think there would be such a close positioning

00:29:35.940 | of neurons that can elicit

00:29:38.260 | such divergent states and behaviors?

00:29:41.280 | I mean, you're talking about this pear shaped structure

00:29:43.580 | where the neurons that generate fear are cheek to jowl

00:29:47.260 | with the neurons that generate offensive aggression

00:29:50.480 | of all things.

00:29:51.680 | It's like putting the neurons that control swallowing

00:29:55.940 | next to the neurons that control vomiting.

00:29:58.000 | It just seems to me that on the one hand,

00:30:00.860 | this is the way that neural circuits are often arranged.

00:30:03.060 | And yet to me, it's always been perplexing

00:30:04.620 | as to why this would be the case.

00:30:06.300 | Yeah, I think that is a very profound question.

00:30:10.200 | And I've wondered about that a lot.

00:30:14.180 | If you think from an evolutionary perspective,

00:30:19.120 | it might have been the case that defensive behaviors

00:30:25.060 | and fear arose before offensive aggression.

00:30:30.740 | Because animals first and foremost

00:30:33.840 | have to defend themselves from predation by other animals.

00:30:38.200 | And maybe it's only when they're comfortable

00:30:41.280 | with having warded off predation and made themselves safe

00:30:45.300 | that they can start to think about

00:30:47.920 | who's gonna be the alpha male in my group here.

00:30:51.900 | And so it could be that if you think that brain regions

00:30:56.420 | and cell populations evolved by duplication

00:31:00.260 | and modification of preexisting cell populations,

00:31:05.260 | that might be the way that those regions

00:31:08.700 | wound up next to each other.

00:31:10.760 | And developmentally, they start out

00:31:14.340 | from a common pool of precursors

00:31:16.780 | that expresses the same gene,

00:31:18.580 | the fear neurons and the aggression neurons.

00:31:21.300 | And then with development,

00:31:22.580 | it gets shut off in the aggression neurons

00:31:25.100 | and maintained in the fear neurons.

00:31:27.660 | Now that view says, oh, it's just an,

00:31:29.980 | it's an accident of evolution and development,

00:31:32.700 | but I think there must be a functional part as well.

00:31:36.180 | So one thing we know about offensive aggression

00:31:38.900 | is that strong fear shuts it down.

00:31:42.540 | Whereas defensive aggression, at least in rats,

00:31:46.180 | is actually enhanced by fear.

00:31:48.780 | It's one of the big differences

00:31:50.500 | between defensive aggression and offensive aggression.

00:31:54.300 | And you think about it, if you think about it,

00:31:55.960 | if offensive aggression is rewarding and pleasurable,

00:31:59.300 | if you start to get really scared,

00:32:01.660 | that tends to take the fun out of it.

00:32:03.780 | And maybe these two regions are close to each other

00:32:07.140 | to facilitate inhibition of aggression by the fear neurons.

00:32:12.140 | We know for a fact that if we deliberately stimulate

00:32:16.600 | those fear neurons at the top of the pair,

00:32:19.420 | when two animals are involved in a fight,

00:32:21.540 | it just stops the fight dead in its tracks

00:32:24.320 | and they go off into the corner and freeze.

00:32:27.040 | So at least hierarchically, it seems like fear

00:32:30.860 | is the dominant behavior over offensive aggression.

00:32:34.380 | And how that inhibition would work is not clear

00:32:37.380 | 'cause all these neurons are pretty much excitatory.

00:32:39.980 | They're almost all glutamatergic.

00:32:42.060 | And so one of the interesting questions for the future

00:32:45.780 | is how exactly does fear dominate over

00:32:49.300 | and shut down offensive aggression in the brain?

00:32:52.700 | How does that work?

00:32:53.700 | Is it all circuitry?

00:32:54.780 | Are there chemicals involved?

00:32:56.540 | What's the mechanism and when is it called into play?

00:33:00.340 | But I think that's the way I tend to think about

00:33:03.260 | why these neurons are all mixed up together.

00:33:06.420 | And it's not just fight and freezing or fight and flight.

00:33:10.520 | There are also metabolic neurons

00:33:13.100 | that are mixed together in VMH as well.

00:33:16.060 | Controlling body-wide metabolism?

00:33:18.380 | Yeah, there are neurons there that respond to glucose.

00:33:21.780 | When glucose goes up in your bloodstream, they're activated.

00:33:25.820 | And VMH has a whole history in the field of obesity

00:33:30.200 | because if you destroy it in a rat, you get a fat rat.

00:33:35.200 | So the way most of the world thinks about VMH

00:33:38.260 | is they think about, oh, that's the thing

00:33:40.300 | that keeps you from getting fat.

00:33:42.140 | It's the anti-obesity area.

00:33:44.200 | But in the area of social behavior,

00:33:47.220 | we see it as a center for control

00:33:49.620 | of aggression and fear behaviors.

00:33:51.860 | And again, why these neurons and these functions,

00:33:56.420 | I like to call them the four Fs,

00:33:58.420 | feeding, freezing, fighting, and mating,

00:34:00.820 | that they all seem to be closely intermingled

00:34:03.340 | with each other, maybe because crosstalk between them

00:34:06.500 | is very important to help the animal's brain

00:34:09.580 | decide what behavior to prioritize

00:34:12.860 | and what behavior to shut down at any given moment.

00:34:17.180 | One of the things that we will do is link

00:34:19.020 | to the incredible videos of these mice

00:34:22.360 | that have selective stimulation of neurons in the VMH,

00:34:26.460 | DAUs and the other studies that you've done.

00:34:28.700 | Whenever I teach, I show those videos at some point

00:34:32.700 | with the caveats and warnings that are required

00:34:36.580 | when one is about to see a video of a mouse

00:34:40.840 | trying to mate with another mouse

00:34:42.060 | or mating with another mouse,

00:34:43.420 | and they seem both to be quite happy

00:34:45.160 | about the mating experience,

00:34:46.540 | at least as far as we know, as observers of mice.

00:34:49.080 | And then upon stimulation of those VMH neurons,

00:34:55.180 | one of the mice essentially tries to kill the other mouse.

00:34:58.900 | And then when that stimulation is stopped,

00:35:02.780 | they basically go back to hanging out.

00:35:04.660 | They don't go right back to mating.

00:35:06.180 | There's some reconciliation, clearly,

00:35:07.580 | that needs to happen first, we assume.

00:35:09.840 | But it's just so striking.

00:35:11.140 | I think equally striking is the video

00:35:12.700 | where the mouse is alone in there

00:35:14.740 | with the glove, the VMH neurons are stimulated,

00:35:18.320 | and the mouse goes into a rage.

00:35:20.140 | It looks like it wants to kill the glove, basically.

00:35:22.980 | So striking.

00:35:23.820 | I encourage people to go watch those

00:35:25.520 | because it really puts a tremendous amount of color

00:35:29.700 | on what we're describing.

00:35:30.840 | And it's just the idea that there are switches in the brain,

00:35:34.920 | to me, really became clear upon seeing that.

00:35:37.420 | One of the concepts, excuse me,

00:35:39.400 | one of the concepts that you've raised

00:35:42.060 | in your lectures before,

00:35:43.140 | and that I think was Hess's idea,

00:35:45.340 | is this idea of a sort of hydraulic pressure,

00:35:47.580 | or maybe it was Conrad, I can't speak now, excuse me,

00:35:51.220 | Conrad Lorenz, who talked about

00:35:54.420 | a kind of hydraulic pressure towards behavior.

00:35:57.260 | I'm fascinated by this idea of hydraulic pressure

00:36:00.100 | because I don't consider myself a hot-tempered person,

00:36:03.220 | but I am familiar with the fact that when I lose my temper,

00:36:06.420 | it takes quite a while for me to simmer down.

00:36:09.740 | I can't think about anything else.

00:36:11.260 | I don't want to think about anything else.

00:36:12.680 | In fact, trying to think about anything else

00:36:15.400 | becomes aversive to me,

00:36:17.420 | which to me underscores this notion of prioritization

00:36:21.940 | of the different states and potentially conflicting states.

00:36:25.400 | What do you think funnels into this idea

00:36:28.620 | of hydraulic pressure toward a state?

00:36:31.060 | And why is it perhaps that sometimes we can be very angry

00:36:36.060 | and if we succeed in winning an argument,

00:36:39.800 | all of a sudden it will subside?

00:36:41.960 | Because clearly that means

00:36:42.860 | that there are external influences.

00:36:44.360 | It's a complex space here that we're creating.

00:36:46.180 | I realize I'm creating a bit of a cloud

00:36:47.700 | and I'm doing it on purpose because to me,

00:36:49.880 | the idea of a hydraulic pressure towards a state,

00:36:51.820 | like sleep, there's a sleep pressure.

00:36:54.140 | There's a pressure towards a, that all makes sense.

00:36:56.460 | But what's involved?

00:36:58.060 | Is it too multifactorial

00:36:59.740 | to actually separate out the variables?

00:37:02.660 | But what's really driving hydraulic pressure

00:37:06.540 | toward a given state?

00:37:08.060 | Yeah, so really important question.

00:37:11.980 | I think one way that is helpful,

00:37:14.440 | at least for me to break this question apart

00:37:17.280 | and think about it,

00:37:18.400 | is to distinguish homeostatic behaviors

00:37:22.960 | that is need-based behaviors,

00:37:25.240 | where the pressure is built up because of a need,

00:37:29.420 | like I'm hungry, I need to eat, I'm thirsty,

00:37:33.360 | I need to drink, I'm hot, I need to get to a cold place.

00:37:38.140 | It's basically the thermostat model of your brain.

00:37:41.680 | You have a set point

00:37:42.960 | and then if the temperature gets too hot,

00:37:44.800 | you turn on the AC and if the temperature gets too cold,

00:37:47.960 | you turn on the heater

00:37:48.920 | and you put yourself back to the set point.

00:37:51.120 | I don't think that's how aggression works.

00:37:53.760 | That is, it's not that we all go around,

00:37:56.780 | at least subjectively.

00:37:57.920 | I don't go around with an accumulating need to fight,

00:38:02.680 | which I then look for something, an excuse to release it.

00:38:07.200 | Now, maybe there are people that do that

00:38:09.000 | and they go out and look for bar fights to get into.

00:38:12.440 | Or Twitter.

00:38:13.280 | Yeah, or Twitter.

00:38:14.200 | Twitter seems to do, I'm sort of half joking

00:38:16.360 | because Twitter seems to draw a reasonably sized crowd

00:38:20.440 | of people that are there for combat of some sort.

00:38:24.440 | Even though the total intellectual power

00:38:26.440 | of any of their comments is about that of a cap gun,

00:38:28.920 | they seem to really like to fire off that cap gun.

00:38:31.480 | But I agree.

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00:39:36.660 | for all sorts of things like hormone health

00:39:38.740 | and metabolic health and K2 for cardiovascular health

00:39:41.140 | and calcium regulation.

00:39:42.340 | Again, you can go to athleticgreens.com/huberman

00:39:45.540 | to claim that special offer.

00:39:46.860 | - So you can think of this accumulated hydraulic pressure

00:39:51.860 | either being based on something that you were deprived of

00:39:55.540 | creating an accumulating need

00:39:57.980 | or something that you want to do,

00:40:00.580 | building up a drive or a pressure to do that.

00:40:04.940 | And the natural way to think about that, at least for me,

00:40:09.020 | is as gradual increases in neural activity

00:40:13.560 | in a particular region of the brain.

00:40:15.980 | And so for example,

00:40:17.540 | in the area of the hypothalamus that controls feeding,

00:40:21.440 | Scott Sternson and others have shown

00:40:23.900 | that the hungrier you get,

00:40:26.260 | the higher the level of activity in that region in the brain.

00:40:30.260 | And then when you eat, boom,

00:40:31.960 | the activity goes right back down again.

00:40:34.620 | And that state is actually negatively valence.

