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Male vs. Female Brain Differences & How They Arise From Genes & Hormones | Dr. Nirao Shah — Transcript

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0:00Welcome to the Huberman Lab podcast
0:02where we discuss science and
0:03science-based tools for everyday life.
0:09I'm Andrew Huberman and I'm a professor
0:11of neurobiology and opthalmology at
0:13Stamford School of Medicine. My guest
0:16today is Dr. Niral Shaw. Dr. Nal Shaw is
0:19a professor of psychiatry and behavioral
0:21sciences and neurobiology at Stanford
0:23University School of Medicine. Dr. Shaw
0:26is both an MD and a PhD and his
0:28laboratory focuses on understanding the
0:30neural and hormonal mechanisms
0:32underlying sex differences in the brain.
0:34During today's episode, we discuss what
0:36is known about male and female
0:37differences in brain structure and
0:39function and how those differences arise
0:41across development both in uterero and
0:44post-natally that is during puberty and
0:46into adulthood. A lot of our discussion
0:48centers around testosterone and estrogen
0:51and how both of those hormones play a
0:52profound impact on the development of
0:54both the male and female brain, but
0:56leads to different outcomes in male
0:59versus female brains. We also discussed
1:01the neural circuits that control sex
1:02behavior and aggressive behavior in both
1:04males and females and how those are
1:06activated by different hormones. As you
1:09all know, there is immense interest and
1:11a lot of controversy around sex
1:12differences and how that relates to
1:14gender. Today's discussion centers
1:16around the biology of sex differences in
1:18the brain and body. And it will provide
1:20a very useful template for everybody in
1:22thinking about male versus female
1:24differences in behavior, in emotions,
1:26and how that intersects with gender and
1:29culture. As you'll soon see, Dr. Shaw is
1:32a true expert in understanding sex
1:34differences in the brain and body and
1:35how those arise. He's also unafraid of
1:37addressing what is known and unknown
1:39about those differences and their
1:40origins. and he embraces that sex
1:42differences are one of the most
1:44impactful aspects of human biology and
1:46health. So, by the end of today's
1:48episode, you will indeed have the most
1:49up-to-date information on this important
1:51topic. Before we begin, I'd like to
1:53emphasize that this podcast is separate
1:55from my teaching and research roles at
1:57Stanford. It is however part of my
1:58desire and effort to bring zero cost to
2:00consumer information about science and
2:02science related tools to the general
2:04public. In keeping with that theme,
2:06today's episode does include sponsors.
2:08And now for my discussion with Dr. Dr.
2:10Nural Shaw. Dr. Nural Shaw, welcome.
2:14>> Thank you, Andrew. Pleasure to be here.
2:15>> You work on one of the most interesting
2:18topics in the entire world, which is sex
2:20differences in the brain and the impact
2:22of hormones on the brain, on behavior.
2:26Let's start with a very straightforward
2:27question.
2:29Are there male female differences in
2:32terms of brain structure and function?
2:34>> Yes. Let me qualify that. So we work on
2:37the mouse on the mouse brain and we and
2:39others have identified lots of
2:41differences in structure and connections
2:43and numbers of neurons numbers of cells
2:45in the brain and also my own lab is
2:47focused on identifying differences in
2:49gene expression between females and
2:50males and there are huge differences for
2:53the topics we're going to discuss today.
2:55I know and we're going to lean heavily
2:56on mouse data, but I think it's fair to
2:59say that because so much of those data
3:01rely on the structure and function of
3:03the hypothalamus, which you'll educate
3:05us on, how conserved is the hypothalamus
3:09between mouse and human. I would say
3:11anatomically from an atlas, if you're
3:13just looking at atlases of humans and
3:15mice, they're very conserved. You can
3:18point to regions in the mouse brain, the
3:20ventromedal hypothalamus for example,
3:21the VMH which we might talk about
3:23controls aggression and other behaviors,
3:25female sexual behavior. You can say this
3:27is the VMH in the mouse and you can
3:29basically pinpoint the same region of
3:31the human brain and it's turning out to
3:32be clinically relevant as well in
3:34humans. You can do the same thing for
3:36the preoptic area which controls
3:38maternal behaviors, preoptic, you know,
3:39male sexual behavior and we can identify
3:42the same region in the human brain as
3:43well. So anatomically there are very
3:46similar analoges in the human
3:47hypothalamus as there are in the mouse
3:49and this region is conserved because it
3:51controls as you pointed out very
3:53fundamental functions reproduction
3:55aggression taking care of young thirst
3:58temperature. So these tend to be
4:00conserved because you don't want to muck
4:02with a circuit that's already
4:03functioning and that's essential for
4:05survival. So you can find analoges of
4:07these structures all the way from birds
4:09across vertebrates from birds, lizards,
4:11rodents, non-human primates, and humans.
4:14>> I think many people lean toward the idea
4:17that humans are so different than mice.
4:19Um, and they like that idea because it
4:23um, somehow I don't believe this, but I
4:25I think it somehow gives them the
4:27impression that they have more degrees
4:29of freedom over their feelings and
4:31behavior than perhaps they would if we
4:34were a slave to our hypothalamus or
4:37something of that sort. But studies on
4:38the human as you and I know uh where
4:41different uh hypothalamic circuitries
4:43have been stimulated reveal that you can
4:46elicit rage, you can elicit sexual
4:47desire, behavior um and on and on in a
4:51human just as you can in a mouse.
4:53>> Yeah. I mean I think we are different in
4:56the sense that we have a huge cortical
4:59sort of neural volume. We have a huge
5:01cortex and that you know gives us many
5:03more degrees of freedom in deciding when
5:05and what to do and where to do it. So
5:08there is flexibility granted by that
5:09enormous expansion of the cortex but the
5:12basil structure for those behaviors the
5:13hypothalamus and the amydala are very
5:15conserved. So the behaviors exist of
5:17course is encoded in the brain but we
5:19can control them or inhibit them if you
5:22will and in appropriate moments. So
5:24we've all heard of nature versus nurture
5:27and I think that's a very kind of
5:28relevant theme as we wade into this
5:30topic of of sex differences in the brain
5:32and sex hormones and behavior. Could you
5:36explain for us how it is that hormones
5:38act on genetics in order to set up a
5:42bias for behavior? And um for those that
5:45are familiar with the idea that nature
5:47and nurture are both involved, which
5:48should be everybody, uh what I'm getting
5:50at here is this notion of organizing
5:52effects of hormones versus activating
5:55effects. You'll educate us on what those
5:56are.
5:57>> So we work on hormones like
5:58testosterone, estrogen, progesterone,
6:00which are steroid hormones. And as you
6:03know, as you pointed out, Andrew, they
6:04act at at least two different stages of
6:06life. Um, and early on in development,
6:10at embryionic stages in some species,
6:12um, like in humans, in in uterro, uh,
6:15when the, you know, when the woman's
6:17pregnant or in mice just at birth,
6:19perinatally, just after birth, um, these
6:22hormones
6:24generate what is thought to be an
6:26irreversible differentiation of the
6:28brain along a female or a male pathway.
6:31So they sort of um set the circuits if
6:34you will so that these behaviors can
6:37then be displayed in adults life after
6:39puberty when the hormones kick back in
6:41again. So after this early critical
6:44period and I know you've talked about
6:45critical periods before in your in your
6:47podcast there's a critical window that
6:50is species specific when hormones sort
6:52of organize the brain sort of
6:53irreversibly set down circuits
6:56and then you know the gonads testes and
6:58ovaries go quscent until puberty hits
7:01and then at puberty the hormones come
7:03back on again and then they activate if
7:05you will these circuits so that adult
7:07behaviors can be displayed. But the
7:09circuits were sort of initially laid
7:10down at some point in development.
7:13>> Correct me if I'm wrong, but my
7:14understanding is that the presence of a
7:15Y chromosome is really the key
7:18differentiating factor for setting up
7:19circuitries to be more malike or
7:22femaleike in the brain. These organizing
7:24effects. Um could you explain what's on
7:27the Y chromosome? Actually uh you should
7:29probably uh remind everybody how
7:31chromosomes and genes work very briefly,
7:33right? 23 sets of chromosomes and we
7:35have the sex chromosomes. if you don't
7:36mind educating us um just on chromosomes
7:39and then how the presence of a Y
7:40chromosome is really the key
7:42deterministic factor not just if you get
7:44a male or a female as it's you know on a
7:47birth certificate but the whole kitten
7:49kaboodleoodle in terms of brain
7:51structure and function as well as
7:53genitalia.
7:53>> Sure. So as you pointed out you know
7:55there are 23 sets of chromosomes and
7:57there's a set of chromosomes called
7:59autotosomes which are simil identical
8:01between males and females and there you
8:02know they're completely conserved
8:04they're the same and then females have a
8:06set of chromosomes the sex chromosomes
8:08referred to as X chromosome and Y
8:10chromosome and females have two I'm
8:12sorry two X chromosomes X and X and
8:14males have an X chromosome and a Y
8:16chromosome
8:16>> those are the sex chromosomes
8:17>> those are the sex chromosomes so males
8:19have XY females have XX okay and the Y
8:22chromosome is very in the sense that it
8:25has it on the chromosome sits a gene
8:27called SRY sex determining region on the
8:29Y SR Y gene and this gene essentially
8:33dictates whether or not the embryo will
8:35have testes or not and then if yes if
8:37the embryo has testes then they'll make
8:39testosterone and masculineize both the
8:42genitalia and the brain and the rest of
8:43the body
8:44>> in uterero
8:45>> in uterero. Okay. So, uh, just to step
8:47back for, uh, people that aren't so
8:49familiar with how chromosomes and genes,
8:51uh, work upstream of of hormones. So,
8:53what you're telling us is 22 sets of
8:55autosomes. Then we have the sex
8:56chromosomes. In females, it's XX. In
8:59males, it's XY. On the Y chromosome,
9:01there's this SRY gene.
9:02>> There's a single gene SRY.
9:04>> And that the presence of that gene uh,
9:07means that there will be RNA and then
9:09protein made.
9:10>> That's correct. And
9:12some of those proteins will cause the
9:15development of the testes and then the
9:18testes will secrete testosterone in
9:19uterero and shape the brain for its
9:22potential to be male when puberty
9:25happens later on. Right?
9:26>> Yes. Uh let me qualify that. Okay. So
9:29SRY is a transcription factor which
9:31means it is a gene that encodes a
9:33protein from RNA. You know it gets
9:35transcribed into RNA and then RNA gets
9:37made into protein and the protein is a
9:38transcription factor. the SRY protein
9:41and what that means is it sort of can
9:43regulate expression of other genes. So
9:45it can sort of switch on or silence
9:47suites of genes that take the
9:49bipotential gonad. So the gonad before
9:52it becomes testes or ovaries is a
9:53bipotential gonad. It can go either way.
9:55>> At what stage of embryionic development
9:57in human is the gonad by potential? It
10:00could become male or female.
10:01>> It's thought that it's early late first
10:04or early second trimester. So as late as
10:07the second trimester,
10:10the gonads are equal potential. They
10:12could become male or female. And which
10:15direction they go depends entirely on
10:17the presence of this SRY transcription
10:18factor.
10:19>> That's right. And the same is true in
10:20the mouse as well. So in the mouse, the
10:21gonads are bipotential until day 12 of
10:24gestation. Mouse gest gestation is about
10:2620 days. So does this mean that prior to
10:29the beginning of the second trimester
10:32because the SRY transcription factor
10:34isn't active yet that the brain of the
10:36fetus is essentially identical between
10:38males and females?
10:39>> That's the thinking. Yes. Yeah.
10:41>> Okay.
10:41>> And that same is true in the mouse. In
10:43fact, in the mouse, which is our model
10:45organism in in the laboratory, the brain
10:47is thought to be by potential right
10:48almost until birth.
10:50>> Really?
10:51>> Yes. So, and I'm sure we'll get into
10:53this, but the organizing effect of
10:55testosterone, as we sort of talked
10:56about, can in fact be detected even as
11:00late as after birth in the mouse. So,
11:02you can take a female mouse and birth
11:05and give it testosterone and you can
11:07mastronize her behaviors down the road,
11:09>> but she doesn't have testes.
11:11>> That's right. So, the simple act of
11:12giving testosterone will do that. So
11:14that's the organizing action of
11:15testosterone. Irreversible
11:16differentiation of a bipotential brain
11:19along a male pathway with testosterone.
11:22>> Okay. But in humans as early as the
11:23second trimester beginning the SRY
11:26transcription factor kicks on.
11:28>> Yes.
11:28>> My understanding based on my training
11:31from some years ago uh hopefully this is
11:33still true. You'll correct me if it's
11:34not. is that some of the genes
11:37downstream of SRY start to suppress the
11:40malarian ducts, the fallopian tubes and
11:42instead you get testes and the
11:44vaspherins and and you know basically
11:46all the uh structure for delivering
11:50sperm out of the penis for culation
11:52later in life.
11:53>> That's right. So SRI sort of takes the
11:56gonad makes it into a test. The testes
11:59secretes at least two hormones that we
12:00know about that are very important for
12:01sexual differentiation. One is
12:03testosterone which you know people have
12:05heard about and the other is an
12:06antimmalarian hormone and this hormone
12:08from the testes sort of suppresses
12:10differentiation of the uterus and the
12:12vaginal tract. Okay. And in the
12:15fallopian tubes and the ovaries, right?
12:17So you get a test that you know
12:18suppresses female gonadal development,
12:20genitalia development and you have
12:22testosterone that takes a bipodential
12:24genitalia and then masculinize them and
12:26you get a penis and a scal sack.
12:29>> And what about the role of
12:30dihydrotestosterone? My understanding is
12:32that the development of the male brain
12:36and the development of male genitalia
12:38was strongly dictated also by
12:40dihydrotestosterone.
12:41So the action of dihydrotestosterone
12:43which is a derivative of testosterone
12:45from a single enzyme you know five five
12:47alpha reductase converts testosterone
12:49and makes it into dihydrotestosterone or
12:51DHT. The action of DHT is best
12:54understood on the external genitalia. So
12:56DHT acts on the same receptor as
12:58testosterone does the androgen receptor
13:00except it binds at much higher affinity.
13:02So it's a much more potent activator of
13:04the receptor. And this activation of the
13:07receptor in the external genitalia
13:08tissue really is what gives you
13:10masculinization of the penis and the
13:12scal sack. So what I'm taking from this
13:14is that the hormones themselves shape
13:18circuitries in the brain. We'll talk
13:20about how that happens. They shape the
13:21external genitalia. But unless you have
13:23the SRY transcription factor, you won't
13:26get the suppression of the ovaries and
13:28the malarian ducts and all of that
13:29stuff. So it's not as if the presence of
13:32androgens testosterone and DHT to a
13:36female XX
13:38chromosomal fetus will make that female
13:41fetus male. It's
13:44really the presence of that SRY gene.
13:46You need suppression of femaleness plus
13:48you need amplification of maleness, so
13:51to speak.
