back to indexDr. David Anderson: The Biology of Aggression, Mating, & Arousal | Huberman Lab Podcast #89
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman, and I'm a professor of neurobiology
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and ophthalmology at Stanford School of Medicine.
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Today, my guest is Dr. David Anderson.
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Dr. Anderson is a professor of biology
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at the California Institute of Technology,
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often commonly referred to as Caltech University.
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Dr. Anderson's research focuses on emotions
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and states of mind and body.
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And indeed, he emphasizes how emotions
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like happiness, sadness, anger, and so on
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are actually subcategories
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of what are generally governed by states,
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that is, things that are occurring in the nervous system
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in our brain and in the connections between brain and body
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that dictate whether or not we feel good
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about how we are feeling and that drive our behaviors,
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that is, bias us to be in action or inaction
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and strongly influence the way we interpret our experience
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and our surroundings.
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Today, Dr. Anderson teaches us, for instance,
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why people become aggressive
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and why that aggression can sometimes take the form of rage.
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I also talk about sexual behavior
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and the boundaries and overlap
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between aggression and sexual behavior.
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And that discussion about aggression and sexual behavior
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also starts to focus on particular aspects
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of neural circuits and states of mind and body
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that govern things like, for instance, male-male aggression
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versus male-female aggression versus female-female aggression.
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So today, you will learn a lot
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about the biological mechanisms
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that govern why we feel the way we feel.
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Indeed, Dr. Anderson is an author
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of a terrific new popular book entitled
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"'The Nature of the Beast, How Emotions Guide Us.'"
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I've read this book several times now.
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I can tell you it contains so many gems
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that are firmly grounded in the scientific research.
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In fact, a lot of what's in the book
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contrasts with many of the common myths
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about emotions and biology.
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So whether or not you're a therapist or you're a biologist
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or you're simply just somebody interested
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in why we feel the way we feel
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and why we act the way we act,
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I cannot recommend the book highly enough.
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Again, the title is,
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"'The Nature of the Beast, How Emotions Guide Us.'"
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Today's discussion also ventures into topics
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such as mental health and mental illness.
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And some of the exciting discoveries
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that have been made by Dr. Anderson's laboratory
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and other laboratories identifying specific peptides,
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that is, small proteins that can govern
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whether or not people feel anxious or less anxious,
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aggressive or less aggressive.
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This is an important area of research
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that has direct implications
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for much of what we read about in the news,
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both unfortunate and fortunate events,
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and that will no doubt drive
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the future of mental health treatments.
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Dr. Anderson is considered one of the most pioneering
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and important researchers in neurobiology of our time.
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Indeed, he is a member of the National Academy of Sciences
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and a Howard Hughes Medical Institute investigator.
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I've mentioned the HHMI once or twice before
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when we've had other HHMI guests on this podcast,
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but for those of you that are not familiar,
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the Howard Hughes Medical Institute
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funds a small number of investigators
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doing particularly high-risk, high-benefit work,
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and it is an extremely competitive process
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to identify those Howard Hughes investigators.
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They're essentially appointed,
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and then every five years,
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they have to compete against one another
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and against a new incoming flock
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of would-be HHMI investigators
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to get another five years of funding.
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They are literally given a grade every five years
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as to whether or not they can continue, not continue,
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or whether or not they should worry about being funded
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for an extended period of time.
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Dr. Anderson has been an investigator
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with the Howard Hughes Medical Institute since 1989.
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I'm pleased to announce that the Huberman Lab Podcast
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is now partnered with Momentus Supplements.
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We partnered with Momentus for several important reasons.
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First of all, they ship internationally
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because we know that many of you are located
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Second of all, and perhaps most important,
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If you'd like to see the supplements
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you can go to livemomentus.com slash Huberman.
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There you'll see those supplements,
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and just keep in mind that we are constantly expanding
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on a regular basis.
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Again, that's livemomentus.com slash Huberman.
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Before we begin, I'd like to emphasize
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that this podcast is separate
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from my teaching and research roles at Stanford.
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It is, however, part of my desire and effort
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to bring zero cost to consumer information
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about science and science-related tools
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to the general public.
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In keeping with that theme,
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I'd like to thank the sponsors of today's podcast.
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Our first sponsor is Levels.
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to get a free sample pack with your order.
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And now for my discussion with Dr. David Anderson.
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David, great to be here
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and great to finally sit down and chat with you.
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Great to be here too.
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Thank you so much.
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Yeah, I have a ton of questions,
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but I want to start with something fairly basic,
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but that I'm aware is a pretty vast landscape.
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And that's the difference between emotions and states,
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if indeed there is a difference,
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and how we should think about emotions.
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They have all these names, happiness, sadness, depression,
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How should we think about them?
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And why might states be at least as useful
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a thing to think about, if not more useful?
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First, the short answer to your question
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is that I see emotions as a type of internal state,
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in the sense that arousal is also a type of internal state,
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motivation's a type of internal state,
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sleep is a type of internal state.
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And the sort of simplest way I think of internal states
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is that, as you've shown in your own work,
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they change the input to output transformation of the brain.
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When you're asleep, you don't hear something
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that you would hear if you were awake,
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unless it's a really, really loud noise.
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So from that broad perspective,
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I see emotion as a class of state that controls behavior.
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The reason I think it's useful to think about it as a state
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is it puts the focus on it as a neurobiological process,
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rather than as a psychological process.
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And this gets around all of the definitional problems
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that people have with the word emotion,
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where many people equate emotion with feeling,
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which is a subjective sense that we can only study in humans
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because to find out what someone's feeling,
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you have to ask them, and people are the only animals
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that can talk that we can understand.
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So that's how I think about emotion.
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It's the, if you think of an iceberg,
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it's the heart of the iceberg
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that's below the surface of the water.
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The feeling part is the tip that's sort of floating
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above the surface of your consciousness.
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Not that that isn't important, it is,
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but you have to understand consciousness
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if you wanna understand feelings,
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and we're not ready to study that in animals yet.
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And so that's how I think about it.
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What are the different components of a state?
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You know, you mentioned arousal as a key component.
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What are some of the other features of states
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that represent this, as you so beautifully put in your book,
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that represent below the tip of the iceberg?
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So you can break states up
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into different facets, or people would call them dimensions.
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And so there have been people who've thought of emotions
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as having just really two dimensions,
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an arousal dimension, how intense is it,
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and also a valence dimension,
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which is, is it positive or negative, good or bad?
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Ralph Adolphs and I have tried to expand that a little bit
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to think about components of emotion,
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particularly those that distinguish emotion states
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from motivational states,
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because they are very closely related.
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One of those important properties is persistence.
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And this is something that distinguishes
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state-driven behaviors from simple reflexes.
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Reflexes tend to terminate when the stimulus turns off,
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like the doctor hitting your knee with a hammer.
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It initiates with the stimulus onset,
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and it terminates with the stimulus offset.
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Emotions tend to outlast, often,
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the stimulus that evoke them.
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If you're walking along a trail here in Southern California,
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you hear a rattlesnake rattling.
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You're gonna jump in the air,
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but your heart is gonna continue to beat,
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and your palms sweat,
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and your mouth is gonna be dry for a while
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after it's slithered off in the bush,
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and you're gonna be hypervigilant.
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If you see something that even remotely
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looks snake-like, a stick, you're gonna stop and jump.
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So persistence is an important feature of emotion states.
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Not all states have persistence.
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So for example, you think about hunger.
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Once you've eaten, the state is gone.
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You're not hungry anymore.
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But if you're really angry,
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and you get into a fight with somebody,
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even after the fight is over,
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you may remain riled up for a long time,
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and it takes you a while to calm down.
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And that may have to do with the arousal dimension
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or some other part of it.
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And then generalization is an important component
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of emotion states that make them,
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if they have been triggered in one situation,
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they can apply to another situation.
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And my favorite example of that is you come home from work
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and your kid is screaming.
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If you had a good day at work,
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you might pick it up and soothe it.
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And if you had a bad day at work,
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you might react very differently to it and scream at it.
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And so that's a generalization of the state
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that was triggered at work by something your boss said
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to you to a completely different interaction.
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And again, that's something that distinguishes
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emotion states from motivation states.
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Motivation states are really specific.
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Find and eat food, obtain and consume water.
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And they're involved in homeostatic maintenance.
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So states are very multifaceted,
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and just asking questions about how these components
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of states are encoded, like what makes a state persist?
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What gives a state a positive or a negative valence?
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How do you crank up or crank down the intensity of the state?
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It just opens up a whole bunch of questions
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that you can ask in the brain
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with the kinds of tools we have now.
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You mentioned arousal a few times,
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and you mentioned valence.
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Realizing that there are these other aspects of states,
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I'd like to just talk about arousal a little bit more
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and valence, because at a very basic level,
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it seems to me that arousal,
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we can be very alert and pissed off,
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stressed, worried, you have insomnia.
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We can also be very alert and be quite happy.
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So the valence flips.
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We could be very, people can be sexually aroused.
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People can be aroused in all sorts of ways.
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Is there any simple or simple-ish neurochemical signature
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that can flip valence?
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So for instance, is there any way that we can safely say
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that arousal with some additional dopamine release
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is going to be of positive valence,
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and arousal with very low dopamine
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is going to be of negative valence?
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I would be reluctant to say that it's a chemical flip.
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I would say it's more likely to be a circuit flip,
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different circuits being engaged,
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and it might be that a given neurochemical, even dopamine,
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is involved in both positively valenced arousal
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and negatively valenced arousal.
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That's why people think about these as different axes.
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So I think the interesting question that you touch on is,
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is arousal something that is just completely generic
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in the brain, or are there actually different kinds
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of arousal that are specific to different behaviors?
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And you raise the question,
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sexual arousal feels different from aggressive arousal,
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And we actually published a paper on this back in 2009
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in Fruit Flies, where we found some evidence
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for two types of arousal states,
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one of which is sleep-wake arousal.
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You're more aroused when you wake up
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than when you're asleep, and flies show that.
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And the other is a startle response, an arousal response,
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to a mechanical stimulus, a noxious mechanical stimulus.
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If you puff air on flies,
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kind of like trying to swat the wasp away
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from your burger at the picnic table,
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they come back more and more and more vigorously.
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And we were able to dissect this and show
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that although both of those forms of arousal
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require dopamine, they were exerted
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through completely separable neural circuits in the fly.
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And so that really put, number one, the emphasis on,
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it's the circuit that determines the type of arousal,
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but also that arousal isn't unitary,
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that there are behavior-specific forms of arousal.
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And I think the jury is still out
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as to whether there is such a thing
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as completely generalized arousal or not.
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I think some people would argue there is,
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but I think more attention needs to be paid
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to this question of domain-specific
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or behavior-specific forms of arousal.
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Yeah, it's a super interesting idea,
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because I always thought of arousal as along a continuum,
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like you can either be in a panic attack
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at the one end of the extreme, or you can be in a coma,
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and then somewhere in the middle, you're alert and calm.
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But then this issue of valence really, as you say,
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presents this opportunity that really
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there might be multiple circuits for arousal
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or multiple mechanisms that would include neurochemicals
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as well as different neural pathways.