00:40:38.660 | So it's like the animal quote unquote,

00:40:41.860 | feels increasingly uncomfortable,

00:40:44.580 | just like we feel increasingly uncomfortable

00:40:47.180 | the hungrier we are.

00:40:48.620 | And then when we eat, it taps it down.

00:40:51.000 | But there is this increased activity.

00:40:53.340 | And I think in the case of aggression,

00:40:55.500 | our data and others show that the more strongly

00:40:59.140 | you drive this region of the brain optogenetically,

00:41:03.680 | the more of just a hair trigger you need

00:41:07.280 | to set the animal off to get it to fight.

00:41:10.300 | Now, the interesting thing is that

00:41:12.600 | if there is nothing for the animal to attack,

00:41:15.820 | it doesn't really do much

00:41:17.580 | when you're stimulating this region.

00:41:19.700 | It sort of wanders around the cage a little bit more,

00:41:23.180 | but it will not actually show overt attack

00:41:27.740 | unless you put something in front of it.

00:41:29.660 | And the same thing is true for the areas we've described

00:41:32.340 | that control mating behavior.

00:41:34.500 | This is what Lindsay is working on.

00:41:36.420 | You can stimulate those areas till you're blue in the face

00:41:40.040 | and the mouse just sort of wanders around.

00:41:42.220 | But if you put another mouse in, wham,

00:41:45.060 | he will try to mount that mouse.

00:41:46.820 | If you put a kumquat in the cage,

00:41:49.060 | he'll try to mount the kumquat.

00:41:51.240 | And so it becomes a sort of any port in the storm.

00:41:54.880 | So there is this idea that the drive is building up pressure

00:41:59.880 | that somehow needs to be released

00:42:03.600 | where that pressure is actually being exerted.

00:42:07.700 | If you accept that it's increased activity

00:42:10.320 | in some circuit or circuits someplace,

00:42:12.960 | what is it pushing up against that needs something else

00:42:18.800 | to sort of unplug it in the Lorentz hydraulic model?

00:42:22.900 | That is, you don't see the behavior

00:42:25.100 | until you release a valve on this bucket

00:42:27.940 | and let the accumulated pressure flow out.

00:42:31.460 | And that's one of the things we're trying to study

00:42:33.980 | in the context of the mating behavior as well.

00:42:37.440 | How does the information that there's an object

00:42:40.620 | in front of you come together with this drive state

00:42:44.060 | that is generated by stimulating these neurons

00:42:47.020 | in the hypothalamus to say, okay, pull the trigger and go,

00:42:50.880 | it's time to mate, it's time to attack.

00:42:53.540 | And we're just starting to get some insights into that now.

00:42:56.840 | - Fascinating, and I should mention to people,

00:42:59.700 | Dr. Anderson mentioned Lindsay.

00:43:01.020 | Lindsay is a former graduate student of mine

00:43:02.640 | that's now a postdoc in David's lab.

00:43:04.480 | And I haven't caught up with her recently

00:43:06.360 | to hear about these experiments, but they sound fascinating.

00:43:09.080 | I would love to spend some time on this issue

00:43:11.660 | of why is it that a mouse won't attack nothing,

00:43:15.980 | but it'll attack even a glove

00:43:18.020 | and why it will only try and mate

00:43:22.060 | if there's another mouse to mate with.

00:43:24.580 | It's actually, I think fortunately for you,

00:43:28.340 | you're not spending a lot of time

00:43:29.460 | on Twitter and Instagram or YouTube,

00:43:32.460 | but there's this whole online community that exists now.

00:43:35.460 | As far as I know, it's almost exclusively young males

00:43:39.900 | who are obsessed with this idea.

00:43:42.860 | I'll just say it, it has a name.

00:43:44.000 | It's called NoFap of no masturbation

00:43:46.440 | as a way to maintain their motivation to go out

00:43:48.520 | and actually seek mates

00:43:49.760 | because of the ready availability of online pornography.

00:43:54.180 | There's probably a much larger population of young males

00:43:57.340 | that are never actually going out and seeking mates

00:43:59.200 | because they're getting porn addicted, et cetera.

00:44:01.740 | There's actually a serious issue that came up in our episode

00:44:04.620 | with Ana Lemke who wrote the book "Dopamine Nation"

00:44:07.400 | because the availability of pornography,

00:44:09.420 | there's a whole social context that's being created

00:44:12.380 | around this and genuine addiction.

00:44:14.760 | So humans are not like the mice

00:44:17.020 | or mice are not like the humans.

00:44:18.520 | Humans seem to resolve the issue on their own

00:44:21.400 | in ways that might actually impede seeking

00:44:23.920 | and finding of sexual partners and or long-term mates.

00:44:26.800 | So serious issue there.

00:44:28.500 | I raise it as a serious issue that I hear a lot about

00:44:30.980 | 'cause I get asked hundreds,

00:44:32.380 | if not thousands of questions about this.

00:44:33.880 | Is there any physiological basis for what they call NoFap?

00:44:36.900 | And I never actually replied 'cause there's no data,

00:44:39.800 | but what you're raising here is a very interesting

00:44:43.080 | mechanistic scenario that can,

00:44:47.640 | as you mentioned, is being explored.

00:44:49.540 | So what do we know about the internal state of a mouse

00:44:54.540 | whose VMH is being stimulated

00:44:57.040 | or a mouse whose other brain region

00:45:00.680 | that can stimulate the desire to mate?

00:45:03.360 | What do we know about the internal state of that mouse

00:45:05.660 | if it's just alone in the cage wandering around?

00:45:07.540 | Is it wandering around really wanting to mate

00:45:09.580 | and really wanting to fight?

00:45:10.700 | We of course don't know, but is its heart rate up?

00:45:15.420 | Is its blood pressure up?

00:45:17.300 | Is it wishing that there was pornography?

00:45:19.940 | Is it something's going on, presumably,

00:45:24.020 | that's different than prior to that stimulation?

00:45:29.020 | And is it arousal?

00:45:31.280 | And what do you think it is about the visual

00:45:33.780 | or olfactory perception of a conspecific

00:45:37.000 | that ungates this tremendous repertoire of behaviors?

00:45:40.400 | Right, that is the central question.

00:45:43.860 | I can say, at least with respect to the fear neurons

00:45:47.760 | that sit on top of the aggression neurons,

00:45:49.760 | we know that when those neurons are activated optogenetically

00:45:54.400 | in the same way we would activate the aggression neurons,

00:45:57.700 | that there's clearly an arousal process that's occurring.

00:46:01.320 | You can see the pupils dilate in the animal.

00:46:04.360 | There is an increase in stress hormone release

00:46:07.700 | into the bloodstream.

00:46:09.140 | We've shown that.

00:46:10.780 | Heart rate goes up.

00:46:12.560 | So in addition to the drive to actually freeze,

00:46:17.340 | which is what those animals do,

00:46:19.700 | there is autonomic arousal and neuroendocrine activation

00:46:24.700 | of stress responses.

00:46:26.220 | And some of that is probably shared

00:46:29.060 | by the aggression neurons and the mating neurons,

00:46:32.220 | although we haven't investigated it in as much detail.

00:46:35.460 | But I wouldn't be surprised because they project

00:46:38.780 | to many of the same regions

00:46:40.960 | that the fear neurons project to,

00:46:44.380 | which is a interesting issue in the context

00:46:47.640 | to discuss later maybe in the context

00:46:49.640 | of why we're comfortable with mental illnesses

00:46:52.660 | that are based on maladaptations of fear,

00:46:55.020 | but not mental illnesses that are based

00:46:57.300 | on maladaptations of aggression

00:46:59.800 | if they have pretty similar circuits in the brain.

00:47:02.540 | But that's how I would imagine

00:47:05.660 | there is an arousal dimension, as you say.

00:47:08.860 | There are stress hormones that are activated.

00:47:10.940 | These regions, VMH projects to about 30 different regions

00:47:15.600 | in the brain, and it gets input

00:47:18.400 | from about 30 different regions.

00:47:20.100 | So I kind of see it as both an antenna

00:47:23.460 | and a broadcasting center.

00:47:25.200 | It's like a satellite dish that takes in information

00:47:28.800 | from different sensory modalities, smell,

00:47:32.260 | maybe vision, mechanosensation,

00:47:36.080 | and then it sort of synthesizes and integrates that

00:47:39.920 | into a fairly low dimensional,

00:47:43.020 | as the computational people call it,

00:47:45.660 | representation of this pressure to attack,

00:47:48.860 | and it broadcasts that all over the brain

00:47:51.820 | to trigger all these systems

00:47:53.740 | that have to be brought into play

00:47:55.820 | if the animal is gonna engage in aggression,

00:47:58.540 | because aggression is a very risky thing

00:48:01.400 | for an animal to engage in.

00:48:03.080 | It could wind up losing and it could wind up getting killed.

00:48:06.800 | And so its brain constantly has to make

00:48:10.340 | a cost benefit analysis of whether to continue on that path

00:48:14.480 | or to back off as well.

00:48:16.440 | And I think that part of this broadcasting function

00:48:19.620 | of this region is engaging all these other brain domains

00:48:24.620 | that play a role in this kind of cost benefit analysis.

00:48:29.320 | I wanna talk more about mating behavior,

00:48:31.380 | but as a segue to that,

00:48:33.660 | as we're talking about aggression and mating behavior,

00:48:37.060 | I think hormones.

00:48:38.440 | And whenever there's an opportunity on this podcast

00:48:41.020 | to shatter a common myth, I grab it.

00:48:44.700 | One of the common myths that's out there,

00:48:46.880 | and I think that persists,

00:48:48.220 | is that testosterone makes animals and humans aggressive,

00:48:52.780 | and estrogen makes animals placid and kind or emotional.

00:48:56.820 | And as we both know,

00:48:58.240 | nothing could be further from the truth,

00:48:59.980 | although there's some truth to the idea

00:49:01.300 | that these hormones are all involved.

00:49:03.880 | Robert Sapolsky supplied some information to me

00:49:08.340 | when he came on this podcast

00:49:09.780 | that if you give people exogenous testosterone,

00:49:12.620 | it tends to make them more of the way they were before.

00:49:15.540 | If they were a jerk before, they'll become more of a jerk.

00:49:17.640 | If they were very altruistic, they'll become more altruistic.

00:49:20.100 | And then eventually I pointed out,

00:49:21.660 | you'll rheumatize that testosterone into estrogen

00:49:23.820 | and you'll start getting opposite effects.

00:49:25.100 | So it's a murky space, it's not straightforward.

00:49:28.020 | But if I'm not mistaken,

00:49:30.780 | testosterone plays a role in generating aggression.

00:49:33.500 | However, the specific hormones that are involved

00:49:38.220 | in generating aggression via VMH

00:49:40.780 | are things other than testosterone.

00:49:44.300 | Can you tell us a little bit more about that?

00:49:45.620 | 'Cause there's some interesting surprises in there.

00:49:47.740 | Yeah, that's a really important question.

00:49:50.220 | So when we finally identified the neurons in VMH

00:49:55.220 | that control aggression with a molecular marker,

00:49:58.840 | we found out that that marker was the estrogen receptor.

00:50:02.660 | So that might strike you as a little strange.

00:50:05.100 | Why should aggression promoting neurons in male mice

00:50:10.100 | be labeled with the estrogen receptor?

00:50:13.540 | Other labs have shown that the estrogen receptor

00:50:17.340 | in adult male mice is necessary for aggression.

00:50:20.980 | If you knock out the gene in VMH, they don't fight.

00:50:24.940 | And it's been shown, and a lot of this is work

00:50:27.380 | from your colleague Nirav Shah at Stanford,

00:50:29.900 | who is one of my former PhD students,

00:50:32.740 | that if you castrate a mouse

00:50:36.220 | and it loses the ability to fight,

00:50:39.220 | not only can you rescue fighting with a testosterone implant

00:50:43.960 | but you can rescue it with an estrogen implant.