13:51>> That's exactly right. Yeah. Okay. So,
13:53the reason I'm asking all of this and
13:54the reason we're um uh painting this
13:57tapestry of hormones and genes etc is
14:00because as you know these days it's very
14:03controversial um out there as to when
14:07sex versus gender uh is established. And
14:12some of that, I think, is born of
14:14political leanings, but it's also born
14:15of this understanding that there's
14:17perhaps a continuum between masculinity
14:20and femininity. That you can find males
14:23that are kind of in the extreme
14:26stereotype of maleness. You can find
14:27females that are at the extreme
14:29stereotype of femaleeness in terms of
14:31behavior and external um pre you know
14:35morphology, right? Presence of breasts
14:37etc. and that but that there is seems to
14:40be a continuum of phenotypes. But when
14:43it comes down to the genetic biology,
14:48it really is about the presence of this
14:50SRY gene. That seems to be the
14:51deterministic factor.
14:53>> That's right. So you can even have SRY
14:55sort of hop chromosomes from a Y
14:58chromosome onto an autotosome.
15:00>> That's happened.
15:00>> That's happened in humans.
15:02>> In humans and in mice. And if that
15:05happens, you can have a full complement
15:07of XX chromosomes can be female, but SRY
15:10is sitting on an autotosome and then
15:11that animal becomes a male. So you can
15:14have XX males as well.
15:16>> So it's not the Y chromosome per se
15:18>> is the gene SRY.
15:19>> So one gene,
15:20>> one gene,
15:21>> SRY determines maleness or femaleness.
15:24>> That's right. And if you take away SR,
15:26if you mutate it for example genetically
15:28with experiments in the mouse or
15:29naturally occurring mutations in humans,
15:32SRY, you know, loss of function of SR,
15:35you will have XY females. Wow.
15:38It's really all about SRY. Yeah. Like
15:40the entire political debate, you know,
15:43uh not sociological debate, but the
15:45entire political debate as to whether or
15:46not um someone is male or female, if you
15:49wanted to boil it down to a biological
15:52factor, it's one factor. Whether it's SR
15:54Y make a female or a male. Yes, a
15:57chromosomal genetic female or male would
15:59be SRY.
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19:09A couple examples that I I learned about
19:11years ago, tell me if these are still
19:13considered true, is that um that for
19:15instance there are XY
19:18people, so they have the SRY gene, they
19:23make testosterone and
19:24dihydrotestosterone, but they have a
19:26mutant copy of the androgen receptor.
19:28>> That's right. Those people do not have
19:31ovaries,
19:33so they're infertile
19:36as a female.
19:38They also, however, don't have testes or
19:42the testes don't descend. They make
19:45testosterone, but the body can't respond
19:47to the testosterone. So, they look
19:49female,
19:50>> maybe a little bit um smaller breast
19:53development, etc., but they look female,
19:55>> but they are infertile. uh as women and
20:00if you were to rely on the presence of
20:01SRY gene as a definition of maleness or
20:04being male they qualify.
20:06>> Yes.
20:07>> If you rely on the presence of
20:08testosterone they qualify but there have
20:10been no action of testosterone.
20:13>> And so they go through life at least
20:15until puberty thinking that they're
20:17female. Is that right?
20:18>> That's correct. The parents think
20:19they're females. They think they're
20:21females. They're piercing they're
20:22females. They look completely feminized.
20:25>> How common is that? It's not that
20:27common. I think it's I'm going to get
20:28the numbers exactly, you know, not going
20:30to get the exact numbers right, but I
20:32think it's one in 10,000 maybe or one in
20:3420,000. I mean, these numbers are
20:36changing all the time as diagnostic
20:38tests get better, but it's not that
20:39common,
20:40>> but there still that's still a
20:42significant number of human beings
20:43you're talking about.
20:44>> And then my understanding is there's
20:47also a mutation where um people lack the
20:52enzyme that converts testosterone to
20:54dihydrotestosterone.
20:55So they're born appearing female. They
20:58have SRY, the gene, this deterministic
21:01gene. They make testosterone. It doesn't
21:03convert to dihydrotestosterone. Then
21:05puberty rolls around and they go from
21:07having what the parents and they thought
21:10was a vagina and a clitoris and they
21:12sprout a penis.
21:13>> That's right.
21:14>> How common is that?
21:15>> It's not that common. I think it's more
21:17common in places where there marriages.
21:19So, you know, in some villages, in some
21:21countries, it's fairly common. and they
21:23even have sort of local dialect names
21:25for this condition. Um I forget what
21:27it's called in in those languages but
21:29there's definitely so it's called a
21:30penis at 12 syndrome in sort of medical
21:32textbooks because as you said they
21:34sprout a penis at 12 because the early
21:36penile development and the scroll sac
21:38development depends on DHT which is a
21:40much much more potent activator of the
21:42androgen receptors. If you can't have
21:44DHT then testosterone alone cannot
21:47masculinize the external genitalia. It's
21:49feminized early on but after puberty
21:52when the testosterone levels go up again
21:54that level of testosterone is now is
21:56sufficient to differentiate the external
21:59genitalia into a penis.
22:02>> So in the strictest sense the presence
22:04of the SRY gene is deterministic for
22:06maleness.
22:08>> Yes.
22:09>> It's not even just the Y chromosome.
22:11It's really SRY gene on the Y chromosome
22:14because as you point out if the SRY gene
22:15is on a different chromosome because it
22:17got transllocated there then you still
22:19get a male fetus.
22:22>> Is it also fair to say that the absence
22:24of the SRY gene is what determines
22:27femaleness or are there a separate set
22:30of deterministic genes that designate
22:32femaleeness? Some people might be
22:34confused by this question only because
22:35what I'm not being clear about is you
22:39could imagine that it's the presence yes
22:41of SRI that creates maleness and in its
22:43absence you just get a female by default
22:46or it could be that there's a
22:47deterministic female gene that makes the
22:49brain and body of females female.
22:52>> Right? So that's not known in mammals at
22:54least there's no single gene that's been
22:57identified in mammals in mouse or humans
22:59that determines femaleness. So no gene
23:02that if placed onto a Y chromosome would
23:05drive the differentiation of that fetus
23:07to to female.
23:08>> That's right.
23:09>> Okay. What does that tell us about human
23:12evolution?
23:13>> I don't know what it says about
23:14evolution. It says that there is a
23:16there's a genetically programmed pathway
23:18that in the fetus in the absence of SR
23:20will give you a female body and a brain.
23:24Right? Right? So that pathway, this
23:25genetic program exists and that SRI sort
23:28of tamps it down and boosts maleness.
23:32>> Okay. I want to get back to sex
23:34differentiation and behavior in a
23:35moment, but I want you to tell me if the
23:37news report from a few years ago, the
23:39California condors can reproduce from
23:42two females. Is that true?
23:45>> I've not seen that report. U I don't
23:47know.
23:47>> Okay. Um years ago when I was at
23:49Berkeley, there was a graduate student
23:51in our program who was studying a
23:52species of um uh moles that live in
23:56Tilden Park. And these moles apparently
24:02can transiate their ovaries into testes
24:06depending on the population numbers of
24:08males versus females. Is why I asked
24:10about evolution. You know, you could
24:12imagine that if such a capacity existed,
24:16um that could be very beneficial for the
24:18propagation of a species. Like if you
24:20run out of males, a female can turn her
24:23ovaries into testes and reproduce with
24:25another female.
24:27>> Or if you run out of females, the males
24:29could transiffate their testes into
24:31ovaries. This sort of alludes to the
24:34idea that this business of X chromosomes
24:37and Y chromosomes and genes on Y
24:38chromosomes in theory um if we were to
24:42zoom out from human existence, you know,
24:45we're at one point in human existence,
24:47you could imagine that there was a a a
24:49kind of a larger control over this so
24:52that our numbers never run out. What are
24:54your thoughts on on on that? I'm not I'm
24:56not talking about a you know where the
24:58origin of control would be, but but how
25:00plastic how variable is this or or is it
25:04like the SRY gene is on the Y chromosome
25:0699.99999%
25:07of the time and therefore like this in
25:10this instances of transllocation on X
25:11chromosomes is kind of rare. It is rare.
25:14So let me point out that SRY
25:18is not even determining sex across all
25:21vertebrates. Okay. So it's not as if
25:23birds have an SRY. You know most genes
25:25as you know Andrew many genes are most
25:28genes are conserved between say birds
25:29and and humans. You know the way you get
25:31the axis of the animal developing from
25:34front to back hawk genes controlled by
25:35hawk genes is very conserved from birds
25:38to humans. Um and there's a similar set
25:40of genes even in flies
25:41>> even the placement of the eyes.
25:43>> That's right.
25:43>> One gene pack six
25:45>> places eyes on the front of the head.
25:47>> So but SR is sort of special. So birds
25:50don't have an SRY. Flies don't have an
25:52SRY. And in fact SRY has been evolving
25:56very quickly. So many genes you can take
25:58from the human genome and put in the
26:00mouse and can get you know mouse
26:03mutations rescued but you can't do that
26:06with SRI. So it's been mutating so fast
26:09uh because it's sort of important for
26:11speciation and protecting the sort of
26:13species advantages that led to the
26:15development of that species. So you
26:17can't take SI and sort of move it
26:19between species. Not only that, but as
26:21you sort of were alluding to, there are
26:22many species in which in vertebrates in
26:25which SI is not even relevant for sexual
26:27differentiation and determination. What
26:29happens is, as you point out, population
26:30densities can regulate that. Temperature
26:32can regulate that, sex differentiation.
26:35Um, I think it's true in alligators and
26:37crocodiles maybe. And certainly adult
26:39fish can transiate from female to male
26:42as well.
26:42>> Wow. I didn't realize it was that
26:43common. Yeah. But it makes sense if uh
26:45for these ectotherms that regulate their
26:46temperature based on the environment.
26:49Um,
26:50look, every species main goal is to make
26:53more of itself and protect it young
26:56>> and protect the advantages it has as a
26:58species in the sort of ecological
27:00environment it finds itself in.
27:02>> Right. So you sort of close you don't
27:04exchange gene pools between species for
27:06example. Right.
27:08>> Yeah. There's a a whole other discussion
27:11um years ago. I think you and I were
27:12attended a talk where Kim, you know,
27:14somebody working on Drosophila, you
27:17know, species of of fly said, you know,
27:19that Drosophila prefer to mate with
27:21Drosophila as opposed to other species.
27:22And they this gets a little bit um kind
27:25of grossed when you start thinking about
27:27yeah, like why is it that species
27:28maintain reproduction basically within
27:30species? Um one hopes um as well as sex
27:34behavior with it within species. And as
27:36you point out, every species is vying
27:38for itself. In fact, we had a plant
27:39biologist on here recently. The plants
27:41are making things to kill off their
27:43predators, you know, limit their their
27:45ficundity. Let's talk about how hormones
27:49downstream of SRY or the absence of
27:51those hormones shape the brain because I
27:54think uh people listening to this uh
27:57certainly know people of both sexes,
27:59right? And
28:02I don't think it's that politically uh
28:05edgy to say that most people probably
28:09believe that men and women, boys and
28:13girls even
28:15respond very differently to the same
28:17stimuli.
28:18>> That's right.
28:18>> You know, and the stereotype here is,
28:20you know, she started playing with dolls
28:22from the beginning. you know, he picked
28:24up a stick and pretended it was a weapon
28:26from the moment that he picked up a
28:29stick
28:29>> prior to puberty, prior to the the
28:31testes secretreting testosterone.
28:34So, what is known about hormone-based
28:37differentiation of the brain in terms of
28:39maleness and femaleness? Uh, and let's
28:43just for the moment suspend all uh all
28:45politics, all stereotypes and just ask
28:47like what does the biology say?
28:50So there are a couple of classic
28:52experiments in the field done in the
28:541950s that really speak to this the sort
28:56of organizational differentiation effect
28:58of hormones and then we've done some
29:00additional work in the mouse that also
29:01relates to this and then there are human
29:03conditions that can inform this
29:05discussion as well. Um so the first
29:07experiment I would like to talk about is
29:08by Charles Phoenix in 1959 I think and
29:11he did this experiment in guinea pigs
29:14and guinea pigs become female masculiniz
29:16or feminized uh in utero prenatally just
29:19like humans do and if he gave
29:21testosterone
29:23to the pregnant female then females that
29:27were born
29:28to that mother had received testo had
29:31seen testosterone their brains had seen
29:32testosterone in development in utero and
29:35when they were born and became adults,
29:37very high probability of mating like a
29:39male like sexual mating you know having
29:41sexual behaviors like a male.
29:42>> So thrusting behavior
29:44>> thrusting behavior and they had very
29:46little receptivity sort of female type
29:48receptive behaviors
29:50>> which in rodents uh is typically
29:52lordosis the arching of the back. People
29:54who have cats know about this, right?
29:56For example,
29:57>> cats in heat will lowerose. Um, so
30:01that and even if he gave the females,
30:04adult females who had seen testosterone
30:06early on, if he g if he gave these adult
30:08females boosts with estrogen and
30:10progesterone to sort of increase female
30:12sexual behavior in these females, they
30:14had very little displays of female
30:16sexuality.
30:17>> They still mounted like males.
30:19>> Okay. So the exposure of females to
30:21testosterone in uterero
30:23>> sets up a program whereby their sexual
30:26behavior appears more malike. That's
30:28right.
30:28>> Thrusting behavior and lack of lordosis.
30:30So there's a there's a the presence of
30:33something and the absence of something.
30:35>> Correct.
30:35>> What about aggression? Were they more uh
30:38aggressive?
30:38>> That paper didn't look at aggression.
30:40We've done that in the mouse and you
30:42basically see the same thing. Now in
30:44mouse sexual defensiation as we talked
30:46about earlier happens right at birth or
30:48just around birth. So we could take day
30:50one pups and if you give them
30:52testosterone
30:54these females became territorial like
30:57males as adults.
30:59>> Interesting. So territorialism is a is a
31:02male specific trait.
31:03>> Mice mice male mice are territorial.
31:05Female mice at least in laboratory don't
31:08fight as much except when they're
31:09mothers and nursing a letter.
31:11>> Maternal aggression is very real.
31:12>> That's right. Is it testosterone
31:14mediated?
31:15>> We don't we don't know.
31:16>> Interesting.
31:17>> Yeah.
31:18>> Okay. So, exposure to testosterone in
31:22uterero sets up male-like behaviors in
31:24female offspring is what I'm hearing.
31:26>> I'm aware of at least one condition in
31:28humans where this might occur, which is
31:31when um there's either a tumor or stress
31:35induced uh stimulation of the or over
31:37stimulation of the adrenal glands. And
31:41of course the adrenals make adrenaline
31:43and cortisol but also they have a layer
31:45of cells that produce and dione which is
31:47a
31:48>> an androgen. Um
31:51what is the outward appearance of female
31:54babies born to women who had an
31:57overactive adrenal during pregnancy?
32:00>> Yeah. So I think you're referring to
32:02congenal adrenal hyperlasia which is you
32:05know a mutation in an enzyme that
32:06typically makes cortisol and this
32:08happens in the baby itself. So the
32:10baby's a mutant for this enzyme. Oh,
32:12>> so the baby's adrenals are the ones that
32:14are uh disrupted in the system.
32:15>> And because they can't make cortisol,
32:18these sort of precursors to cortisol get
32:21shunted into making, as you pointed out,
32:22androgens
32:24>> because there excess precursor, it just
32:25gets shunted off into a different
32:26pathway.
