Skip to content
Huberman LabHuberman Lab

Dr. Nirao Shah on Huberman Lab: How SRY Gene Shapes Sex

One gene, SRY, controls hormone cascades that permanently wire male and female brains. Shah explains organizational effects, mating circuits, and libido.

Andrew HubermanhostNirao Shahguest
Jul 28, 20252h 26mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 2:11

    Nirao Shah

    1. AH

      Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Nirav Shah. Dr. Nirav Shah is a professor of psychiatry and behavioral sciences and neurobiology at Stanford University School of Medicine. Dr. Shah is both an MD and a PhD, and his laboratory focuses on understanding the neural and hormonal mechanisms underlying sex differences in the brain. During today's episode, we discuss what is known about male and female differences in brain structure and function and how those differences arise across development, both in utero and postnatally. That is during puberty and into adulthood. A lot of our discussion centers around testosterone and estrogen and how both of those hormones play a profound impact on the development of both the male and female brain, but leads to different outcomes in male versus female brains. We also discuss the neural circuits that control sex behavior and aggressive behavior in both males and females and how those are activated by different hormones. As you all know, there is immense interest and a lot of controversy around sex differences and how that relates to gender. Today's discussion centers around the biology of sex differences in the brain and body, and it will provide a very useful template for everybody in thinking about male versus female differences in behavior, in emotions, and how that intersects with gender and culture. As you'll soon see, Dr. Shah is a true expert in understanding sex differences in the brain and body and how those arise. He's also unafraid of addressing what is known and unknown about those differences and their origins, and he embraces that sex differences are one of the most impactful aspects of human biology and health. So by the end of today's episode, you will indeed have the most up-to-date information on this important topic. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Nirav Shah.

  2. 2:11 – 5:25

    Mice, Humans & Brain, Biological Conservation

    1. AH

      Dr. Nirav Shah, welcome.

    2. NS

      Thank you, Andrew. Pleasure to be here.

    3. AH

      You work on one of the most interesting topics in the entire world, which is sex differences in the brain and the impact of hormones on the brain, on behavior. Let's start with a very straightforward question. Are there male/female differences in terms of brain structure and function?

    4. NS

      Yes. Let me qualify that. So we work on the mouse, on the mouse brain, and we and others have identified lots of differences in structure, in connections, in numbers of neurons, numbers of cells in the brain, and also, my own lab is focused on identifying differences in gene expression between females and males, and there are huge differences.

    5. AH

      For the topics we're going to discuss today, I know, and we're gonna lean heavily on mouse data, but I think it's fair to say that because so much of those data re- rely on the structure and function of the hypothalamus, which you'll educate us on, how conserved is the hypothalamus between mouse and human?

    6. NS

      I would say anatomically, from an atlas, if you're just looking at atlases of humans and mice, they're very conserved. You can point to regions in the mouse brain, the ventromedial hypothalamus, for example, the VMH, which we might talk about, controls aggression and other behaviors, female sexual behavior. You can say this is the VMH in a mouse, and you can basically pinpoint the same region of the human brain, and it's turning out to be clinically relevant as well in humans. You can do the same thing for the preoptic area, which controls maternal behaviors, preoptic, you know, male sexual behavior, and we can identify the same region in the human brain as well. So anatomically, there are very similar analogs in the human hypothalamus as there are in the mouse. And this region is conserved because it controls, as you point out, very fundamental functions: reproduction, aggression, taking care of young, thirst, temperature. So these tend to be conserved 'cause you don't want to muck with a circuit that's already functioning that's essential for survival. So you can find analogs of these structures all the way from birds, across vertebrates, from birds, lizards, rodents, nonhuman primates, and humans.

    7. AH

      I think many people lean toward the idea that humans are so different than mice, um, and they like that idea because it, um, somehow, I don't believe this, but I- I think it somehow gives them the impression that they have more degrees of freedom over their feelings and behavior than perhaps they would if we were a slave to our hypothalamus or something of that sort. But studies on the human, as you and I know, uh, where different, uh, hypothalamic circuitries have been stimulated reveal that you can elicit rage, you can elicit sexual desire, behavior, um, and on and on in a human just as you can in a mouse.

    8. NS

      Yeah. I mean, I think we are different in the sense that we have a huge cortical sort of neural volume. We have a huge cortex, and that, you know, gives us many more degrees of freedom in deciding when and what to do and where to do it. So there is flexibility granted by that enormous expansion of the cortex. But the basal structure for those behaviors, the hypothalamus and the amygdala, are very conserved. So the behaviors exist, of course. It's encoded in the brain, but we can control them or inhibit them, if you will, and in appropriate moments.

    9. AH

      So we've

  3. 5:25 – 7:13

    Hormones, Nature vs Nurture

    1. AH

      all heard of nature versus nurture, and I think that's a very kind of relevant theme as we wade into this topic of- of sex differences in the brain and sex hormones and behavior. Could you explain for us how it is that hormones act on genetics in order to set up a bias for behavior? And, um, for those that are familiar with the idea that nature and nurture are both involved, which should be everybody, uh, what I'm getting at here is this notion of organizing effects of hormones versus activating effects. You'll educate us on what those are.

    2. NS

      So we work on hormones like testosterone, estrogen, progesterone, which are steroid hormones, and as, you know, as you pointed out, Andrew, they act at at least two different stages of life. Um, and early on in development, uh, at embryonic stages in some species, um, like in humans in- in utero.... uh, when the, wh- you know, when the woman's pregnant, or in mice just at birth, perinatally, just after birth. Um, these hormones, uh, generate what is thought to be an irreversible differentiation of the brain along a female or a male pathway. So they sort of, um, set the circuits, if you will, so that these behaviors can then be displayed in adult life after puberty when the hormones kick back in again. So after this early critical period, and I know you've talked about critical periods before in your, in your podcast, there's a critical window that is species-specific when hormones sort of organize the brain, sort of irreversibly set down circuits. And then, you know, the gonads, testes, and ovaries go quiescent until puberty hits, and then at puberty, the hormones come back on again and then they activate, if you will, these circuits so that adult behaviors can be displayed. But the circuits were sort of initially laid down at some point in development.

  4. 7:13 – 16:01

    Biological Sex Differences, Chromosomes & SRY Gene, Hormones

    1. NS

    2. AH

      Correct me if I'm wrong, but my understanding is that the presence of a Y chromosome is really the key differentiating factor for setting up circuitries to be more male-like or female-like in the brain, so these organizing effects. Um, could you explain what's on the Y chromosome? Actually, uh, you should probably, uh, remind everybody how chromosomes and genes work very briefly, right? 23 sets of chromosomes, and then we have the sex chromosomes. If you don't mind educating us, um, just on chromosomes and then how the presence of a Y chromosome is really the key deterministic factor, not just if you get a male or a female as it's, uh, you know, on a birth certificate, but the whole kit and caboodle, uh, in terms of brain structure and function as well as genitalia.

    3. NS

      Sure. So as you pointed out, you know, there are 23 sets of chromosomes, and there's a set of chromosomes called autosomes which are similar, identical between males and females and thus, you know, they're completely conserved, they're the same. And then females have a set of chromosomes, the sex chromosomes, referred to as X chromosome and Y chromosome. And females have two, I'm sorry, two X chromosomes, X and X, and males have an X chromosome and a Y chromosome.

    4. AH

      Those are the sex chromosomes.

    5. NS

      Those are the sex chromosomes. So males have XY, females have XX. Okay? And the Y chromosome is very special in the sense that it has, uh, on the chromosome sits a gene called SRY, sex-determining region on the Y, SRY gene. And this gene essentially dictates whether or not the embryo will have testes or not, and then if, uh, he has, if the embryo has testes, then they'll make testosterone and masculinize both genitalia and the brain and the rest of the body.