00:50:46.780 | So you can bypass completely the requirement

00:50:50.040 | for testosterone to restore aggressiveness to the mice.

00:50:54.020 | And as you say, it's because many of the effects

00:50:57.420 | of testosterone, although not all,

00:51:00.160 | many of them are mediated by its conversion to estrogen

00:51:04.620 | by a process called aromatization.

00:51:07.420 | It's carried out by an enzyme called aromatase.

00:51:10.980 | In fact, people may have, most of your listeners

00:51:13.580 | may have heard of aromatase 'cause aromatase inhibitors

00:51:17.600 | are widely used in female humans

00:51:20.560 | as adjuvant chemotherapy for breast cancer.

00:51:23.600 | They are a way of reducing the production of estrogen

00:51:28.600 | by preventing testosterone

00:51:31.000 | from being converted into estrogen.

00:51:33.220 | And in fact, there are a lot of animal experiments

00:51:35.380 | showing if you give males aromatase inhibitors,

00:51:38.920 | they stop fighting,

00:51:40.260 | as well as also stop being sexually active.

00:51:44.880 | And so that's one of the counterintuitive ideas.

00:51:48.460 | And Nirao has shown that progesterone

00:51:51.500 | also seems to play a role in aggression

00:51:54.160 | because these aggression neurons

00:51:55.720 | also express the progesterone receptor.

00:51:58.660 | So here are two hormones that are classically thought of

00:52:02.180 | as female reproductive hormones.

00:52:04.700 | This is what goes up and goes down during the estrus cycle,

00:52:08.140 | estrogen and progesterone.

00:52:10.080 | And yet they're playing a very important role

00:52:13.340 | in controlling aggression in male mice

00:52:17.200 | and presumably in male humans as well.

00:52:20.000 | Fascinating.

00:52:21.280 | So estrogen is doing many more things

00:52:24.760 | than I think most people believe.

00:52:26.420 | And testosterone is doing maybe different

00:52:29.500 | and fewer things in some cases and more in others.

00:52:32.140 | I've known some aggressive females

00:52:35.940 | over the time I've been alive.

00:52:38.480 | What's involved in female aggression

00:52:40.260 | that's unique from the pathways

00:52:42.440 | that generate male aggression?

00:52:43.900 | Great, great question.

00:52:45.700 | So we and other labs have studied this

00:52:49.160 | in both mice and also in fruit flies.

00:52:52.500 | So one thing in mice that distinguishes

00:52:56.360 | aggression in females from males

00:52:58.140 | is that male mice are pretty much ready to fight

00:53:00.620 | at the drop of a hat.

00:53:02.240 | Female mice only fight when they are nurturing

00:53:08.020 | and nursing their pups after they've delivered a litter.

00:53:11.800 | And there's a window there

00:53:13.660 | where they become hyper aggressive.

00:53:16.580 | And then after their pups are weaned,

00:53:19.160 | that aggressiveness goes away.

00:53:20.700 | So this is pretty remarkable

00:53:23.180 | that you take a virgin female mouse

00:53:25.980 | and expose it to a male.

00:53:27.600 | And her response is to become sexually receptive

00:53:30.640 | and to mate with him.

00:53:32.020 | And now you let her have her pups

00:53:34.540 | and you put the same male or another male mouse

00:53:37.500 | in the cage with her.

00:53:38.540 | And instead of trying to mate with him, she attacks him.

00:53:41.620 | So there is some presumably hormonal

00:53:44.900 | and also neuronal switch that's occurring

00:53:48.100 | in the brain that switches the response

00:53:50.940 | of the female from sex to aggression

00:53:55.060 | when she goes from virginity to maternity.

00:53:57.640 | And we recently showed in a paper,

00:53:59.740 | this is work from one of my students, Mung Yew Liu,

00:54:03.140 | that within VMH in females,

00:54:05.580 | there are two clearly divisible subsets

00:54:09.940 | of estrogen receptor neurons.

00:54:12.660 | And she showed that one of those subsets controls fighting

00:54:17.100 | and the other one controls mating.

00:54:19.400 | And in fact, if you stimulate the fighting specific subset

00:54:23.660 | in a virgin, you can get the virgin to attack,

00:54:27.160 | which is something that we were never able to do before.

00:54:31.260 | And if you stimulate the mating one, you enhance mating.

00:54:34.580 | The reason we could never get these results

00:54:37.060 | when we stimulated the whole population

00:54:39.940 | of estrogen receptor neurons is that these effects

00:54:42.560 | are opposite and they cancel out.

00:54:45.300 | And so it turns out that if you measure the activity

00:54:49.100 | of the fighting and the mating neurons going from a virgin

00:54:53.020 | to a maternal female, the aggression neurons are very low

00:54:58.020 | in their activity in the virgin.

00:55:01.180 | But once the female has pups,

00:55:04.140 | the activation ability of those neurons goes way up

00:55:08.820 | and the mating neurons stay the same.

00:55:11.060 | So if you think of the balance between them like a seesaw

00:55:14.700 | in the virgin, there is more activity in the mating neurons

00:55:19.080 | than in the fighting neurons.

00:55:20.440 | Whereas in the nursing mother, there's more activity

00:55:24.340 | or more activation in the other way around,

00:55:27.660 | the fighting neurons in the mating.

00:55:28.980 | Did I say fighting and mating in the first?

00:55:31.220 | Mating neurons dominate fighting in the virgin,

00:55:33.940 | fighting neurons dominate mating in the mother.

00:55:37.500 | So that's a really cool observation

00:55:41.700 | and it's not something that happens in males

00:55:44.220 | and we don't know what causes that or controls that.

00:55:48.460 | Interestingly, this gets into the whole issue of neurons

00:55:53.460 | that are present in females, but not in males.

00:55:57.180 | So we've known for, the field has known for a long time

00:56:00.560 | that male and female fruit flies have sex specific neurons.

00:56:04.740 | And most of the neurons that we've identified

00:56:07.380 | in fruit flies that control fighting in males

00:56:10.420 | are male specific.

00:56:11.760 | They're not found in the female brain.

00:56:14.400 | But recently we discovered a set

00:56:17.220 | of female specific fighting neurons in the female brain

00:56:21.620 | together with a couple of other laboratories.

00:56:24.620 | Now they do share one common population of neurons

00:56:28.900 | in both male and female flies that in females

00:56:32.660 | activates the female specific fighting neurons

00:56:35.500 | and in males activates the male specific fighting neurons.

00:56:38.900 | So it's kind of a hierarchy with this common neuron on top.

00:56:42.720 | And in mice, we discovered that there are

00:56:46.560 | male specific neurons in VMH and those neurons

00:56:50.940 | are activated during male aggression.

00:56:54.140 | Now the neurons that are active in females

00:56:57.040 | when females fight in VMH are not sex specific.

00:57:01.020 | So they are also found in males.

00:57:03.920 | So this is already showing you some complexity.

00:57:06.420 | The male mouse VMH has both male specific aggression neurons

00:57:11.420 | and generic aggression neurons.

00:57:13.820 | And then the female VMH, the mating cells

00:57:17.080 | are only found in females.

00:57:18.740 | They are female specific and not found in the male brain.

00:57:22.340 | And so we're trying to find out

00:57:23.880 | what these sex specific populations of neurons are doing.

00:57:27.300 | But that indicates that that is some of the mechanism

00:57:30.780 | by which different sexes show different behaviors.

00:57:34.180 | I'm fixated on this transition from the virgin female mouse

00:57:38.400 | to the maternal female mouse.

00:57:39.760 | I have a couple of questions about whether or not,

00:57:42.500 | for instance, the transition is governed

00:57:45.260 | by the presence of pups.

00:57:46.460 | So for instance, if you take a virgin female,

00:57:48.080 | she'll mate with a male.

00:57:49.260 | Once she's had pups, she'll try and fight that male

00:57:53.380 | or presumably another intruder female, right?

00:57:56.280 | Equally towards females and male intruders.

00:57:59.060 | Does that require the presence of her pups?

00:58:00.980 | Meaning if you were to take those pups

00:58:02.420 | and give them to another mother,

00:58:03.980 | does she revert to the more virgin-like behavior?

00:58:06.700 | Is it related to, is it triggered by lactation

00:58:09.180 | or could it actually be triggered

00:58:10.980 | by the mating behavior itself?

00:58:12.660 | 'Cause it's possible for the virgin to become a non-virgin

00:58:16.060 | but not actually have a litter of pups.

00:58:18.260 | Right, those are all great questions

00:58:20.580 | and we don't know the answer.

00:58:22.820 | Most of them, what I can say is that a nursing mother

00:58:27.380 | doesn't have to have her pups with her in the cage

00:58:30.640 | in order to attack an intruder male or an intruder female.

00:58:35.420 | She is just in a state of brain

00:58:40.180 | that makes her aggressive to any intruder.

00:58:43.420 | And those aggression neurons in that female's brain

00:58:47.200 | are activated by both male and female intruders equally.

00:58:51.860 | Whereas in male mice, the aggression neurons

00:58:54.920 | are only ever activated by males, not by females

00:58:59.140 | because males are never supposed to attack females.

00:59:02.380 | They're only supposed to mate with them.

00:59:04.580 | So that's another difference in how those neurons

00:59:07.300 | are tuned to signals from different conspecifics.

00:59:11.580 | Does it require lactation?

00:59:13.860 | I don't know the answer to that.

00:59:15.420 | I think there are some experiments

00:59:17.300 | where people have tried to, classical experiments,

00:59:20.440 | people have tried to reproduce the changes in hormones

00:59:24.540 | that occur during pregnancy in female rats

00:59:28.040 | to see if it can make them aggressive.

00:59:30.180 | And some of those manipulations do to some extent,

00:59:33.840 | but there's a whole biology there

00:59:36.140 | that remains to be explored

00:59:38.300 | about how much of this is hormones,

00:59:40.700 | how much of this is circuitry and electricity,

00:59:43.840 | and how much of it is other factors

00:59:46.600 | that we haven't identified yet.

00:59:48.680 | I don't want to anthropomorphize,

00:59:50.060 | but well, I'll just ask the question.

00:59:52.880 | So the other day I was watching ferrets mate, right?

00:59:56.480 | Mustelids, they're mustelids and they're mating behavior.

01:00:00.620 | I guess I didn't say why I was watching this.

01:00:02.260 | Doesn't matter.

01:00:03.100 | It simply doesn't matter.

01:00:05.940 | But if one observes the mating behaviors

01:00:08.460 | of different animals,

01:00:09.580 | we know that there's a tremendous range

01:00:11.320 | of mating behaviors in humans.

01:00:13.400 | There can be no aggressive component.

01:00:15.500 | There could be aggressive component.

01:00:16.580 | Humans have all sorts of kinks and fetishes and behaviors

01:00:19.800 | and most of which probably has never been documented

01:00:21.760 | 'cause most of this happens in private.

01:00:23.700 | And here I always say on this podcast,

01:00:25.000 | anytime we're talking about sexual behavior in humans,

01:00:27.520 | we're always making the presumption

01:00:28.780 | that it's consensual, age appropriate,

01:00:31.320 | context appropriate and species appropriate.

01:00:33.420 | Let's say we're talking about a lot of different species.

01:00:35.560 | With that said, just to set context,

01:00:38.960 | I was watching this video of ferrets mating

01:00:41.920 | and it's quite violent actually.

01:00:44.540 | There's a lot of neck biting.

01:00:45.960 | There's a lot of squealing.

01:00:47.280 | If I were gonna project an anthropomorphize, I'd say,

01:00:49.960 | it's not really clear they both want to be there.

01:00:52.880 | You would just, one would make that assumption.

01:00:54.880 | And of course we don't know.

01:00:56.360 | We have no idea.

01:00:57.200 | This could be the ritual.