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So I'd like to talk a bit about a state,
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if it is indeed a state, which is aggression.
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Your lab's worked extensively on this.
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And if you would, could you highlight
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some of the key findings there,
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which brain areas that are involved,
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the beautiful work of Dai-Yu Lin and others in your lab,
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that point to the idea that indeed there are
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kind of switches in the brain,
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but that thinking of switches for aggression
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might be too simple.
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How should we think about aggression?
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And I'll just sort of skew the question a bit more
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by saying we see lots of different kinds of aggression,
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this terrible school shooting down in Texas recently,
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clearly an act that included aggression,
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and yet you could imagine
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that's a very different type of aggression
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than an all-out rage or a controlled aggression.
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There's a lot of variation there.
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So what are your thoughts on aggression,
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how it's generated the neural circuit mechanisms,
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and some of the variation in what we call aggression?
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Yeah, this is a great question, and it's a large area.
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I would say that the, first of all,
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the word aggression in my mind
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refers more to a description of behavior
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than it does to an internal state.
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Aggression could reflect an internal state
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that we would call anger in humans,
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or could reflect fear, or it could reflect hunger
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if it's predatory aggression.
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And so this gets at the issue that you raised
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of the different types of aggression that exist.
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The work that Dayu did when she was in my lab
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that really broke open the field
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to the application of modern genetic tools
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for studying circuits in mice
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is that she found a way to evoke aggression in mice
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using optogenetics to activate specific neurons
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in a region of the hypothalamus,
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the ventromedial hypothalamus, VMH,
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which people had been studying and looking at for decades,
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following first the work in Katz,
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the famous Nobel Prize winning work of Walter Hess,
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and then followed by work done by Meno Crook
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in the Netherlands in rats
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where they would stick electrical wires into the brain
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and send electric currents into the brain,
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and they could trigger a placid cat
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to suddenly bare its teeth, hiss,
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and almost strike out at the experimenter,
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and they could trigger rats to fight with each other.
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And even in Hess's original experiments,
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he describes two types of aggression
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that he evokes from Katz
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depending on where in the hypothalamus
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he puts his electrode,
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one of which he calls defensive rage,
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that's the ears laid back, teeth bared and hissing,
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and the other one is predatory aggression
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where the cat has its ears forward
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and it's like batting with its paw at a mouse-like object
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like it wants to catch it and eat it.
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So he already had at that stage some information
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about segregation in the brain
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of different forms of aggression.
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So fast forward to 2008, 2009
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when Dayu came to the lab
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and we had started working on aggression in fruit flies
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and I wanted to bring it into mice
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so that we could apply genetic tools.
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And we started by having Dayu,
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who was an electrophysiologist,
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just repeat the electrical stimulation
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of the ventromedial hypothalamus in the mouse,
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just like people had done in rats, in cats, in hamsters,
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And she could not get that experiment to work
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over 40 different trials.
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It just didn't work.
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What she got instead was fear behaviors.
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She got freezing, cornering, and crouching.
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And finally in desperation,
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and we got a lot of input from Meno Crook on this,
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he really was mystified.
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Why doesn't it work in mice?
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We realized why there had been no paper
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on brain stimulated aggression in mice in 50 years
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because the experiment doesn't work.
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And the one bit of credit I can claim there
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is I convinced Dayu to try optogenetics
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because it just had sort of come into use deep in the brain
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from Carl Deiss-Roth and others' work.
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And I thought maybe because it could be directed
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more specifically to a region of the brain
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and types of cells and optogenetic stimulation,
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than electrical stimulation,
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And Dayu said, never, never gonna work.
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If it doesn't work with electricity,
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why should it work with optogenetics?
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And the fact is that it did work
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and we were able to trigger aggression in this region
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using optogenetic stimulation of ventromedial hypothalamus.
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And in retrospect, I think the reason
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that we were seeing all these fear behaviors
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is because right at the upper part,
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if you think of ventromedial hypothalamus
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like a pear sitting on the ground,
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the fat part of the pear near the ground
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is where the aggression neurons are,
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but the upper part of the pear has fear neurons.
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And it could be because it's so small in a mouse,
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when you inject electrical current anywhere in the pear,
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it flows up through the entire pear
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and it activates the fear circuits
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and those totally dominate aggression.
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And so that's why we were never able to see
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any fighting with electrical stimulation.
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Whereas when you use optogenetics,
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you confine the stimulation just to the region
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where you've implanted the channelrhodopsin gene
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into those neurons.
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And so fast forward from that,
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from a lot of work from Dayu now on her own at NYU
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and with her postdoc, Anna-Gret Faulkner,
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there's, as well as work of other people,
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there's evidence that the type of fighting
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that we elicit when we stimulate VMH
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is offensive aggression that is actually rewarding
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to male mice. They like it.
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Male mice will press, learn to poke their nose
link |
or press a bar to get the opportunity
link |
to beat up a subordinate male mouse.
link |
And in more recent experiments,
link |
if you activate those neurons and the mouse has a chance
link |
to be in one of two compartments in a box,
link |
they will gravitate towards the compartment
link |
where those neurons are activated.
link |
It has a positive valence.
link |
And when I went into this field and I was thinking,
link |
well, what goes on in my brain and my body when I'm furious?
link |
It certainly doesn't feel like a rewarding experience.
link |
It's not something that I would want to repeat
link |
because it feels good when I'm in that state.
link |
It doesn't feel good at all when I'm in that state.
link |
And it is still, I think, a mystery
link |
as to where that type of aggression,
link |
which is more defensive aggression,
link |
the kind of aggression you feel if you're being attacked
link |
or if you've been cheated by somebody,
link |
where that is encoded in the brain and how that works still,
link |
I think, is a very important mystery
link |
that we haven't solved.
link |
And predatory aggression there has been some progress on.
link |
So mice show predatory aggression.
link |
They use that to catch crickets that they eat,
link |
and that involves different circuits
link |
than the ventromedial hypothalamic circuits.
link |
So it's become clear that if you want to call it
link |
the state of aggressiveness is multifaceted.
link |
It depends on the type of aggression,
link |
and it involves different sorts of circuits.
link |
There is, there's a paper suggesting
link |
that there might be a final common pathway
link |
for all aggression in a region,
link |
which is one of my favorites.
link |
It's called the substantia in naminata,
link |
the substance with no name.
link |
Anatomists are so creative.
link |
Or the nucleus ambiguous, you know, or the zona inserta.
link |
These are places that no one can think of what they are.
link |
Anyhow, that might be a final common pathway
link |
for predatory aggression and offensive
link |
and defensive aggression.
link |
But it can be really hard to tell
link |
just from looking at a mouse fight,
link |
whether it's engaged in offensive or defensive aggression.
link |
We've tried to take that apart
link |
using machine learning analysis of behavior.
link |
But in rats, for example, it's much clearer
link |
when the animal is engaged in offensive
link |
versus defensive aggression.
link |
They direct their bites at different parts
link |
of the opponent's body.
link |
Neck versus, offensive aggression is flank directed.
link |
Defensive aggression goes for the neck,
link |
goes for the throat.
link |
I've seen some nature specials
link |
where in a very barbaric way, at least to me,
link |
it seems like hyenas will try and go after
link |
the reproductive axis.
link |
They'll go after testicles and penis.
link |
And they basically want to,
link |
it seems they want to limit future breeding potential.
link |
Or create pain or both.
link |
Yeah, I mean, in terms of offensive aggression
link |
and your reflection that it doesn't feel good,
link |
I mean, I can say,
link |
I know some people who really enjoy fighting.
link |
I have a relative who is a lawyer.
link |
He loves to argue and fight.
link |
I don't think of him as physically aggressive.
link |
In fact, he's not,
link |
but loves to fight and loves to prosecute
link |
and go after people and he's pretty effective at it.
link |
I have a friend, former military special operations
link |
and very calm guy,
link |
had a great career in military special operations.
link |
And he'll quite plainly say, I love to fight.
link |
It's one of my great joys.
link |
He really enjoyed his work.
link |
And also respected the other side
link |
because they offered the opportunity to test that
link |
and to experience that joy.
link |
So in a kind of bizarre way to somebody like me
link |
who I'll certainly defend my stance if I need to,
link |
but I certainly don't consider myself
link |
somebody who offensively goes after people
link |
just to go after them.
link |
There's no quote unquote dopamine hit here,
link |
acknowledging that dopamine does many things, of course.
link |
I have a couple of questions
link |
about the way you describe the circuitry.
link |
I should say the way the circuitry is arranged.
link |
And of course we don't know
link |
because we weren't consulted at the design phase,
link |
but why do you think there would be such a close positioning
link |
of neurons that can elicit
link |
such divergent states and behaviors?
link |
I mean, you're talking about this pear shaped structure
link |
where the neurons that generate fear
link |
are cheek to jowl with the neurons
link |
that generate offensive aggression of all things.
link |
It's like putting the neurons that control swallowing
link |
next to the neurons that control vomiting.
link |
It just seems to me that on the one hand,
link |
this is the way that neural circuits are often arranged.
link |
And yet to me, it's always been perplexing
link |
as to why this would be the case.
link |
Yeah, I think that is a very profound question.
link |
And I've wondered about that a lot.
link |
If you think from an evolutionary perspective,
link |
it might have been the case that defensive behaviors
link |
and fear arose before offensive aggression,
link |
because animals first and foremost
link |
have to defend themselves from predation by other animals.
link |
And maybe it's only when they're comfortable
link |
with having warded off predation and made themselves safe
link |
that they can start to think about
link |
who's gonna be the alpha male in my group here.
link |
And so it could be that if you think that brain regions
link |
and cell populations evolved by duplication
link |
and modification of preexisting cell populations,
link |
that might be the way that those regions
link |
wound up next to each other.
link |
And developmentally, they start out
link |
from a common pool of precursors
link |
that expresses the same gene,
link |
the fear neurons and the aggression neurons.
link |
And then with development,
link |
it gets shut off in the aggression neurons
link |
and maintained in the fear neurons.
link |
Now that view says, oh, it's an accident
link |
of evolution and development,
link |
but I think there must be a functional part as well.
link |
So one thing we know about offensive aggression
link |
is that strong fear shuts it down.
link |
Whereas defensive aggression, at least in rats,
link |
is actually enhanced by fear.
link |
It's one of the big differences between defensive aggression
link |
and offensive aggression.
link |
And you think about it, if you think about it,
link |
if offensive aggression is rewarding and pleasurable,
link |
if you start to get really scared,
link |
that tends to take the fun out of it.
link |
And maybe these two regions are close to each other
link |
to facilitate inhibition of aggression by the fear neurons.
link |
We know for a fact that if we deliberately stimulate
link |
those fear neurons at the top of the pair,
link |
when two animals are involved in a fight,
link |
it just stops the fight dead in its tracks
link |
and they go off into the corner and freeze.
link |
So at least hierarchically,
link |
it seems like fear is the dominant behavior
link |
over offensive aggression.
link |
And how that inhibition would work is not clear
link |
because all these neurons are pretty much excitatory.
link |
They're almost all glutamatergic.