32:27>> So these babies, these females are born
32:30with sort of masculineized external
32:32genitalia
32:33>> based not on the presence of testes or
32:35testosterone
32:36>> or SR but presence of testosterone of
32:38androgens, right? because the adrenals
32:40are now pumping out androgens rather
32:42than cortisol.
32:43>> Are the uh androgens that come from the
32:45adrenals um the same in terms of they
32:48bind the androgen receptor just like
32:50testosterone would? So they look like
32:51testosterone actually some years ago and
32:54dione uh was the topic of a lot of news
32:56stories because of uh Mark Magguire the
32:59baseball player
33:00>> uh was accused of taking and dione. I
33:03mean, it's not hard to see the
33:04differences in his physical size from
33:07one season to the next. Whether or not
33:09he did that or not, I don't know if it
33:10was ever confirmed. I think it was.
33:12>> I see.
33:13>> Um, we can ask him. I um I don't want to
33:16put anything on him that uh wasn't true,
33:18but that's what the news claimed. And
33:19you could buy and dione in the GNC.
33:23>> Huh. But the adrenals make testosterone
33:27like substances in this person that
33:30doesn't have the capacity to make enough
33:32cortisol.
33:34>> So what does the female offspring look
33:36like?
33:36>> She has sort of masculinized external
33:38genitalia.
33:40>> Mhm.
33:40>> And that can be surgically corrected
33:42because now doctors are aware of this
33:43condition. So they can surgically sort
33:45of correct that and you can give the
33:46baby when she's born cortisol because
33:48that's absolutely essential for
33:50survival. So she's XX genetically
33:54female. She has no SRY gene.
33:58>> She made too much testosterone in
33:59uterero. So the clitoris resembles a
34:02penis.
34:03>> More or less.
34:04>> Yes.
34:05>> And the reason I say more or less is uh
34:08not to be faciticious, it's it's that
34:10there's a continuum there,
34:11>> right?
34:12>> And it depends on exactly when the
34:13androgens kicked in from the adrenals.
34:15Yeah.
34:15>> So it could be a uh an enlarged clitoris
34:18or it could be a small penis or it could
34:19be a normal sized penis. It just depends
34:21on how much androgen in
34:22>> she's verilized as we say, right?
34:23>> Viralized. Okay. Does she have facial
34:25hair
34:26>> as a baby? No.
34:27>> Okay. Later.
34:28>> No, I mean the surgically corrected for,
34:30right? As I pointed out, you give
34:31cortisol to the to the females,
34:33>> but she's fertile as a female because
34:35she still makes ovaries because she
34:37doesn't have the SR gene. Correct.
34:39>> Yeah.
34:39>> Wow. All right. Um, what about stress
34:43induced androgen release in the pregnant
34:45mother? Does that arrive to the fetus?
34:47So let's assume there's a female fetus.
34:50Everything's progressing normally. She
34:53has normal adrenal function. But mom,
34:56who also has normal adrenals, no CH
34:59mutation, uh goes through a period of
35:01extreme stress, is making a lot of
35:04cortisol, but also a lot of interesting
35:05Dione or maybe she has a challenge
35:08stress that requires she produce more
35:09androgens, which happens. Does the baby
35:12see those androgens and does it
35:14partially masculineize or viralize as
35:17you said uh the fetus?
35:18>> There's no reason why the baby won't see
35:20the testosterone or the androgens
35:21because it's a lipid. It should cross
35:23over into cells. Whether or not it
35:25affects her behavior, I don't know
35:27actually the human data on that or
35:28whether or not it viralizes. I don't
35:30know the data on that.
35:31>> But we know stress during pregnancy is
35:33not good.
35:34>> It's not good. Yeah.
35:34>> It's associated with higher incidence of
35:36schizophrenia and things like that. But
35:38we don't know that it's because of
35:39stress induced release of androgens. Is
35:41that right? Yeah. Okay.
35:42>> He's out on the right.
35:43>> I think it's just an important thing to
35:44distinguish because people will hear,
35:45"Oh goodness, I had a stressful second
35:47trimester or um something of that sort."
35:51>> To step back for a moment um before
35:53going into more of these um kind of
35:55naturally occurring experiments. Um I
35:58don't know if that's the proper way to
35:59think about, but they are. They're
36:01naturally occurring outcomes. Um, how
36:04much variation is there in terms of
36:07masculine to feminine phenotypes at
36:10birth? Has anyone ever looked at that?
36:12Like, you know, I mean, we we sort of
36:14pres like you, it's a baby girl, it's a
36:16girl, it's a boy, right? You know, the
36:18the gender reveal thing or whatever.
36:19Yeah. You know, um, on the ultrasound,
36:22it's a boy. Okay. There's no penis, it's
36:24a girl, you know, and there's other
36:25markers, too. you know that people have
36:27gotten quite good at recognizing male
36:29versus female fetus on the basis of a
36:31number of different things but most
36:33notably the absence of a penis is
36:35generally the the the uh the driving the
36:38conclusion it's a female um until
36:42chromosomal typing is done
36:43>> that's right
36:44>> but what is the range in terms of um
36:47phenotypes right has anyone ever
36:49actually explored that
36:51>> I think John's Hopkins had a program to
36:53do that back in the you know about 50
36:55years ago Um, and I think at back then
36:58at least it was just the size
37:00>> of the penis that said this is a boy or
37:02not
37:02>> or the external genitalia. I don't know
37:04what the current criteria are. I'm not a
37:05practicing MD.
37:07>> You are an MD though.
37:08>> I am an MD. I don't practice though.
37:09Yes.
37:10>> Um,
37:11>> so I don't know what the current
37:12criteria are, but with carotyping you
37:14can easily tell.
37:14>> You look whether or not it's XX or XY.
37:16>> That's right.
37:17>> Okay. Well, thank you for saying that
37:18because the reason I asked that question
37:20is that some years ago there there were
37:22these um reports of people who had grown
37:25up uh being treated as a male having
37:29received testosterone injections or
37:31something like that and then later
37:33discovered that they have XX
37:35chromosomes.
37:37Other people reported having XX
37:40chromosomes, never been treated with
37:41anything, but they thought they they
37:43were, you know, appeared male because
37:45they had one of these conditions that
37:46increased testosterone. And my
37:47understanding at the time was that the
37:50level of okayness, I don't even know
37:52what the word is. The level of okayess
37:55of the person with how they were raised
37:58oriented very strongly with whether or
37:59not they were XX or XY, not which
38:02hormones they had seen during
38:04development. In other words, if somebody
38:06uh had XX chromosomes, no SRY gene, but
38:10was exposed to a lot of androgens, maybe
38:13from their adrenals or elsewhere, a drug
38:15that the mom was treated with during
38:17pregnancy perhaps, that they would hit
38:20puberty and they they didn't feel quote
38:22unquote right. And in fact, genetically
38:24they were female. And then the reverse
38:26cases were also true. And often times
38:29these people would seek corrective
38:31hormone therapy or surgeries. So what
38:33I'm talking about here is actually the
38:34opposite of what we hear so much
38:36controversy about today where people
38:37want to switch. These are people who
38:39were forced by their parents and their
38:41doctors to be raised a certain way that
38:43did not match their chromosomes and it
38:46generally did not feel good to them.
38:48>> That's right. Yeah.
38:49>> What does that tell us about the role of
38:51genes in establishing maleness or
38:54femaleness of the brain? So we can go
38:56back to the condition we talked about
38:57earlier, you know, where the at puberty
39:00you sprout penis because you had a
39:01deficiency in alpha reductase. So you're
39:03not picking DHT, right? So these kids
39:06were raised as girls because there's no
39:08the extrogenitalia look like they're
39:10feminized.
39:12But as soon as you know they hit puberty
39:14and they start getting realized, they
39:15get this part of penis as you put it. Um
39:18many of them switch over to being boys
39:20and becoming men happily I guess. So I
39:24mean they switch, right? It's not forced
39:25on them.
39:26>> Okay. So, they voluntarily
39:27>> Yeah.
39:28>> go in the direction of their XY
39:30chromosomes,
39:31>> right?
39:31>> Because in theory, they could
39:33>> Well, it's tricky because they're now
39:35making testosterone. So, they're sort of
39:36in a
39:37>> Well, they've always been making
39:38testosterone. It's just they had not
39:39been making DHT.
39:41>> Sorry to interrupt, but
39:42>> No, no, no, please. You're you're you're
39:44being accurate.
39:45>> Which so testosterone can still act on
39:46the brain, remember, during development.
39:48>> So, what you're basically saying is that
39:49the growth of the penis is largely
39:50determined by DHT,
39:52>> right? Early on. Yes. pre-pubertal
39:54>> and then after puberty it's controlled
39:56by testosterone
39:57>> testosterone sufficient to drive penal
39:58development. Yeah,
39:59>> got it. Okay.
40:01>> Goodness. What does this tell us? Does
40:02this tell us again
40:05that
40:06XX
40:08versus XY is really the driver of one's
40:12own
40:14um sex preference?
40:17And I don't mean sexual preference for
40:19partner. I mean sex preference like of
40:21their own sexual identity. Yeah, at
40:23least that's what these natural
40:24variations tell us, right? These as you
40:26put natural experiments tell us.
40:28>> Um the same is true for complete
40:30androgen insensits
40:32syndrome in which humans have this
40:34mutation in the androgen receptor. So
40:36they can't see testosterone
40:38and you know as we discussed they are
40:40completely feminized externally but they
40:42have testes because they are they have
40:44ex they're xy.
40:46>> Wow.
40:46>> Right. So they have testes but they're
40:48feminized and they think of themselves
40:49as females. They're race as females.
40:51They look like females. It's just at
40:52puberty, you know, they don't they don't
40:54start menstruating. See, they go to the
40:56clinic, they're diagnosed as XY with an
40:59SRY, but not responsive to testosterone.
41:03>> So, their inability to respond to
41:04testosterone sort of masculineized,
41:06>> feminize them.
41:07>> This is a tricky topic because we
41:09haven't injected kind of how people are
41:12socialized. We haven't uh talked about,
41:14you know, pink versus blue clothing, uh
41:16which is socialization. Uh it's a choice
41:19obviously um but a strong choice that's
41:21very you know um statistically you just
41:24see that right
41:25>> almost across the board unless people
41:27deliberately go against that
41:29>> it all seems so
41:32clear and straightforward based on the
41:33presence or absence of this SRY gene
41:37until I start looking at the genetics
41:39and I which I did in in anticipation of
41:42this episode and I discovered that one
41:44in 12 people which is a very high number
41:47is heterero heterozygus for congenital
41:49adrenal hyperlasia, meaning they have
41:51one mutant copy, one healthy copy.
41:53They're fertile, which is probably why
41:55it's so prevalent. Um, and yet those
41:59people make less cortisol and more
42:02androgen
42:04in response to a stressor.
42:07So then you say, well, okay, maybe as a
42:10fetus they were making a bit more
42:12androgen. So is that going to drive a
42:14kind of hyper maleness or is it going to
42:16make in in a XY baby and it's maybe
42:18going to drive a little bit more
42:19maleness a little bit less femaleness in
42:22an XX baby. I mean it starts getting
42:24really tricky. It is very tricky. What
42:27is known is that boys who have
42:30congenital adrenal hyperlasia
42:33seem to be completely like boys.
42:35>> They're fertile.
42:36>> They're fertile and the behavior seems
42:38to be unchanged as well.
42:39>> So it's not as if they're hyper. They're
42:41not hyper masculineized.
42:42>> They're not hyper masculineized.
42:43>> At least that's what the data suggests.
42:44Yes.
42:45>> But of course, we don't know what the
42:46measures are.
42:47>> We don't know what the measures are. And
42:48we don't know what social cultural
42:50exposures they had as well in the
42:51environment.
42:52>> Having grown up in a very uh
42:54conventional home with respect to these
42:56things. I mean, it's like looking back
42:58and comparing to what I see now, it's
43:00just so vastly different. And I was born
43:02in 1975. So, it kind of blows my mind
43:05how different things are even in the
43:06last, you know, 20, 30 years in terms of
43:08how boys and girls are socialized. I
43:10mean things were um I remember the first
43:13television show coming out in the I
43:15forget when it came out exactly but all
43:17in the family where like the the mother
43:18is going to work you know this this was
43:20like a revolutionary thing at the time
43:23right but it wasn't terribly long ago.
43:26Okay so let's talk about hormones
43:29shaping brain structure and function. Uh
43:32what are some of the anatomical and or
43:34functional differences in brains? Let's
43:37say with the the most typical scenario,
43:40XY chromosomes makes testosterone, makes
43:45DHT,
43:46um all the receptors are functional
43:49versus XX, no SRY uh gene, um all the
43:54all the all the stuff testosterone and
43:56estrogen uh are functional, receptors
43:59are functional, the typical pattern.
44:00Yes.
44:01>> How are the brains of those babies
44:04>> and later adults different? What what do
44:06we know about that?
44:08>> Yeah. So there are a lot of cells in the
44:10brain that express receptors for
44:12testosterone, and receptor and estrogen
44:14and progesterone. So people have looked
44:16over the last 40, 50 years to see what
44:19how these cells are responding to these
44:21hormones. And it seems that at least one
44:25major theme that emerges is that early
44:27on at least in the mouse, right? This is
44:30you can still see that the brain is
44:31bipotential at the first day of life.
44:33it's looks sort of somewhat neutral and
44:36then if you have testosterone then in
44:38some brain regions more neurons will
44:40survive
44:42and in those regions in the female those
44:44neurons would die. So then as adults you
44:47end up with a male brain that has more
44:48neurons in one region compared to a
44:51female and conversely in the female
44:53brain there are structures that you know
44:55survive and the males you lose cells. So
44:58in those structures in the adult females
45:00will have more neurons than males or
45:02cells than males. So you have cell death
45:04that can be sex specific you know female
45:07specific or male specific. Actually I
45:09should step back. It's not specific.
45:11It's more statistical. There are more
45:13cell death in one than the other. So you
45:15end up with different numbers of neurons
45:17in the adult animal.
45:19>> And you're not getting those neurons
45:21back.
45:21>> You're not getting those neurons back.
45:23>> So it's
45:24>> and the same is true for connectivity.
45:26So it's fair to say that
45:30as a consequence of genes and hormones
45:33in uterero,
45:35males have certain neurons and circuits
45:38that females don't have and females have
45:40certain neurons and circuits that males
45:41don't have. And it doesn't matter how
45:43much testosterone or estrogen
45:46you put into the adult ver the adult of
45:50of those people, they're not getting
45:51those circuits back.
45:53>> Right? In uterro, they're the same where
45:55once they've been exposed to
45:56testosterone or estrogen progesterone,
45:59you get cell loss in one or the other
46:00sex. And once you get that cell loss,
46:03you're not going to recover that as an
46:04adult. Is there any evidence in humans
46:08or in mouse that the loss of these cells
46:11or the maintenance of these cells, we
46:13can look at it through either lens, is
46:15along a continuum or is it pretty strict
46:18divide? Like if we were to plot the
46:20number of cells in one of these brain
46:22areas, would it be a binary distribution
46:25uh where you know you get a a big, you
46:27know, big pile of of of neurons um on
46:30one side of the graph and and and many
46:33fewer in the female with a big trough
46:35between or are we talking about a more a
46:37single hole? Some regions it looks
46:39pretty binary and these are regions that
46:41control innate behaviors
46:43>> like mating or aggression for example
46:46but others there's going to be overlap
46:48and the animals we work in in the mouse
46:50they're sort of specifically bred to be
46:52genetically identical to each other so
46:54we can sort of really parse out what the
46:56differences look like and if you will
46:58there are more extreme examples these
47:00animals and and there in some regions we
47:02can really see that you know there's
47:04always about two to threefold more cells
47:06in one text compared to the other and
47:09that's pretty much true for all animals
47:11for that region. But other regions there
47:14might be more overlap.