    6. AH

      In utero?

    7. NS

      In utero.

    8. AH

      Okay, so, uh, just to step back for, uh, people that aren't so familiar with how chromosomes and genes, uh, work upstream of, of hormones. So what you're telling us is, uh, 22 sets of autosomes, then we have the sex chromosomes. In females it's XX, in males it's XY. On the Y chromosome, there's this SRY gene.

    9. NS

      There's a single gene, SRY.

    10. AH

      And that, the presence of that gene, uh, means that there will be RNA and then protein made.

    11. NS

      That's correct.

    12. AH

      And some of those proteins will cause the development of the testes, and then the testes will secrete testosterone in utero and shape the brain for its potential to be male when puberty happens later on, right?

    13. NS

      Yes. Uh, let me qualify that.

    14. AH

      Mm-hmm.

    15. NS

      Okay. So SRY is a transcription factor, which means it is a gene that encodes a protein from RNA, you know, it gets transcribed into RNA and then RNA gets made into protein, and the protein's a transcription factor, uh, the SRY protein, and what that means is it sort of can regulate expression of other genes. So it can sort of switch on or silence suites of genes that take the bipotential gonad, so the gonad before it becomes testes or ovaries is a bipotential gonad, it can go either way.

    16. AH

      At what stage of embryonic development in human is the gonad bipotential, it could become male or female?

    17. NS

      It's thought that it's early, late first or early second trimester.

    18. AH

      So as late as the second trimester, the gonads are equipotential, they could become male or female, and which direction they go depends entirely on the presence of this SRY transcription factor.

    19. NS

      That's right. And the same's true in the mouse as well, so in the mouse, the gonads are bipotential until day 12 of gestation. Mouse gestain- gestation's about 20 days.

    20. AH

      So does this mean that prior to the beginning of the second trimester, because the SRY transcription factor isn't active yet, that the brain of the fetus is essentially identical between males and females?

    21. NS

      That's the thinking, yes. Yeah.

    22. AH

      Okay.

    23. NS

      And that same's true in the mouse, and in fact, in the mouse, which is our model organism in, in the laboratory, the brain is thought to be bipotential right almost um, uh, until birth.

    24. AH

      Really?

    25. NS

      Yes.

    26. AH

      Okay.

    27. NS

      So, and I'm sure we'll get into this, but the organizing effect of testosterone as we sort of talked about can in fact be detected even as late as after birth in the mouse. So you can take a female mouse at birth and give her testosterone and you can masculinize her behaviors down the road.

    28. AH

      But she doesn't have testes.

    29. NS

      That's right. So the simple act of giving testosterone will do that. So that's the organizing action of testosterone, irreversible differentiation off a bipotential brain along a male pathway with testosterone.

    30. AH

      Okay, but in humans as early as the second trimester beginning, the SRY transcription factor kicks on.

  5. 16:01 – 19:09

    Sponsors: Maui Nui & Eight Sleep

    1. NS

    2. AH

      I'd like to take a quick break and acknowledge our sponsor, Maui Nui Venison. Maui Nui Venison is the most nutrient-dense and delicious red meat available. It's also ethically sourced. Maui Nui hunts and harvests wild axis deer on the island of Maui. This solves the problem of managing an invasive species while also creating an extraordinary source of protein. As I've discussed on this podcast before, most people should aim for getting one gram of quality protein per pound of body weight each day. This allows for optimal muscle protein synthesis while also helping to reduce appetite and support proper metabolic health. Given Maui Nui's exceptional protein-to-calorie ratio, this protein target is achievable without having to eat too many calories. Their venison delivers 21 grams of protein with only 107 grams per serving, which is an ideal ratio for those of us concerned with maintaining or increasing muscle mass while supporting metabolic health. They have venison steaks, ground venison, and venison bone broth. I personally love all of them. In fact, I probably eat a Maui Nui venison burger pretty much every day, and if I don't do that, I eat one of their steaks, and sometimes I also consume their bone broth. And if you're on the go, they have Maui Nui venison sticks which have 10 grams of protein per stick with just 55 calories. I eat at least one of those a day to meet my protein requirements. Right now, Maui Nui is offering Huberman Podcast listeners a limited collection of my favorite cuts and products. It's perfect for anyone looking to improve their diet with delicious, high-quality protein. Supplies are limited, so go to mauinuivenison.com/huberman to get access to this high-quality meat today. Again, that's mauinuivenison.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure a great night's sleep is to make sure that the temperature of your sleeping environment is correct, and that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep automatically regulates the temperature of your bed throughout the night according to your unique needs. Eight Sleep has just launched their latest model, the Pod 5, and the Pod 5 has several new important features. One of these new features is called Auto Pilot. Auto Pilot is an AI engine that learns your sleep patterns to adjust the temperature of your sleeping environment across different sleep stages. It also elevates your head if you're snoring and it makes other shifts to optimize your sleep. The base on the Pod 5 also has an integrated speaker that syncs to the Eight Sleep app and can play audio to support relaxation and recovery. The audio catalog includes several NSDR, non-sleep deep rest, scripts that I worked on with Eight Sleep to record. If you're not familiar, NSDR involves listening to an audio script that walks you through a deep body relaxation combined with some very simple breathing exercises. It's an extremely powerful tool that anyone can benefit from the first time and every time. If you'd like to try Eight Sleep, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350.A

  6. 19:09 – 22:04

    Androgen Mutations, Feminization & Masculinization

    1. AH

      couple examples that I, I learned about years ago, tell me if these are still considered true, is that, um, that for instance there are XY people, so they have the SRY gene. They make testosterone and dihydrotestosterone, but they have a mutant copy of the androgen receptor.

    2. NS

      That's right.

    3. AH

      Those people do not have ovaries, s- so they're infertile as a female. They also, however, don't have testes or the testes don't descend. They make testosterone, but the body can't respond to the testosterone.

    4. NS

      Right.

    5. AH

      So they look female, maybe a little bit, um, smaller breast development, et cetera, but they look female, but they are infertile-

    6. NS

      Mm-hmm.

    7. AH

      ... uh, as women. And if you were to rely on the presence of SRY gene as a definition of maleness, or being male, they qualify.

    8. NS

      Yes.

    9. AH

      If you rely on the presence of testosterone, they qualify, but there've been no action of testosterone.

    10. NS

      Right.

    11. AH

      And so they go through life, at least until puberty, thinking that they're female.

    12. NS

      Right.

    13. AH

      Is that right?

    14. NS

      That's correct.

    15. AH

      Okay.

    16. NS

      The parents think they're females, they think they're females, their peers think they're females. They look f- completely feminized.

    17. AH

      How common is that?

    18. NS

      It's not that common. I think it's... I'm gonna get the numbers exactly, you know, I'm not gonna get the exact numbers right, but I think it's 1 in 10,000 maybe, or 1 in 20,000. I mean, these numbers are changing all the time as diagnostic tests get better, but it's not that common. But there's still that, s- still a significant number of human beings-

    19. AH

      Mm-hmm.

    20. NS

      ... you're talking about.

    21. AH

      And then my understanding is there's also a mutation where, um, people lack the enzyme that converts testosterone to dihydrotestosterone.

    22. NS

      That's right.

    23. AH

      So they're born appearing female. They have SRY, the gene, this deterministic gene. They make testosterone, it doesn't convert to dihydrotestosterone. Then puberty rolls around and they go from having what the parents and they thought was a vagina and a clitoris, and they sprout a penis.