link |
And so one of the interesting questions for the future
link |
is how exactly does fear dominate over
link |
and shut down offensive aggression in the brain?
link |
How does that work?
link |
Is it all circuitry?
link |
Are there chemicals involved?
link |
What's the mechanism and when is it called into play?
link |
But I think that's the way I tend to think about
link |
why these neurons are all mixed up together.
link |
And it's not just fight and freezing or fight and flight.
link |
There are also metabolic neurons
link |
that are mixed together in VMH as well.
link |
Controlling body-wide metabolism?
link |
Yeah, there are neurons there that respond to glucose.
link |
When glucose goes up in your bloodstream,
link |
they're activated.
link |
And VMH has a whole history in the field of obesity
link |
because if you destroy it in a rat, you get a fat rat.
link |
So the way most of the world thinks about VMH
link |
is they think about,
link |
oh, that's the thing that keeps you from getting fat.
link |
It's the anti-obesity area.
link |
But in the area of social behavior,
link |
we see it as a center for control of aggression
link |
and fear behaviors.
link |
And again, why these neurons and these functions,
link |
I like to call them the four Fs,
link |
feeding, freezing, fighting, and mating,
link |
that they all seem to be closely intermingled
link |
with each other, maybe because crosstalk between them
link |
is very important to help the animal's brain
link |
decide what behavior to prioritize
link |
and what behavior to shut down at any given moment.
link |
One of the things that we will do
link |
is link to the incredible videos of these mice
link |
that have selective stimulation of neurons in the VMH,
link |
DAUs and the other studies that you've done.
link |
Whenever I teach, I show those videos at some point
link |
with the caveats and warnings that are required
link |
when one is about to see a video of a mouse
link |
trying to mate with another mouse
link |
or mating with another mouse.
link |
And they seem both to be quite happy
link |
about the mating experience,
link |
at least as far as we know as observers of mice.
link |
And then upon stimulation of those VMH neurons,
link |
one of the mice essentially tries to kill the other mouse.
link |
And then when that stimulation is stopped,
link |
they basically go back to hanging out.
link |
They don't go right back to mating.
link |
There's some reconciliation clearly
link |
that needs to happen first, we assume.
link |
But it's just so striking.
link |
I think equally striking is the video
link |
where the mouse is alone in there with the glove.
link |
The VMH neurons are stimulated and the mouse goes into a rage
link |
it looks like it wants to kill the glove basically.
link |
So striking, I encourage people to go watch those
link |
because it really puts a tremendous amount of color
link |
on what we're describing.
link |
And it's just the idea that there are switches in the brain
link |
to me really became clear upon seeing that.
link |
One of the concepts, excuse me,
link |
one of the concepts that you've raised
link |
in your lectures before and that I think was Hess's idea
link |
is this idea of a sort of hydraulic pressure,
link |
or maybe it was Conrad, I can't speak now, excuse me,
link |
Conrad Lorenz, Martin, who talked about
link |
a kind of hydraulic pressure towards behavior.
link |
I'm fascinated by this idea of hydraulic pressure
link |
because I don't consider myself a hot tempered person,
link |
but I am familiar with the fact that when I lose my temper,
link |
it takes quite a while for me to simmer down.
link |
I can't think about anything else.
link |
I don't want to think about anything else.
link |
In fact, trying to think about anything else
link |
becomes aversive to me,
link |
which to me underscores this notion of prioritization
link |
of the different states and potentially conflicting states.
link |
What do you think funnels into this idea
link |
of hydraulic pressure toward a state?
link |
And why is it perhaps that sometimes we can be very angry
link |
and if we succeed in winning an argument,
link |
all of a sudden it will subside?
link |
Because clearly that means that there are external influences
link |
it's a complex space here that we're creating.
link |
I realize I'm creating a bit of a cloud
link |
and I'm doing it on purpose because to me,
link |
the idea of a hydraulic pressure towards a state like sleep,
link |
there's a sleep pressure, there's a pressure towards,
link |
that all makes sense, but what's involved?
link |
Is it too multifactorial to actually separate out
link |
the variables, but what's really driving hydraulic pressure
link |
toward a given state?
link |
Yeah, so a really important question.
link |
I think one way that is helpful, at least for me,
link |
to break this question apart and think about it
link |
is to distinguish homeostatic behaviors
link |
that is need-based behaviors where the pressure is built up
link |
because of a need, like I'm hungry, I need to eat,
link |
I'm thirsty, I need to drink, I'm hot,
link |
I need to get to a cold place.
link |
It's basically the thermostat model of your brain.
link |
You have a set point and then if the temperature
link |
gets too hot, you turn on the AC
link |
and if the temperature gets too cold,
link |
you turn on the heater and you put yourself
link |
back to the set point.
link |
I don't think that's how aggression works.
link |
That is, it's not that we all go around,
link |
at least subjectively, I don't go around
link |
with an accumulating need to fight,
link |
which I then look for something to,
link |
an excuse to release it.
link |
Now, maybe there are people that do that
link |
and they go out and look for bar fights to get into.
link |
Twitter seems to, I'm sort of half joking
link |
because Twitter seems to draw a reasonably sized crowd
link |
of people that are there for combat of some sort,
link |
even though the total intellectual power
link |
of any of their comments is about that of a cap gun.
link |
They seem to really like to fire off that cap gun.
link |
Before we continue with today's discussion,
link |
I'd like to just briefly acknowledge our sponsor,
link |
Athletic Greens, now called AG1.
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Athletic Greens, AKA AG1, is an all-in-one
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The reason I started taking Athletic Greens
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and the reason I still drink Athletic Greens twice a day
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Again, you can go to athleticgreens.com slash Huberman
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to claim that special offer.
link |
So you can think of this accumulated hydraulic pressure
link |
either being based on something that you were deprived of,
link |
creating an accumulating need,
link |
or something that you want to do,
link |
building up a drive or a pressure to do that.
link |
And the natural way to think about that, at least for me,
link |
is as gradual increases in neural activity
link |
in a particular region of the brain.
link |
And so for example, in the area of the hypothalamus
link |
that controls feeding, Scott Stearnsen and others
link |
have shown that the hungrier you get,
link |
the higher the level of activity in that region
link |
And then when you eat, boom,
link |
the activity goes right back down again.
link |
And that state is actually negatively valence.
link |
So it's like the animal, quote unquote,
link |
feels increasingly uncomfortable,
link |
just like we feel increasingly uncomfortable
link |
the hungrier we are.
link |
And then when we eat, it taps it down.
link |
But there is this increased activity.
link |
And I think in the case of aggression,
link |
our data and others show that the more strongly
link |
you drive this region of the brain optogenetically,
link |
the more of just a hair trigger you need
link |
to set the animal off to get it to fight.
link |
Now, the interesting thing is that if there is nothing
link |
for the animal to attack, it doesn't really do much
link |
when you're stimulating this region.
link |
It sort of wanders around the cage a little bit more,
link |
but it will not actually show overt attack
link |
unless you put something in front of it.
link |
And the same thing is true for the areas we've described
link |
that control mating behavior.
link |
This is what Lindsay is working on.
link |
You can stimulate those areas till you're blue in the face
link |
and the mouse just sort of wanders around.
link |
But if you put another mouse in, wham,
link |
he will try to mount that mouse.
link |
If you put a kumquat in the cage,
link |
he'll try to mount the kumquat.
link |
And so it becomes a sort of any port in the storm.
link |
So there is this idea that the drive is building up pressure
link |
that somehow needs to be released
link |
where that pressure is actually being exerted.
link |
If you accept that it's increased activity
link |
in some circuit or circuits someplace,
link |
what is it pushing up against that needs something else
link |
to sort of unplug it in the Lorentz hydraulic model?
link |
That is, you don't see the behavior
link |
until you release a valve on this bucket
link |
and let the accumulated pressure flow out.
link |
And that's one of the things we're trying to study
link |
in the context of the mating behavior as well.
link |
How does the information that there's an object
link |
in front of you come together with this drive state
link |
that is generated by stimulating these neurons
link |
in the hypothalamus to say, okay, pull the trigger and go,
link |
it's time to mate, it's time to attack.
link |
And we're just starting to get some insights into that now.
link |
Fascinating, and I should mention to people,
link |
Dr. Anderson mentioned Lindsay.
link |
Lindsay is a former graduate student of mine
link |
that's now a postdoc in David's lab.
link |
And I haven't caught up with her recently
link |
to hear about these experiments, but they sound fascinating.
link |
I would love to spend some time on this issue
link |
of why is it that a mouse won't attack nothing,
link |
but it'll attack even a glove or,
link |
and why, well, we'll only try and mate
link |
if there's another mouse to mate with.
link |
It's actually, I think fortunately for you,
link |
you're not spending a lot of time
link |
on Twitter and Instagram or YouTube,
link |
but there's this whole online community that exists now.
link |
As far as I know, it's almost exclusively young males
link |
who are obsessed with this idea.
link |
I'll just say it has a name,
link |
it's called NoFap of no masturbation
link |
as a way to maintain their motivation to go out
link |
and actually seek mates because of the ready availability
link |
of online pornography.
link |
There's probably a much larger population of young males
link |
that are never actually going out and seeking mates
link |
because they're getting porn addicted, et cetera.
link |
There's actually a serious issue that came up
link |
in our episode with Anna Lemke who wrote the book,
link |
Dopamine Nation, because the availability of pornography,
link |
there's a whole social context that's being created
link |
around this and genuine addiction.
link |
So humans are not like the mice
link |
or mice are not like the humans.
link |
Humans seem to resolve the issue on their own
link |
in ways that might actually impede seeking and finding
link |
of sexual partners and or long-term mates.
link |
So serious issue there.
link |
I raise it as a serious issue that I hear a lot about
link |
because I get asked hundreds, if not thousands
link |
of questions about this.
link |
Is there any physiological basis for what they call NoFap?
link |
And I never actually replied because there's no data,
link |
but what you're raising here is a very interesting
link |
mechanistic scenario that can,
link |
as you mentioned, is being explored.
link |
So what do we know about the internal state
link |
of a mouse whose VMH is being stimulated
link |
or a mouse whose other brain region
link |
that can stimulate the desire to mate?
link |
What do we know about the internal state of that mouse
link |
if it's just alone in the cage wandering around?
link |
Is it wandering around really wanting to mate
link |
and really wanting to fight?
link |
We of course don't know, but is its heart rate up?
link |
Is its blood pressure up?
link |
Is it wishing that there was pornography?
link |
Is it, something's going on presumably
link |
that's different than prior to that stimulation
link |
and is it arousal?
link |
And what do you think it is about the visual
link |
or olfactory perception of a conspecific
link |
that ungates this tremendous repertoire of behaviors?
link |
Right, that is the central question.
link |
I can say at least with respect to the fear neurons
link |
that sit on top of the aggression neurons,
link |
we know that when those neurons are activated
link |
optogenetically in the same way we would activate
link |
the aggression neurons that there's clearly an arousal
link |
process that's occurring.
link |
You can see the pupils dilate in the animal.
link |
There is an increase in stress hormone release
link |
into the bloodstream.
link |
We've shown that heart rate goes up.