47:16>> I'd like to take a quick break and
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50:25some of the um sociological, political,
50:28and other sorts of biases that
50:30understandably kind of get into people's
50:32minds when you start talking about this.
50:34If you just look back in history,
50:37>> were there examples of interex people
50:41just born of, you know, without any
50:44knowledge of of chromosomes, without any
50:46knowledge of hormones? um people
50:49intuitively understood hormones but um
50:51based on damage to the testes or things
50:54like that, right? What what would
50:55happen? But I think you get the idea.
50:58Were there examples that were cultures
51:01where it was kind of understood that
51:04this was along a continuum because
51:07everything you're describing makes it
51:08sound pretty darn binary.
51:11And you know, again, this isn't a
51:14political discussion, it's a biological
51:15discussion. SR Y yes or no?
51:18>> Yes,
51:19>> that seems to be pretty much what it's
51:20about.
51:21>> Yeah. So, but there are cultures I mean
51:22we mentioned about these consanguinous
51:24marriages where people you know would
51:25have kids where they would look
51:27feminized early on because they have a
51:29deficiency in five alpha reductase no
51:31DHT production and then at 12 they would
51:35become you know mascized they' sprout a
51:36penis
51:37>> but never in the other direction. No
51:39>> males converting to females,
51:41>> right?
51:42>> Yeah.
51:42>> Physically, no. Right. So, at least in
51:44these cultures, it's it's a known thing
51:46that there will be
51:47>> a subset of kids who are born with this,
51:50if you will, interex condition,
51:52>> right? And there are descriptions of,
51:53you know, what people used to call, it's
51:54no longer politically correct to say
51:56call them hermaphrodites, but there are
51:58examples of, you know, interex
51:59individuals across history.
52:00>> Hermaphrodite is not a politically
52:02correct.
52:02>> That's what I've been told. Interex is
52:03the medically sort of accepted term.
52:05>> Got it. And people have also known that
52:07testosterone or hormones, sex hormones
52:09play a huge role in regulating behavior,
52:12right? So Unix and castrits, castrades
52:14have been used in palaces and and courts
52:18sort of to guard hers for example. Um
52:21>> that was the motivation.
52:22>> Yep.
52:22>> Wouldn't you favor a more aggressive uh
52:26testicularly intact male if they goal is
52:29protection? I think the idea was that if
52:31you had, you know, a cast guarding a
52:33hair of females, then they can't sort
52:35of, you know, have sexual behavior with
52:37them. They can't have sex with them.
52:38>> Oh, they weren't going to do what the
52:39cuttlefish do, right?
52:40>> Cuttlefish males will pretend they're
52:42females, befriend females, and then
52:44they'll and then they'll mate with them.
52:45>> And also in opera singing, right, you
52:47would have cast who would have a higher
52:49pitched voice
52:50>> and they were castrated early in life
52:52>> to maintain the high pitched voice.
52:54>> Yes.
52:55Anyway, um just going to refrain from
52:58any I mean the poor kids that presumably
53:01they didn't get a choice
53:03>> presumably. Yeah.
53:04>> Yikes. Um okay.
53:08So
53:10here's where here's where I'm um stuck,
53:14right? I can hear all this biology
53:17and it's very clear that the genes and
53:20hormones are affecting peripheral what
53:23we call phenotype. Presence or absence
53:25of penis, presence or absence of
53:26descended testes, presence or absence of
53:28ministration. But in the brain, it just
53:31seems that there are different circuits
53:33that kind of pile up more neurons or
53:35maintain more neurons in males versus
53:36females. In females, what are the what
53:38are the circuits that get favored? Are
53:40they circuits for um lactation, for
53:43child rearing? I mean,
53:45>> for sexual behavior, for example,
53:48>> uh
53:48>> ovulation.
53:50So cells that control ovulation, for
53:52example, would be very dimorphic,
53:53>> but not in terms of behavior, right?
53:55Like it it seems like it's the presence
53:57or absence of rough and tumble play,
53:58presence or absence of thrusting
54:01behavior. Um, I mean, maybe this is for
54:04historical reasons or maybe it's for
54:05biological reasons, but um, I guess what
54:08I'm getting at here is what are the
54:10things that babies that are XX that are
54:14females, how are their brains
54:15specialized? I mean, or is it just the
54:17absence of copulatory thrusting and
54:19aggressive behavior? It seems to me that
54:21there would be circuits that were female
54:23specific.
54:24>> That's right. So, there are circuits
54:25that are specific of female sexual
54:26behavior. So you can take an adult male
54:29for example and you can remove
54:32testosterone you can castrate him and
54:33you can give him female hormones
54:35estrogen and progesterone and ask this
54:38is in mice now um you can ask will he
54:40now be sexually receptive will he loose
54:43like a female mouse would
54:44>> arched back sexual
54:45>> arched back that's right sexual
54:46receptivity posture and most in most
54:48cases he won't
54:49>> he won't
54:50>> no he won't because the circuit's
54:51missing
54:51>> right the neurons just aren't there
54:53>> that's right or at least they're not
54:54responsive to the hormones
54:56>> right we don't know the circuit's there
54:57but it's all responding to hormones or
54:59we don't know the circuit's not there.
55:00We now know that there are connections
55:02in the female brain that are simply
55:04missing in the male brain and these
55:06connections are from neurons that
55:08regulate sexual behavior. So we know
55:09that some circuits are missing in the
55:11male brain for sexual female sexual
55:13behavior.
55:14>> So lordosis behavior in females seems to
55:17be a very XX
55:19uh chromosomal driven outcome
55:23>> but it's not as black and white like
55:25that. There are circuits that seem to be
55:28conserved in both sexes for the behavior
55:30of the opposite sex. And I'll give you
55:32two examples of that. Okay. Um if you
55:34take an adult female mouse and this is
55:37an experiment done in the 70s by David
55:39Edwards and Katherine Burgie. Um it's a
55:41really beautiful experiment and it came
55:43around because he was doing a control
55:45experiment. He was simply giving
55:47testosterone to adult females, adult
55:49female mice.
55:52And the idea was to sort of see if he
55:54got the same results
55:57as, you know, Charles Phoenix did with
55:59guinea pigs. So he gave testosterone to
56:01young females at birth as well as to
56:03adult females. And the adult females
56:04were controls. The idea was, well, these
56:06females mount like males if they've seen
56:08testosterone early on. The surprising
56:11result that he got was that adult
56:13females given testosterone mounted like
56:15males. So they have the circuit for male
56:17sexual behavior, but it's not activated
56:19because there's no testosterone.
56:21Similarly, if you take and this is a
56:23work by Katherine Dak at Harvard. If you
56:26take mice um and you sort of remove
56:29pheromone sensing from them, you know,
56:30pherommones are these chemical cues that
56:33animals use to sort of uh recognize sex
56:36and social status of other individuals
56:38of their species. If you sort of disable
56:40pheromone sensing in mice, females will
56:42now show male type sexual behavior. It's
56:45as if that pherommonal input is
56:47inhibiting
56:49male sexual behavior. But if you take
56:50away the pheromone sensing capacity then
56:53the females will start mounting like
56:54males. So you have at least two sort of
56:57control mechanisms if you will to
57:00inhibit adult male sexual behavior in
57:02adult female mice. One is the absence of
57:04testosterone or very low levels of
57:06testosterone and the other is the sort
57:08of pherommonal input. This chemosensory
57:10alactory input that is inhibiting male
57:13sexual behavior. You take either one of
57:14those I mean you give testosterone or
57:16you take away the inhibition from those
57:18pherommones you get male sexual
57:19behavior. So it seems that parts of the
57:21circuit for male sexual behavior to
57:23display the behavior are there in the
57:25female in the adult female brain.
57:28So in some cases the circuit seems to be
57:30missing like the female sexual behavior
57:31circuit because you can give an adult
57:33male estrogen and progesterone to mimic
57:35estrus or heat and he doesn't lurose. We
57:39can take an adult female and give a
57:40testosterone and she'll have you know
57:43she'll show sexual behavior like a male.
57:45And because it's probably in the back of
57:47people's minds and because I'm very
57:48familiar with this literature, uh, we
57:51should just point out that all data
57:55point to the fact that you don't see
57:59market differences in androgens or
58:02estrogen. If you were to look between
58:05women who define themselves as
58:08heterosexual versus homosexual, so
58:11heterosexual women versus lesbians, or
58:14heterosexual men versus homosexual men.
58:16If anything, the data point to
58:20homosexual men having higher levels of
58:22testosterone. It's been difficult to
58:24tease apart from um some lifestyle and
58:27behavioral things, but when teased apart
58:30it and it's been done, you're not going
58:31to find anything that that screams
58:34hormone levels define sexual
58:36orientation. You just you just don't
58:38find that.
58:38>> You don't see that. No,
58:39>> you see a lot of data that points to
58:41changes in uterro that may be hormone
58:44driven, but nothing um
58:46>> as adults.
58:47>> Nothing as adults.
58:48>> No. And in fact, if you can take, you
58:49know, what we call wild type male mice,
58:51if you will, right? meaning they're sort
58:53of completely uh typical or normal male
58:56mice and you can measure their
58:58testosterone levels and you get a huge
59:00range of circulating testosterone in
59:03otherwise normal mice of you know or
59:05five to 10fold difference in
59:06testosterone
59:07>> or humans for that matter
59:08>> or humans for that matter and they still
59:10you know these mice will still behave
59:11like males
59:12>> I won't out this person um but uh I'm
59:16not talking about um sexual orientation
59:18um the CEO of one of the most successful
59:22ful media companies in the world came up
59:24to me at a gathering um like two years
59:26ago and he said, "Listen, I I have this
59:29uh have a problem." So, usually when a
59:31guy says that to me, it's going to be
59:33something about uh testosterone or or
59:35sexual dysfunction or something. And he
59:36said his testosterone is down in the
59:39300s, kind of lower end of of reference
59:42range. He said, "But I feel great." He's
59:44like, he's he's saying, "My libido is
59:46great. My my work drive is great. I feel
59:48great." And I said, "Well, your free
59:49testosterone is probably um normal and
59:52high." And he goes, "No, that's also
59:53low, but I feel great. Should I take
59:55testosterone?" And I said, "Uh, listen,
59:58I'm not an endocrinologist, but my
59:59advice would be no." Right? So, and I I
1:00:01point this out. I think he's probably in
1:00:03his late 50s, early 60s. And uh what he
1:00:07was revealing uh was you know unique
1:00:10among the questions I typically get
1:00:11around testosterone. But I think it
1:00:13points to the fact that who knows maybe
1:00:16he has a higher than normal receptor
1:00:17density that can make use of of those
1:00:20levels of testosterone. I mean there's
1:00:21so many ways in which hormone levels can
1:00:23play out in one direction or another or
1:00:25something in between. I think it's worth
1:00:27people knowing that. That's right. Um, I
1:00:29have so many questions, but um, this
1:00:31feels like thorny territory and um, I've
1:00:35learned when doing this podcast whenever
1:00:36something feels like thorny territory
1:00:39that uh, to go right into it.
1:00:42These days we hear a lot
1:00:45endlessly it seems about the debate as
1:00:49to whether or not sex differentiation
1:00:53uh and gender are biologically
1:00:56determined or are um more mutable than
1:00:59that. Uh we're certainly not going to
1:01:01resolve that question here. Certainly
1:01:03not for everybody. I'm sure you have
1:01:04your stance and I have mine. But how is
1:01:07it that we bring together our
1:01:08understanding of sex differentiation
1:01:10versus this gender word? Right. It seems
1:01:14to me that in a lot of talks you've
1:01:16given, you use the word gender. I know
1:01:17because I've listened to those talks and
1:01:19we've I'll reveal it now. We've been
1:01:21friends for a long time. That's right.
1:01:22>> And you'll sometimes say sex and you'll
1:01:24sometimes say gender. And I understand
1:01:25that sex is a confusing word because the
1:01:27moment they hear it, they think of the
1:01:28verb sex,
1:01:30>> right? How do we think about sex versus
1:01:32gender when it comes to understanding
1:01:35brain and uh
1:01:38yeah just brain? Let's just stay with
1:01:40that. Not even body because clearly the
1:01:42data in mice and humans point to the
1:01:44fact that the administration of hormones
1:01:45can change the body. It can it can shift
1:01:48things in one direction or the other
1:01:49>> given at the right time.
1:01:50>> Given at the right time and we can talk
1:01:51about that. Um
1:01:54but what about the brain piece?
1:01:57How mutable is this? And what are your
1:02:00thoughts on the controversy and how
1:02:02should we be thinking about this?
1:02:04Forgive me for stumbling, but it is it's
1:02:05it's not that I'm trying to avoid
1:02:07upsetting anyone. It's like we don't
1:02:08have a good language to differentiate
1:02:10these things. And I think part of the
1:02:12issue part of the problem for not having
1:02:14a good language and good understanding
1:02:16is we don't have an animal model for it.
1:02:18Gender is such a humanpecific construct,
1:02:21you know, as the sort of constellation
1:02:23of behaviors and expectations
1:02:25generated from within and by our society
1:02:27and culture, but what gender is. And
1:02:31gender sort of includes not only sort of
1:02:33identification of yourself as a male or
1:02:35a female or something in between having
1:02:38sort of attraction for one sex or the
1:02:40other or not having any attraction for
1:02:41anybody or sort of having this sort of
1:02:44compartment of behaviors like dressing
1:02:47in a particular way, sort of speaking in
1:02:48a particular way or having meeting
1:02:50societal expectations. All of those sort
1:02:52of comprise gender and it's hard to do
1:02:54that in the mouse. We don't know enough
1:02:56about mice. We don't even we don't even
1:02:58know about mice enough to say they have
1:03:00a gender. We know that they have sexes,
1:03:01females and males based on SRY,
1:03:04testosterone, estrogen, and
1:03:05progesterone.
1:03:06>> Okay.
1:03:06>> So, it's hard to have an animal model
1:03:08for something like this, which is so
1:03:10complex. And so, it seems human
1:03:12specific.
1:03:14Well, you said one thing that um at
1:03:16least
1:03:17my understanding um checks off one box,
1:03:22which is that sexual orientation and how
1:03:26people self-identify in terms of
1:03:28maleness or femaleness is separable. We
1:03:31know that because there are people who
1:03:33are homosexual and we know that because
1:03:35there are people who switch gender by
1:03:38way of hormones,
1:03:40obviously not from birth, but later in
1:03:42life. And
1:03:45in many cases they don't change sexual
1:03:47orientation. Sometimes they do, but my
1:03:50read of the data is that usually they
1:03:51don't. In other words, if somebody
1:03:53preferred females before, they they they
1:03:56might uh administer hormones, change
1:03:58their body, but they'll continue to to
1:04:00like females or vice versa. Right?