    24. NS

      That's right. A-

    25. AH

      How common is that?

    26. NS

      It's not that common. I think it's more common in places where there's consanguineous marriages, so, you know, in some villages and some countries it's fairly common and they even have sort of local dialect names for this condition. Um, I forget what it's called in, in those languages. Uh, but there's definitely... So it's called a penis at 12 syndrome in sort of medical textbooks, 'cause as you said they sprout a penis at 12, because the early penile development and the scrotal sac development depends on DHT, which is a much po- much more potent activator of the androgen receptors. If you can't have DHT, then testosterone alone cannot masculinize the external genitalia. It's feminized early on, but after puberty when the testosterone levels go up again, that level of testosterone is now, is sufficient to differentiate the external genitalia into a penis.

    27. AH

      So in the strictest sense,

  7. 22:04 – 27:49

    SRY Gene; Animals & Sexual Trans-Differentiation

    1. AH

      the presence of the SRY gene is deterministic for maleness.

    2. NS

      Yes.

    3. AH

      It's not even just the Y chromosome, it's really SRY-

    4. NS

      This one gene.

    5. AH

      ... gene on the Y chromosome, 'cause as you pointed out, if the SRY gene is on a different chromosome, because it got translocated there, then you still get a male fetus. Is it also fair to say that the absence of the SRY gene is what determines femaleness or are there a separate set of deterministic genes that designate femaleness? Some people might be confused by this question only because what I'm, uh, not being clear about is, you could imagine that it's the presence, yes, of SRY that creates maleness, and in its absence you just get a female by default, or it could be that there's a deterministic female gene that makes the brain and body of females female.

    6. NS

      Right. So that's not known in mammals at least. There's no single gene that's been identified in mammals, in mouse or humans, that determines femaleness.

    7. AH

      So no gene that if placed onto a Y chromosome would drive th- the differentiation of that fetus to, to female.

    8. NS

      That's right.

    9. AH

      Okay. What does that tell us about human evolution?

    10. NS

      I don't know what it says about evolution. It says that there is a pr- there's a genetically programmed pathway, that in the fetus in the absence of SRY will give you a female body and a brain. And so that pathway, this genetic program exists, and that SRY sort of tamps it down and boosts maleness.

    11. AH

      Okay, I wanna get back to sex differentiation and behavior in a moment, but I want you tell me if the news report from a few years ago, that California condors can reproduce from two females, is that true?

    12. NS

      I've not seen that report. Uh, I don't know.

    13. AH

      Okay. Um, years ago when I was at Berkeley, there was a graduate student in our program who was studying a species of, um, uh, moles that live in Tilden Park, and these moles apparently can transdifferentiate their ovaries into testes depending on the population numbers of males versus females. This is why I asked about evolution. You know, you could imagine that if such a capacity existed, um, that could be very beneficial for the propagation of a species. Like, if you run out of males-

    14. NS

      Right.

    15. AH

      ... a female can turn her ovaries into testes and, uh, reproduce with another female.

    16. NS

      Right.

    17. AH

      Or if you run out of females, the males could transdifferentiate, uh, their testes into ovaries. This sort of alludes to the idea that this business of X chromosomes and Y chromosomes and genes on Y chromosomes, in theory, um, if we were to zoom out from human existence, you know, where at one point in human existence you could imagine that there was a, a, a kind of a larger control over this so that our numbers never run out. What are your thoughts on, on, on that? I'm not, I'm not talking about, uh, you know, where the origin of control would be, but, but how plastic, how, uh, variable is this or, or is it like the SRY gene is on the Y chromosome 99.9999% of the time, and therefore, like, this in- these instances of translocation onto X chromosomes is kinda rare?

    18. NS

      It is rare. So let me point out that SRY...... is not even determining sex across all vertebrates. Okay? So it's not as if birds have an SRY. You know, most genes, as you know, A- Andrew, many genes ha- most genes are conserved between, say, birds and, and humans, you know, the way you get the axis of the animal developing from front to back, Hox genes controlled by Hox genes is very conserved from births to humans. Um, and there's a similar set of genes even in flies.

    19. AH

      Even the placement of the eyes.

    20. NS

      That's right.

    21. AH

      One gene, PAX6-

    22. NS

      PAX6.

    23. AH

      ... places eyes on the front of the head.

    24. NS

      So, but SRY is sort of special. So birds don't have an SRY. Flies don't have an SRY. And in fact, SRY has been evolving very quickly. So many genes you can take from the human genome and put it in the mouse and can get, you know, mouse mutations rescued. But you can't do that with SRY. So it's been mutating so fast, uh, because it's sort of important for speciation and protecting the sort of species' advantages that led to the development of that species. So you can't take SRY and sort of move it between species. Not only that, but as you sort of were alluding to, there are many species in which, in vertebrates in which SRY is not even relevant for sexual differentiation and determination. What happens is, as you point out, population densities can regulate that. Temperature can regulate that sex differentiation. Um, I think it's true in alligators and crocodiles maybe. And certainly adult fish can transdifferentiate from female to male as well.

    25. AH

      Wow, I didn't realize it was that common.

    26. NS

      Yeah.

    27. AH

      But it makes sense if, uh, for these ectotherms that regulate their temperature based on the environment. Um, look, every species' main goal is to make more of itself and protect-

    28. NS

      And protect its-

    29. AH

      ... its young.

    30. NS

      That's right.

  8. 27:49 – 31:22

    Hormones & Biological Brain Differentiation

    1. AH

      downstream of SRY, or the absence of those hormones, shape the brain. Because I think, uh, people listening to this, uh, certainly know people of both sexes, right? And I don't think it's that politically, uh, edgy to say that most people probably believe that men and women, boys and girls even, respond very differently to the same stimuli.

    2. NS

      That's right.

    3. AH

      You know, and the stereotype here is, you know, she started playing with dolls from the beginning.

    4. NS

      That's right.

    5. AH

      You know, he picked up a stick and pretended it was a weapon from the moment that he picked up a stick-

    6. NS

      Right.

    7. AH

      ... prior to puberty, prior to the, the testes secreting testosterone. So what is known about hormone-based differentiation of the brain in, in terms of maleness and femaleness? Uh, and let's just for the moment suspend all, uh, all politics, all stereotypes, and just ask, like, "What does the biology say?"

    8. NS

      So there are a couple of classic experiments in the field, uh, done in the 1950s that really speak to this, this sort of organizational differentiation effect of hormones. And then we've done some additional work in the mouse that also relates to this, and then there are human conditions that can inform this discussion as well. Um, so the first experiment I would like to talk about is by Charles Phoenix in 1959, I think, and he did this experiment in guinea pigs. And guinea pigs become female, masculinized or feminized, uh, in utero, prenatally, just like humans do. And if he gave testosterone to the pregnant female, then females that were born to that mother had received testo- had seen testosterone, their brains had seen testosterone in development in utero, and when they were born and became adults, very high probability of mating like a male, like sexual mating, you know, having sexual behaviors like a male.

    9. AH

      So thrusting behavior.

    10. NS

      Thrusting behavior. And they had very little receptivity, uh, sort of female-type receptive behaviors.

    11. AH

      Which in rodents, uh, is typically lordosis.

    12. NS

      Right. People have-

    13. AH

      The arching of the back. Right.

    14. NS

      People who have cats know about this, right, for example.

    15. AH

      Mm-hmm.

    16. NS

      Cats in heat will lordose. Um, so th- that w- uh, and even if he gave the females, adult females who had seen testosterone early on, if he give, if he give these adult females boosts with estrogen and progesterone to sort of increase female sexual behavior in these females, they had very little displays of female sexuality.