link |
So in addition to the drive to actually freeze
link |
which is what those animals do,
link |
there is autonomic arousal and neuroendocrine activation
link |
of stress responses.
link |
And some of that is probably shared
link |
by the aggression neurons and the mating neurons
link |
although we haven't investigated it in as much detail.
link |
But I wouldn't be surprised because they project
link |
to many of the same regions that the fear neurons
link |
project to which is a interesting issue in the context
link |
to discuss later maybe in the context of why
link |
we're comfortable with mental illnesses that are based
link |
on maladaptations of fear but not mental illnesses
link |
that are based on maladaptations of aggression
link |
if they have pretty similar circuits in the brain.
link |
But that's how I would imagine there is
link |
an arousal dimension as you say.
link |
There are stress hormones that are activated.
link |
These regions, VMH projects to about 30 different regions
link |
in the brain and it gets input
link |
from about 30 different regions.
link |
So I kind of see it as both an antenna
link |
and a broadcasting center.
link |
It's like a satellite dish that takes in information
link |
from different sensory modalities, smell,
link |
maybe vision, mechanosensation and then it sort
link |
of synthesizes and integrates that into
link |
a fairly low dimensional as the computational people
link |
call it representation of this pressure to attack
link |
and it broadcasts that all over the brain
link |
to trigger all these systems that have to be brought
link |
into play if the animal is gonna engage in aggression
link |
because aggression is a very risky thing
link |
for an animal to engage in.
link |
It could wind up losing and it could wind up getting killed
link |
and so its brain constantly has to make
link |
a cost benefit analysis of whether to continue
link |
on that path or to back off as well.
link |
And I think that part of this broadcasting function
link |
of this region is engaging all these other brain domains
link |
that play a role in this kind of cost benefit analysis.
link |
I wanna talk more about mating behavior,
link |
but as a segue to that, as we're talking about aggression
link |
and mating behavior, I think hormones.
link |
And whenever there's an opportunity on this podcast
link |
to shatter a common myth, I grab it.
link |
One of the common myths that's out there
link |
and I think that persists is that testosterone
link |
makes animals and humans aggressive
link |
and estrogen makes animals placid and kind or emotional.
link |
And as we both know, nothing could be further
link |
from the truth, although there's some truth to the idea
link |
that these hormones are all involved.
link |
Robert Sapolsky supplied some information to me
link |
when he came on this podcast that if you give people
link |
exogenous testosterone, it tends to make them more
link |
of the way they were before.
link |
If they were a jerk before, they'll become more of a jerk.
link |
If they were very altruistic, they'll become more altruistic.
link |
And then eventually I pointed out you'll aromatize
link |
that testosterone and estrogen
link |
and you'll start getting opposite effects.
link |
So it's a murky space, it's not straightforward.
link |
But if I'm not mistaken, testosterone plays a role
link |
in generating aggression.
link |
However, the specific hormones that are involved
link |
in generating aggression via VMH are things other
link |
than testosterone.
link |
Can you tell us a little bit more about that?
link |
Because there's some interesting surprises in there.
link |
Yeah, that's a really important question.
link |
So when we finally identified the neurons in VMH
link |
that control aggression with a molecular marker,
link |
we found out that that marker was the estrogen receptor.
link |
So that might strike you as a little strange.
link |
Why should aggression promoting neurons in male mice
link |
be labeled with the estrogen receptor?
link |
Other labs have shown that the estrogen receptor
link |
in adult male mice is necessary for aggression.
link |
If you knock out the gene in VMH, they don't fight.
link |
And it's been shown, and a lot of this is work
link |
from your colleague Nirav Shah at Stanford,
link |
who is one of my former PhD students,
link |
that if you castrate a mouse and it loses the ability
link |
to fight, not only can you rescue fighting
link |
with a testosterone implant, but you can rescue it
link |
with an estrogen implant.
link |
So you can bypass completely the requirement
link |
for testosterone to restore aggressiveness to the mice.
link |
And as you say, it's because many of the effects
link |
of testosterone, although not all, many of them
link |
are mediated by its conversion to estrogen
link |
by a process called aromatization.
link |
It's carried out by an enzyme called aromatase.
link |
In fact, people may have, most of your listeners
link |
may have heard of aromatase, because aromatase inhibitors
link |
are widely used in female humans
link |
as adjuvant chemotherapy for breast cancer.
link |
They are a way of reducing the production of estrogen
link |
by preventing testosterone
link |
from being converted into estrogen.
link |
And in fact, there are a lot of animal experiments
link |
showing if you give males aromatase inhibitors,
link |
they stop fighting as well as also stop
link |
being sexually active.
link |
And so that's one of the counterintuitive ideas.
link |
And Nirao has shown that progesterone also seems
link |
to play a role in aggression,
link |
because these aggression neurons also express
link |
the progesterone receptor.
link |
So here are two hormones that are classically thought of
link |
as female reproductive hormones.
link |
This is what goes up and goes down during the estrus cycle,
link |
estrogen and progesterone,
link |
and yet they're playing a very important role
link |
in controlling aggression in male mice,
link |
and presumably in male humans as well.
link |
So estrogen is doing many more things
link |
than I think most people believe,
link |
and testosterone is doing maybe different
link |
and fewer things in some cases and more in others.
link |
I've known some aggressive females
link |
over the time I've been alive.
link |
What's involved in female aggression that's unique
link |
from the pathways that generate male aggression?
link |
Great, great question.
link |
So we and other labs have studied this
link |
in both mice and also in fruit flies.
link |
So one thing in mice that distinguishes aggression
link |
in females from males is that male mice
link |
are pretty much ready to fight at the drop of a hat.
link |
Female mice only fight when they are nurturing
link |
and nursing their pups after they've delivered a litter,
link |
and there's a window there
link |
where they become hyper aggressive,
link |
and then after their pups are weaned,
link |
that aggressiveness goes away.
link |
So this is pretty remarkable
link |
that you take a virgin female mouse
link |
and expose it to a male,
link |
and her response is to become sexually receptive
link |
and to mate with him,
link |
and now you let her have her pups
link |
and you put the same male or another male mouse
link |
in the cage with her,
link |
and instead of trying to mate with him, she attacks him.
link |
So there is some presumably hormonal
link |
and also neuronal switch that's occurring in the brain
link |
that switches the response of the female
link |
from sex to aggression
link |
when she goes from virginity to maternity,
link |
and we recently showed in a paper,
link |
this is work from one of my students, Mungu Liu,
link |
that within VMH in females,
link |
there are two clearly divisible subsets
link |
of estrogen receptor neurons,
link |
and she showed that one of those subsets controls fighting
link |
and the other one controls mating,
link |
and in fact, if you stimulate
link |
the fighting-specific subset in a virgin,
link |
you can get the virgin to attack,
link |
which is something that we were never able to do before,
link |
and if you stimulate the mating one, you enhance mating.
link |
The reason we could never get these results
link |
when we stimulated the whole population
link |
of estrogen receptor neurons
link |
is that these effects are opposite and they cancel out,
link |
and so it turns out that if you measure the activity
link |
of the fighting and the mating neurons
link |
going from a virgin to a maternal female,
link |
the aggression neurons are very low
link |
in their activity in the virgin,
link |
but once the female has pups,
link |
the activation ability of those neurons goes way up
link |
and the mating neurons stay the same,
link |
so if you think of the balance between them like a seesaw,
link |
in the virgin, there is more activity in the mating neurons
link |
than in the fighting neurons,
link |
whereas in the nursing mother,
link |
there's more activity or more activation
link |
in the other way around, the fighting neurons in the mating.
link |
Did I say fighting and mating in the first?
link |
Mating neurons dominate fighting in the virgin,
link |
fighting neurons dominate mating in the mother,
link |
so that's a really cool observation,
link |
and it's not something that happens in males,
link |
and we don't know what causes that or controls that.
link |
Interestingly, this gets into the whole issue
link |
of neurons that are present in females but not in males,
link |
so we've known for, the field has known for a long time
link |
that male and female fruit flies have sex-specific neurons,
link |
and most of the neurons that we've identified
link |
in fruit flies that control fighting in males
link |
are male-specific.
link |
They're not found in the female brain,
link |
but recently, we discovered a set of female-specific
link |
fighting neurons in the female brain,
link |
together with a couple of other laboratories.
link |
Now, they do share one common population of neurons
link |
in both male and female flies
link |
that in females activates the female-specific
link |
fighting neurons and in males activates
link |
the male-specific fighting neurons,
link |
so it's kind of a hierarchy with this common neuron on top,
link |
and in mice, we discovered that there are
link |
male-specific neurons in VMH,
link |
and those neurons are activated during male aggression.
link |
Now, the neurons that are active in females
link |
when females fight in VMH are not sex-specific,
link |
so they are also found in males,
link |
so this is already showing you some complexity.
link |
The male mouse VMH has both male-specific
link |
aggression neurons and generic aggression neurons,
link |
and then the female VMH, the mating cells,
link |
are only found in females.
link |
They are female-specific and not found in the male brain,
link |
and so we're trying to find out
link |
what these sex-specific populations of neurons are doing,
link |
but that indicates that that is some of the mechanism
link |
by which different sexes show different behaviors.
link |
I'm fixated on this transition
link |
from the virgin female mouse to the maternal female mouse,
link |
I have a couple of questions about whether or not,
link |
for instance, the transition is governed
link |
by the presence of pups.
link |
So for instance, if you take a virgin female,
link |
she'll mate with a male.
link |
Once she's had pups, she'll try and fight that male
link |
or presumably another intruder female, right?
link |
Equally towards females and male intruders.
link |
Does that require the presence of her pups,
link |
meaning if you were to take those pups
link |
and give them to another mother,
link |
does she revert to the more virgin-like behavior?
link |
Is it related to, is it triggered by lactation
link |
or could it actually be triggered
link |
by the mating behavior itself?
link |
Because it's possible for the virgin to become a non-virgin,
link |
but not actually have a litter of pups.
link |
Right, those are all great questions
link |
and we don't know the answer to most of them.
link |
What I can say is that a nursing mother
link |
doesn't have to have her pups with her in the cage
link |
in order to attack an intruder male or an intruder female.
link |
She is just in a state of brain
link |
that makes her aggressive to any intruder.
link |
And those aggression neurons in that female's brain
link |
are activated by both male and female intruders equally.
link |
Whereas in male mice, the aggression neurons
link |
are only ever activated by males, not by females,
link |
because males are never supposed to attack females.
link |
They're only supposed to mate with them.
link |
So that's another difference in how those neurons
link |
are tuned to signals from different conspecifics.
link |
Does it require lactation?
link |
I don't know the answer to that.
link |
I think there are some experiments
link |
where people have tried to, classical experiments,
link |
people have tried to reproduce the changes in hormones
link |
that occur during pregnancy in female rats
link |
to see if it can make them aggressive.
link |
And some of those manipulations do to some extent,
link |
but there's a whole biology there
link |
that remains to be explored
link |
about how much of this is hormones,
link |
how much of this is circuitry and electricity,
link |
and how much of it is other factors
link |
that we haven't identified yet.
link |
I don't want to anthropomorphize,
link |
but well, I'll just ask the question.