1:04:03That's my understanding of the data. And
1:04:04I went into the data looking prior to
1:04:06this conversation. And there are a lot
1:04:08of data. Now, the problem is it's
1:04:10difficult to find unbiased data. I'll be
1:04:12very honest. I feel like the data are
1:04:13biased on both sides. People seem to be
1:04:15arguing for something going in. Okay.
1:04:18So, sexual orientation and how people
1:04:20self-identify,
1:04:22we know is separable. That's not a a a
1:04:25uh controversial thing. We just know
1:04:27because that's what happens. But when it
1:04:30comes to when people are administered
1:04:32hormones, how that changes the brain in
1:04:34human, what do we know? You said it
1:04:36depends on whether or not they're
1:04:36administered hormones early versus later
1:04:39in life. Well, I think the early data
1:04:41and you know we talked about congenital
1:04:43adrenal hyperplasia, we talked about
1:04:44antigen insensitivity syndrome. Those
1:04:47data really say that hormones at a point
1:04:49in development maybe in utero have a
1:04:51profound effect on masculineization of
1:04:54feminization external
1:04:56>> as well as of the of the brain.
1:04:58>> Right? These kids that make uh that
1:05:01don't make DHT that are raised as girls
1:05:03but later sprout a penis are at least as
1:05:06you described it for all the world
1:05:08raised as girls and happy being raised
1:05:10as girls identify as girls until
1:05:13testosterone kicks in and then uh and
1:05:16then it but it's interesting right
1:05:17because their body changes so it's
1:05:20unclear to what extent the bodily
1:05:21changes are driving the psychological
1:05:23changes but presumably if the brain is
1:05:25organized male because they're X Y and
1:05:28they have the SRY gene
1:05:29>> and they have testosterone
1:05:29>> and they have testosterone
1:05:32there's a there's a substrate for it
1:05:33like it's it's waiting for that for that
1:05:36testosterone there's something to for it
1:05:38to act on
1:05:38>> and similarly if you're if you're
1:05:40insensitive to testosterone if you have
1:05:42androgen insensitivity syndrome then
1:05:44you've not seen testosterone sort of
1:05:46biologically it's present in the
1:05:47circulation but your brain for example
1:05:49can't respond to it so you're feminized
1:05:52externally and you also behaving as a
1:05:55female all the way through adult's life
1:05:57So that's the early action of
1:05:59testosterone, right? So I think what
1:06:01you're referring to is people deciding
1:06:04to sort of take hormones
1:06:06at a later point in life after birth,
1:06:08much later after birth to switch
1:06:10genders,
1:06:11>> right? Um and maybe the starting place
1:06:14to really understand this is when people
1:06:16take hormones uh but don't want to
1:06:19switch genders. So these days it's very
1:06:21common for more common now uh for men
1:06:25typically but women also. Let's just say
1:06:27men taking testosterone or augmenting
1:06:29testosterone or for women to augment
1:06:31estrogen. This is now um because of the
1:06:34increasing attention on menopause and
1:06:36pmenopause and the the the women's
1:06:38health uh initiative and trials that
1:06:41looked at this. It's very clear that
1:06:42there are some u advantages to estrogen
1:06:46therapy in women who identify as women.
1:06:48I'm just making this like I'm trying to
1:06:50simplify this as much as possible. Our
1:06:53colleague Robert Seapolski, who knows a
1:06:55lot about testosterone, um has written
1:06:57books about it, said when somebody
1:07:00increases their testosterone
1:07:02pharmacologically, it just makes them
1:07:04more the way they are. If they're an
1:07:05aggressive jerk, it makes them more an
1:07:07aggressive jerk. If it if they're
1:07:08altruistic, it makes them more
1:07:09altruistic. But it's really about
1:07:11hierarchy. It's really about um uh a
1:07:14willingness to lean into effort to
1:07:17suppress amydala activation and to lean
1:07:20into effort within the domains where
1:07:21they feel a lot of agency. It's kind of
1:07:23what he describes as the main effect of
1:07:25testosterone.
1:07:27It's a little unclear what the main
1:07:28effect of estrogen is when given uh to a
1:07:32woman in adulthood besides the ones that
1:07:34have been described like um preservation
1:07:36of cognitive function
1:07:38>> um skin texture uh but you know vaginal
1:07:41lubrication like a b bunch of things
1:07:43that that are kind of uh youthful
1:07:46restoration type phenotypes. It's it's I
1:07:49don't think there are a lot of data
1:07:50about the psychological changes but they
1:07:52seem to be in the direction of feeling
1:07:53better because there are a lot of women
1:07:54now who are seeking estrogen uh
1:07:56replacement therapy
1:07:57>> with menopause there's a sharp increase
1:08:00in the incidence of Alzheimer's disease
1:08:02in women right so as you pointed out you
1:08:04know taking estrogen at after menopause
1:08:06if it's medically sort of you know fine
1:08:08once you've consulted your doctor then
1:08:10that will at least prevent the decline
1:08:13in cog in cognition because you now have
1:08:15estrogen on board so that's the thinking
1:08:17behind you know sort hormone replacement
1:08:19therapies for cognition at least.
1:08:21>> Um coming back to the testosterone um
1:08:26thing that you mentioned from Robert
1:08:27Spolski, we did a similar experiment in
1:08:29the mouse where we just mutated the
1:08:32androgen receptor only in the brain.
1:08:34>> H
1:08:35>> and this is going to get complicated I
1:08:36think.
1:08:37>> No, it's cool experiment. So um penis
1:08:39can respond to testosterone, muscle can
1:08:41respond to testosterone, connective
1:08:43tissue can respond to testosterone,
1:08:45brain can't respond. You did that from
1:08:47from birth in these?
1:08:48>> Yes. It's going to get interesting
1:08:49because we're going to have to talk
1:08:50about aromatization. Now, u So, these
1:08:53males are still masculineized.
1:08:56They just mate and fight less than
1:09:00normal males would.
1:09:02>> Okay. So, their brains are a little I
1:09:04it's again there's a der of language
1:09:06here, but these these mice that don't
1:09:10have testosterone acting on their brain
1:09:12are a little less stereotypically male.
1:09:16That's right. That's right.
1:09:17>> They fight, but they don't like to fight
1:09:18as much.
1:09:19>> They don't They mark territory, but not
1:09:20so much.
1:09:22>> Interesting.
1:09:22>> Right.
1:09:23>> Some Someone's in the comments already
1:09:24saying beta male,
1:09:26>> right? That's the kind of YouTube speak.
1:09:28YouTube, by the way, because it's
1:09:30male-dominated in terms of its audience,
1:09:32is if you look at the comments on
1:09:33YouTube, not just for this podcast, but
1:09:35other podcasts, it's a um it's a rich
1:09:38data set for how males compete when
1:09:41anonymous and when physical strength is
1:09:44not um involved. Very interesting. lot
1:09:48lot of uh um lot of hierarchies in
1:09:52comment sections
1:09:54>> um that are removed from the
1:09:55stereotypical um uh kind of notions of
1:09:59of how hierarchies were played out
1:10:01>> because aggression is
1:10:03>> right
1:10:03>> it's all words right and memes well you
1:10:08mentioned aromatization so we should
1:10:10tell people what aromatization is this
1:10:12always throws people for a loop when you
1:10:14tell men that they're very male-like
1:10:17because of estrogen
1:10:18freaks them out,
1:10:19>> right?
1:10:19>> Well, go ahead. Freak them out.
1:10:21>> So, this all started with classic work
1:10:22by Frank Neftlin in the 70s when he was
1:10:25sort of working on human embryionic
1:10:27tissue, brain tissue. And he realized
1:10:31that the embryionic human brain
1:10:34contained an enzyme that converted
1:10:36androgen into estrogen. And the enzyme
1:10:38is called aromatase. And this is in fact
1:10:41the primary way that the ovaries make
1:10:44estrogen. They first make testosterone
1:10:46then gets aromatized from by this enzyme
1:10:48aromatase and gets made into estrogen.
1:10:52Okay. So it turns out that Napalin's
1:10:54sort of discovery is exactly right. Even
1:10:56in the mouse brain in the mouse male
1:10:58brain we and others have shown that
1:11:00there is aromatase the enzyme expressed
1:11:02in very specific circuits in the brain.
1:11:04>> Can I just stop you? You mentioned this
1:11:06early experiment by this gentleman.
1:11:08Yeah. Was done on human brain tissue.
1:11:10>> Yes. And rats and you know others.
1:11:12>> It's a very important point. Uh I think
1:11:13she will appreciate uh hearing this, but
1:11:16a long while ago I mentioned this thing
1:11:19about arro aromatization of testosterone
1:11:21to estrogen is really what masculinizes
1:11:23the male brain. And a very prominent
1:11:26author in the testosterone space, a
1:11:28female author wrote to me and said,
1:11:29"It's just mice."
1:11:30>> Um so but but she's very scholarly and
1:11:33and I think she'll appreciate hearing
1:11:34that the original data come from human.
1:11:37Great. Thank you. Um so it's not just
1:11:40mice. Yet another way that we're
1:11:42conserved.
1:11:43>> To be fair though, I think the idea with
1:11:45what she might have been referring to is
1:11:47that aromatization in the human brain
1:11:51may not be playing as dominant a role in
1:11:54masculineizing the brain as it does in
1:11:56rodents and other animals.
1:11:57>> So that you know we can't really speak
1:11:59to that because you can't do those
1:12:00experiments in humans.
1:12:02>> But if you have a male mouse lacking
1:12:04aromatase so he can't make estrogen then
1:12:08you know his behaviors won't be
1:12:09mascized. He appears more female.
1:12:11>> Not appears behaves more like doesn't
1:12:13behave like a male because he's not
1:12:16converting testosterone into estrogen.
1:12:18And this happens very early at birth in
1:12:20mice. So testosterone gets made by the
1:12:22testes, gets in the brain, gets
1:12:24converted into estrogen. And then, you
1:12:26know, as we talked about earlier, there
1:12:28are some cells that die or survive
1:12:29depending on the sex. And this
1:12:31conversion of testosterone into estrogen
1:12:34enables specific sets of cells in the
1:12:36male brain to survive.
1:12:38This is probably a good place for us to
1:12:40inform people that these steroid
1:12:42hormones, testosterone and estrogen are
1:12:45very interesting because they can have
1:12:46immediate effects and they can also
1:12:48change gene expression. This is a good
1:12:51opportunity for you to teach us some
1:12:52cell biology. So, is it by virtue of the
1:12:55fact that they're lipid soluble? They
1:12:57can go all the way into the nucleus of a
1:13:00cell. Um, I mean, you know, this is very
1:13:02different than like dopamine, right?
1:13:03Dopamine can impact cells. you know,
1:13:05don't do this folks, but you know, if
1:13:06you were to take methamphetamine or
1:13:07something, you'd your brain would go
1:13:09very dopamineergic very fast. Um, but
1:13:11it's not going to change gene expression
1:13:12in the short term. Maybe in the long
1:13:14term, but not in the short term. But
1:13:16testosterone administration or estrogen
1:13:18administration is literally changing the
1:13:21genes that are expressed in the cells
1:13:23they interact with.
1:13:25>> How does that work? I mean, what what's
1:13:27going on? What what are they actually
1:13:28controlling? So the receptors for these
1:13:31hormones testosterone, estrogen,
1:13:32progesterone um they sit in the
1:13:34cytoplasm of cells not in the nucleus
1:13:36and as you pointed out these are you
1:13:38know steroid hormones are lipids they
1:13:39can cross cell boundary cell membranes
1:13:42and once they bind to the receptor the
1:13:44receptor bound to the hormone is
1:13:46transllocated into the nucleus where it
1:13:49finds stretches of DNA that it
1:13:51recognizes it sort of sits on them binds
1:13:54them and then changes or regulates gene
1:13:56expression of what we call target genes.
1:13:59And that's how you know you get gene
1:14:01expression changes by these hormones.
1:14:03>> So this is why whenever I hear like the
1:14:05Seapolski argument which I totally agree
1:14:06with that you know you give uh someone
1:14:09testosterone and they become a lot more
1:14:11like themselves they don't if they're a
1:14:12nice person they become that much nicer.
1:14:14If they're aggressive they become that
1:14:16much more aggressive. But those are
1:14:17short-term studies right? So, we don't
1:14:19really know how the administration of
1:14:21hormones, testosterone or estrogen to a
1:14:25self-declared male or female uh or XYX,
1:14:28doesn't matter. But the the point is
1:14:30that we don't know how the long-term
1:14:32administration of these hormones
1:14:34literally change the genes and therefore
1:14:37the thought patterns and behaviors and
1:14:39feelings of these people.
1:14:40>> That's right. You're basically changing
1:14:41the molecular fingerprints
1:14:43of specific sets of cells in the brain
1:14:45with hormone action. A big debate these
1:14:47days is whether or not um people if they
1:14:51seek to change their gender identity
1:14:54whether or not they're in a position to
1:14:56make that decision because they're a
1:14:58minor rights are not legally allowed to
1:15:00make all sorts of decisions like vote
1:15:03drive a car uh all sorts of things work
1:15:07in this country anyway work a job I
1:15:09think you have to be used to be 14 I
1:15:10don't know what it is now but it's an
1:15:13interesting biological question when you
1:15:15just say okay at um forgetting uh all of
1:15:18that and and just asking, okay, what is
1:15:20the condition of a uh like a a
1:15:2310-year-old brain versus a 14-year-old
1:15:26brain that's entering puberty versus a
1:15:2916-year-old brain that's still
1:15:30transitioning through puberty, maybe in
1:15:32late phases of puberty, versus 25, which
1:15:34is when we know brain development is
1:15:36more or less coming to a to a close,
1:15:38although brain development continues
1:15:39forever. I mean, how is anyone going to
1:15:43eventually come to a an agreement one
1:15:46way or the other on this? Is there real
1:15:48biology that we can look at uh in mice
1:15:51or in humans and say like, okay, here's
1:15:53here's the dynamic tension. The dynamic
1:15:54tension out there is
1:15:58there are people saying they're kids
1:15:59that are too young to know what they
1:16:01are, let alone choose what they want to
1:16:03be,
1:16:03>> right? And then on the other side,
1:16:05you've got people battling saying, "No,
1:16:07it's essential to get in early because
1:16:09then the trajectory is is is more
1:16:11malleable." And then you don't want um
1:16:13somebody to end up in a place where uh
1:16:15change isn't possible. And then you have
1:16:17people saying, "Well, wait, I changed
1:16:20gender and then now they want to reverse
1:16:22later because and they're angry that
1:16:23they they were allowed to make the
1:16:24decision." So, it's a mess. It's a it's
1:16:27a it's it's a genuine mess in terms of
1:16:30defining what the key parameters are. Do
1:16:33you think it will ever be resolved?
1:16:34>> Let me step back and say we don't even
1:16:36know much about this in the mouse yet.
1:16:38Right? So we don't know what happens to
1:16:40the mouse brain at puberty
1:16:41>> really
1:16:42>> there are experiments being done but not
1:16:45certainly not the same detail as in the
1:16:46adult mouse brain.
1:16:48>> So how circuits are made plastic or how
1:16:50they're malleable at puberty is still
1:16:52sort of being worked out in the mouse.