01:00:58.640 | It seems to me that there is some crossover

01:01:02.760 | of aggression and mating behavior circuitry

01:01:06.480 | during the act of mating.

01:01:08.560 | And do you think that reflects this sort of

01:01:13.520 | stew of competing neurons that are prioritizing

01:01:17.960 | in real time?

01:01:19.160 | Because of course, as states, they have persistence,

01:01:22.480 | as you point out, and you can imagine that

01:01:24.320 | states overlapping in four different states,

01:01:26.280 | the motivational drive to mate,

01:01:27.780 | the motivational drive to get away from this experience,

01:01:30.360 | the motivational drive to eat at some point,

01:01:34.720 | to defecate at some point,

01:01:35.920 | all of these things are competing.

01:01:37.460 | And what we're really seeing is a bias in probabilities.

01:01:41.320 | But when you look at mating behavior of various animals,

01:01:44.120 | you see an aggressive component sometimes, but not always.

01:01:47.800 | Is it species specific?

01:01:49.320 | Is it context specific?

01:01:51.320 | And more generally,

01:01:52.140 | do you think that there is crosstalk

01:01:54.940 | between these different neuronal populations

01:01:57.120 | and the animal itself might be kind of confused

01:01:58.920 | about what's going on.

01:02:00.000 | - Right. Great, great questions.

01:02:02.320 | I can't really speak to the issue

01:02:04.160 | of whether this is species specific

01:02:06.480 | 'cause I'm not a naturalist or a zoologist.

01:02:09.240 | I've seen like you have in the wild,

01:02:11.640 | for example, lions when they mate.

01:02:14.000 | I've seen them in Africa.

01:02:15.160 | There's often a biting component of that as well.

01:02:18.480 | One of the things that surprised us

01:02:20.620 | when we identified neurons in VMHVL

01:02:24.440 | that control aggression in males

01:02:27.240 | is that within that population,

01:02:29.920 | there is a subset of neurons that is activated by females

01:02:34.840 | during male-female mating encounters.

01:02:37.380 | Now, you don't generally think of mouse sex as rough sex,

01:02:42.380 | but there is a lot of what superficially

01:02:48.040 | looks like violent behavior sometimes,

01:02:50.520 | especially if the female rejects the male and runs away.

01:02:54.960 | And there's some evidence

01:02:57.420 | that those female selective neurons in VMH

01:03:02.000 | are part of the mating behavior.

01:03:06.480 | If you shut them down,

01:03:08.360 | the animals don't mate as effectively

01:03:11.240 | as they otherwise would.

01:03:13.280 | What happens when you stimulate them?

01:03:15.480 | We don't yet know because we don't have a way

01:03:17.660 | to specifically do that

01:03:19.600 | without activating the male aggression neurons.

01:03:22.840 | But I think they must be there for a reason

01:03:26.440 | because VMH is not traditionally the brain region

01:03:30.440 | to which male sexual behavior has been assigned.

01:03:34.140 | That's another area called the medial preoptic area.

01:03:38.000 | And there we have shown that there are neurons

01:03:41.100 | that definitely stimulate mating behavior.

01:03:44.120 | In fact, if we activate those mating neurons in a male

01:03:47.640 | while it's in the middle of attacking another male,

01:03:50.780 | it will stop fighting, start singing to that male,

01:03:54.400 | and start to try to mount that male

01:03:57.020 | until we shut those neurons off.

01:03:58.900 | So those are the make-love-not-war neurons,

01:04:02.280 | and VMH are the make-war-not-love neurons.

01:04:05.460 | And there are dense interconnections

01:04:08.160 | between these two nuclei,

01:04:10.520 | which are very close to each other in the brain.

01:04:13.740 | And we've shown that some of those connections

01:04:16.360 | are mutually inhibitory to prevent the animal

01:04:20.360 | from attacking a mate that it's supposed to be mating with,

01:04:24.780 | or to prevent it from mating with an animal

01:04:28.520 | it's supposed to be attacking.

01:04:30.000 | But it's also possible that there are some cooperative

01:04:33.520 | interactions between those structures,

01:04:36.260 | as well as antagonistic interactions.

01:04:39.960 | And the balance of whether it's the cooperative

01:04:42.880 | or antagonistic interactions that are firing

01:04:46.120 | at any given moment in a mating encounter, as you suggest,

01:04:50.380 | may determine whether a moment of coital bliss

01:04:57.120 | among two lions may suddenly turn into a snap or a growl

01:05:02.120 | and a bearing of fangs.

01:05:04.480 | We don't know that, but certainly the substrate,

01:05:07.840 | the wiring is there for that to happen.

01:05:10.980 | - I'm sure people's minds are running wild with all this.

01:05:14.100 | I'll just use this as an opportunity to raise something

01:05:16.800 | I've wondered about for far too long,

01:05:19.880 | which is I have a friend who's a psychiatrist

01:05:23.240 | who works on the treatment of fetishes.

01:05:25.600 | This is not a psychiatrist that I was treated by.

01:05:27.720 | I'll just point that out.

01:05:29.280 | But they mentioned something very interesting to me

01:05:32.160 | long ago, which is that when you look at true fetishes

01:05:36.200 | and what meets the criteria for fetish,

01:05:38.220 | that there does seem to be some,

01:05:40.840 | what one would think would be competing circuitry

01:05:43.800 | that suddenly becomes aligned.

01:05:46.980 | For instance, avoidance of feces, dead bodies, feet,

01:05:51.980 | things that are very infectious,

01:05:55.160 | typically those states of disgust are antagonistic

01:05:58.880 | to states of desire as one would hope is present

01:06:03.880 | during sexual behavior.

01:06:05.760 | Fetishes often involve exactly those things

01:06:09.680 | that are aversive, feet, dead bodies, disgusting things

01:06:14.680 | to most people and true fetishes in the pathologic sense

01:06:20.040 | exist when people have basically a requirement

01:06:24.880 | for thinking about or even the presence

01:06:26.520 | of those ordinarily disgusting things

01:06:29.560 | in order to become sexually aroused.

01:06:31.460 | As if the circuitry has crossed over

01:06:33.800 | and the statement that rung in my mind was

01:06:35.960 | people don't develop fetishes to mailboxes

01:06:39.560 | or to the color red or to random objects and things.

01:06:44.280 | They develop fetishes to things that are highly infectious

01:06:47.260 | and counter reproductive, repetitive states.

01:06:50.200 | So I find that interesting.

01:06:51.920 | I don't know if you have any reflections on that

01:06:53.880 | as to why that might be.

01:06:55.700 | I'm tempted to ask whether or not you've ever observed

01:06:58.020 | fetish like behavior in mice, but I find it fascinating

01:07:01.440 | that you have this area of the brain

01:07:02.940 | that's so highly conserved, the hypothalamus,

01:07:04.880 | which you have these dense populations intermixed

01:07:07.040 | and that the addition of a forebrain, especially in humans

01:07:11.120 | that can think and make decisions could in some ways

01:07:13.800 | facilitate the expression of these primitive behaviors,

01:07:17.000 | but could also complicate the expression

01:07:19.180 | of primitive behaviors.

01:07:20.600 | - Right, I would agree.

01:07:22.720 | I think one way of looking at fetishes

01:07:26.120 | from a neurobiological standpoint

01:07:28.680 | is that they represent a kind of a repetitive conditioning

01:07:33.680 | where something that is natively aversive or disgusting

01:07:39.240 | by being repeatedly paired with a rewarding experience

01:07:44.440 | changes its valence, its sign,

01:07:49.120 | so that now it somehow produces the anticipation of reward

01:07:54.120 | the next time a person sees it.

01:07:57.840 | Now, I don't know how, I don't know that literature

01:08:00.340 | in animals, so I don't know if you could condition a mouse

01:08:04.760 | to eat feces, for example, although there are animals

01:08:08.500 | that are naturally coprophagic.

01:08:10.320 | That is, and maybe mice do that occasionally, I'm not sure,

01:08:14.680 | but that is one way to think about it,

01:08:17.960 | and that could certainly involve in humans

01:08:20.880 | the more recently evolved parts of the brain,

01:08:23.360 | the cortex that is sort of orchestrating

01:08:27.360 | both what behaviors are happening

01:08:29.920 | and whether reward states are turning on

01:08:33.320 | in association with those behaviors that are happening.

01:08:37.040 | And that's the part that I think is difficult

01:08:41.240 | and challenging to study in a mouse,

01:08:44.340 | but certainly bears thinking about

01:08:48.280 | because it's a really interesting,

01:08:50.820 | again, sort of counterintuitive aspect,

01:08:53.760 | again, like rough sex, people that want to have fighting

01:08:57.280 | or violence or aggressiveness

01:08:58.940 | in order to be sexually aroused and fetishes.

01:09:02.880 | And in fact, when we made that discovery initially,

01:09:05.800 | it raised the question in my mind

01:09:08.060 | whether some people that are serial rapists, for example,

01:09:14.060 | and engage in sexual violence might in some level

01:09:18.040 | have their wires crossed in some way

01:09:21.200 | that these states that are supposed to be

01:09:23.680 | pretty much separated and mutually antagonistic are not

01:09:27.520 | and are actually more rewarding and reinforcing.

01:09:31.480 | I think it's gonna be a long time

01:09:33.860 | before we have figured it out.

01:09:36.000 | But when you think about it,

01:09:37.800 | there is no treatment that we have

01:09:41.440 | for a violent sexual offender that eliminates the violence,

01:09:46.440 | but not the sexual desire and sexual urge,

01:09:50.600 | whether it's physical castration or chemical castration,

01:09:54.820 | it eliminates both.

01:09:57.280 | Definitely an area that I think,

01:09:59.180 | well, human neuroscience in general needs a lot of tools

01:10:03.440 | in terms of how to probe and manipulate neural circuitry.

01:10:06.800 | I'd love to turn to this area that you mentioned,

01:10:09.740 | the medial preoptic area.

01:10:12.020 | I'm fascinated by it because just as within the VMH,

01:10:15.040 | you have these neurons for mating and fighting or aggression.

01:10:19.140 | My understanding is medial preoptic area

01:10:21.660 | contains neurons for mating,

01:10:24.080 | but also for temperature regulation.

01:10:26.360 | And perhaps I'm making too much of a leap here,

01:10:28.480 | but I've always wondered about this phrase in heat.

01:10:30.980 | Certainly the menstrual or estrous cycle in females

01:10:37.000 | is related to changes in body temperature.

01:10:38.880 | In fact, measuring body temperature is one way

01:10:40.560 | that women can fairly reliably predict ovulation, et cetera.

01:10:44.840 | Although this is not a show about contraception,

01:10:48.380 | please rely on multiple methods as necessary.

01:10:50.560 | Don't use this discussion as your guide for contraception

01:10:54.300 | based on temperature.

01:10:55.360 | But if you stimulate certain neurons

01:10:58.200 | in the medial preoptic area,

01:10:59.360 | you can trigger dramatic changes in body temperature

01:11:02.600 | and/or mating behavior.

01:11:06.160 | What's the relationship, if any,

01:11:07.480 | between temperature and mating, or do we simply not know?

01:11:10.660 | I don't know what the relationship is

01:11:15.120 | between temperature and mating neurons in the preoptic area.

01:11:20.120 | I suspect that they are different populations of neurons

01:11:25.320 | because it's become pretty clear that the preoptic area

01:11:29.800 | has many different subsets of neurons

01:11:32.540 | that are specifically active during different behaviors,

01:11:36.160 | even different phases of mating behavior.

01:11:38.800 | So there are mounting neurons,

01:11:40.560 | there are intermission, thrusting neurons,

01:11:43.160 | and ejaculation neurons, and sniffing neurons.

01:11:46.080 | - Wait, wait, so I think I've heard this before,

01:11:48.660 | but I just wanna make sure that people get this,

01:11:50.240 | and I wanna make sure I get this.