    17. AH

      So-

    18. NS

      They still mounted like males.

    19. AH

      Okay. So the exposure of females to testosterone in utero-

    20. NS

      Mm-hmm.

    21. AH

      ... sets up a program whereby their sexual behavior appears more male-like.

    22. NS

      That's right.

    23. AH

      Thrusting behavior and lack of lordosis. So there's a, there's a, the presence of something and the absence of something.

    24. NS

      Right.

    25. AH

      What about aggression? Were they more, uh, aggressive?

    26. NS

      That paper didn't look at aggression. We've done that in the mouse, and you basically see the same thing. Now, in mouse, sexual differentiation, as we talked about earlier, happens right at birth or just around birth. So we could take day one pups and if you give them testosterone, these females become territorial like males as adults.

    27. AH

      Interesting. So territorialism is a, is a male-specific trait?

    28. NS

      In mice.

    29. AH

      In mice.

    30. NS

      Mice that... Male mice are territorial. Female mice, at l- at least in laboratory, don't fight as much, except when they're mothers and nursing a litter.

  9. 31:22 – 35:56

    Congenital Adrenal Hyperplasia, Androstenedione; Stress & Pregnancy

    1. AH

      utero sets up male-like behaviors in female offspring, is what I'm hearing.

    2. NS

      Mm-hmm. Yeah.

    3. AH

      I'm aware of at least one condition in humans where this might occur, which is when, um, there's either a tumor or stress-induced, uh, stimulation of the... or overstimulation of the adrenal glands. Uh, and of course the adrenals make adrenaline and cortisol, but also they have a layer of cells that produce androstenedione, which is a-

    4. NS

      Mm-hmm.

    5. AH

      ... uh, an androgen. Um, what is the outward appearance of female babies born to women who had an overactive adrenal during pregnancy?

    6. NS

      Yeah, so I think you're referring to congenital adrenal hyperplasia, which i- is, you know, a mutation in an enzyme that typically makes cortisol. And this happens in the baby itself. So the baby's a mutant for this enzyme.

    7. AH

      Oh, so the baby's adrenals are the ones that are, uh, d- disrupted in this condition.

    8. NS

      And because they can't make cortisol, these sort of precursors to cortisol get shunted into making, as you pointed out, androgens.

    9. AH

      Mm-hmm.

    10. NS

      'Cause there's excess precursor, it just gets shunted off into a different pathway.

    11. AH

      Mm-hmm.

    12. NS

      So these babies, if these f- females are born with sort of masculinized external genitalia.

    13. AH

      Based not on the presence of testes or testosterone, but-

    14. NS

      Or SRY. But presence of testosterone, of androgens, right? 'Cause the adrenals are now pumping out androgens, rather than cortisol.

    15. AH

      Are the, uh, androgens that come from the adrenals, um, the same in terms of they bind the androgen receptor just like testosterone would? So they look like testosterone.

    16. NS

      Yes.

    17. AH

      Actually some years ago, androstenedione, uh, was the topic of a lot of news stories because of, uh, Mark McGwire, the baseball player-

    18. NS

      I see.

    19. AH

      ... uh, was accused of taking androstenedione. I mean, it's not hard to see the differences in his physical size from one season to the next. Whether or not he did that or not, I don't know if it was ever confirmed. I think it was.

    20. NS

      I see.

    21. AH

      Um, we can ask him. I, um, I don't wanna put anything on him that, uh-

    22. NS

      Yeah.

    23. AH

      ... wasn't true, but that's what the news claimed. And you could buy androstenedione in the GNC.

    24. NS

      Oh.

    25. AH

      But the adrenals make testosterone-like substances-

    26. NS

      Androgens, yes.

    27. AH

      ... in this person that doesn't have the capacity to make enough cortisol. So what does the female offspring look like?

    28. NS

      She has ex- sort of masculinized external genitalia.

    29. AH

      Mm-hmm.

    30. NS

      And that can be surgically corrected, because now doctors are aware of this condition, so they can surgically sort of correct that and you can give the baby, uh, when she's born, cortisol, because that's absolutely essential-

  10. 35:56 – 43:37

    Genes, Brain Differentiation & Sexual Identity; Congenital Adrenal Hyperplasia

    1. AH

      occurring experiments, um, I don't know if that's the proper way to think about it, but they are. They're nat- naturally occurring outcomes. Um, how much variation is there in terms of masculine to feminine phenotypes at birth? Has anyone ever looked at that? Like, you know, I mean, we, we sort of pres- like, you know, "It's a baby girl. It's a girl."

    2. NS

      Right.

    3. AH

      "It's a boy." Right? You know, the, the gender reveal thing or whatever. (laughs)

    4. NS

      Yeah.

    5. AH

      Uh, you know, um, on the ultrasound, "It's a boy." Okay, there's no penis. "It's a girl." You know, and there's other markers too, you know-

    6. NS

      Right.

    7. AH

      ... that, uh, people have gotten quite good at recognizing male versus female fetus on the basis of a number of different things, but most notably the absence of a penis is generally the, the, the, uh, the, driving the conclusion that it's a female, um, until chromosomal typing is done.

    8. NS

      That's right.

    9. AH

      But what is the range in terms of, um, phenotypes, right? Has anyone ever actually explored that?

    10. NS

      Uh, I think Johns Hopkins had a program to do that back in the, you know, about 50 years ago. Um, and I think at b- back then at least, it was just the size-

    11. AH

      Mm-hmm.

    12. NS

      ... of the penis that said this is a boy or not.

    13. AH

      Mm-hmm.

    14. NS

      Or the external genitalia. I don't know what the current criteria are.

    15. AH

      Mm-hmm.

    16. NS

      I'm not a practicing MD.

    17. AH

      Mm-hmm.

    18. NS

      Um, so-

    19. AH

      You are an MD though.

    20. NS

      I am an MD.

    21. AH

      Mm-hmm.

    22. NS

      I don't practice though. Yes.

    23. AH

      Mm-hmm. Mm-hmm.

    24. NS

      Um, so I don't know what the current criteria are, but with karyotyping you can easily tell.

    25. AH

      You look whether or not it's XX or XY.

    26. NS

      That's right.

    27. AH

      Okay. Well, thank you for saying that, because the reason I ask that question is that some years ago there, there were these, um, reports of people who had grown up, uh-... being treated as a male, having received testosterone injections or something like that, and then later discovered that they have XX chromosomes. Other people reported having XX chromosomes, never been treated with anything, but they thought they w- they were, you know, appeared male because they had one of these conditions that increased testosterone. And my understanding at the time was that the level of okayness, I don't even know what the word is. The level of okayness of the person with how they were raised oriented very strongly with whether or not they were XX or XY, not which hormones they had seen during development. In other words, if somebody ha- uh, had XX chromosomes, no SRY gene, but was exposed to a lot of androgens, maybe from their adrenals or elsewhere, a drug that the mom was treated with d- during pregnancy, perhaps, that they would hit puberty and they, they didn't feel "right." And in fact, genetically, they were female. And then the reverse, eh, cases were also true. And oftentimes, these people would seek corrective hormone therapy or surgeries. So what I'm talking about here is actually the opposite of what we hear so much controversy about today, where people want to switch. These are people who were forced by their parents and their doctors to be raised a certain way that did not match their chromosomes, and it-

    28. NS

      Right.

    29. AH

      ... generally did not feel good to them.

    30. NS

      That's right, yeah.