1:16:54Right? So that so that's the first
1:16:56answer. The second one, the reason I
1:16:58think it's contentious is a it's both
1:17:00deeply personal what the kids are
1:17:02feeling, but also there's these huge
1:17:04sort of societal political forces that
1:17:06come into play. So I think the tension
1:17:09there has to be resolved I think
1:17:11politically and sort of socially rather
1:17:13than you know just resorting to science.
1:17:15I think science will give you data but
1:17:17you will still have to make a decision
1:17:18as to whether or not you know that'll be
1:17:21allowed. So I think that's the reason it
1:17:22is so contentious. the data is not there
1:17:25in terms at least in the mouse or other
1:17:27animal models or it's coming out it's
1:17:29coming out slowly. Um and socially and
1:17:33politically it's very volatile
1:17:35because it's not clear how you sort of
1:17:38you know have kids rights, parental
1:17:39rights, societal expectations intersect
1:17:42and give a result that is satisfactory
1:17:44to everybody. So that's where we are.
1:17:47I'm not saying I'm pro one or against
1:17:48the other. I'm just saying that's why
1:17:50it's so contentious in my mind. Today is
1:17:52a biological discussion because that's
1:17:54what we can say uh things about for
1:17:57sure, right? We can talk about biology
1:18:00for sure. The the other pieces are um
1:18:03they're even prone to um trip wires
1:18:05related to language and and that uh for
1:18:08biologists is is uh no fun. Um and uh
1:18:12the whole reason to become a biologist
1:18:14as opposed to a psychologist is because
1:18:16um while I have tremendous respect for
1:18:18the field, biologists
1:18:20have nomenclature committees. We agree
1:18:22this is because you could make this
1:18:24argument about anything. Uh again by way
1:18:27of example I mean you could say oh the
1:18:28SRY gene is the SRY gene. But what if
1:18:31it's just two amino acids different it's
1:18:33still functional. Is it still the SRY
1:18:34gene? Well there are nomenclature
1:18:35committees where people decide yes or
1:18:37no. You have a you have a community
1:18:40agreement
1:18:41in order to go forward and you don't
1:18:43have that in terms of the discussion
1:18:45around gender but you have it around the
1:18:47discussion of sex.
1:18:48>> Yes.
1:18:49>> Right.
1:18:49>> And circuits. and circuits. So, let's
1:18:52talk about circuits for sex. Start
1:18:55there. Let's start with a recent
1:18:57discovery your laboratory made, which is
1:18:59about sexual behavior
1:19:02in males and the frequency of sexual
1:19:05behavior. I think u most everyone who
1:19:08has gone through sex education in one
1:19:10form or another understands that males
1:19:13have a refractory period after
1:19:15ejaculation in which they
1:19:19don't mate again and in some cases can't
1:19:22mate again. What did you discover about
1:19:25the neural circuits responsible for
1:19:27mating and the refractory period? Yeah.
1:19:30So this is in the mouse and we were
1:19:31working in male mice and we sort of hit
1:19:34upon these neurons. We identified these
1:19:36neurons using genetics that expressed a
1:19:38specific set of genes in the
1:19:39hypothalamus that if we activate them um
1:19:43male mice no longer have a refractory
1:19:45period. And the strain of mouse we're
1:19:47working on has a post ejaculation
1:19:49refractory period of about four to five
1:19:51days
1:19:51>> typically.
1:19:52>> Typically so he won't mate for up to
1:19:53four days with the female after
1:19:55ejaculation. So if he is presented a
1:19:57female and they mate, he ejaculates, you
1:20:00remove that female, you give him a new
1:20:02female, he won't mate with her for four
1:20:03or five days,
1:20:04>> correct?
1:20:04>> He's content or he's not able or
1:20:08whatever. Okay?
1:20:10>> So we sort of switch these cells on with
1:20:11optogenetics. You know, we sort of
1:20:13electrically activate these cells with
1:20:15light and they lose their refractory
1:20:17period. They start mating within a
1:20:18second. As soon as the light comes on,
1:20:20the cells start firing. They start
1:20:21mating again and they can ejaculate
1:20:23again. So you reduce the refractory
1:20:25period from four to five days to 1
1:20:27second.
1:20:27>> That's right.
1:20:28>> How long can they keep this up? No pun
1:20:31intended.
1:20:31>> As long as the light is on, they'll keep
1:20:32mating.
1:20:33>> And you're not talking about light
1:20:34presented to the eyes. You're talking
1:20:35about um basically a light driven way to
1:20:38stimulate the neurons.
1:20:39>> That's right.
1:20:39>> What are these neurons? What what are
1:20:41they called?
1:20:42>> Uh they're in the hypothalamus. They're
1:20:43in the preoptic area, which is one of
1:20:45the most sexually different
1:20:47differentiated areas in the brain across
1:20:49vertebrates. And they express the gene
1:20:51tachikinan receptor one tac r1.
1:20:54>> I thought tachikinan is associated with
1:20:55aggression
1:20:56>> social behaviors
1:20:58depending on the circuit.
1:21:00>> Right? So flies has been shown David
1:21:02Anderson shown for example the tac one
1:21:04the tachikin genus regulates aggression.
1:21:07In this circuit in the male mouse it
1:21:09regulates sexual behavior.
1:21:10>> How many neurons?
1:21:12>> Maybe about 1,200 1500 on each side. So
1:21:14about 2,00 2500 cells total.
1:21:18I'd like to take a quick break and
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1:23:03to get early access to function. If we
1:23:06were to scale the size of the preoptic
1:23:07area from the mouse to the human, back
1:23:09of the envelope calculation, how many
1:23:12neurons is this in humans?
1:23:13>> Roughly the same range because the human
1:23:15hypothalamus hasn't expanded that much.
1:23:17It's a human cortex that's expanded.
1:23:19Yeah, we should we should uh remind
1:23:20people of this or or let them know the
1:23:24hypothalammus in your brain is what the
1:23:26size of a couple of marbles sitting
1:23:29above the roof of your mouth controlling
1:23:30all of this stuff. That's right. So in
1:23:32the mouse, you know, these cells account
1:23:34for you know about 3,000 cells account
1:23:36for I don't know um 110,000th
1:23:41of the mouse brain. So take the same
1:23:44number to the human brain which has you
1:23:45know 80 billion neurons. Um so it's
1:23:48really a tiny tiny subset of cells. So a
1:23:51few thousand maybe 100 thousand on the
1:23:53human 10,000 in the human.
1:23:54>> So if stimulation of this of these cells
1:23:58reduces the refractory period to
1:24:00essentially zero one second. It's not
1:24:02zero seconds but um and that's with the
1:24:04same female or you can replace females.
1:24:06He'll just keep he'll just keep mating.
1:24:08>> Without the light, without the
1:24:09activation, he wouldn't have ejaculated
1:24:10again for four or five days. So this
1:24:12tells us that these neurons control the
1:24:14entire circuit down to ejaculation.
1:24:17So because the the words refractory
1:24:20period um encompass a bunch of things,
1:24:22right? The um difficulty in achieving
1:24:25erection as easily as one did prior to
1:24:28the first mating,
1:24:29>> right?
1:24:30>> Um
1:24:32presumably this bypasses all the
1:24:34dopamine aspect of it. What about
1:24:36prolactin controlling the refractory
1:24:38period?
1:24:38>> Yeah, I don't think the data on that is
1:24:40super strong. I think Susanna Lima has
1:24:41done some work and she doesn't find any
1:24:43sort of relation with prolactin and
1:24:45refactoric period
1:24:46>> although in humans um there's a
1:24:51practice
1:24:53of people taking um I forget what the uh
1:24:57I'm not pretending to forget what the
1:24:59the drug is. um kbergoline
1:25:03which is a dopamineergic agonist which
1:25:05is used to treat hyperp prolactinmia to
1:25:08reduce prolactin
1:25:09>> and it seems to be very uh pro libido in
1:25:14males and females people and I do not
1:25:16recommend this people take it
1:25:18recreationally there's actually a a
1:25:19slippery slope of this where um people
1:25:22will take it in an effort to
1:25:26have more sex but they can't achieve
1:25:28orgasm Um, and so it drives them crazy
1:25:31and they're institutionalized. I'm just
1:25:33kidding. They're not institutionalized,
1:25:34but it drives them crazy and they decide
1:25:36it's not a good choice.
1:25:36>> So, yeah, I mean, I think that's a great
1:25:39point. Let me circle back to the same
1:25:41circuit and also sort of take you on a
1:25:43tangent. I think people with Parkinson's
1:25:45taking L-dopa
1:25:47>> also augmenting dopamine levels because
1:25:49they are giving the precursor to dop to
1:25:51dopamine, right? And there are reports
1:25:52in the literature saying that there is
1:25:54an increase in hypersexual type
1:25:56behavior. You see this in um the the
1:25:58case that I heard years ago on the radio
1:26:01uh was of a woman who was taking L-dopa
1:26:04to treat her Parkinson's and she became
1:26:06a gambling addict.
1:26:07>> That's right. So part of the spectrum of
1:26:10the sort of taking L-dopa and
1:26:11Parkinson's is you become sort of you
1:26:13get these compulsive behaviors coming
1:26:15out or hypersexual behaviors coming out.
1:26:18And coming back to our circuit, the TAC
1:26:20R1, the Tachikan receptor circuit, we
1:26:22also show we also found that activating
1:26:25these cells leads to dopamine release in
1:26:28the nucleus circumbent.
1:26:29>> Oh, interesting. Which well it makes
1:26:31sense. But so but these neurons
1:26:34themselves are not respons responsive to
1:26:36dopamine, are they?
1:26:37>> No, they don't express receptors for
1:26:38dopamine. They project to the vententral
1:26:40tegmental area which is dopamineergic
1:26:42which has a lot of dopamine neurons and
1:26:44they activate these cells which then
1:26:47release dopamine in the nucleus
1:26:48encumbent.
1:26:48>> So these cells are like switches.
1:26:50>> Yes. And they're also we think encoding
1:26:54the rewarding aspects of sexual
1:26:56behavior.
1:26:57>> H tell me more about that.
1:26:59>> So you know people would describe sexual
1:27:01behavior as pleasurable. It is
1:27:03pleasurable.
1:27:04And
1:27:06about 70 years ago, James Olds and Peter
1:27:09Miller in classic studies showed that
1:27:11there were areas in the brain that if
1:27:14you put an electrode in that region and
1:27:16you gave a rat an option to press a
1:27:18lever to deliver electric current into
1:27:21that brain region, many areas were
1:27:24identified by by Milner where the rats
1:27:27would keep pressing the lever to get a
1:27:29hit of the current if you will, right?
1:27:32And he identified such a sort of
1:27:34rewarding center, reinforcing center in
1:27:37the hypothalamus of the rat. And he said
1:27:39this must be the pleasure center for
1:27:40sex.
1:27:42Right? He had a piece in the scientific
1:27:43American on this. And but the identity
1:27:46of these cells wasn't known as you know
1:27:48as we talked about the hypothalamus is
1:27:49super complex. It regulates not only
1:27:52mating and aggression and maternal
1:27:54behaviors. It regulates body
1:27:55temperature, thirst, feeding, regulates
1:27:58many different behaviors. So which cells
1:28:00are sort of encoding rewarding
1:28:02properties of sexual behavior. So these
1:28:04TAC R1 cells um if you give mice the
1:28:09opportunity to activate these cells with
1:28:12optogenetics. So instead of pressing a
1:28:14lever they just poke their nose their
1:28:16nose in a hole and if they poke their
1:28:19nose in a hole that has the correct hole
1:28:21they get light stimulation into these
1:28:23neurons. So these mice once they learn
1:28:24once they figure out that this port or
1:28:27hole delivers light and therefore
1:28:29electrical activation on these cells
1:28:30they tack our one cells they'll keep
1:28:32doing that repeatedly.
1:28:33>> Got it?
1:28:34>> Okay. So it says
1:28:35>> they like it.
1:28:36>> They love it. Right. And in fact they
1:28:38could be sexually naive. They could be
1:28:40virgins
1:28:41>> and they still love it.
1:28:43>> Right. So this rewarding property of
1:28:46these neurons doesn't depend on past
1:28:48sexual experience. These neurons are
1:28:50naturally encoding some form of reward
1:28:52or reinforcing behavior.
1:28:53>> Does it require sexual behavior itself?
1:28:56>> No, that's what I said. So, virgin males
1:28:58will do it, too.
1:28:58>> Oh, you mean while they're still
1:28:59virgins? I thought you meant having
1:29:00never had sexual experience before.
1:29:03>> This is important because um as you and
1:29:05I know, uh Du Lynn's work from NYU
1:29:09showed that these neurons in the
1:29:10ventromedial hypothalamus when
1:29:12stimulated, mice will attack another
1:29:14mouse,
1:29:14>> right?
1:29:16>> They'll even attack a glove,
1:29:18>> right?
1:29:19Um, we can put a link to these videos.
1:29:21They're very dramatic to see this. You
1:29:23know, the the stimulation of these
1:29:24neurons goes on and they just will
1:29:26attack the glove, attack the other
1:29:27mouse, stop the stimulation, they stop.
1:29:29It's like rage switch.
1:29:32But if there's no glove or mouse to
1:29:34attack, they don't attack anything at
1:29:36all. They just cruise around their cage.
1:29:38These neurons are different. These these
1:29:40neurons seem to make the what you're
1:29:43calling virgin males. uh they'll work to
1:29:46stimulate the these cells, but are they
1:29:49I can't get around this. Are they
1:29:51masturbating? What are they doing?
1:29:53>> Well, the brain's getting activated. So,
1:29:55the center for mating is getting
1:29:56activated.
1:29:57>> But what are they doing with that
1:29:58activation?
1:29:58>> They're not doing anything else. They're
1:30:00just going into the port again and again
1:30:02and again.
1:30:02>> Okay. So, in a lot of ways, it's it's
1:30:03it's like these ventromedial
1:30:05hypothalamus neurons. They need
1:30:06something to mate with. It's not like
1:30:08they start mating with the hole in the
1:30:10wall. No,
1:30:11>> it's not like they start mating with
1:30:12inanimate objects.
1:30:15They like the feeling of these neurons
1:30:18being stimulated, but the neurons
1:30:20themselves don't trigger mating.
1:30:22>> Let me step back. I think we're
1:30:24confusing two things, right? So, not
1:30:25confusing, we're conflating two things.
1:30:27One is do the mice like activation of
1:30:30the neurons? And the answer is yes. They
1:30:32love it because they keep doing it even
1:30:34if they've never made it before.
1:30:35>> Okay. So, the analogous experiment for
1:30:36the Dulin stuff would be uh will animals
1:30:39work for stimulation of the VMH? And we
1:30:42know the answer is yes. Male animals
1:30:44will work will work to fight. They like
1:30:46to fight.
1:30:47>> But if you activate these neurons, just
1:30:49like you know, if you activate the VMH,
1:30:50you get aggression towards the glove. If
1:30:51you activate these neurons and you give
1:30:53them an object, they will try and mount
1:30:56with it as long as it looks like a
1:30:57mouse. So if you give it a toy mouse,
1:31:00the males will try and mount the toy
1:31:02mouse.