link |
So the other day I was watching ferrets mate, right?
link |
Mustelids, they're mustelids and they're mating behavior.
link |
I guess I didn't say why I was watching this.
link |
Doesn't matter, it simply doesn't matter.
link |
But if one observes the mating behaviors
link |
of different animals,
link |
we know that there's a tremendous range
link |
of mating behaviors in humans.
link |
There can be no aggressive component,
link |
there could be aggressive component.
link |
Humans have all sorts of kinks and fetishes and behaviors,
link |
and most of which probably has never been documented
link |
because most of this happens in private.
link |
And here I always say on this podcast,
link |
anytime we're talking about sexual behavior in humans,
link |
we're always making the presumption
link |
that it's consensual, age appropriate,
link |
context appropriate, and species appropriate.
link |
Let's say we're talking about a lot of different species.
link |
With that said, just to set context,
link |
I was watching this video of ferrets mating
link |
and it's quite violent actually.
link |
There's a lot of neck biting, there's a lot of squealing.
link |
If I were going to project an anthropomorphize,
link |
I'd say it's not really clear they both want to be there.
link |
One would make that assumption.
link |
And of course we don't know, we have no idea.
link |
This could be the ritual.
link |
But it seems to me that there is some crossover
link |
of aggression and mating behavior circuitry
link |
during the act of mating.
link |
And do you think that reflects this sort of
link |
stew of competing neurons
link |
that are prioritizing in real time?
link |
Because of course, as states, they have persistence,
link |
And you can imagine that states overlapping
link |
in four different states, the motivational drive to mate,
link |
the motivational drive to get away from this experience,
link |
the motivational drive to eat at some point,
link |
to defecate at some point,
link |
all of these things are competing.
link |
And what we're really seeing is a bias in probabilities.
link |
But when you look at mating behavior of various animals,
link |
you see an aggressive component sometimes, but not always.
link |
Is it species specific?
link |
Is it context specific?
link |
And more generally, do you think that there is crosstalk
link |
between these different neuronal populations
link |
and the animal itself might be kind of confused
link |
about what's going on?
link |
Right, great, great questions.
link |
I can't really speak to the issue
link |
of whether this is species specific
link |
because I'm not a naturalist or a zoologist.
link |
I've seen, like you have, in the wild,
link |
for example, lions when they mate.
link |
I've seen them in Africa.
link |
There's often a biting component of that as well.
link |
One of the things that surprised us
link |
when we identified neurons in VMHVL
link |
that control aggression in males
link |
is that within that population,
link |
there is a subset of neurons that is activated by females
link |
during male-female mating encounters.
link |
Now, you don't generally think of mouse sex as rough sex,
link |
but there is a lot of what superficially looks
link |
like violent behavior sometimes,
link |
especially if the female rejects the male and runs away.
link |
And there's some evidence
link |
that those female selective neurons in VMH
link |
are part of the mating behavior.
link |
If you shut them down, the animals don't mate
link |
as effectively as they otherwise would.
link |
What happens when you stimulate them?
link |
We don't yet know because we don't have a way
link |
to specifically do that without activating
link |
the male aggression neurons.
link |
But I think they must be there for a reason
link |
because VMH is not traditionally the brain region
link |
to which male sexual behavior has been assigned.
link |
That's another area called the medial preoptic area.
link |
And there we have shown that there are neurons
link |
that definitely stimulate mating behavior.
link |
In fact, if we activate those mating neurons
link |
in a male while it's in the middle
link |
of attacking another male, it will stop fighting,
link |
start singing to that male and start to try
link |
to mount that male until we shut those neurons off.
link |
So those are the make love not war neurons
link |
and VMH are the make war not love neurons.
link |
And there are dense interconnections
link |
between these two nuclei,
link |
which are very close to each other in the brain.
link |
And we've shown that some of those connections
link |
are mutually inhibitory to prevent the animal
link |
from attacking a mate that it's supposed to be mating with
link |
or to prevent it from mating with an animal
link |
it's supposed to be attacking.
link |
But it's also possible that there are
link |
some cooperative interactions between those structures
link |
as well as antagonistic interactions
link |
and the balance of whether it's the cooperative
link |
or antagonistic interactions that are firing
link |
at any given moment in a mating encounter,
link |
as you suggest, may determine whether a moment
link |
of coital bliss among two lions may suddenly turn
link |
into a snap or a growl and a bearing of fangs.
link |
We don't know that, but certainly the substrate,
link |
the wiring is there for that to happen.
link |
I'm sure people's minds are running wild with all this.
link |
I'll just use this as an opportunity to raise something
link |
I've wondered about for far too long,
link |
which is I have a friend who's a psychiatrist
link |
who works on the treatment of fetishes.
link |
This is not a psychiatrist that I was treated by.
link |
I'll just point that out.
link |
But they mentioned something very interesting to me
link |
long ago, which is that when you look at true fetishes
link |
and what meets the criteria for fetish,
link |
that there does seem to be some,
link |
what one would think would be competing circuitry
link |
that suddenly becomes aligned.
link |
For instance, avoidance of feces, dead bodies, feet,
link |
things that are very infectious.
link |
Typically, those states of disgust are antagonistic
link |
to states of desire, as one would hope is present
link |
during sexual behavior.
link |
Fetishes often involve exactly those things
link |
that are aversive, feet, dead bodies,
link |
disgusting things to most people.
link |
And true fetishes in the pathologic sense
link |
exist when people have basically a requirement
link |
for thinking about, or even the presence
link |
of those ordinarily disgusting things
link |
in order to become sexually aroused,
link |
as if the circuitry has crossed over.
link |
And the statement that rung in my mind was
link |
people don't develop fetishes to mailboxes
link |
or to the color red or to random objects and things.
link |
They develop fetishes to things that are highly infectious
link |
and counter reproductive, repetitive states.
link |
So I find that interesting.
link |
I don't know if you have any reflections on that
link |
as to why that might be.
link |
I'm tempted to ask whether or not you've ever observed
link |
fetish-like behavior in mice,
link |
but I find it fascinating that you have this area
link |
of the brain that's so highly conserved, the hypothalamus,
link |
which you have these dense populations intermixed
link |
and that the addition of a forebrain,
link |
especially in humans that can think and make decisions
link |
could in some ways facilitate the expression
link |
of these primitive behaviors,
link |
but could also complicate the expression
link |
of primitive behaviors.
link |
Right, I would agree.
link |
I think one way of looking at fetishes
link |
from a neurobiological standpoint
link |
is that they represent a kind of repetitive conditioning
link |
where something that is natively aversive or disgusting
link |
by being repeatedly paired with a rewarding experience
link |
changes its valence, its sign,
link |
so that now it somehow produces the anticipation of reward
link |
the next time a person sees it.
link |
Now, I don't know how,
link |
I don't know that literature in animals,
link |
so I don't know if you could condition a mouse
link |
to eat feces, for example,
link |
although there are animals that are naturally coprophagic.
link |
That is, and maybe mice do that occasionally, I'm not sure,
link |
but that is one way to think about it,
link |
and that could certainly involve in humans
link |
the more recently evolved parts of the brain,
link |
the cortex that is sort of orchestrating
link |
both what behaviors are happening
link |
and whether reward states are turning on
link |
in association with those behaviors that are happening,
link |
and that's the part that I think is difficult
link |
and challenging to study in a mouse,
link |
but certainly bears thinking about
link |
because it's a really interesting,
link |
again, sort of counterintuitive aspect,
link |
again, like rough sex,
link |
people that want to have fighting or violence
link |
or aggressiveness in order to be sexually aroused
link |
and fetishes, and in fact,
link |
when we made that discovery initially,
link |
it raised the question in my mind
link |
whether some people that are serial rapists,
link |
for example, and engage in sexual violence
link |
might in some level have their wires crossed in some way
link |
that these states that are supposed to be
link |
pretty much separated and mutually antagonistic
link |
are not and are actually more rewarding and reinforcing.
link |
I think it's gonna be a long time
link |
before we have figured it out,
link |
but when you think about it,
link |
there is no treatment that we have
link |
for a violent sexual offender that eliminates the violence,
link |
but not the sexual desire and sexual urge,
link |
whether it's physical castration or chemical castration,
link |
it eliminates both.
link |
Definitely an area that I think,
link |
well, human neuroscience in general needs a lot of tools,
link |
in terms of how to probe and manipulate neural circuitry.
link |
I'd love to turn to this area that you mentioned,
link |
the medial preoptic area.
link |
I'm fascinated by it because just as within the VMH,
link |
you have these neurons for mating and fighting or aggression,
link |
my understanding is medial preoptic area
link |
contains neurons for mating, but also for
link |
temperature regulation.
link |
And perhaps I'm making too much of a leap here,
link |
but I've always wondered about this phrase in heat.
link |
As certainly the menstrual or estrous cycle in females
link |
is related to changes in body temperature.
link |
In fact, measuring body temperature is one way
link |
that women can fairly reliably predict ovulation, et cetera.
link |
Although additional, this is not a show about contraception,
link |
please rely on multiple methods as necessary.
link |
Don't use this discussion as your guide for contraception
link |
based on temperature.
link |
But if you stimulate certain neurons
link |
in the medial preoptic area,
link |
you can trigger dramatic changes in body temperature
link |
and or mating behavior.
link |
What's the relationship, if any,
link |
between temperature and mating, or do we simply not know?
link |
I don't know what the relationship is
link |
between temperature and mating neurons
link |
in the preoptic area.
link |
I suspect that they are different populations of neurons
link |
because it's become pretty clear that the preoptic area
link |
has many different subsets of neurons
link |
that are specifically active during different behaviors,
link |
even different phases of mating behavior.
link |
So there are mounting neurons,
link |
there are intermission, thrusting neurons,
link |
and ejaculation neurons, and sniffing neurons.
link |
Wait, wait, so I think I've heard this before,
link |
but I just wanna make sure that people get this,
link |
and I wanna make sure I get this.
link |
So you're telling me within the medial preoptic area,
link |
there are specific neurons that if you stimulate them
link |
will make males thrust as if they're mating?
link |
No, so this is not based on stimulation experiments.
link |
It's based on imaging experiments right now
link |
that we see when we look in the preoptic area
link |
at what neurons are active
link |
during different phases of aggression,
link |
we see that there are different neurons
link |
that are active during sniffing,
link |
mounting, thrusting, and ejaculation,
link |
and they become repeatedly activated
link |
each time the animal goes through that cycle.
link |
During the mating cycle.
link |
There are also some neurons there
link |
that are active during aggression, which are distinct,
link |
and we don't know whether those neurons are there
link |
to promote aggression or to inhibit mating
link |
when animals are fighting.
link |
We have some evidence that suggests it may be the latter,
link |
but we don't know for sure yet.
link |
The thermosensitive neurons are really interesting
link |
because you mentioned the phrase in heat,
link |
and then in the context of aggression,
link |
you talk about hot-blooded people or hotheads.
link |
There's just recently a paper showing
link |
there are thermoregulatory neurons in VMH as well.
link |
So all of these homeostatic systems for metabolic control
link |
and temperature control are intermingled in these nuclei,
link |
these zones that control these basic survival behaviors
link |
like mating and aggression and predator defense.