  11. 43:37 – 47:27

    Testosterone, Estrogen & Brain Circuits

    1. AH

      let's say with the, the most typical scenario-... XY chromosomes makes testosterone, makes DHT. Um, all the receptors are functional versus XX, no SRY, uh, gene, um, all the, all the, all the stuff, testosterone and estrogen, uh, are functional, receptors are functional. The typical pattern.

    2. NS

      Yes.

    3. AH

      How are the brains of those babies and later adults different? What, what do we know about that?

    4. NS

      Yeah, so there are a lot of cells in the brain that express receptors for testosterone, androgen receptor and estrogen and progesterone. So people have looked over the last 40, 50 years to see what ... how these cells are responding to these hormones. And it seems that at least one major theme that emerges is that early on, at least in the mouse, right, this is ... You can still see that the brain is bipotential at the first day of life. It's ... looks sort of somewhat neutral. And then if you have testosterone, then in some brain regions, more neurons will survive. And in those regions in the female, those neurons would die. So then as adults, you end up with a male brain that has more neurons in one region compared to a female. And conversely, in the female brain, there are structures that, you know, survive. In the males, you lose cells. So in those structures in the adult, females will have more neurons than males or cells than males. So you have cell death that can be sex specific, you know, female specific or male specific. I, I ... Actually, I should step back. It's not specific. It's more statistical. There are more cell death in one than the other so you end up with different numbers of neurons in the adult animal.

    5. AH

      And you're not getting those neurons back.

    6. NS

      You're not getting those neurons back.

    7. AH

      So it's-

    8. NS

      And the same is true for connectivity.

    9. AH

      So it's fair to say that as a consequence of genes and hormones, in utero, males have certain neurons and circuits that females don't have and females have certain neurons and circuits that males don't have, and it doesn't matter how much testosterone or estrogen you put into the adult ver- the adult of, of those people, they're not getting those circuits back?

    10. NS

      Right. In utero, they are the same. But once they've been exposed to testosterone or estrogen, progesterone, you get cell loss in one or the other sex. And once you get that cell loss, you're not gonna recover that as an adult.

    11. AH

      Is there any evidence in humans or in mouse that the loss of these cells or the maintenance of these cells, we can look at it through either lens, is along a continuum? Or is it pretty s- a strict divide? Like, if we were to plot the number of cells in one of these brain areas, would it be a binary distribution, uh, where, you know, you get a, a big, you know, a big pile of, of, of neurons (laughs) um, on one side of the graph and, uh, and, and many fewer in the female with a big trough between it? Or are we talking about a, a more ... a single

    12. NA

      (music)

    13. AH

      ... hump?

    14. NS

      In some regions, it looks pretty binary.

    15. AH

      Mm-hmm.

    16. NS

      And these are regions that control innate behaviors like mating or aggression, for example. Um, but others, there's gonna be overlap. And the animals we work in, in the mouse, they're sort of specifically bred to be genetically identical to each other so we can sort of really parse out what the differences look like. And if you will, there are more extreme examples of these animals. And, and there, in some regions, we can really see that, you know, there's always about two to threefold more cells in one sex compared to the other. And that's pretty much true for all animals for that region. But other regions, there might be more overlap.

    17. AH

      I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As somebody who's been involved in

  12. 47:27 – 50:36

    Sponsors: AG1 & LMNT

    1. AH

      research science for almost three decades and in health and fitness for equally as long, I'm constantly looking for the best tools to improve my mental health, physical health and performance. I discovered AG1 back in 2012, long before I ever had a podcast, and I've been taking it every day since. I find it improves all aspects of my health, my energy, my focus, and I simply feel much better when I take it. AG1 uses the highest quality ingredients in the right combinations and they're constantly improving their formulas without increasing the cost. In fact, AG1 just launched their latest formula upgrade. This next gen formula is based on exciting new research on the effects of probiotics on the gut microbiome and it now includes several clinically studied probiotic strains shown to support both digestive health and immune system health, as well as to improve bowel regularity and to reduce bloating. Whenever I'm asked if I could take just one supplement, what that supplement would be, I always say AG1. If you'd like to try AG1, you can go to drinkag1.com/huberman. For a limited time, AG1 is giving away a free one-month supply of omega-3 fish oil along with a bottle of vitamin D3 plus K2. As I've highlighted before on this podcast, omega-3 fish oil and vitamin D3K2 have been shown to help with everything from mood and brain health to heart health to healthy hormone status and much more. Again, that's drinkag1.com/huberman to get a free one-month supply of omega-3 fish oil plus a bottle of vitamin D3 plus K2 with your subscription. Today's episode is also brought to us by LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes sodium, magnesium and potassium in the correct amounts, but no sugar. Proper hydration is critical for optimal brain and body function. Even a slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium and potassium, are vital for functioning of all the cells in your body, especially your neurons or your nerve cells. Drinking LMNT dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. To make sure that I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of LMNT in about 16 to 32 ounces of water when I first wake up in the morning and I drink that basically first thing in the morning. I'll also drink LMNT dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. LMNT has a bunch of great tasting flavors. I love the raspberry, I love the citrus flavor. Right now, LMNT has a limited edition lemonade flavor that is absolutely delicious. I hate to say that I love one more than all the others, but this lemonade flavor is right up there with my favorite other one, which is raspberry or watermelon. Again, I can't pick just one flavor. I love them all. If you'd like to try LMNT, you can go to drinklmnt.com/huberman, spelled drink L-M-N-T dot com slash huberman to claim a free LMNT sample pack with a purchase of any LMNT drink mix. Again, that's drinklmnt.com/huberman to claim a free sample pack.To remove some of the, um, sociological, political, and other sorts of biases that understandably kind of get into people's minds when you start talking about this, if you just look back in history,

  13. 50:36 – 52:23

    Intersex Individuals, Castration

    1. AH

      were there examples of intersex people? Just b- born of, uh, you know, without any knowledge of, of chromosomes, without any knowledge of hormones (laughs) -

    2. NS

      Yes.

    3. AH

      Um, uh, people intuitively understood hormones, but, um, based on damage to the testes or things like that, right? What, what would happen. But I think you get the idea. W- were there examples that were cultures where it was kind of understood that this was along a continuum? Because everything you're describing makes it sound pretty darn binary. And, you know, again, n- this isn't a political discussion, it's a biological discussion. SRY, yes or no?

    4. NS

      Yes.

    5. AH

      That seems to be pretty much what it's about.

    6. NS

      Yeah. So, but there are cultures, I mean, we mentioned about these consanguineous marriages where people, you know, w- would have kids. Where they would look feminized early on because they have a deficiency in 5-alpha reductase, no DHT production, and then at 12, they would become, you know, masculinized. They would sprout a penis.

    7. AH

      But never in the other direction.

    8. NS

      No.

    9. AH

      Males converting to females.

    10. NS

      No. Right.

    11. AH

      Yeah.

    12. NS

      Physically, no. Right.

    13. AH

      Mm-hmm.

    14. NS

      So at least in these cultures, it's n- it's a known thing that there will be a subset of kids who are born with this, if you will, intersex condition. Right? And there are descriptions of, you know, what people used to call, it's no longer politically correct to say, call them hermaphrodites, but there are examples of, you know, intersex individuals across history.

    15. AH

      Hermaphrodite is not a politically correct...

    16. NS

      That's what I've been told. Intersex is the medically sort of accepted term.

    17. AH

      Got it.

    18. NS

      And people have also known that testosterone or hormones, sex hormones play a huge role in regulating behavior, right? So eunuchs and castrates, castratis have been used in palaces and co- and courts sort of to guard harems, for example. Um, they also-

    19. AH

      That was the motivation?

    20. NS

      Yep.