01:11:51.440 | So you're telling me within medial preoptic area,

01:11:55.540 | there are specific neurons that if you stimulate them

01:11:57.840 | will make males thrust as if they're mating?

01:12:00.800 | - No, so this is not based on stimulation experiments.

01:12:05.960 | It's based on imaging experiments right now

01:12:08.940 | that we see when we look in the preoptic area

01:12:11.840 | at what neurons are active

01:12:14.140 | during different phases of aggression,

01:12:17.280 | we see that there are different neurons

01:12:19.280 | that are active during sniffing, mounting,

01:12:22.520 | thrusting, and ejaculation,

01:12:24.920 | and they become repeatedly activated

01:12:28.040 | each time the animal goes through that cycle.

01:12:30.280 | - During mating.

01:12:31.120 | - During the mating cycle.

01:12:32.920 | There are also some neurons there

01:12:34.400 | that are active during aggression, which are distinct,

01:12:37.400 | and we don't know whether those neurons are there

01:12:40.480 | to promote aggression or to inhibit mating

01:12:44.660 | when animals are fighting.

01:12:46.240 | We have some evidence that suggests it may be the latter,

01:12:49.560 | but we don't know for sure yet.

01:12:51.440 | The thermosensitive neurons are really interesting

01:12:54.240 | because you mentioned the phrase in heat,

01:12:57.480 | and then in the context of aggression,

01:12:59.820 | you talk about hot-blooded people or hotheads.

01:13:02.960 | There's just recently a paper showing

01:13:04.760 | there are thermoregulatory neurons in VMH as well.

01:13:08.900 | So all of these homeostatic systems

01:13:11.800 | for metabolic control and temperature control

01:13:15.200 | are intermingled in these nuclei,

01:13:18.600 | these zones that control these basic survival behaviors

01:13:22.900 | like mating and aggression and predator defense.

01:13:26.900 | And I would imagine that the thermoregulation

01:13:31.280 | is tightly connected to energy expenditure

01:13:35.560 | and that, again, these neurons are mixed together

01:13:39.180 | to facilitate integration of all these signals

01:13:43.080 | by the brain in some way that we don't understand

01:13:46.640 | to maintain the proper balance

01:13:48.520 | between energy conservation and energy consumption

01:13:53.520 | during this particular behavior or that behavior.

01:13:56.800 | I mean, I've always been fascinated by the question,

01:13:58.960 | why is it that violence goes up in the summertime

01:14:03.020 | when the temperatures are high?

01:14:04.840 | Does it really have something to do with the idea

01:14:08.400 | that increased temperature increases violence?

01:14:12.080 | It seems hard to believe because we're homeothermic

01:14:15.360 | and we pretty much stay around 98.6 Fahrenheit.

01:14:20.360 | Could be other social reasons why that happens.

01:14:23.640 | People are outside, out on the street,

01:14:25.600 | bumping into each other.

01:14:27.080 | But I think there could well be something

01:14:30.280 | that ties thermoregulation to aggressiveness

01:14:34.020 | as well as to mating behavior.

01:14:38.200 | - Fascinating, yeah.

01:14:39.120 | I asked in the hopes that maybe in the years to come,

01:14:43.360 | your lab will parse some of the temperature relationships.

01:14:46.400 | And I realized it could be also regulated

01:14:49.320 | by hormones in general.

01:14:50.480 | So it's tapping into two systems

01:14:51.880 | for completely different reasons.

01:14:53.080 | But anyway, an area that intrigues me

01:14:57.000 | because of this notion of hotheadedness

01:14:58.600 | or cool, common, collected.

01:15:00.440 | And also the fact that,

01:15:02.880 | I probably should have asked about this earlier,

01:15:04.400 | that arousal itself is tethered

01:15:07.240 | to the whole mating and reproductive process.

01:15:09.640 | I mean, without a sort of seesawing back

01:15:12.040 | between the sympathetic and parasympathetic arousal,

01:15:16.080 | relaxed states, there is no mating that will take place.

01:15:19.520 | So it's fascinating the way these different competing forces

01:15:23.440 | and seesaws operate.

01:15:25.760 | Several times during the discussion so far,

01:15:27.920 | we've hit on this idea that the same behavior

01:15:32.920 | can reflect different states

01:15:34.780 | and different states can converge

01:15:36.480 | on multiple behaviors as well.

01:15:39.380 | You had a paper not long ago about mounting behavior,

01:15:42.420 | which I found fascinating.

01:15:45.520 | Maybe you could tell us about that result.

01:15:47.760 | Because to me, it really speaks to the fact

01:15:49.800 | that mounting behavior can in one context be sexual

01:15:53.880 | and in another context actually be related to,

01:15:56.440 | we presume dominance.

01:15:57.960 | And I think that my friends who practice jujitsu will say,

01:16:02.960 | when I talk about that result, they say, of course,

01:16:05.920 | mounting the other person and dominating them,

01:16:08.840 | there's nothing sexual about it.

01:16:10.240 | It's about overtaking them physically,

01:16:12.420 | literally being on their next side

01:16:14.360 | as opposed to on their own, lying on their own back.

01:16:18.400 | Just fascinating, very primitive.

01:16:20.100 | And yet I think speaks to this idea

01:16:23.100 | that mounting behavior might be one

01:16:24.920 | of the most fundamental ways in which animals

01:16:27.720 | and perhaps even humans express dominance

01:16:30.880 | and/or sexual interactions.

01:16:34.060 | Yep, that's a fascinating question.

01:16:37.540 | And it was harder to figure out

01:16:39.880 | than you might've thought.

01:16:41.240 | So there's been this debate for a long time in the field

01:16:44.700 | when you see two male mice mounting each other.

01:16:48.740 | Is this homosexual behavior?

01:16:50.900 | Is this a case of mistaken sexual identification

01:16:54.320 | or is this dominance behavior?

01:16:56.440 | And if you train an AI algorithm

01:16:59.560 | to try to distinguish male-male mounting

01:17:03.820 | from male-female mounting, it does not do a very good job

01:17:07.160 | because motorically those behaviors look so similar.

01:17:11.480 | And so how did we wind up figuring out

01:17:16.360 | that most male-male mounting is dominance mounting?

01:17:20.940 | There are two important clues.

01:17:23.940 | One is the context.

01:17:26.860 | And so male-male mounting tends to be more prominent

01:17:31.260 | among mice when they haven't had a lot

01:17:33.820 | of fighting experience.

01:17:35.620 | And then as they become more experienced in fighting,

01:17:40.460 | they will show relatively less mounting

01:17:43.780 | towards the other male and more attack.

01:17:46.120 | And they'll transition quickly from mounting to attack.

01:17:50.180 | And so the mounting is always seen in this context

01:17:54.620 | of an overall aggressive interaction.

01:17:58.060 | And then the second thing, which believe it or not,

01:18:00.280 | was suggested by a computational theoretical person

01:18:04.820 | in my lab, Anne Kennedy,

01:18:06.900 | who now has her own lab at Northwestern.

01:18:09.180 | She said, well, males are known to sing

01:18:12.540 | when they mount females, ultrasonic vocalizations.

01:18:15.640 | Why don't you see what kinds of songs they're singing

01:18:19.020 | when they're mounting males?

01:18:20.320 | Maybe it's a different kind of song.

01:18:21.820 | Well, what we found out is they don't sing at all

01:18:25.100 | when they're mounting a male.

01:18:26.880 | So you can easily distinguish whether mounting behavior

01:18:31.880 | by a male mouse is reproductive or agonistic, aggressive,

01:18:36.880 | according to whether it's accompanied

01:18:40.180 | by ultrasonic vocalizations or not.

01:18:43.580 | And it turns out that different brain regions

01:18:47.080 | are maximally active during these different types

01:18:50.520 | of mounting.

01:18:51.360 | So VMH, the aggression locus,

01:18:55.120 | is actually active during dominance mounting.

01:18:58.380 | And you can stimulate mounting if you, dominance mounting,

01:19:02.340 | if you weakly activate VMH.

01:19:05.440 | Whereas MPOA is most strongly activated

01:19:08.860 | during sexual mounting.

01:19:10.820 | And that's always accompanied by the ultrasonic vocalization.

01:19:14.700 | So this shows how difficult and dangerous it can be

01:19:18.540 | to try to infer an animal state or intent or emotion

01:19:23.400 | from the behavior that it's exhibiting,

01:19:25.900 | because the same behavior can mean very different things

01:19:29.140 | depending on the context or the interaction with the animal.

01:19:32.180 | And I would say even more so with when that animal

01:19:34.980 | is a human or is multiple humans.

01:19:37.660 | That's right.

01:19:38.500 | And there are many examples.

01:19:40.460 | Animals show chasing to obtain food,

01:19:44.420 | a prey animal that they're gonna kill and eat.

01:19:47.100 | And they show chasing to obtain a mate

01:19:49.840 | that they're gonna have sex with.

01:19:51.620 | And so the intent of the chasing is completely different.

01:19:55.540 | And we don't know in all these cases,

01:19:57.420 | whether there are separate circuits or common circuits

01:20:00.580 | that are being activated.

01:20:01.820 | I'm obsessed with dogs and dog breeds and et cetera, et cetera.

01:20:06.140 | And one thing I can tell you is that female dogs

01:20:10.580 | will mount and thrust.

01:20:12.780 | We had a female pit bull mix, a very sweet dog,

01:20:17.040 | but in observing her, it convinced me

01:20:20.660 | that one can never assume that male dogs

01:20:23.880 | are more aggressive than female dogs.

01:20:25.680 | There's a, it turns out in talking to people

01:20:27.760 | who are quite skilled at dog genetics and dog breeding,

01:20:31.280 | that there is a dominance hierarchy within a litter

01:20:33.900 | and it crosses over male/female delineations.

01:20:38.900 | So you can get a female in the litter

01:20:40.840 | that's very dominant, a male that's very subordinate.

01:20:43.180 | And no one really knows what relates to.

01:20:45.860 | This is also why little dogs sometimes

01:20:47.460 | will get right up in the face of a big Doberman Pinscher

01:20:50.580 | and just start barking,

01:20:51.420 | which is an idiotic thing for it to do,

01:20:53.080 | but they can be dominant over a much larger dog.

01:20:56.300 | Very strange to me anyway.

01:20:58.560 | Female/female mounting.

01:21:00.820 | Do you observe it in mice?

01:21:03.140 | Are there known circuits

01:21:04.660 | and what evokes female/female mounting

01:21:07.260 | or female to male mounting if it occurs?

01:21:10.460 | Good.

01:21:11.280 | Yes, there is females.

01:21:13.520 | There are clear examples of females

01:21:16.460 | displaying male type mounting behavior

01:21:19.060 | towards other females.

01:21:20.580 | We see this most commonly in the lab

01:21:23.940 | where we are housing females with their sisters,

01:21:27.420 | say three or four in a cage.

01:21:29.580 | We take one out and we have her mate with a male

01:21:33.500 | where the male's doing the mounting.

01:21:35.260 | Now we take that female and we put her back in the cage

01:21:39.020 | with her litter mates and she starts mounting them.

01:21:42.840 | Now what the function of that is,

01:21:45.980 | if it has any function or what it means, what's driving it,

01:21:50.300 | we don't know.

01:21:51.180 | But we do know that if we stimulate

01:21:54.220 | the neurons that control mounting in males

01:21:58.280 | in the medial preoptic area,

01:21:59.800 | if we stimulate that same population in females,

01:22:03.760 | it evokes male type mounting

01:22:07.180 | towards either a male or a female target.

01:22:09.700 | In fact, we have a movie where we have a female

01:22:13.960 | that has just been mounted by a male.

01:22:16.560 | So the male's on top and she's underneath

01:22:19.640 | and we stimulate that region of MPOA in the female

01:22:24.060 | and she crawls out from underneath the male

01:22:27.420 | who has just mounted her, circles around behind him

01:22:31.560 | and climbs up on top of him

01:22:33.420 | and starts to try to mount him and thrust at him.