link |
And I would imagine that the thermoregulation
link |
is tightly connected to energy expenditure
link |
and that, again, these neurons are mixed together
link |
to facilitate integration of all these signals
link |
by the brain in some way that we don't understand
link |
to maintain the proper balance
link |
between energy conservation and energy consumption
link |
during this particular behavior or that behavior.
link |
I mean, I've always been fascinated by the question,
link |
why is it that violence goes up in the summertime
link |
when the temperatures are high?
link |
Does it really have something to do with the idea
link |
that increased temperature increases violence?
link |
Seems hard to believe because we're homeothermic
link |
and we pretty much stay around 98.6 Fahrenheit.
link |
Could be other social reasons why that happens.
link |
People are outside out on the street
link |
bumping into each other.
link |
But I think there could well be something
link |
that ties thermoregulation to aggressiveness
link |
as well as to mating behavior.
link |
I asked in the hopes that maybe in the years to come,
link |
your lab will parse some of the temperature relationships.
link |
And I realized it could be also regulated
link |
by hormones in general.
link |
So it's tapping into two systems
link |
for completely different reasons.
link |
But anyway, an area that intrigues me
link |
because of this notion of hotheadedness
link |
or cool, common, collected.
link |
And also the fact that,
link |
I probably should have asked about this earlier,
link |
that arousal itself is tethered
link |
to the whole mating and reproductive process.
link |
I mean, without a sort of seesawing back
link |
between the sympathetic and parasympathetic arousal,
link |
relaxed states, there is no mating that will take place.
link |
So it's fascinating the way these different competing forces
link |
and seesaws operate.
link |
Several times during the discussion so far,
link |
we've hit on this idea that the same behavior
link |
can reflect different states
link |
and different states can converge on multiple behaviors
link |
You had a paper not long ago about mounting behavior,
link |
which I found fascinating.
link |
Maybe you could tell us about that result
link |
because to me, it really speaks to the fact
link |
that mounting behavior can in one context be sexual
link |
and in another context actually be related
link |
to we presume dominance.
link |
And I think that my friends who practice jujitsu
link |
will say they, when I talk about that result,
link |
they say, of course, you know,
link |
mounting the other person and dominating them,
link |
there's nothing sexual about it.
link |
It's about overtaking them physically,
link |
literally being on their next side
link |
as opposed to on their own, lying on their own back.
link |
Just fascinating, very primitive.
link |
And yet I think speaks to this idea
link |
that mounting behavior might be one
link |
of the most fundamental ways in which animals
link |
and perhaps even humans express dominance
link |
and or sexual interactions.
link |
Yep, that's a fascinating question.
link |
And it was harder to figure out
link |
than you might've thought.
link |
So we've, there's been this debate for a long time
link |
in the field when you see two male mice mounting each other,
link |
is this homosexual behavior?
link |
Is this a case of mistaken sexual identification
link |
or is this dominance behavior?
link |
And if you train an AI algorithm
link |
to try to distinguish male-male mounting
link |
from male-female mounting, it does not do a very good job
link |
because motorically those behaviors look so similar.
link |
And so how did we wind up figuring out
link |
that most male-male mounting is dominance mounting?
link |
There are two important clues.
link |
One is the context.
link |
And so male-male mounting tends
link |
to be more prominent among mice
link |
when they haven't had a lot of fighting experience.
link |
And then as they become more experienced in fighting,
link |
they will show relatively less mounting
link |
towards the other male and more attack.
link |
And they'll transition quickly from mounting to attack.
link |
And so the mounting is always seen in this context
link |
of an overall aggressive interaction.
link |
And then the second thing, which believe it or not,
link |
was suggested by a computational theoretical person
link |
in my lab, Anne Kennedy,
link |
who now has her own lab at Northwestern.
link |
She said, well, males are known to sing
link |
when they mount females, ultrasonic vocalizations.
link |
Why don't you see what kinds of songs they're singing
link |
when they're mounting males?
link |
Maybe it's a different kind of song.
link |
Well, what we found out is they don't sing at all
link |
when they're mounting a male.
link |
So you can easily distinguish whether mounting behavior
link |
by a male mouse is reproductive or agonistic,
link |
aggressive according to whether it's accompanied
link |
by ultrasonic vocalizations or not.
link |
And it turns out that different brain regions
link |
are maximally active
link |
during these different types of mounting.
link |
So VMH, the aggression locus,
link |
is actually active during dominance mounting,
link |
and you can stimulate mounting if you,
link |
dominance mounting, if you weakly activate VMH,
link |
whereas MPOA is most strongly activated
link |
during sexual mounting,
link |
and that's always accompanied
link |
by the ultrasonic vocalization.
link |
So this shows how difficult and dangerous it can be
link |
to try to infer an animal's state or intent or emotion
link |
from the behavior that it's exhibiting,
link |
because the same behavior can mean very different things
link |
depending on the context
link |
or the interaction with the animal.
link |
And I would say even more so
link |
with when that animal is a human or is multiple humans.
link |
And there are many examples.
link |
Animals show chasing to obtain food,
link |
a prey animal that they're gonna kill and eat,
link |
and they show chasing to obtain a mate
link |
that they're gonna have sex with.
link |
And so the intent of the chasing is completely different,
link |
and we don't know in all these cases
link |
whether there are separate circuits
link |
or common circuits that are being activated.
link |
I'm obsessed with dogs and dog breeds
link |
and et cetera, et cetera.
link |
And one thing I can tell you
link |
is that female dogs will mount and thrust.
link |
We had a female pit bull mix, very sweet dog,
link |
but in observing her, it convinced me
link |
that one can never assume
link |
that male dogs are more aggressive than female dogs.
link |
There's a, it turns out in talking to people
link |
who are quite skilled at dog genetics and dog breeding,
link |
that there's a dominance hierarchy within a litter,
link |
and it crosses over male-female delineations.
link |
So you can get a female in the litter
link |
that's very dominant, a male that's very subordinate,
link |
and no one really knows what relates to.
link |
This is also why little dogs sometimes
link |
will get right up in the face of a big Doberman Pinscher
link |
and just start barking,
link |
which is an idiotic thing for it to do,
link |
but they can be dominant over a much larger dog.
link |
Very strange, to me anyway.
link |
Female-female mounting, do you observe it in mice?
link |
Are there known circuits?
link |
And what evokes female-female mounting,
link |
or female-to-male mounting, if it occurs?
link |
Yes, there is female,
link |
there are clear examples of females
link |
displaying male-type mounting behavior
link |
towards other females.
link |
We see this most commonly in the lab
link |
where we are housing females with their sister,
link |
say three or four in a cage.
link |
We take one out and we have her mate with a male
link |
where the male's doing the mounting.
link |
Now we take that female and we put her back in the cage
link |
with her litter mates and she starts mounting them.
link |
Now what the function of that is,
link |
if it has any function or what it means,
link |
what's driving it, we don't know.
link |
But we do know that if we stimulate the mount,
link |
the neurons that control mounting in males
link |
in the medial preoptic area,
link |
if we stimulate that same population in females,
link |
it evokes male-type mounting
link |
towards either a male or a female target.
link |
In fact, we have a movie where we have a female
link |
that has just been mounted by a male.
link |
So the male's on top and she's underneath
link |
and we stimulate that region of MPOA in the female
link |
and she crawls out from underneath the male
link |
who has just mounted her, circles around behind him
link |
and climbs up on top of him
link |
and starts to try to mount him and thrust at him.
link |
That has a name online, it's called a switch.
link |
Don't ask me how I know that.
link |
But it's a pretty, yeah, it's a term that you hear.
link |
You also hear the term topping from the bottom,
link |
which it sounds like that is a literal topping
link |
from the bottom. I see.
link |
That's more of a psychological phrase from what I hear.
link |
I have friends that are educating me in this language,
link |
mostly because I find this kind
link |
of neurobiological discussion fascinating.
link |
At some point, right, I attempt in my mind
link |
to superimpose observations from the online communities
link |
that I've been told about and asked about to this,
link |
but I should point out it's always dangerous
link |
and in fact, inappropriate to make a one-to-one link.
link |
Humans are, they maintain all the same neural circuitry
link |
and pathways that we're talking about today in mice,
link |
but that forebrain does allow for context, et cetera.
link |
So what the function is of female mounting,
link |
I don't know, it could be a type of dominance display.
link |
It's hard to measure that because people haven't worked
link |
on female dominance hierarchies to the same extent
link |
that they've worked on male dominance hierarchies,
link |
but it indicates that the circuits for male type mounting
link |
are there in females as early work
link |
from Catherine Dulock suggested some years ago.
link |
Fascinating, fascinating.
link |
I love that paper because as you pointed out for Chase,
link |
you know, for mounting behavior, you know,
link |
we see it and we think one thing specifically.
link |
And after hearing this result, actually,
link |
I'm not a big fan of fight sports.
link |
I watch them occasionally because friends are into them,
link |
but I've seen boxing matches, MMA matches,
link |
where at the end of a round,
link |
if someone felt that they dominated,
link |
they will do the unsportsmanlike thing of the thrusting
link |
on the back of the other person before they get off,
link |
almost like I dominated you.
link |
And so mimicking sexual like behavior,
link |
but there's no reason to think that it's sexual,
link |
but they're sending a message of dominance is what implies.
link |
I'd love to talk about something slightly off
link |
from this circuitry, but I think that's related
link |
to the circuitry, at least in some way,
link |
which is this structure that I've always been fascinated by
link |
and I can't figure out what the hell it's for
link |
because it seems to be involved in everything,
link |
which is the PAG, the periaqueductal gray,
link |
which is a little bit further back in the brain
link |
for people that don't know.
link |
It's been studied in the context of pain.
link |
It's been studied in the context
link |
of the so-called lordosis response,
link |
the receptivity or arching of the back of the female
link |
to receive intromission and mating from the male.
link |
How should we think about PAG?
link |
Clearly it can't be involved in everything.
link |
I'm guessing it's at least as complex
link |
as some of these other regions
link |
that we've been talking about,
link |
different types of neurons controlling different things,
link |
but how does PAG play into this?
link |
In particular, I wanna know,
link |
is there some mechanism of pain modulation and control
link |
during fighting and or mating?
link |
And the reason I ask is that,
link |
while I'm not a combat sports person,
link |
years ago I did a little bit of martial arts
link |
and it always was impressive to me
link |
how little it hurt to get punched during a fight
link |
and how much it hurt afterwards, right?
link |
So there clearly is some endogenous pain control
link |
that then wears off and then you feel beat up,
link |
at least in my case, I felt beat up.
link |
What's PAG doing vis-a-vis pain and vis-a-vis,
link |
and what's pain doing vis-a-vis these other behaviors?
link |
So I think of PAG like a old fashioned telephone switchboard
link |
where there are calls coming in
link |
and then the cables have to be punched into the right hole
link |
to get the information to be routed to the right recipient
link |
on the other end of it,
link |
because pretty much every type of innate behavior
link |
you can think of has had the PAG implicated.
link |
There's a whole literature showing the involvement
link |
of the PAG in fear, different regions of the PAG.