    21. AH

      Wouldn't

  14. 52:23 – 57:58

    Female Sexual Behavior, Brain, Testosterone & Pheromones

    1. AH

      you favor a more aggressive n- uh, testicularly intact male if you think the goal is protection?

    2. NS

      No, I think the, I think the idea was that if you had, you know, a castrate guarding a harem of females, then they can't sort of, you know, have sexual behavior with them. They can't have sex with them.

    3. AH

      Oh, they weren't gonna do what the cuttlefish do.

    4. NS

      Right.

    5. AH

      Cuttlefish males will pretend they're females-

    6. NS

      That's right. Camouflage.

    7. AH

      ... befriend females, and then they'll, and then they'll mate with them. Yeah.

    8. NS

      And also in opera singing, right, you would have castratis who would have a higher pitched voice. <|agent|><|en|>

    9. AH

      And they were castrated early in life to maintain the high pitched voice.

    10. NS

      Yes.

    11. AH

      Anyway, um, just gonna refrain from any... I mean, the poor kids that presumably they didn't get a choice.

    12. NS

      Presumably, yeah.

    13. AH

      Yikes. Um, okay. So here's where, here's where I'm, um, stuck, right? I can hear all this biology, and it's very clear that the genes and hormones are affecting peripheral, what we call phenotype. Presence or absence of penis, presence or absence of descended testes, presence or absence of menstruation. But in the brain, it just seems that there are different circuits that kind of pile up more neurons or maintain more neurons in males versus females. In females, what are the, what are the circuits that get favored? Are they circuits for, um, lactation, for child-rearing? I mean, what are-

    14. NS

      For sexual behavior, for example.

    15. AH

      Uh-

    16. NS

      Ovulation. So cells that control-

    17. AH

      Got it.

    18. NS

      ... ovulation, for example, would be very dimorphic.

    19. AH

      But not in terms of behavior, right? Like it, it seems like it, it's the presence or absence of rough and tumble play, presence or absence of thrusting behavior. Um, I mean, maybe this is for historical reasons or maybe it's for biological reasons, but, um, I guess what I'm getting at here is what are the things that babies that are XX, that are females, how are their brains specialized? I mean, or is it just the absence of copulatory thrusting and aggressive behavior? It seems to me that there would be s- circuits that were female-specific.

    20. NS

      That's right. So there are circuits that are specific of female sexual behavior. So you can take an adult male, for example, and you can remove testosterone, you can castrate him, and you can give him female hormones, estrogen and progesterone. And ask, this is in mice now, um, and you can ask, will he now be sexually receptive? Will he lordose like a female mouse would?

    21. AH

      Arched back sexual-

    22. NS

      Arched back.

    23. AH

      Yeah.

    24. NS

      That's right. Sexual receptivity p- posture. And most, in most cases he won't.

    25. AH

      He won't?

    26. NS

      No, he won't, 'cause the circuit's missing.

    27. AH

      Right. The neurons just aren't there.

    28. NS

      That's right. Or at least they're not responsive to the hormones.

    29. AH

      Mm-hmm.

    30. NS

      Right? We don't know if the circuit's there, but it's not responding to hormones, or we don't know if the circuit's not there. We now know that there are connections in the female brain that are simply missing in the male brain. And these connections are from neurons that regulate sexual behavior. So we know that some circuits are missing in the male brain for sexual, female sexual behavior.

  15. 57:58 – 1:00:42

    Identify as Heterosexual or Homosexual, Difference in Hormone Levels?

    1. AH

      don't see marked differences in androgens or estrogen if you were to look between women who define themselves as heterosexual versus homosexual, so heterosexual women versus lesbians or heterosexual men versus homosexual men. If anything, (laughs) the data point to n- homosexual men having higher levels of testosterone. It's been difficult to tease apart from, um, some lifestyle and behavioral things, but when teased apart, it, it, and it's been done, you're not gonna find anything that, that screams, "Hormone levels define sexual orientation." You just, you just don't find that.

    2. NS

      You don't see that, no.

    3. AH

      Ye- you see a lot of data that points to changes in utero that may be hormone driven, but nothing, um...

    4. NS

      As adults.

    5. AH

      Nothing as adults.

    6. NS

      No. And in fact, if you can take, you know, what we call wild type male mice, if you will, right, m- meaning they're sort of completely, uh, typical or normal male mice, and you can measure their testosterone levels, and you get a huge range of circulating testosterone in otherwise normal mice of, you know, or five to tenfold difference in testosterone.

    7. AH

      Or humans for that matter.

    8. NS

      Or humans for that matter.

    9. AH

      Mm-hmm.

    10. NS

      And they still, you know, these mice will still behave like males.

    11. AH

      I won't out this person, um, but, uh, I'm not talking about, um, sexual orientation, um, the CEO of one of the most successful media companies in the world came up to me at a gathering, uh, like two years ago, and he said, "Listen, I, I have this, uh, I have a problem." I said, "Well, usually when a guy says that to me, it's gonna be something about, uh, testosterone or, or sexual dysfunction or something." And he said his testosterone is down in the 300s, kinda lower end of, of reference range. He said, "But I feel great." He's like, he's, he's saying, "My libido is great. My, my work drive is great. I feel great." And I said, "Well, your free testosterone is probably, um, normal and high." And he goes, "No, that's also low, but I feel great. Should I take testosterone?" (laughs) And I said, "Uh, listen, I'm not an endocrinologist, but my advice would be no." Right? So, and I, I point this out, I, I think he's probably in his late 50s, early 60s, and, uh, what he was revealing, uh, was, you know, unique among the questions I typically get around testosterone, but I think it points to the fact that who knows? Maybe he has a higher than normal receptor density...

    12. NS

      That's right.

    13. AH

      ... that can make use of, of th- those levels of testosterone. I mean, there's so many ways in which hormone levels can play out in one direction or another or something in between.

    14. NS

      That's right.

    15. AH

      And I think it's worth it, people h- knowing that.

    16. NS

      That's right.

    17. AH

      Um, I have so many questions, but, um, this feels like thorny territory, and, um, I've learned when doing this podcast, whenever something feels like thorny territory, that, uh, to go right into it.

  16. 1:00:42 – 1:10:21

    Gender, Sexual Orientation & Hormones; Hormone Replacement Therapy

    1. AH

      These days, we hear a lot, endlessly it seems, about the debate as to whether or not sex differentiation, uh, and gender are biologically determined or are, um, more mutable than that. Uh, we're certainly not gonna resolve that question here, certainly not for everybody. I'm sure you have your stance, and I have mine. But how is it that we bring together our understanding of sex differentiation versus this gender word, right? It seems to me that in a lot of talks you've given, you use the word gender. I know 'cause I've listened to those talks, and we've ... I'll reveal it now. We've been friends for a long time.

    2. NS

      That's right.

    3. AH

      And you'll sometimes say sex, and you'll sometimes say gender. And I understand that sex is a confusing word because the moment they hear it, they think of the verb sex.

    4. NS

      Right.

    5. AH

      How do we think about sex versus gender when it comes to understanding brain and, uh, b- yeah, just brain. Let's just stay with that, not even body, because clearly the data in mice and humans point to the fact that the administration of hormones can change the body. It can, it can shift things in one direction or the other.

    6. NS

      Given at the right time.

    7. AH

      Given at the right time, and we can talk about that. Um, but what about the brain piece? I- i- how mutable is this? And what are your thoughts on the controversy, and how should we be thinking about this? Forgive me for stumbling, but it is a, it's, it's not that I'm trying to avoid upsetting anyone. It's like we don't have a good language to differentiate these things.