01:22:36.560 | That has a name on line, it's called a switch.

01:22:39.020 | Is that right?

01:22:40.700 | Don't ask me how I know that.

01:22:41.800 | Okay.

01:22:42.880 | But it's a pretty, yeah, it's a term that you hear.

01:22:47.060 | You also hear the term topping from the bottom,

01:22:50.680 | which it sounds like that is a literal topping

01:22:52.480 | from the bottom. I see.

01:22:53.320 | That's a more of a psychological phrase from what I hear.

01:22:55.800 | I have friends that are educating me in this language,

01:22:59.960 | mostly because I find this kind

01:23:02.040 | of neurobiological discussion fascinating at some point.

01:23:06.060 | I attempt in my mind to superimpose observations

01:23:09.960 | from the online communities that I've been told about

01:23:12.920 | and asked about to this, but I should point out,

01:23:15.600 | it's always dangerous and in fact,

01:23:17.800 | inappropriate to make a one-to-one link.

01:23:20.760 | Humans are, they maintain all the same neural circuitry

01:23:23.640 | and pathways that we're talking about today in mice,

01:23:26.040 | but that forebrain does allow for context, et cetera.

01:23:30.240 | Yep.

01:23:31.080 | So what the function is of female mounting, I don't know,

01:23:36.080 | it could be a type of dominance display.

01:23:39.600 | It's hard to measure that because people haven't worked

01:23:42.420 | on female dominance hierarchies to the same extent

01:23:46.120 | that they've worked on male dominance hierarchies,

01:23:49.100 | but it indicates that the circuits for male type mounting

01:23:54.100 | are there in females as early work

01:23:56.920 | from Catherine Dulock suggested some years ago.

01:24:00.220 | Fascinating, fascinating.

01:24:01.740 | I love that paper because as you pointed out for Chase,

01:24:04.980 | for mounting behavior, we see it

01:24:08.660 | and we think one thing specifically.

01:24:11.440 | And after hearing this result,

01:24:12.820 | actually I'm not a big fan of fight sports.

01:24:14.940 | I watch them occasionally 'cause friends are into them,

01:24:16.880 | but I've seen boxing matches, MMA matches,

01:24:21.320 | where at the end of a round,

01:24:23.140 | if someone felt that they dominated,

01:24:25.120 | they will do the unsportsmanlike thing of thrusting

01:24:29.240 | on the back of the other person before they get off,

01:24:30.880 | almost like I dominated you.

01:24:33.020 | So mimicking sexual-like behavior,

01:24:35.080 | but there's no reason to think that it's sexual,

01:24:37.360 | but they're sending a message of dominance is what implies.

01:24:40.320 | I'd love to talk about something slightly off

01:24:45.520 | from this circuitry, but I think that's related

01:24:47.620 | to the circuitry, at least in some way,

01:24:49.300 | which is this structure that I've always been fascinated by

01:24:52.560 | and I can't figure out what the hell it's for

01:24:54.940 | 'cause it seems to be involved in everything,

01:24:56.100 | which is the PAG, the periaqueductal gray,

01:25:00.340 | which is a little bit further back in the brain

01:25:01.800 | for people that don't know.

01:25:03.380 | It's been studied in the context of pain.

01:25:05.040 | It's been studied in the context

01:25:06.600 | of the so-called lordosis response,

01:25:08.140 | the receptivity or arching of the back of the female

01:25:10.960 | to receive intromission and mating from the male.

01:25:14.560 | How should we think about PAG?

01:25:16.460 | Clearly, it can't be involved in everything.

01:25:19.600 | I'm guessing it's at least as complex

01:25:21.640 | as some of these other regions

01:25:22.640 | that we've been talking about,

01:25:23.580 | different types of neurons controlling different things,

01:25:25.400 | but how does PAG play into this?

01:25:27.860 | In particular, I want to know,

01:25:29.960 | is there some mechanism of pain modulation

01:25:32.560 | and control during fighting and/or mating?

01:25:37.400 | And the reason I ask is that,

01:25:39.600 | while I'm not a combat sports person,

01:25:42.240 | years ago, I did a little bit of martial arts,

01:25:44.560 | and it always was impressive to me

01:25:46.800 | how little it hurt to get punched during a fight

01:25:49.320 | and how much it hurt afterwards, right?

01:25:51.920 | So there clearly is some endogenous pain control

01:25:54.440 | that then wears off and then you feel beat up.

01:25:58.760 | Or at least in my case, I felt beat up.

01:26:00.760 | What's PAG doing vis-a-vis pain and vis-a-vis,

01:26:04.220 | and what's pain doing vis-a-vis these other behaviors?

01:26:06.240 | - Good, good.

01:26:07.080 | So I think of PAG like a old-fashioned type

01:26:12.080 | in telephone switchboard,

01:26:14.000 | where there are calls coming in,

01:26:17.480 | and then the cables have to be punched into the right hole

01:26:20.860 | to get the information to be routed to the right recipient

01:26:24.820 | on the other end of it,

01:26:26.520 | because pretty much every type of innate behavior

01:26:30.640 | you can think of has had the PAG implicated.

01:26:34.400 | There's a whole literature showing the involvement

01:26:37.520 | of the PAG in fear, different regions of the PAG,

01:26:41.700 | the dorsal PAG is involved in panic-like behavior,

01:26:45.360 | running away.

01:26:46.400 | The ventral PAG is involved in freezing behavior.

01:26:49.880 | Both the MPOA and VMH send projections to the PAG

01:26:55.940 | to different regions of the PAG.

01:26:58.920 | So in cross-section, I hate to say this,

01:27:02.800 | but in cross-section,

01:27:04.200 | the PAG kind of looks like the water in a toilet

01:27:06.940 | when you're standing over an open toilet bowl.

01:27:10.000 | And if you imagine a clock face projected onto that,

01:27:15.000 | it's like the PAG has sectors from one to 12,

01:27:19.960 | maybe even more of them.

01:27:21.300 | And in each of those sectors,

01:27:22.920 | you find different neurons from the hypothalamus

01:27:25.740 | are projecting.

01:27:26.880 | So could turn out that there is a topographic arrangement

01:27:31.220 | along the dorsal ventral axis of the PAG

01:27:34.240 | and the medial lateral axis of the PAG

01:27:37.040 | that determines the type of behavior

01:27:39.860 | that will be emitted

01:27:41.400 | when neurons in that region are stimulated.

01:27:44.000 | And I think sort of all of the evidence

01:27:46.060 | is pointing in that direction,

01:27:47.840 | but by no means has it been mapped out.

01:27:50.560 | Now, the thing that you mentioned about it not hurting

01:27:54.040 | when you got beat up during martial arts,

01:27:56.920 | there is a well-known phenomenon

01:27:59.240 | called fear-induced analgesia,

01:28:03.800 | where when an animal is in a high state of fear,

01:28:08.760 | like if it's trying to defend itself,

01:28:11.220 | there is a suppression of pain responses.

01:28:16.220 | And I'm not sure completely about the mechanisms

01:28:20.660 | and how well that's understood.

01:28:22.720 | But for example, the adrenal gland has a peptide in it

01:28:27.720 | that is released from the adrenal medulla,

01:28:32.220 | which controls the fight or flight responses.

01:28:34.880 | And that peptide has analgesic activities.

01:28:38.920 | Now whether- Ask what that peptide is.

01:28:40.000 | It's called bovine adrenal medullary peptide

01:28:43.320 | of 22 amino acid residues.

01:28:45.480 | And I only know about it because it activates a receptor

01:28:49.520 | that we discovered many years ago that's involved in pain.

01:28:53.200 | And we thought it promoted pain,

01:28:54.800 | but it turns out that this actually inhibits pain.

01:28:57.680 | It's like an endogenous analgesic.

01:29:00.480 | Whether this is happening, this type of analgesia

01:29:05.360 | is happening when an animal is engaged

01:29:08.100 | in offensive aggression or in mating behavior,

01:29:13.100 | I don't know, but it certainly is possible.

01:29:16.400 | And I don't know whether these analgesic mechanisms

01:29:20.480 | are happening in the PAG.

01:29:22.480 | They could also be happening a little further down

01:29:25.560 | in the spinal cord.

01:29:26.600 | The PAG is really continuous with the spinal cord.

01:29:30.000 | If you just follow it down towards the tail of an animal,

01:29:33.900 | you will wind up in the spinal cord.

01:29:36.700 | And so it could be that there are influences

01:29:40.600 | acting at many levels on pain in the PAG

01:29:44.040 | and in the spinal cord as well.

01:29:46.360 | And it may well be known, I just don't know it.

01:29:49.080 | I wanna distinguish clearly between things

01:29:51.780 | that are not known, that I know are unknown,

01:29:55.100 | which is in a fairly small area where I have expertise

01:29:58.780 | from things that may be known, but I'm ignorant of them

01:30:01.820 | because I just don't have a broad enough knowledge base

01:30:04.300 | to know that.

01:30:05.140 | - Sure, we appreciate those delineations.

01:30:08.220 | Thank you.

01:30:10.100 | My PAG is, I think this description of it

01:30:11.740 | is an old fashioned telephone switchboard.

01:30:14.100 | And now every time I look into the toilet,

01:30:16.420 | I'll think about the periaqueductal gray.

01:30:18.140 | And every time I see an image of periaqueductal gray,

01:30:20.260 | I think about a toilet.

01:30:21.260 | That is an excellent description because in fact,

01:30:24.540 | I drew a circle with a little thing at the bottom.

01:30:27.640 | Well, I'll put a post or a link to a picture of PAG

01:30:30.300 | and you'll understand why David and I are chuckling here

01:30:33.220 | because indeed it looks like a toilet

01:30:35.420 | when staring into a toilet.

01:30:36.820 | Tell us about tachykinin.

01:30:40.360 | I've talked about this a couple of times

01:30:41.700 | on different podcast episodes

01:30:42.940 | because of its relationship to social isolation.

01:30:47.420 | And in part, because the podcast was launched

01:30:51.100 | during a time when there was more social isolation.

01:30:53.700 | My understanding is that tachykinin,

01:30:56.820 | and you'll tell us what it is in a moment,

01:30:59.360 | is present in flies and mice and in humans

01:31:01.820 | and may do similar things in those species.

01:31:05.860 | That's right.

01:31:06.700 | So tachykinin is, refers to a family

01:31:11.020 | of related neuropeptides.

01:31:12.980 | So these are brain chemicals.

01:31:15.180 | They're different from dopamine and serotonin

01:31:19.420 | in that they're not small organic molecules.

01:31:23.080 | They're actually short pieces of protein

01:31:25.860 | that are directly encoded by genes

01:31:28.760 | that are active in specific neurons and not in others.

01:31:32.300 | And when those neurons are active,

01:31:34.100 | those neuropeptides are released together

01:31:36.900 | with classical transmitters like glutamate, whatever.

01:31:40.560 | Tachykinins have been famously implicated in pain,

01:31:45.540 | particularly tachykinin one, which is called substance P,

01:31:50.400 | one of the original pain modulating.

01:31:53.340 | This is something that promotes inflammatory pain,

01:31:57.480 | but there are other tachykinin genes.

01:32:00.020 | In mice, there are two, in humans, I think there are three,

01:32:03.980 | and in Drosophila, there's one.

01:32:06.700 | And the way we got into tachykinins

01:32:09.260 | is from studying aggression in flies.

01:32:12.540 | We thought since neuropeptides have this remarkable

01:32:17.300 | parallel evolutionary conservation of structure and function

01:32:22.060 | like neuropeptide Y controls feeding in worms,

01:32:26.360 | in flies and mice and in people.

01:32:28.980 | Oxytocin-like peptides control reproduction

01:32:32.200 | in worms and mice and in people.

01:32:35.580 | We thought we might find peptides that control aggression

01:32:39.260 | in flies and in people.