link |
The dorsal PAG is involved in panic-like behavior,
link |
The ventral PAG is involved in freezing behavior.
link |
Both the MPOA and VMH send projections to the PAG,
link |
to different regions of the PAG.
link |
So in cross-section, I hate to say this,
link |
but in cross-section,
link |
the PAG kind of looks like the water in a toilet
link |
when you're standing over an open toilet bowl.
link |
And if you imagine a clock face projected onto that,
link |
it's like the PAG has sectors from one to 12,
link |
maybe even more of them.
link |
And in each of those sectors,
link |
you find different neurons from the hypothalamus
link |
So could turn out that there is a topographic arrangement
link |
along the dorsal ventral axis of the PAG
link |
and the medial lateral axis of the PAG
link |
that determines the type of behavior
link |
that will be emitted when neurons in that region
link |
And I think sort of all of the evidence
link |
is pointing in that direction,
link |
but by no means has it been mapped out.
link |
Now, the thing that you mentioned about it not hurting
link |
when you got beat up during martial arts,
link |
there is a well-known phenomenon
link |
called fear-induced analgesia,
link |
where when an animal is in a high state of fear,
link |
like if it's trying to defend itself,
link |
there is a suppression of pain responses.
link |
And I'm not sure completely about the mechanisms
link |
and how well that's understood.
link |
But for example, the adrenal gland has a peptide in it
link |
that is released from the adrenal medulla,
link |
which controls the fight or flight responses.
link |
And that peptide has analgesic activities.
link |
Now whether- Ask what that peptide is.
link |
It's called bovine adrenal medullary peptide
link |
of 22 amino acid residues.
link |
And I only know about it because it activates a receptor
link |
that we discovered many years ago
link |
that's involved in pain, and we thought it promoted pain,
link |
but it turns out that this actually inhibits pain.
link |
It's like an endogenous analgesic.
link |
Whether this is happening, this type of analgesia
link |
is happening when an animal is engaged
link |
in offensive aggression or in mating behavior,
link |
I don't know, but it certainly is possible.
link |
And I don't know whether these analgesic mechanisms
link |
are happening in the PAG.
link |
They could also be happening a little further down
link |
in the spinal cord.
link |
The PAG is really continuous with the spinal cord.
link |
If you just follow it down towards the tail of an animal,
link |
you will wind up in the spinal cord.
link |
And so it could be that there are influences
link |
acting at many levels on pain in the PAG
link |
and in the spinal cord as well.
link |
And it may well be known, I just don't know it.
link |
I wanna distinguish clearly between things
link |
that are not known, that I know are unknown,
link |
which is in a fairly small area where I have expertise
link |
from things that may be known, but I'm ignorant of them
link |
because I just don't have a broad enough knowledge base
link |
Sure, we appreciate those delineations.
link |
I think this description of it
link |
is an old-fashioned telephone switchboard.
link |
And now every time I look into the toilet,
link |
I'll think about the periaqueductal gray.
link |
And every time I see an image of periaqueductal gray,
link |
I'll think about a toilet.
link |
That is an excellent description
link |
because in fact, I drew a circle
link |
with a little thing at the bottom.
link |
Well, I'll put a link to a picture of PAG
link |
and you'll understand why David and I are chuckling here
link |
because indeed it looks like a toilet
link |
when staring into a toilet.
link |
Tell us about tachykinin.
link |
I've talked about this a couple of times
link |
on different podcast episodes
link |
because of its relationship to social isolation.
link |
And in part because the podcast was launched
link |
during a time when there was more social isolation.
link |
My understanding is that tachykinin,
link |
and you'll tell us what it is in a moment,
link |
is present in flies and mice and in humans
link |
and may do similar things in those species.
link |
So, tachykinin is,
link |
refers to a family of related neuropeptides.
link |
So these are brain chemicals.
link |
They're different from dopamine and serotonin
link |
in that they're not small organic molecules.
link |
They're actually short pieces of protein
link |
that are directly encoded by genes
link |
that are active in specific neurons and not in others.
link |
And when those neurons are active,
link |
those neuropeptides are released together
link |
with classical transmitters like glutamate, whatever.
link |
Tachykinins have been famously implicated in pain,
link |
particularly tachykinin-1, which is called substance P,
link |
one of the original pain modulating.
link |
This is something that promotes inflammatory pain.
link |
But there are other tachykinin genes.
link |
In mice, there are two.
link |
In humans, I think there are three.
link |
And in Drosophila, there is one.
link |
And the way we got into tachykinins
link |
is from studying aggression in flies.
link |
We thought, since neuropeptides have this remarkable
link |
parallel evolutionary conservation of structure
link |
and function, like neuropeptide Y controls feeding
link |
in worms, in flies, and mice, and in people,
link |
oxytocin-like peptides control reproduction
link |
in worms and mice and in people,
link |
we thought we might find peptides
link |
that control aggression in flies and in people.
link |
And so we did a screen, unbiased screen of peptides
link |
and found indeed that one of the tachykinins,
link |
Drosophila tachykinin, those neurons,
link |
when you activate them, strongly promote aggression
link |
and it depends on the release of tachykinin.
link |
Now, the interesting thing is that in flies,
link |
just like in people and practically any other social animal
link |
that shows aggression,
link |
social isolation increases aggressiveness.
link |
So putting a violent prisoner in solitary confinement
link |
is absolutely the worst,
link |
most counterproductive thing you could do to them.
link |
And indeed we found in flies that social isolation
link |
increases the level of tachykinin in the brain.
link |
And if we shut that gene down,
link |
it prevents the isolation from increasing aggression.
link |
So since my lab also works on mice,
link |
it was natural to see whether tachykinins
link |
might be upregulated in social isolation
link |
and whether they play a role in aggression.
link |
And this is work done by a former postdoc,
link |
Moriel Zelikovsky,
link |
now at University of Salt Lake City in Utah.
link |
And she found remarkably that when mice
link |
are socially isolated for two weeks,
link |
there is this massive upregulation of tachykinin II
link |
In fact, if you tag the peptide
link |
with a green fluorescent protein from a jellyfish,
link |
genetically, the brain looks green
link |
when the mice are socially isolated
link |
because there's so much of this stuff released.
link |
And she went on to show that that increase in tachykinin
link |
is responsible for the effect of social isolation
link |
to increase aggressiveness and to increase fear
link |
and to increase anxiety.
link |
And in fact, there are drugs that block the receptor
link |
for tachykinin, which were tested in humans and abandoned
link |
because they had no efficacy in the tests
link |
that they were analyzed for.
link |
If you give those drugs to a socially isolated mouse,
link |
it blocks all of the effects of social isolation.
link |
It blocks the aggression,
link |
it blocks the increased fear and the increased anxiety.
link |
And that Moriel described it, the mice just look chill.
link |
It's not a sedative, which is really important.
link |
It's not that the mice are going to sleep.
link |
Most remarkably is once you socially isolate a mouse
link |
and it becomes aggressive,
link |
you can never put it back in its cage with its brothers
link |
from its litter because it will kill them all overnight.
link |
But if you give it this drug, which is called Osanatant,
link |
that blocks tachykinin II,
link |
that mouse can be returned to the cage with its brothers
link |
and will not attack them and seems to be happy about that
link |
for the rest of the time.
link |
So this is an incredibly powerful effect of this drug.
link |
And I've been really interested
link |
in trying to get pharmaceutical companies
link |
to test this drug,
link |
which has a really good safety profile in humans,
link |
in testing it in people who are subjected
link |
to social isolation stress or bereavement stress.
link |
And this is one of the areas
link |
where I learned an eye-opening lesson
link |
as a basic scientist who naively thought
link |
that if you make a discovery
link |
and it has translational applications to humans,
link |
that pharmaceutical companies are going to be falling
link |
all over themselves to try it.
link |
And they're not interested because once burned, twice shy.
link |
These drugs were tested for efficacy in schizophrenia.
link |
I have no idea why.
link |
There's very little preclinical data to suggest that.
link |
Not surprisingly, they failed.
link |
When a drug fails in clinical trials in phase three,
link |
it costs $100 million to the company
link |
that carried out that clinical trial.
link |
So there's a huge slag heap of discarded pharmaceuticals.
link |
Many of them inhibitors of neuropeptide action
link |
that could be useful in other indications,
link |
such as the one we discovered.
link |
But there's a huge economic disincentive
link |
for pharmaceutical companies to test them again,
link |
because the conclusion that they drew
link |
from all these failed tests,
link |
particularly in the 2010s and before that,
link |
is that the reason they failed
link |
is because animal experiments with drugs
link |
don't predict how humans will respond to the drugs.
link |
And therefore, we shouldn't try to extrapolate
link |
from any other data that we get from animal experiments,
link |
mouse or rat experiments, to humans,
link |
because they'll lead us down the wrong track.
link |
And I think that that is probably wrong.
link |
In some cases, it may be right,
link |
but in other cases, there's good reason to think,
link |
because these brain regions and molecules
link |
are so evolutionarily conserved
link |
that they ought to be playing a similar role in humans.
link |
In fact, there is a paper showing
link |
that in humans that have borderline personality disorder,
link |
there's a strong correlation
link |
between their self-reported level of aggressiveness
link |
and serum levels of a tachykinin,
link |
in this case, tachykinin-1,
link |
as detected by radioimmunoassay.
link |
This is work of Emil Coccaro,
link |
who's a clinical psychiatrist at the University of Chicago.
link |
So there is a smoking gun in the case of humans as well.
link |
And I was actually trying
link |
to interest a pharmaceutical company
link |
that was testing these drugs,
link |
actually for treatment of hot flashes in females, in humans,
link |
where there is actually good animal data
link |
to think that it might be useful.
link |
But I realized that this clinical trial
link |
was going on during the COVID pandemic.
link |
And I approached them and said,
link |
look, nature may have actually done for you
link |
the experiment that I want you to do,
link |
because some of the people who are getting drug or placebo
link |
are gonna have been socially isolated,
link |
and some of them will have not.
link |
Why don't you get them to fill out questionnaires
link |
and see whether the ones who are given the drug
link |
and socially isolated felt less stressed and less anxious
link |
than the ones who were not socially isolated,
link |
and they would not touch it
link |
because they're in the middle of a clinical trial
link |
for a different indication for this drug,
link |
and they have to report any observation
link |
that they make about that drug in their patient population.
link |
So if they were to ask these questions
link |
and get an unfavorable answer,
link |
oh my God, I felt even worse when I took this drug
link |
and I was isolated,
link |
they would be obliged to report that to the FDA,
link |
and that could torpedo the chances
link |
for the drug being approved
link |
in the thing that it was in clinical trials for.
link |
So it's better not to ask and not to know
link |
than it is to try to find out more information
link |
that could lead to another clinical indication.
link |
So I remain convinced that this family of drugs
link |
could have very powerful uses in treating some forms
link |
of stress-induced anxiety or aggressiveness in humans,
link |
but it's just very difficult for economic reasons
link |
to find a way to get somebody to test that.