    8. NS

      And I think part of the issue, part of the problem for not having a good language and good understanding is we don't have an animal model for it. Gender is such a human-specific construct, you know? It's these sort of constellation of behaviors and expectations generated from within and by our society and culture about what gender is.And gender sort of includes not only sort of identification of yourself as a male or a female or something in between, having sort of attraction for one sex or the other, or not having any attraction for anyone, or sort of having this sort of com- comportment of behaviors, like dressing in a particular way, sort of speaking in a particular way, or having, meeting societal expectations. All of those sort of comprise gender, and it's hard to do that in a mouse. We don't know enough about mice. We don't even, we don't even know about mice enough to say they have a gender. We know that they have sexes, females and males, based on SRY, testosterone, estrogen, and progesterone.

    9. AH

      Okay. Well-

    10. NS

      So it's hard to have an animal model for something like this, which is so complex and so, it seems, human-specific.

    11. AH

      Well, you said one thing that, um, at least my understanding, um, checks off one box, which is that sexual orientation and how people self-identify in terms of maleness or femaleness is separable. We know that because-

    12. NS

      Yes.

    13. AH

      ... there are people who-

    14. NS

      Right.

    15. AH

      ... are homosexual.

    16. NS

      Right.

    17. AH

      And we know that because there are people who switch gender by way of hormones, obviously not from birth, but later in life. And in many cases, they don't change sexual orientations.

    18. NS

      That's right.

    19. AH

      Sometimes they do, but my read of the data is that usually they don't. In other words, if somebody preferred females before, they, they, they might, uh, administer hormones, change their body, but they'll continue to, to like females.

    20. NS

      Right.

    21. AH

      Or vice versa, right? That's my understanding of the data.

    22. NS

      Right.

    23. AH

      And I went into the data looking, prior to this conversation, and there are a lot of data now. The problem is, it's difficult to find unbiased data. I'll be very honest. I feel like the data are biased on both sides. People seem to be arguing for something going in. Okay, so sexual orientation and how people self-identify we know is separable. That's not a, a, an, a, uh, controversial thing. We just know 'cause that's what happens. But when it comes to when people are administered hormones, how that changes the brain in human, what do we know? You said it depends on whether or not they're administered hormones early versus later in life.

    24. NS

      Well, I think the early data, and, you know, we talk about congenital adrenal hyperplasia, we talked about androgen insensitivity syndrome, those data really say that hormones at a point in development, maybe in utero, have a profound effect on masculinization or feminization external-

    25. AH

      Mm-hmm.

    26. NS

      ... as well as of the, of the brain.

    27. AH

      Right. These kids that make, uh, that don't make DHT that are raised as girls but later sprout a penis are, at least as you described it for all the world, raised as girls and happy being raised as girls-

    28. NS

      Right.

    29. AH

      ... identify as girls until testosterone kicks in-

    30. NS

      Right.

  17. 1:10:21 – 1:15:00

    Aromatization; Steroid Hormones & Gene Expression

    1. AH

    2. NS

      So this all started with classic work by Frank Naftalin in the '70s, when he was sort of working on human embryonic tissue, uh, brain tissue, and he realized that the embryonic human brain contained an enzyme that converted androgen into estrogen, and the enzyme's called aromatase. And this is, in fact, uh, the primary way that the ovaries make estrogen. They first make testosterone that gets aromatized from, by this enzyme aromatase, and gets made into estrogen. Okay, so it turns out that Fr- Naftalin's sort of discovery was exactly right. Even in the mouse brain, in the mouse male brain, uh, we and others have shown that there is aromatase, the enzyme, expressed in very specific circuits in the brain.

    3. AH

      Can I just stop you? You mentioned this early experiment by this gentleman.

    4. NS

      Yeah.

    5. AH

      Was done on human brain tissue?

    6. NS

      Yes. And rats, and, you know, other s-

    7. AH

      Yeah. It's a very important point. Uh, I think she will appreciate, uh, hearing this, but a long while ago, I mentioned this thing about aro- aromatization-

    8. NS

      Yeah.

    9. AH

      ... of testosterone to estrogen is really what masculinizes the male brain, and a very prominent author in the testosterone space, a female author, wrote to me and said, "It's just mice." Um, so... But, but she's very scholarly, and, and I think she'll appreciate hearing that the original data come from human. Great. Thank you. Um, so it's not just mice.

    10. NS

      Mm-mm.

    11. AH

      Yet another way that we're conserved.

    12. NS

      To be fair, though, I think the idea with what she might've been referring to is that aromatization in the human brain may not be playing as dominant a role in masculinizing the brain as it does in rodents and other animals.

    13. AH

      Okay.

    14. NS

      So that, you know... We can't really speak to that 'cause you can't do those experiments in humans.

    15. AH

      Mm-hmm.

    16. NS

      But if you have a male mouse lacking aromatase, so he can't make estrogen, then, you know, his behaviors won't be masculinized.

    17. AH

      He appears more female.

    18. NS

      Not appears, behaves more like a m- Doesn't behave like a male 'cause he's not converting testosterone into estrogen, and this happens very early, uh, at birth in mice. So testosterone gets made by the testes, gets in the brain, gets converted into estrogen, and then, you know, as we talked about earlier, there are some cells that die or survive depending on the sex. And this conversion of testosterone into estrogen enables specific sets of cells in the male brain to survive.

    19. AH

      This is probably a good place for us to inform people that these steroid hormones, testosterone and estrogen, are very interesting because they can have immediate effects, and they can also change gene expression. This is a good opportunity for you to teach us some cell biology. So is it by virtue of the fact that they are lipid-soluble, they can go all the way into the nucleus of a cell? Um, I mean, th- you know, this is very different than, like, dopamine, right? Dopamine can impact cells. You know, don't do this, folks, but, you know, if you were to take methamphetamine or something, you'd... Your brain would go very dopaminergic very fast. (laughs) Um, but it's not gonna change gene expression in the short term. Maybe in the long term, but not in the short term. But testosterone administration or estrogen administration is literally changing the genes that are expressed-

    20. NS

      That's right.

    21. AH

      ... in, in the cells they interact with.

    22. NS

      Yeah.

    23. AH

      How does that work? I mean, what, what's going on? What, what are they actually controlling?

    24. NS

      So the receptors for these hormones, testosterone, estrogen, progesterone, um, they sit in the cytoplasm of cells, not in the nucleus. And as you pointed out, these are, you know, steroid hormones or lipids that can cross cell boundaries, cell membranes. And once they bind to the receptor, the receptor-bound of the hormone is translocated into the nucleus, where it finds stretches of DNA that it recognizes and sort of sits on them, binds them, and then changes or regulates gene expression of what we call target genes. And that's how, you know, you get gene expression changes by these hormones.

    25. AH

      So this is why whenever I hear, like, the Sapolsky argument, which I totally agree with, that, you know, you give, uh, someone testosterone, and they become a lot more like themselves. They don't... If they're a nice person, they become that much nicer. Uh, if they're aggressive, they become that much, uh, more aggressive. But those are short-term studies. Right? So we don't really know how the administration of hormones, testosterone or estrogen, to a self-declared male or female, uh, or XY, XX, doesn't matter. What... Th- the point is that we don't know how the long-term administration of these hormones literally change the genes, and therefore the thought patterns and behaviors and feelings of these people.

    26. NS

      That's right. You're basically-

    27. AH

      Okay?

    28. NS

      ... changing the molecular fingerprints...... of specific sets of cells in the brain with hormone action.

    29. AH

      A big debate these days is whether or not, um, p- people, if they seek to change their gender identity, whether or not they're in a position to make that decision 'cause they're a minor, right? Minors w- are not legally

  18. 1:15:00 – 1:19:05

    Kids & Changing Gender Identity

    1. AH

      allowed to make all sorts of decisions-

    2. NS

      Right.