01:32:40.660 | And so we did a screen, unbiased screen of peptides

01:32:44.720 | and found indeed that one of the tachykinins,

01:32:48.660 | Drosophila tachykinin, those neurons,

01:32:51.580 | when you activate them strongly promote aggression

01:32:54.780 | and it depends on the release of tachykinin.

01:32:57.540 | Now, the interesting thing is that in flies,

01:33:00.580 | just like in people and practically any other social animal

01:33:05.440 | that shows aggression,

01:33:06.940 | social isolation increases aggressiveness.

01:33:10.420 | So putting a violent prisoner in solitary confinement

01:33:14.940 | is absolutely the worst, most counterproductive thing

01:33:17.760 | you could do to them.

01:33:19.060 | And indeed we found in flies that social isolation

01:33:23.060 | increases the level of tachykinin in the brain.

01:33:26.900 | And if we shut that gene down,

01:33:29.160 | it prevents the isolation from increasing aggression.

01:33:32.640 | So since my lab also works on mice,

01:33:35.660 | it was natural to see whether tachykinins

01:33:38.960 | might be upregulated in social isolation

01:33:42.260 | and whether they play a role in aggression.

01:33:44.500 | And this is work done by a former postdoc,

01:33:46.860 | Marielle Zelikovsky, now at University of Salt Lake City

01:33:50.120 | in Utah, and she found remarkably

01:33:52.980 | that when mice are socially isolated for two weeks,

01:33:56.860 | there is this massive upregulation

01:34:00.220 | of tachykinin-2 in their brain.

01:34:03.420 | In fact, if you tag the peptide

01:34:06.300 | with a green fluorescent protein

01:34:08.880 | from a jellyfish genetically,

01:34:10.780 | the brain looks green when the mice are socially isolated

01:34:14.940 | 'cause there's so much of this stuff released.

01:34:17.740 | And she went on to show that that increase in tachykinin

01:34:22.740 | is responsible for the effect of social isolation

01:34:27.820 | to increase aggressiveness and to increase fear

01:34:31.620 | and to increase anxiety.

01:34:33.260 | And in fact, there are drugs that block the receptor

01:34:36.860 | for tachykinin, which were tested in humans and abandoned

01:34:41.180 | because they had no efficacy in the tests

01:34:43.820 | that they were analyzed for.

01:34:45.600 | If you give those drugs to a socially isolated mouse,

01:34:49.740 | it blocks all of the effects of social isolation.

01:34:53.420 | It blocks the aggression, it blocks the increased fear

01:34:57.480 | and the increased anxiety.

01:34:58.920 | And that Marielle described it, the mice just look chill.

01:35:02.540 | It's not a sedative, which is really important.

01:35:05.260 | It's not that the mice are going to sleep.

01:35:08.240 | Most remarkably is once you socially isolate a mouse

01:35:13.220 | and it becomes aggressive, you can never put it back

01:35:16.500 | in its cage with its brothers from its litter

01:35:19.660 | because it will kill them all overnight.

01:35:22.100 | But if you give it this drug, which is called Osanatant

01:35:25.940 | that blocks tachykinin too, that mouse can be returned

01:35:30.940 | to the cage with its brothers and will not attack them

01:35:34.700 | and seems to be happy about that for the rest of the time.

01:35:38.700 | So this is an incredibly powerful effect of this drug.

01:35:42.540 | And I've been really interested in trying to get

01:35:46.220 | pharmaceutical companies to test this drug,

01:35:49.300 | which has a really good safety profile in humans

01:35:52.980 | in testing it in people who are subjected

01:35:56.380 | to social isolation stress or bereavement stress.

01:36:00.620 | And this is one of the areas where I learned

01:36:05.120 | an eye-opening lesson as a basic scientist

01:36:08.380 | who naively thought that if you make a discovery

01:36:11.340 | and it has translational applications to humans

01:36:15.220 | that pharmaceutical companies are gonna be falling

01:36:17.740 | all over themselves to try it.

01:36:20.020 | And they're not interested because once burned, twice shy.

01:36:25.020 | These drugs were tested for efficacy and schizophrenia.

01:36:30.260 | I have no idea why.

01:36:32.260 | There's very little preclinical data to suggest that.

01:36:35.360 | Not surprisingly, they failed.

01:36:37.980 | When a drug fails in clinical trials in phase three,

01:36:42.500 | it costs $100 million to the company

01:36:46.500 | that carried out that clinical trial.

01:36:49.340 | So there's a huge slag heap of discarded pharmaceuticals,

01:36:54.140 | many of them inhibitors of neuropeptide action

01:36:58.340 | that could be useful in other indications

01:37:02.260 | such as the one we discovered.

01:37:04.140 | But there's a huge economic disincentive

01:37:07.540 | for pharmaceutical companies to test them again

01:37:11.880 | because the conclusion that they drew

01:37:14.340 | from all these failed tests,

01:37:16.180 | particularly in the 2010s and before that,

01:37:20.260 | is that the reason they failed

01:37:22.780 | is because animal experiments with drugs

01:37:26.580 | don't predict how humans will respond to the drugs.

01:37:31.200 | And therefore, we shouldn't try to extrapolate

01:37:35.120 | from any other data that we get from animal experiments,

01:37:38.760 | mouse or rat experiments, to humans

01:37:40.880 | because they'll lead us down the wrong track.

01:37:43.560 | And I think that that is probably wrong.

01:37:46.000 | In some cases, it may be right,

01:37:48.240 | but in other cases, there's good reason to think

01:37:51.200 | because these brain regions and molecules

01:37:54.060 | are so evolutionarily conserved

01:37:56.760 | that they ought to be playing a similar role in humans.

01:38:00.540 | In fact, there is a paper showing

01:38:04.300 | that in humans that have borderline personality disorder,

01:38:09.300 | there's a strong correlation

01:38:11.500 | between their self-reported level of aggressiveness

01:38:15.540 | and serum levels of a tachykinin,

01:38:18.660 | in this case, tachykinin-1,

01:38:20.700 | as detected by radioimmunoassay.

01:38:22.900 | This is work of Emil Coccaro,

01:38:25.140 | who's a clinical psychiatrist at the University of Chicago.

01:38:28.660 | So there is a smoking gun in the case of humans as well.

01:38:33.260 | And I was actually trying

01:38:36.260 | to interest a pharmaceutical company

01:38:38.820 | that was testing these drugs

01:38:41.740 | actually for treatment of hot flashes in females, in humans,

01:38:46.740 | where there is actually good animal data

01:38:49.900 | to think that it might be useful.

01:38:51.980 | But I realized that this clinical trial

01:38:55.140 | was going on during the COVID pandemic.

01:38:58.700 | And I approached him and said,

01:38:59.920 | "Look, nature may have actually done for you

01:39:02.860 | the experiment that I want you to do

01:39:05.020 | 'cause some of the people who are getting drug or placebo

01:39:08.160 | are gonna have been socially isolated

01:39:10.620 | and some of them will have not.

01:39:12.140 | Why don't you get them to fill out questionnaires

01:39:14.780 | and see whether the ones who were given the drug

01:39:17.380 | and socially isolated felt less stressed and less anxious

01:39:21.540 | than the ones who were not socially isolated

01:39:23.900 | and they would not touch it

01:39:26.180 | because they're in the middle of a clinical trial

01:39:29.300 | for a different indication for this drug

01:39:31.820 | and they have to report any observation

01:39:35.220 | that they make about that drug in their patient population.

01:39:38.980 | So if they were to ask these questions

01:39:41.460 | and get an unfavorable answer,

01:39:43.960 | "Oh my God, I felt even worse when I took this drug

01:39:46.740 | and I was isolated,"

01:39:47.980 | they would be obliged to report that to the FDA

01:39:51.220 | and that could torpedo the chances

01:39:53.200 | for the drug being approved

01:39:54.860 | in the thing that it was in clinical trials for.

01:39:56.920 | So it's better not to ask and not to know

01:40:01.700 | than it is to try to find out more information

01:40:05.200 | that could lead to another clinical indication.

01:40:07.820 | So I remain convinced that this family of drugs

01:40:12.700 | could have very powerful uses in treating some forms

01:40:17.140 | of stress-induced anxiety or aggressiveness in humans,

01:40:21.280 | but it's just very difficult for economic reasons

01:40:24.460 | to find a way to get somebody to test that.

01:40:26.980 | Yeah, a true shame that these companies won't do this

01:40:30.500 | and especially given the fact that many of these drugs exist

01:40:34.180 | and their safety profiles are established

01:40:36.900 | 'cause that's always a serious consideration

01:40:39.540 | when embarking on a clinical trial.

01:40:41.780 | Perhaps in hearing this discussion,

01:40:44.460 | someone out there will understand the key importance of this

01:40:47.640 | and will reach out to us,

01:40:49.620 | will provide ways to do that

01:40:52.300 | to get such a study going in humans.

01:40:55.140 | Because I think if enough laboratories

01:40:57.520 | ran small-scale clinical trials,

01:40:59.820 | pharma certainly would perk up their ears, right?

01:41:02.060 | I mean, they're so strategic sometimes to their own.

01:41:05.660 | I mean, I would like to say also,

01:41:07.540 | I'd like to see this tested on pets.

01:41:10.340 | I mean, there's a huge number of pets right now

01:41:13.060 | that are suffering separation anxiety

01:41:15.660 | because humans bought them to keep them company

01:41:18.540 | during the COVID pandemic.

01:41:19.900 | And now they're home alone.

01:41:20.720 | And now they're home alone, okay?

01:41:22.340 | And if this thing works in mice,

01:41:24.540 | there's certainly a higher chance

01:41:26.380 | it's gonna work in dogs or in cats

01:41:28.980 | than it is gonna work in humans.

01:41:30.780 | And if it did, that would be even more encouragement

01:41:33.740 | to continue along those lines.

01:41:35.660 | People sometimes forget that although we work on animals

01:41:39.180 | and we ultimately wanna understand humans,

01:41:41.500 | we care about how our results apply

01:41:44.220 | to the welfare of animals as well,

01:41:46.740 | and particularly domestic pets,

01:41:48.780 | which is a billion, multi-billion dollar industry

01:41:51.980 | in this country.

01:41:52.900 | So if there's ways that they can be made to feel better

01:41:56.300 | when they're separated from their owners,

01:41:59.500 | that would certainly be a good thing.

01:42:01.280 | - Absolutely.

01:42:02.760 | We will put out the call.

01:42:03.800 | We are putting out the call.

01:42:05.020 | And I know for sure there will be a response.

01:42:08.320 | Just underscoring what we've been talking about even more,

01:42:13.420 | every time we hear about a school shooting,

01:42:16.700 | like in Texas recently,

01:42:18.060 | or I happened to be in New York

01:42:19.660 | during the time when there was a subway shooting,

01:42:23.020 | for whatever reason, I listened to the book about Columbine

01:42:28.020 | that went into a very detailed way

01:42:30.020 | about the origin of those boys and that committed that.

01:42:33.260 | And every single time the person who commits those acts

01:42:38.260 | is socially isolated, as far as I know.

01:42:41.460 | There might be some exceptions there.

01:42:43.000 | And sometimes this crosses over

01:42:44.300 | with other mental health issues,

01:42:45.460 | but sometimes no, no apparent mental health issues.

01:42:48.180 | So social isolation clearly drives powerful neurochemical

01:42:52.420 | and neurobiological changes.

01:42:54.340 | I really hope that tachykinin one and two,

01:42:57.060 | those are the main ones in humans,

01:42:58.880 | will be explored in more detail.

01:43:01.460 | Also, I didn't know that tachykinin one is substance P

01:43:03.900 | and substance P is tachykinin one.

01:43:05.900 | - Tachykinin one is the gene name

01:43:08.060 | and tachykinin two in humans is called neurokinin B.

01:43:12.300 | That's the name of the protein.