link |
Yeah, a true shame that these companies won't do this,
link |
and especially given the fact
link |
that many of these drugs exist
link |
and their safety profiles are established,
link |
because that's always a serious consideration
link |
when embarking on a clinical trial.
link |
And perhaps in hearing this discussion,
link |
someone out there will understand
link |
the key importance of this and will reach out to us,
link |
will provide ways to do that
link |
to get such a study going in humans.
link |
Because I think if enough laboratories
link |
ran small-scale clinical trials,
link |
pharma certainly would perk up their ears, right?
link |
I mean, they're so strategic sometimes to their own.
link |
I mean, I would like to say also,
link |
I'd like to see this tested on pets.
link |
I mean, there's a huge number of pets right now
link |
that are suffering separation anxiety
link |
because humans bought them to keep them company
link |
during the COVID pandemic.
link |
And now they're home alone.
link |
And now they're home alone, okay?
link |
And if this thing works in mice,
link |
there's certainly a higher chance
link |
it's gonna work in dogs or in cats
link |
than it is gonna work in humans.
link |
And if it did, that would be even more encouragement
link |
to continue along those lines.
link |
People sometimes forget that although we work on animals
link |
and we ultimately wanna understand humans,
link |
we care about how our results apply
link |
to the welfare of animals as well,
link |
and particularly domestic pets,
link |
which is a billion, multi-billion dollar industry
link |
So if there's ways that they can be made to feel better
link |
when they're separated from their owners,
link |
that would certainly be a good thing.
link |
We will put out the call.
link |
We are putting out the call.
link |
And I know for sure there will be a response.
link |
Just underscoring what we've been talking about even more,
link |
every time we hear about a school shooting,
link |
like in Texas recently,
link |
or I happened to be in New York during the time
link |
when there was a subway shooting,
link |
for whatever reason, I listened to the book about Columbine
link |
that went into a very detailed way
link |
about the origin of those boys and that committed that.
link |
And every single time the person who commits those acts
link |
is socially isolated, as far as I know.
link |
There might be some exceptions there.
link |
And sometimes this crosses over
link |
with other mental health issues, but sometimes no,
link |
no apparent mental health issues.
link |
So social isolation clearly drives powerful neurochemical
link |
and neurobiological changes.
link |
I really hope that tachykinin 1 and 2,
link |
those are the main ones in humans,
link |
will be explored in more detail.
link |
Also, I didn't know that tachykinin 1
link |
is substance P and substance P is tachykinin 1.
link |
Tachykinin 1 is the gene name
link |
and tachykinin 2 in humans is called neurokinin B.
link |
That's the name of the protein.
link |
I just referred to it by the gene name
link |
because it makes it easier
link |
and I don't have to keep remembering
link |
two names for each thing.
link |
And I, if I'm not mistaken,
link |
you put yourself in the company of geneticists
link |
because of your original training
link |
was in genetics, immunology and areas related to that.
link |
It was in cell biology
link |
and I didn't actually have formal training in genetics
link |
as a graduate student,
link |
but I think I'm a geneticist at heart.
link |
That's just the way I like to think about things.
link |
And when I started working on flies,
link |
that sort of, I came out of the closet
link |
as a geneticist, as it were.
link |
As long as we're talking about humans,
link |
I'd love to get your thoughts
link |
about human studies of emotion.
link |
I know you wrote this book with Ralph Adol.
link |
So you have this new book,
link |
which we'll provide a link to,
link |
which I've read front to back twice.
link |
I've mentioned it before on the podcast.
link |
It's really, there are books that are worth reading
link |
and then there are books that are important.
link |
And I think this book is truly important
link |
for the general population to read and understand.
link |
And neuroscientists should read and understand the contents
link |
because we, as a culture,
link |
are way off in terms of how we think about emotions
link |
and states and behaviors.
link |
So we'll put a link to that.
link |
It's really worth the time and energy to read it.
link |
And it's written beautifully, I should say.
link |
Very accessible, even for non-scientists.
link |
There's a heat map diagram in that book that I think about.
link |
This is a heat map diagram of subjective reports
link |
that people gave of where they experience an emotion
link |
or a feeling, a somatic feeling in their body
link |
or in their head or both when they are angry, sad, calm,
link |
lonely, et cetera, et cetera.
link |
And I wouldn't want people to think that those heat maps
link |
were generated by any physiological measurement
link |
because they were not.
link |
And yet, I don't think we can have a discussion
link |
about emotions and states and the sorts of behaviors
link |
that we're talking about today
link |
without thinking about the body also.
link |
And I'm not coming to this
link |
as a Northern California mind body.
link |
I've been to Esalen once.
link |
I didn't go in the baths.
link |
I went there, I gave a talk and I left.
link |
It is very beautiful.
link |
If anyone wants to know what it looks like,
link |
I think that final scene of Mad Men is shot at Esalen.
link |
It's a very beautiful place.
link |
And yet, mind body to me is a neurobiological construct
link |
because the nervous system extends
link |
through the out of the cranial vault
link |
and into the spinal cord and body and back and forth.
link |
Okay, how should we think about the body
link |
and in terms of states?
link |
And at some point, I'd love for you to comment
link |
on that heat map experiment
link |
because it does seem that there's some regularity
link |
as to where people experience emotions.
link |
When people are in a rage, for instance,
link |
they seem to feel it both in their gut and in their head,
link |
it seems, on average.
link |
And people love to extrapolate to gut intuition
link |
or that the chakras or anger is in the stomach
link |
and this goes to Eastern medicine, et cetera.
link |
How should we think about mind body in the context of states
link |
and think about it as scientists,
link |
maybe even as neuroscientists or geneticists?
link |
So for the answer to the first question about the heat maps
link |
and people associating certain parts of their body
link |
with certain emotional feelings,
link |
this goes back to something called
link |
the somatic marker hypothesis
link |
that was proposed by Antonio Damasio,
link |
who is a neurologist at USC.
link |
The idea that our subjective feeling
link |
of a particular emotion is in part associated
link |
with a sensation of something happening
link |
in a particular part of our body.
link |
The gut, the heart, I don't see the liver invoked very much
link |
in emotional characterization.
link |
But gall and the gallbladder?
link |
Somebody having a lot of gall.
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I don't know why I make a fist when I say that,
link |
but I'm guessing the gallbladder is shaped like a fist.
link |
And if there is a physiology underlying these heat maps,
link |
it could reflect increased blood flow
link |
to these different structures.
link |
And that in turn reflects what you were talking about,
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that is emotion definitely involves communication
link |
between the brain and the body,
link |
and it's bi-directional communication.
link |
And it's mediated by the peripheral nervous system,
link |
the sympathetic and the parasympathetic nervous system,
link |
which control heart rate, for example,
link |
blood vessel, blood pressure,
link |
and those neurons receive input from the hypothalamus
link |
and other blood brain regions, central brain regions,
link |
that control their activity.
link |
And when the brain is put in a particular state,
link |
it activates sympathetic and parasympathetic neurons,
link |
which have effects on the heart and on blood pressure.
link |
And these in turn feed back onto the brain
link |
through the sensory system.
link |
And a large part of this bi-directional communication
link |
is also mediated through the vagus nerve,
link |
which many of your listeners and viewers
link |
may have heard about,
link |
because it's become a topic of intense activity now.
link |
People have known for a long time.
link |
So the vagus nerve is a bundle of nerve fibers
link |
that comes out basically of your skull,
link |
out of the central nervous system,
link |
and then sends fibers in to your heart,
link |
your gut, all sorts of visceral organs.
link |
So when you have, and that information is both,
link |
you used the words earlier in our discussion,
link |
afferent and efferent.
link |
So the vagal fibers sense things
link |
that are happening in the body.
link |
So when you're, the reason you feel your stomach
link |
hide up in knots if you're tense
link |
is that those vagal fibers are sensing
link |
the contraction of the gut muscles.
link |
And they're also afferents,
link |
which means that information coming out of the brain
link |
can influence those peripheral organs as well.
link |
And there's work from a number of labs
link |
just in the last six months or so
link |
where people are starting to decode
link |
the components of the different fibers in the vagus nerve.
link |
And it's amazing how much specificity is.
link |
There are specific vagal nerves that go to the lung,
link |
that control breathing responses,
link |
that go to the gut, that go to other organs.
link |
It's almost like a set of color-coded lines,
link |
labeled lines for those things.
link |
And now how those vagal afferents play a role
link |
in the playing out of emotion states
link |
is a fascinating question that people
link |
are just beginning to scrape the surface of.
link |
But I think what's exciting now
link |
is that people are gonna be developing tools
link |
that will allow us to turn on or turn off
link |
specific subsets of fibers within the vagus nerve
link |
and ask how that affects particular emotional behaviors.
link |
So you're absolutely right.
link |
This brain-body connection is critical,
link |
not just for the gut, but for the heart, for the lungs,
link |
for all kinds of other parts of your body.
link |
And Darwin recognized that as well.
link |
And I think it's a central feature of emotion state.
link |
And I think what underlies
link |
are subjective feelings of an emotion.
link |
David, I have to say, as a true fan of the work
link |
that your lab has been doing over so many decades,
link |
and first of all, I was delighted
link |
when you stopped working on stem cells,
link |
not because you weren't doing incredible work there,
link |
but because I saw a talk where you showed a movie
link |
of an octopus spitting out, or not spitting,
link |
but squirting out a bunch of ink and escaping.
link |
And you said you were gonna work on things of the sort
link |
that we're talking about today,
link |
fear, aggression, mating behaviors, social behaviors.
link |
It's been incredible to see the work that your lab has done.
link |
And I know I speak on behalf of a tremendous number of people
link |
when I say thank you for taking time
link |
out of your important schedule
link |
to share with us what you've learned.
link |
My last question is a simple one,
link |
which is will you come back and talk to us again
link |
in the future about the additional work that's sure to come?
link |
I would be happy to do that.
link |
And I really have appreciated your questions.
link |
They've all been right on the money.
link |
You've hit all of the critical,
link |
important issues in this field,
link |
and you've uncovered what is known,
link |
the little bit is known, and how much is not known.
link |
And I think it's important to emphasize the unknown things
link |
because that's what the next generation
link |
of neuroscientists has to solve.
link |
And so I hope this will help to attract young people
link |
into this field because it's so important,
link |
particularly for our understanding of mental illness
link |
and mental health and psychiatry,
link |
we've got to figure out how emotion systems are controlled
link |
in a causal way if we ever want to improve
link |
on the psychiatric treatments that we have now.
link |
And that's gonna require the next generation
link |
of people coming into the field.
link |
Absolutely, I second that.
link |
Well, thank you, it's been a delight.
link |
Thank you, great, really appreciate it.
link |
Thank you for joining me today
link |
for my discussion with Dr. David Anderson.
link |
Please also be sure to check out his new book,
link |
The Nature of the Beast, How Emotions Guide Us.
link |
It's a truly masterful exploration of the biology
link |
and psychology behind what we call emotions
link |
and states of mind and body.
link |
If you're learning from and are enjoying this podcast,
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please subscribe to our YouTube channel.
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That's a simple zero cost way to support us.
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I'd also like to point out that the Huberman Lab podcast
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And last, but certainly not least,
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I'll see you in the next one.