    3. AH

      ... like vote, dr- drive a car, uh, all sorts of things.

    4. NS

      Marry, yes.

    5. AH

      Uh, work, i- in this country anyway, work a job, I think you have to be, used to be 14. I don't know what it is now. But it's an interesting biological question when you just say, "Okay, at..." Um, forgetting, uh, all of that and, and just asking, okay, what is the condition of a, uh, like a, a 10-year-old brain versus a 14-year-old brain that's entering puberty versus a 16-year-old brain that's still transitioning through puberty, maybe in late phases of puberty, versus 25, which is when we know brain development is more or less coming to a, to a close, although brain development continues forever.

    6. NS

      Right.

    7. AH

      I mean, how is anyone going to eventually come to a, an agreement one way or the other on this? Is there real biology that we can look at, uh, in mice or in humans and say like, "Okay, here's, here's the dynamic tension." The dynamic tension out there is there are people saying there're kids that are too young to know what they are, let alone choose what they want to be.

    8. NS

      Right.

    9. AH

      And then on the other side, you've got people battling saying, "No, it's essential to get in early because then the trajectory is, is, is more malleable," and then you don't want, um, somebody to end up in a place where, uh, change isn't possible. And then you have people saying, "Well, wait, uh, they changed gender and then now they wanna reverse later because..." And they're angry that they, they were allowed to make the decision. So it's a mess. It's a, it's a j- it's, it's a genuine mess in terms of defining what the key parameters are. Do you think it will ever be resolved?

    10. NS

      Let me step back and say we don't even know much about this in the mouse yet, right? So we don't know what happens to the mouse brain at puberty.

    11. AH

      Really?

    12. NS

      There are experiments being done-

    13. AH

      Mm-hmm.

    14. NS

      ... but not, certainly not in the same detail as in the adult mouse brain. So how circuits are made plastic or how they're malleable at puberty is still sort of being worked out in the mouse. Right? So tha- so that's the first answer. The second one, the reason I think it's contentious is, A, it's both deeply personal, what the kids are feeling, but also there's these huge sort of societal, political forces that come into play. So I think the tension there has to be resolved, I think, politically and sort of socially rather than, you know, just resorting to science. I think the science will give you data, but you will still have to make a decision as to whether or not, you know, that'll be allowed. So I think that's the reason it is so contentious. The data's not there, in terms of at least in the mouse or other animal models, or it's coming out, it's coming out slowly. Um, and socially and politically, it's very volatile 'cause it's not clear how you sort of, you know, have kids' rights, parental rights, societal expectations intersect and give a result that is satisfactory to everybody. So that's where we are. I'm not saying I'm pro one or against the other. I'm just saying that's why it's so contentious in my mind.

    15. AH

      Today is a biological discussion because that's what we can say, uh, things about for sure, right? We, we can talk about biology for sure. The, the other pieces are, um, they're even prone to, um, trip wires related to language. And, and that, uh, for biologists is, is, uh, no fun. Um, and, uh, the whole reason to become a biologist as opposed to a psychologist is because, um, while I have tremendous respect for the field, biologists have nomenclature committees. "We agree, this is-"

    16. NS

      Right.

    17. AH

      Y- Because y- you could make this argument about anything. Uh, again, by way of example, I mean, you could say, "Oh, the SRY gene is the SRY gene." But what if it's just two amino acids different and it's still functional? Is it still the SRY gene? Well, there are nomenclature committees where people decide yes or no. You have a, you have a community agreement in order to go forward, and you don't have that in terms of the discussion around gender, but you have it around the discussion of sex-

    18. NS

      Yes.

    19. AH

      ... right?

    20. NS

      And circuits.

    21. AH

      And circuits. So let's talk about circuits for sex. Let's start there. Let's start with a recent discovery your laboratory made, which is about sexual behavior in males and the frequency of sexual

  19. 1:19:05 – 1:21:31

    Sexual Behavior, Refractory Period & Male Brain, Tacr1 Cells

    1. AH

      behavior. I think, um, most everyone who has gone through sex education in one form or another understands that males have a refractory period after ejaculation in which they don't mate again, and in some cases can't mate again. What did you discover about the neural circuits responsible for mating and the refractory period?

    2. NS

      Yeah. So this is in the mouse, and we are working in male mice, and we sort of hit upon these neurons. We identified these neurons using genetics that expressed a specific set of genes in the hypothalamus, that if we activate them, um, male mice no longer have a refractory period. And the strain of mouse we're working on has a post-ejaculation refractory period of about four to five days.

    3. AH

      Typically.

    4. NS

      Typically, so he won't mate for up to four days with a female after ejaculation.

    5. AH

      So if he is presented a female and they mate, he ejaculates, you remove that female, you give him a new female, he won't mate with her for four or five days.

    6. NS

      Correct.

    7. AH

      He's content or he's not able or whatever. Okay.

    8. NS

      So we sort of switch these cells on with optogenetics, you know, we sort of electrically activate these cells with light, and they lose their refractory period. They start mating within a second. As soon as the light comes on, the cells start firing, they start mating again and they can ejaculate again.

    9. AH

      So you reduce the refractory period from four to five days to one second.

    10. NS

      That's right.

    11. AH

      How long can they keep this up? Uh, no pun intended.

    12. NS

      As long as the light is on, they'll keep mating.

    13. AH

      And you're not talking about light presented to the eyes. You're talking about, um, elect- basically a, a light-driven way to stimulate the neurons.

    14. NS

      That's right.

    15. AH

      What are these neurons? What, what are they called? (laughs)

    16. NS

      Uh, they're in the hypothalamus. They're in the preoptic area, which is one of the most...... sexually different- differentiated areas in the brain across vertebrates, and they express the gene tachykinin receptor one, TACR1.

    17. AH

      I thought tachykinin is associated with aggression.

    18. NS

      Social behaviors, depending on the circuit.

    19. AH

      Mm-hmm.

    20. NS

      Right? So flies, it's been shown, David Anderson's shown, for example, the TAC1, the tachykinin gene re- regulates aggression. In this circuit in the male mouse, it regulates sexual behavior.

    21. AH

      How many neurons?

    22. NS

      Maybe about 1,200, 1,500 on each side, so about 2,000, 2,500 cells total.

    23. AH

      I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over 100 advanced lab tests that give you a

  20. 1:21:31 – 1:23:19

    Sponsor: Function

    1. AH

      key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFASes or forever chemicals. Function not only provides testing of over 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with Function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption, I'd been eating a lot of tuna, while also making an effort to eat more leafy greens and supplementing with NAC, N-acetylcysteine, both of which can support glutathione production and detoxification, and I should say by taking a second Function test, that approach worked. Comprehensive blood testing is vitally important. There's so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by Function's simplicity and at the level of cost. It is very affordable. As a consequence, I decided to join their scientific advisory board, and I'm thrilled that they're sponsoring the podcast. If you'd like to try Function, you can go to functionhealth.com/huberman. Function currently has a wait list of over 250,000 people, but they're offering early access to Huberman podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function. If we were to scale the size of the preoptic area from the mouse to the human, back of the envelope calculation, how many neurons is this in humans?

Episode duration: 2:26:43

Install uListen for AI-powered chat & search across the full episode — Get Full Transcript

Transcript of episode k8SBJzsIWAo

Get more out of YouTube videos.

High quality summaries for YouTube videos. Accurate transcripts to search & find moments. Powered by ChatGPT & Claude AI.

Add to Chrome