1:31:02>> But if you give them say a um I don't
1:31:05know a marble,
1:31:06>> no. A beaker, no. A block of a wooden
1:31:09block, no. But if you take a test tube
1:31:11>> Yeah. they won't mount it. But if you
1:31:13give if you take a toy mouse tail and
1:31:16glue it to the test tube so it now has a
1:31:18you know has some mouse-like elements
1:31:20they will mount it.
1:31:22>> Very low threshold for for activating
1:31:25the behavior.
1:31:26>> Yeah. I think what it says just like the
1:31:28aggression sort of experiment says is
1:31:30that there are these innate circuits
1:31:32these hardwired circuits that if you
1:31:34activate them and you have the right
1:31:36stimulus the animals will attempt to do
1:31:39the behavior that these circuits are
1:31:40wired for
1:31:41>> or even the wrong stimulus but one that
1:31:44resembles it just barely a tail on a
1:31:47test tube by stimul
1:31:51for who they'll mate with and what
1:31:52they'll mate with but that's pretty
1:31:54that's pretty
1:31:55>> by simul I mean by activating these
1:31:57cells with optogenetics. So if you
1:31:59activate these cells and you give them
1:32:01an inanimate object, if it roughly
1:32:04resembles something that they're
1:32:06familiar with that looks like a mouse in
1:32:08this case, they'll try and mount it.
1:32:10>> But if you give a a mouse with no
1:32:11stimulation of these neurons a test tube
1:32:14with a tail,
1:32:14>> nothing happens. They'll sniff it.
1:32:16They'll they'll sort of, you know, maybe
1:32:17play with it and then they'll walk away.
1:32:19>> That's a significant result to reduce
1:32:21the refractory period from 4 days to or
1:32:235 days to to 1 second. What is the
1:32:26theory as to why there's a refractory
1:32:28period at all? Is this female driven? Is
1:32:31it it based on the female sexual
1:32:33behavior um preferences or
1:32:35non-preferences or is it um something
1:32:38related to controlling population
1:32:39numbers like you would end up with I
1:32:42don't know too many pregnancies from one
1:32:44male? What what's what's the idea there?
1:32:46>> Actually, every species has a different
1:32:48refractive period and in the mouse you
1:32:50know because of genetic inbreeding there
1:32:52are lots of strains of mice. you know,
1:32:53people have been raising breeding mice
1:32:55for as pets and whatnot. And different
1:32:58strains of mice will also have different
1:33:00refractory periods.
1:33:02So, there's definitely a sort of a
1:33:04genetic basis for refractive period that
1:33:07may be species specific and also strain
1:33:09specific in the mouse. As to why you've
1:33:12genetically sort of selected for a
1:33:14specific refractive perc, I think it's
1:33:16generally unknown. Um it could depend on
1:33:19the kinds of um
1:33:23mating strategies different species use.
1:33:26>> Well, in humans um who mate not just to
1:33:29reproduce but also for pleasure. Uh
1:33:34you know what is known about the
1:33:36relationship between age and the
1:33:39refractory period duration? um that some
1:33:43years ago I was reading this book as I
1:33:47did again this weekend um about hormones
1:33:49and behavior and it's really interesting
1:33:51when you look at the distribution of
1:33:52testosterone levels in in males from age
1:33:55say 20 up to 90 there's a big range at
1:33:58any given age and it's not clear that
1:34:01absolute testosterone numbers are that
1:34:03uh informative anyway but they they
1:34:05point in a certain direction but you
1:34:08also look at um sort of copulatory
1:34:11frequency, sex frequency as a function
1:34:13of age. And it's also highly variable. I
1:34:16mean, there are these famous/infamous
1:34:18cases of like Franklidd Wright who was
1:34:21um purportedly um you know, having sex
1:34:24up to, you know, four, five, six, seven
1:34:25times a day and did that well into his
1:34:28his 80s, you know, to the point where
1:34:30his wife at one point was really
1:34:31concerned like is this okay for his
1:34:32health? And um he was also uh an
1:34:35incredibly productive person in other
1:34:37domains of life. Also, by the way, an
1:34:39incredible procrastinator. apparently
1:34:41did all his sketches on the like cab
1:34:43ride over to the the deadline. Like he
1:34:45he would um he he sort of functioned in
1:34:48this like kind of thoughtful/impulsive
1:34:51manner. So people say,
1:34:53>> but he certainly never contested the
1:34:55these rumors. And then some people
1:34:56probably just have lower libido, right?
1:34:59But as a function of age, it is the idea
1:35:01that it's all testosterone driven. If
1:35:03testosterone levels drop, then frequency
1:35:05of of mating, assuming someone is, you
1:35:07know, has a partner that they mate with
1:35:10um drops off. Like what what's known
1:35:12about this?
1:35:12>> As you pointed out, you know,
1:35:13testosterone levels vary all over the
1:35:15place, right? And it's not just you
1:35:18could have normal levels of
1:35:19testosterone, quote unquote normal
1:35:20levels, and there's already a huge range
1:35:22of normal tighters circulating levels of
1:35:25testosterone, but also you could have
1:35:27different receptor densities in
1:35:29different regions. M so it's hard to
1:35:31just take one parameter testosterone
1:35:33levels and say that that correlates with
1:35:35libido or with um with the desire to
1:35:39mate in humans why sexual behavior
1:35:43changes or the factor changes I don't I
1:35:45don't think it's generally known
1:35:48it could be biological could be social
1:35:50it could be many things
1:35:52>> I neglected to ask um the obvious
1:35:55question which is do these neurons also
1:35:57exist in the female brain
1:35:59>> yes they
1:36:00And what are they controlling in the
1:36:02female brain?
1:36:03>> We don't know yet. But um each awe a
1:36:07postdocctoral fellow in my lab when he
1:36:09was a graduate student uh activated
1:36:13a larger subset of these cells in the
1:36:15preoptic hypothalamus in the females and
1:36:18they all express estrogen receptor
1:36:20estrogen receptor alpha ESR1
1:36:23and these females also mated like males.
1:36:25So this sort of harks back to something
1:36:27we talked about earlier that the circuit
1:36:29for male sexual behavior is present in
1:36:32the female brain and he sort of
1:36:34identified a node in the female brain
1:36:36that lets them mate like males if he
1:36:38activates this optogenetically.
1:36:41Whether the TAC R1 cells that we
1:36:43identified do the same, we don't know
1:36:45yet. We're working on that.
1:36:46>> Okay. Without getting um too down in the
1:36:49nitty-gritty of circuit biology, but
1:36:51also getting down into the nitty-gritty
1:36:52of circuit biology, I have to know. So,
1:36:54where do these cells connect to? You
1:36:55mentioned that they're in communication
1:36:56with the dopamine system to activate
1:36:58this kind of sense of reward, pleasure,
1:37:01and reinforcement to drive more of the
1:37:03behavior. Where else are these cells
1:37:05projecting? I mean, it's um it's a long
1:37:08way from a couple, you know, from 1,200
1:37:10neurons to uh the penis. Um what's in
1:37:15between?
1:37:16>> Yeah. So one big area they project to a
1:37:19really dense projection from these cells
1:37:20is to the peracoductal gray
1:37:22>> an area involved in pain regulation
1:37:24>> and many other sort of innate behavioral
1:37:26displays
1:37:28>> so fight or flight freezing behavior
1:37:31>> and also sort of lordosis behavior
1:37:33>> and for folks that aren't familiar with
1:37:34neuro anatomy that the period ductal
1:37:36gray sits kind of in the back of the
1:37:38brain um and backish of the brain and I
1:37:42always imagine it kind of like a pizza.
1:37:43It's got these like segments. It has
1:37:45these sectors like you activate one
1:37:46brain area, it's involved in suppressing
1:37:48the pain response. You activate another
1:37:50area, it's involved in femalordos. You
1:37:52activate another area, it's involved in
1:37:54kind of fleeing. You activate another
1:37:56area, it's an approach. So either it
1:37:58hasn't been parsed finely enough or it's
1:38:01um in fact, it's kind of like a it's
1:38:04almost like a mirror of the hypothalamus
1:38:06further back in the brain.
1:38:07>> That's right. So they project to the P A
1:38:11>> and then from there
1:38:12>> and the Pag goes to the brain stem
1:38:14you're part it's already already in in
1:38:15the back of the brain as you pointed out
1:38:17and then goes further down through
1:38:18multiple connections to the spinal cord
1:38:20>> and then it intervates with the bulb
1:38:21coverosis or whatever controls
1:38:23>> muscles and the thoracic muscles
1:38:25involved in thrusting and
1:38:27>> it's a it's a program that's a um innate
1:38:31program I mean most animals um have to
1:38:34learn the socialization of mating
1:38:38um dating, consent, all other things,
1:38:42but they don't have to learn the motor
1:38:43programs. The motor programs are
1:38:45activated during puberty. Is that right?
1:38:46>> Yeah.
1:38:47>> Some years ago, I recall a paper um
1:38:50showing that mounting behavior could be
1:38:52both aggressive or reproductive.
1:38:57What's what's the story there? Because
1:39:00females do it too,
1:39:01>> right? So, you're saying by aggressive
1:39:02you mean like a form of dominance
1:39:03display?
1:39:04>> Yeah, like jiu-jitsu,
1:39:05>> right? So it certainly that's what
1:39:08people have certainly said that it could
1:39:09be a dominance display because males
1:39:10will sometimes mount males although once
1:39:12males start fighting and once they've
1:39:14had sexual experience they tend less
1:39:16often to mount other males they just go
1:39:18straight for the kill if you will
1:39:20>> um and in other species you know many
1:39:22non-human primates sort of animals will
1:39:24just mount each other as sort of a play
1:39:26behavior or also for giving pleasure
1:39:30right so that's a known thing so mount
1:39:31you know female female male male mounts
1:39:33they will do it as play behavior in
1:39:34uneven primates So there are many
1:39:37presumably many reasons to engage in
1:39:39that sort of behavior.
1:39:41>> So it's not always sexual is the idea.
1:39:43>> Not necessarily. Right.
1:39:45>> So what other collections of neurons
1:39:46live in this part of our brain that when
1:39:49activated give uh critters us or
1:39:52otherwise um these kind of supernatural
1:39:55uh let's just say extreme um uh
1:39:59functions.
1:40:00>> Thirst neurons feeding neurons right? So
1:40:02you can activate specific sets of cells
1:40:03that express AGP for example or other
1:40:05sets of cells animals start drinking
1:40:07water or start eating.
1:40:09>> Uh I thank you. I mean within the
1:40:10context of of mating and and sexual
1:40:13behavior are there are there for
1:40:15instance like neurons that when you
1:40:16stimulate them um mice start building
1:40:19nests.
1:40:20>> We don't have those sets of neurons yet.
1:40:22But there are so many sets of neurons in
1:40:24the same vicinity that regulate
1:40:25parenting behaviors. Right? So they'll
1:40:27start taking care of pups for example.
1:40:29So you can take virgin mice who don't
1:40:31normally take care of pups. It can
1:40:33activate these circuits and it can
1:40:35prevent these mice from hurting the
1:40:37pups.
1:40:38>> So normally mice will hurt Yes.
1:40:40>> will hurt other mice pups.
1:40:42>> Yes. Not their own, right?
1:40:44>> That sucks.
1:40:44>> Yeah.
1:40:45>> Doesn't say much for mice,
1:40:46>> right? Well, a lot of animal species do
1:40:48that.
1:40:48>> Yeah.
1:40:49>> Right. They ex sort of exhibit
1:40:50infanticile behavior where there are
1:40:52other species like vos that take that
1:40:56show fostering behavior. They take care
1:40:57of pups not their own. So, it depends on
1:40:59the species you're talking about.
1:41:00>> Yeah. Years ago, I worked with ferrets
1:41:02and um they're perfectly happy to raise
1:41:04other ferrets, they they kind of don't
1:41:07even seem to notice if it's theirs or or
1:41:09some some other ferrets, pups, kits.
1:41:11Interesting. Do you think when people
1:41:14get dogs, bulldogs in particular, I'm
1:41:17just joking. dogs. Uh Nural has like one
1:41:20of the world's cutest uh French
1:41:21bulldogs. That some of the caretaking of
1:41:25of dogs activate some of the same
1:41:29circuitries in the brain that are
1:41:30responsible for for rearing our own
1:41:33species.
1:41:34>> I don't know to be honest.
1:41:35>> I'm disappointed to hear you say that.
1:41:38I must say I'm disappointed. When I got
1:41:41Costello as a puppy, I'll never forget
1:41:44that for the first, I don't know, three
1:41:46weeks that I had him, I had very little
1:41:48appetite. I my work drive was certainly
1:41:52still there, but I just felt like it 99%
1:41:56of my cognition was on his well-being.
1:41:58And um
1:41:59>> but that's certainly true.
1:42:00>> And I could have sworn it was a surge in
1:42:03oxytocin or or prolactin.
1:42:05>> Oxytocin or prolactin?
1:42:06>> No, I didn't. I would have had I had the
1:42:08means to do it, but there aren't very
1:42:09good tests to do that that are sold over
1:42:11the counter. I should have, but if I get
1:42:12another puppy, I'll do it. Although now
1:42:14I think I'll I'll I'll go about it a
1:42:15little bit more differently, you know,
1:42:16but it was my first dog
1:42:18>> and I
1:42:20>> was just it was like all about him.
1:42:22Nothing else really mattered except the
1:42:24basics of maintaining. That's how
1:42:26parents describe having a newborn.
1:42:28>> That's right. So that's certainly true.
1:42:29Cooper's our first dog as well. And you
1:42:31know, if he needs something, it
1:42:33basically, you know, takes precedence
1:42:35over everything else. Mhm.
1:42:36>> Like feed if he needs food or if he
1:42:38needs to go out for a walk
1:42:40>> then you know I have to I do drop things
1:42:42and I just take care of him.
1:42:43>> So that part is certainly true. So if
1:42:45you
1:42:45>> Yeah. It inhibits selfishness
1:42:48>> or inhibits your doing other things.
1:42:50Yes.
1:42:51>> Yeah.
1:42:52>> Makes you more altruistic. Yeah.
1:42:53>> This was really just my ploy to uh bring
1:42:55up oxytocin.
1:42:57>> Okay.
1:42:57>> We hear that oxytocin is the chemical
1:43:00responsible for bonding between romantic
1:43:03partners. um bonding between mother and
1:43:06infant, maybe even bonding between
1:43:08friends, etc. What's the real deal on
1:43:11oxytocin? Because I think um like so
1:43:13many things in neuroscience that were
1:43:15first discussed in roughly the '9s,
1:43:17early 2000s, we're getting a lot more
1:43:19data now. So, what's the real deal on
1:43:21oxytocin? I'm not trying to burst any
1:43:23oxytocin bubbles, but uh what's the deal
1:43:25with oxytocin? So the paradigm that
1:43:28people have mostly used to study the
1:43:30role of oxytocin in pair bonding in
1:43:32animal models has been the prairie v. So
1:43:35so these are like mouse-sized rodents
1:43:37with very short tails. And unlike mice
1:43:41or rats for that matter, vos after
1:43:44having sex with one another, they will
1:43:46pair bond for life, they form these
1:43:47long-term enduring relationships,
1:43:49>> completely monogous.
1:43:50>> Well, they actually just like humans,
1:43:52they will have extra pair mings as well.
1:43:54So they will cheat if you will
1:43:55>> at a Coldplay concert.