01:43:14.220 | I just referred to it by the gene name

01:43:16.160 | 'cause it makes it easier.

01:43:17.320 | And I don't have to keep remembering

01:43:18.820 | two names for each thing.

01:43:20.340 | And I, if I'm not mistaken, you put yourself

01:43:24.260 | in the company of geneticists

01:43:25.580 | because of your original training

01:43:26.860 | was in genetics, immunology, and areas related to that.

01:43:29.940 | - It was in cell biology.

01:43:31.580 | And I didn't actually have formal training in genetics

01:43:34.700 | as a graduate student, but I think I'm a geneticist at heart.

01:43:38.180 | That's just the way I like to think about things.

01:43:41.300 | And when I started working on flies,

01:43:43.400 | that sort of, I came out of the closet

01:43:46.020 | as a geneticist, as it were.

01:43:48.220 | - Wonderful.

01:43:49.660 | As long as we're talking about humans,

01:43:50.880 | I'd love to get your thoughts

01:43:51.780 | about human studies of emotion.

01:43:53.200 | I know you wrote this book with Ralph Adol.

01:43:55.140 | So you have this new book, which we'll provide a link to,

01:43:57.380 | which I've read front to back twice.

01:43:59.840 | It's phenomenal.

01:44:01.020 | I mentioned it before on the podcast.

01:44:02.460 | It's really, there are books that are worth reading

01:44:05.140 | and then there are books that are important.

01:44:06.620 | And I think this book is truly important

01:44:08.220 | for the general population to read and understand.

01:44:10.800 | And neuroscientists should read and understand the contents

01:44:13.220 | because we, as a culture, are way off

01:44:17.980 | in terms of how we think about emotions

01:44:19.500 | and states and behaviors.

01:44:21.340 | So we'll put a link to that.

01:44:22.460 | It's really worth the time and energy to read it.

01:44:25.880 | And it's written beautifully, I should say.

01:44:27.520 | Very accessible, even for non-scientists.

01:44:30.280 | There's a heat map diagram in that book that I think about.

01:44:35.280 | This is a heat map diagram of subjective reports

01:44:38.660 | that people gave of where they experience an emotion

01:44:43.660 | or a feeling, somatic feeling in their body

01:44:46.540 | or in their head, or both when they are angry, sad, calm,

01:44:51.100 | lonely, et cetera, et cetera.

01:44:53.780 | And I wouldn't want people to think that those heat maps

01:44:56.480 | were generated by any physiological measurement

01:45:00.860 | because they were not.

01:45:01.840 | And yet, I don't think we can have a discussion

01:45:04.860 | about emotions and states and the sorts of behaviors

01:45:08.320 | that we're talking about today

01:45:09.160 | without thinking about the body also.

01:45:11.700 | And I'm not coming to this

01:45:12.820 | as a Northern California mind body.

01:45:14.900 | I've been to Esalen once.

01:45:16.220 | I didn't go in the baths.

01:45:17.420 | I went there, I gave a talk and I left.

01:45:18.940 | It is very beautiful.

01:45:20.460 | If anyone wants to know what it looks like,

01:45:21.620 | I think that final scene of "Mad Men" is shot at Esalen.

01:45:24.660 | It's a very beautiful place.

01:45:26.620 | And yet, mind body to me is a neurobiological construct

01:45:31.620 | because the nervous system extends

01:45:33.180 | through the out of the cranial vault

01:45:35.100 | and into the spinal cord and body and back and forth.

01:45:37.340 | Okay.

01:45:38.500 | How should we think about the body in terms of states?

01:45:43.460 | And at some point, I'd love for you to comment

01:45:45.760 | on that heat map experiment

01:45:47.580 | because it does seem that there's some regularity

01:45:50.280 | as to where people experience emotions.

01:45:52.860 | When people are in a rage, for instance,

01:45:54.580 | they seem to feel it both in their gut and in their head,

01:45:58.080 | it seems, on average.

01:46:00.560 | And people love to extrapolate to gut intuition

01:46:05.280 | or that the chakras or anger is in the stomach

01:46:08.720 | and this goes to Eastern medicine, et cetera.

01:46:11.780 | How should we think about mind body in the context of states

01:46:14.980 | and think about it as scientists,

01:46:16.760 | maybe even as neuroscientists or geneticists?

01:46:20.040 | Good.

01:46:21.120 | So for the answer to the first question about the heat maps

01:46:25.120 | and people associating certain parts of their body

01:46:28.420 | with certain emotional feelings,

01:46:30.840 | this goes back to something called

01:46:33.400 | the somatic marker hypothesis

01:46:35.620 | that was proposed by Antonio Damasio,

01:46:38.280 | who is a neurologist at USC.

01:46:41.360 | The idea that our subjective feeling

01:46:45.480 | of a particular emotion is in part associated

01:46:50.480 | with a sensation of something happening

01:46:55.160 | in a particular part of our body, the gut, the heart.

01:46:59.840 | I don't see the liver invoked very much

01:47:02.720 | in emotional characterization.

01:47:06.700 | But gall and the gallbladder?

01:47:08.420 | Yes.

01:47:09.360 | Somebody having a lot of gall.

01:47:10.200 | That's right.

01:47:11.040 | I'll make a fist when I say that,

01:47:12.100 | but I'm guessing the gallbladder is shaped like a fist.

01:47:14.120 | That's right.

01:47:15.640 | And if there is a physiology underlying these heat maps,

01:47:20.260 | it could reflect increased blood flow

01:47:22.840 | to these different structures.

01:47:24.360 | And that in turn reflects what you were talking about.

01:47:28.040 | That is emotion is definitely involves communication

01:47:31.800 | between the brain and the body

01:47:33.920 | and it's bi-directional communication.

01:47:36.880 | And it's mediated by the peripheral nervous system,

01:47:41.280 | the sympathetic and the parasympathetic nervous system,

01:47:44.520 | which control heart rate, for example,

01:47:47.480 | blood vessel, blood pressure.

01:47:50.240 | And those neurons receive input from the hypothalamus

01:47:54.720 | and other blood brain regions, central brain regions

01:47:58.380 | that control their activity.

01:48:00.380 | And when the brain is put in a particular state,

01:48:05.040 | it activates sympathetic and parasympathetic neurons,

01:48:09.000 | which have effects on the heart and on blood pressure.

01:48:13.800 | And these in turn feed back onto the brain

01:48:18.140 | through the sensory system.

01:48:20.040 | And a large part of this bi-directional communication

01:48:23.860 | is also mediated through the vagus nerve,

01:48:27.220 | which many of your listeners and viewers

01:48:30.840 | may have heard about because it's become a topic

01:48:33.800 | of intense activity now.

01:48:35.680 | People have known for a long time.

01:48:38.360 | So the vagus nerve is a bundle of nerve fibers

01:48:43.360 | that comes out basically of your skull,

01:48:47.280 | out of the central nervous system and then sends fibers

01:48:51.920 | in to your heart, your gut, all sorts of visceral organs.

01:48:56.920 | So when you have, and that information

01:49:00.960 | is both used the words earlier in our discussion,

01:49:04.760 | afferent and efferent.

01:49:06.960 | So the vagal fibers sense things

01:49:11.720 | that are happening in the body.

01:49:13.860 | So when you're, the reason you feel your stomach

01:49:16.920 | tied up in knots, if you're tense,

01:49:19.560 | is that those vagal fibers are sensing

01:49:22.960 | the contraction of the gut muscles.

01:49:25.900 | And they're also afferents,

01:49:27.780 | which means that information coming out of the brain

01:49:31.140 | can influence those peripheral organs as well.

01:49:34.800 | And there's work from a number of labs

01:49:37.120 | just in the last six months or so

01:49:40.380 | where people are starting to decode the components

01:49:44.840 | of the different fibers in the vagus nerve.

01:49:48.240 | And it's amazing how much specificity is.

01:49:51.240 | There are specific vagal nerves that go to the lung,

01:49:55.360 | that control breathing responses, that go to the gut,

01:49:59.600 | that go to other organs.

01:50:01.620 | It's almost like a set of color-coded lines,

01:50:06.260 | labeled lines for those things.

01:50:08.120 | And now how those vagal afferents play a role

01:50:13.120 | in the playing out of emotion states

01:50:16.600 | is a fascinating question that people are just beginning

01:50:20.320 | to scrape the surface of.

01:50:21.700 | But I think what's exciting now

01:50:23.820 | is that people are gonna be developing tools

01:50:25.960 | that will allow us to turn on or turn off

01:50:28.940 | specific subsets of fibers within the vagus nerve

01:50:33.360 | and ask how that affects particular emotional behaviors.

01:50:37.060 | So you're absolutely right.

01:50:38.680 | This brain-body connection is critical,

01:50:41.340 | not just for the gut, but for the heart, for the lungs,

01:50:45.020 | for all kinds of other parts of your body.

01:50:48.060 | And Darwin recognized that as well.

01:50:50.560 | And I think it's a central feature of emotion state.

01:50:54.680 | And I think what underlies

01:50:56.360 | are subjective feelings of an emotion.

01:50:59.860 | Incredible.

01:51:01.440 | David, I have to say, as a true fan of the work

01:51:04.320 | that your lab has been doing over so many decades.

01:51:07.080 | And first of all, I was delighted

01:51:09.160 | when you stopped working on stem cells,

01:51:10.640 | not because you weren't doing incredible work there,

01:51:12.580 | but because I saw a talk where you showed a movie

01:51:16.160 | of an octopus spitting out or not spitting,

01:51:19.880 | but squirting out a bunch of ink and escaping.

01:51:22.360 | And you said you were gonna work on

01:51:24.120 | things of the sort that we're talking about today,

01:51:25.600 | fear, aggression, mating behaviors, social behaviors.

01:51:29.100 | It's been incredible to see the work that your lab has done.

01:51:31.440 | And I know I speak on behalf of a tremendous number of people

01:51:36.440 | and I say thank you for taking time

01:51:39.260 | out of your important schedule

01:51:40.780 | to share with us what you've learned.

01:51:42.720 | My last question is a simple one,

01:51:45.500 | which is will you come back and talk to us again

01:51:48.360 | in the future about the additional work that's sure to come?

01:51:50.880 | I would be happy to do that.

01:51:52.360 | And I really have appreciated your questions.

01:51:55.760 | They've all been right on the money.

01:51:57.480 | You've hit all of the critical important issues

01:52:00.860 | in this field and you've uncovered what is known,

01:52:05.660 | the little bit is known and how much is not known.

01:52:08.840 | And I think it's important to emphasize the unknown things

01:52:13.140 | because that's what the next generation

01:52:15.440 | of neuroscientists has to solve.

01:52:18.120 | And so I hope this will help to attract young people

01:52:21.160 | into this field because it's so important,

01:52:24.320 | particularly for our understanding of mental illness

01:52:27.640 | and mental health and psychiatry.

01:52:31.720 | We've got to figure out how emotion systems are controlled

01:52:36.040 | in a causal way if we ever want to improve

01:52:39.920 | on the psychiatric treatments that we have now.

01:52:42.580 | And that's gonna require the next generation

01:52:44.960 | of people coming into the field.

01:52:46.760 | - Absolutely, I second that.

01:52:48.800 | Well, thank you, it's been a delight.

01:52:50.360 | - Thank you, great, really appreciate it.

01:52:53.460 | - Thank you for joining me today

01:52:54.560 | for my discussion with Dr. David Anderson.

01:52:56.640 | Please also be sure to check out his new book,

01:52:58.820 | "The Nature of the Beast, How Emotions Guide Us."

01:53:01.800 | It's a truly masterful exploration of the biology

01:53:04.640 | and psychology behind what we call emotions

01:53:07.120 | and states of mind and body.

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01:55:30.320 | [upbeat music]

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Dr. David Anderson: The Biology of Aggression, Mating, & Arousal | Huberman Lab Podcast #89

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