1:43:57>> Exactly. Right. Um or but for the most
1:44:00part they're monogous. Right. So if you
1:44:02give them a potential mate of of
1:44:04opposite sex, they will reject it
1:44:05aggressively. Right. So they have this
1:44:08monogous behaviors and classic work from
1:44:10many labs had shown that oxytocin was
1:44:13maybe a really huge driver of the sort
1:44:15of monogous spawning behavior.
1:44:18So over the last 10, it took us about 10
1:44:2015 years to develop the technology to
1:44:22make knockout v. And we've done that.
1:44:25Um, and this is a work of really heroic
1:44:26posttos in my laboratory. Um, and
1:44:30knocking out the oxytocin receptor
1:44:31prairie vols, we saw that these vos
1:44:34continued to form pair bonds. They were
1:44:37just as monogous as their wild type
1:44:40siblings were.
1:44:42So in fairness to oxytocin and to
1:44:45experimental biology generally when you
1:44:48see an experiment like that um go darn
1:44:52everything we thought about oxytocin is
1:44:54wrong or you say pair bonding is so
1:44:57important that there's redundancy in the
1:45:00system that other things can compensate
1:45:03which one do you think it is
1:45:04>> so the most likely other candidate it's
1:45:06going to be vaseesscent because the same
1:45:09folks who had sort of identified
1:45:10oxytocin as being sort of really
1:45:12important for pair bonding. It also
1:45:13suggested vasopressin might play sort of
1:45:16you know a similar role and vasopressin
1:45:18like oxytocin is a neuropeptide hormone.
1:45:20So it's about nine amino acids. Um so
1:45:22it's a short peptide um and it binds a
1:45:26different receptor vasopressin receptor
1:45:281A that regulates pair bonding behavior.
1:45:30So that's the next experiment for us is
1:45:32it vasopresscent receptor and
1:45:33vasopressin that's required for pair
1:45:35bonding behavior.
1:45:36>> Okay. So we shouldn't give up on
1:45:37oxytocin just yet.
1:45:38>> Let me also step back. Let me push back
1:45:40against this idea of I'm going to get
1:45:42some heat for this uh for saying that if
1:45:44it's so important you want to sort of
1:45:46have redundancies built in the system.
1:45:48We just talked a while ago about SRY.
1:45:51You just have one copy. You just have
1:45:52one SRI. In fact, it's only on one
1:45:54chromosome. So you only have one copy.
1:45:56If you don't have it, you're not going
1:45:58to become a male. So there's no
1:45:59redundancy for perhaps the most
1:46:01important decision the embryo is going
1:46:03to make, male or female. And there's no
1:46:06redundancy built in there. So I think it
1:46:08depends on what process we're talking
1:46:10about. If you if there are going to be
1:46:11redundancies or not
1:46:13>> for something extremely critical. If you
1:46:14don't have a redundancy, then I think it
1:46:16could be that other processes also don't
1:46:18have as many redundancies as we thought.
1:46:20>> Did you think you were going to get some
1:46:22heat because somebody would say, "Well,
1:46:23that implies the SRY gene is not
1:46:25important and therefore males aren't
1:46:27important."
1:46:27>> No, I think as you and I both were
1:46:29taught during developmental biology
1:46:30classes that we took as grad students,
1:46:32redundancies and sort of multiple
1:46:34pathways regulating a process is a
1:46:36thing. And it's definitely true for many
1:46:38things as we've learned during
1:46:39development and developmental biology.
1:46:41But also there may be processes where
1:46:43you don't have redundancies that are
1:46:44equally important for life
1:46:47where if you don't have the gene, you're
1:46:49done. Because evolution is agnostic,
1:46:53right?
1:46:54If you're not successful, it doesn't
1:46:55care. It just moves on. So you won't
1:46:57reproduce. Evolution doesn't care.
1:47:00>> If you're not fit, you're not fit.
1:47:01>> Yeah. The bad ideas died literally. or
1:47:05the bad experiments died, right?
1:47:07>> Okay. So, speaking of hormones and
1:47:09behavior and language and where language
1:47:12can be a little bit complicated,
1:47:15let's talk about libido, right? Most
1:47:17people know what that word means. It's a
1:47:19a drive to to have sex for reproduction
1:47:22or pleasure or both. And you discovered
1:47:26these neurons that effectively eliminate
1:47:28the refractory period. I don't know how
1:47:30an animal could mate any faster than
1:47:32once a second. I guess I guess there's
1:47:35>> no once it's after one second.
1:47:36>> After one second, I guess. Yeah. Okay.
1:47:38So, I mean, there needs to be some time
1:47:42in between. 1 second is about as as as
1:47:44short a refractory period as possible,
1:47:46but we don't really know what's going on
1:47:49in the in the in the mind of the mouse.
1:47:51Um but when a discovery like this is
1:47:54made uh and because of the conservation
1:47:56between the mouse hypothalamus and the
1:47:59human hypothalamus I think many people
1:48:01probably thinking oh you know is this a
1:48:03druggable target is this the sort of
1:48:05thing that um could be used to enhance
1:48:07libido and or reduce the refractory
1:48:09period in males and that opens up a a
1:48:12larger discussion I think about biology
1:48:14druggable targets and sex behavior in
1:48:18humans. So there is an FDA approved um
1:48:21drug um that targets the melanoorton
1:48:25pathway I believe. That's right. That's
1:48:27used to uh enhance libido in females.
1:48:30>> That's right.
1:48:31>> Although I hear I would say if I had but
1:48:34I've never tried it but I hear that men
1:48:37take it also and it has a similar effect
1:48:40although not as pronounced as in women.
1:48:42uh tell us about melanoortin and why a
1:48:45drug that stimulates melanoortin would
1:48:47increase libido and then we'll talk
1:48:50about whether or not the tachikin
1:48:51neurons that you discovered uh represent
1:48:53a good drugable target for increasing
1:48:55male libido.
1:48:56>> Right. So actually
1:49:00removing menoordin signaling in the
1:49:02mouse brain in male or female mice does
1:49:05impact sexual behavior in both sexes.
1:49:07>> It does. Yes,
1:49:07>> it does.
1:49:08>> Okay. So it seems to be import playing a
1:49:10role in sexual behavior in both sexes.
1:49:12Um the effect though of me the of the
1:49:16drug seems to be you know pretty small.
1:49:18It affects it helps a subset of women
1:49:20not all women I think and there are
1:49:22significant side effects as well of um
1:49:24what's it called? Visi
1:49:26>> I think the drug is called vile and my
1:49:28understanding is melanocorton
1:49:30comes from the medial um pituitary and
1:49:34is involved in pigmentation of the skin
1:49:36as well. So it it tends to darken
1:49:38people's skin.
1:49:39>> It can cause hyper hyperpigmentation in
1:49:41some women taking it. It's injectable, I
1:49:43think.
1:49:44>> Mhm.
1:49:45>> So it definitely seems to help a subset
1:49:47of women. Um
1:49:50so that's I think that's one of the few
1:49:51libido enhancing drugs out there and
1:49:54it's very different than Viagra and
1:49:56which works in men as you know, right?
1:49:58Which that because Viagra acts on a more
1:50:00peripheral vascular thing. It doesn't
1:50:03act on libido. It acts on the ability to
1:50:05have interaction,
1:50:06>> right? It's prerectile and I think women
1:50:09will take um some of these
1:50:11vasoddilators.
1:50:12>> That's right.
1:50:12>> As well,
1:50:13>> right,
1:50:14>> for enhanced sexual function.
1:50:16>> That's right. But libido is pretty
1:50:18separable from erectile function. Right.
1:50:21As you pointed out, libido is more the
1:50:23desire to engage in sexual behavior,
1:50:25whereas, you know, erectile function is
1:50:27the ability to enact on that desire. So,
1:50:31those are pretty separable. And I don't
1:50:32think there are very many good libido
1:50:34enhancing drugs for men or for women.
1:50:36Right? We talked about this drug vi
1:50:39that is helpful and seems to have a
1:50:42positive effect. But there's certainly a
1:50:44big der out there of drugs that would
1:50:47enhance libido.
1:50:48>> So is any
1:50:49>> or inhibit libido for that matter,
1:50:50>> right? I think uh when people think
1:50:52about drugs that in that inhibit libido,
1:50:54it's naturally occurring experiments
1:50:57like uh opioid use does that excessive
1:51:00alcohol intake.
1:51:02>> Um
1:51:04uh anything that diminishes
1:51:06dopamineergic function will do that.
1:51:10>> Um so after you made this discovery uh
1:51:14did people approach you about developing
1:51:16a drug to enhance libido in men andor
1:51:18women? Yeah. Mutual friend of ours, Mike
1:51:21Eisenberg at Stanford.
1:51:22>> Oh, yeah. He was a guest on this
1:51:23podcast. Our head of male sexual health
1:51:24in Urology.
1:51:25>> Exactly. He approached me and he says,
1:51:27"Can we do something about this target?"
1:51:29And I said, "There's no agonist. There's
1:51:32no drug that would activate the TAC R1
1:51:34receptor that we know about that's
1:51:36clinically proven to be safe. There is
1:51:37an antagonist for it that's clinically,
1:51:40you know, that's FDA approved that's
1:51:42used for other purposes,
1:51:43>> but that would uh diminish libido. That
1:51:44would
1:51:45>> diminish li." Did Mike approach you
1:51:46because he has a lot of patients that
1:51:48have diminished libido who want to
1:51:50enhance libido?
1:51:51>> That's exactly right.
1:51:52>> Why do you think there's such a der of
1:51:53drugs to enhance libido?
1:51:55>> I think for a long time pharmaceutical
1:51:57companies have stayed away from drugs
1:51:59that act on the CNS because you know
1:52:01back in the '9s there are a lot of
1:52:03studies developing drugs to sort of uh
1:52:07enhance different functions in the brain
1:52:09and there are always some offt target
1:52:10effects. So companies have typically
1:52:11stayed away from those
1:52:14>> not SSRIs. I mean SSRIs were a boom
1:52:16industry until recently when everybody
1:52:18kind of turned on them. That's right.
1:52:20>> Um and I I say this uh every time SSRIs
1:52:24come up. Yes, they can have pronounced
1:52:26side effects. No, I don't think they are
1:52:28always the solution.
1:52:29>> Increing decreasing libido
1:52:31>> for certain populations of people like
1:52:33who have clinically diagnosed OCD. SSRIs
1:52:36have been very helpful. That's right. So
1:52:37we we don't want to completely uh you
1:52:39know
1:52:40>> I'm just saying that's why there's a
1:52:41general der of many many drugs being
1:52:44developed for different conditions that
1:52:45affect different you know different
1:52:47functions
1:52:48>> so drug companies don't want to make
1:52:49drugs that act on the brain
1:52:52>> I think now there's a change right with
1:52:53glip R1 with the glip agonist coming out
1:52:55people there's a huge interest suddenly
1:52:57>> which which drug
1:52:58>> vgoi and ampic
1:53:00>> oh what did for people lose body fat
1:53:02>> that's right so but those act on the
1:53:04brain as well right so there's now a
1:53:05sudden surge in interest again
1:53:07developing agonists if you will or
1:53:09antagonist to modulate different
1:53:11pathways in the brain because this is a
1:53:12huge success story. So now people are
1:53:14energized again I think well and if
1:53:16nothing else those drugs prove that one
1:53:19of the main reasons perhaps the main
1:53:21reason why so many people are overweight
1:53:23or obese is that they eat more than they
1:53:25burn. You know that people debated that
1:53:28until very recently. Now, hardly anyone
1:53:30debates that people will say, "Oh, well,
1:53:31it's the you need to think about blood
1:53:33sugar regulation and you know, and but
1:53:35when it comes down to it, you need to
1:53:37ingest roughly less than you you burn."
1:53:40Uh there's some noise there, but it's um
1:53:44it's clear that
1:53:46that set of experiments, the heal
1:53:48monster that doesn't eat very much,
1:53:49which makes a peptide, which then is
1:53:52turned into a drug, makes people not eat
1:53:53as much. Boom. You have a trillion
1:53:55dollar industry. So here you have a
1:53:57discovery where um you discover an
1:54:00animal that when these neurons are
1:54:02stimulated can has kind of an insatiable
1:54:05libido. Um so it seems that a the
1:54:09appropriate dose of a drug that targets
1:54:11the tachikin one neurons might might
1:54:13make a reasonable druggable target.
1:54:15>> I would think so. Yeah.
1:54:16>> Well, someone listening to this will
1:54:18will take interest. It's a uh what's
1:54:20involved? What does it take to to go
1:54:22from like a desire to make a drug like
1:54:24that to a drug that can go into humans?
1:54:27I mean, how first you go pre-clinical
1:54:29testing obviously,
1:54:29>> right? First, you actually make sure
1:54:31that the circuit exists, that those same
1:54:33neurons in the human brain express the
1:54:35same receptors.
1:54:36>> Well, that's easy to do nowadays, right?
1:54:38There's some brain banks, you cut, you
1:54:39take some brain sections from some
1:54:41deceased people who've said it's okay
1:54:43with them, and you and you do the mRNA
1:54:45and C2 forward. Yeah. Okay. All right.
1:54:47So, the neurons are there.
1:54:48>> Um, and then you do what? dose response
1:54:51curves in mice.
1:54:52>> That's right. And then you do right and
1:54:54you go into pre-clinical trials and ask
1:54:56is are there agonists you can develop
1:54:57that are safe
1:54:58>> that have the desired effects with
1:55:00minimal offtarget effects.
1:55:02>> I promise you that just by virtue of
1:55:04this discussion somebody someplace and
1:55:06I'm not recommending this is going to
1:55:09develop or acquire a tachikin peptide
1:55:11and inject that peptide. The reason I
1:55:13say that is that these GLP agonists that
1:55:15many people are now using were used for
1:55:18many years in the fitness industry by
1:55:20people who would read a couple papers
1:55:23based on animal models and uh be willing
1:55:25to acquire or develop the peptide and
1:55:28inject the peptide. Not something I
1:55:30recommend, but you can be absolutely
1:55:32sure,
1:55:32>> okay,
1:55:33>> that um someone will try this. The
1:55:36reason I say that is that there's a
1:55:37peptide in the hypothalamus called kiss
1:55:39peptin, I think, which regulates
1:55:41puberty.
1:55:42>> That's right. And there is a subculture
1:55:44of people that take kissepin as a
1:55:45peptide as a libido enhancer.
1:55:48>> I can't uh avoid asking um because we're
1:55:51on the topic. Uh do we know what
1:55:53switches on puberty?
1:55:54>> Kiss pepin is certainly important.
1:55:56Right. So mutations in the receptor for
1:55:57kspepin seem to block puberty in humans
1:56:00>> and in mice as well.
1:56:01>> So there are people that never undergo
1:56:03puberty.
1:56:03>> That's right.
1:56:04>> Really? And it's a mutation in kissepin
1:56:06>> receptor. Do they grow in size despite
1:56:09not being um like like sexually able to
1:56:15what happens?
1:56:16>> I think if you don't undergo puberty
1:56:17then you are not going to make the
1:56:18hormones the sex hormones that you
1:56:20normally make. So you don't get the
1:56:22boost in testosterone or estrogen or
1:56:23progesterone. So
1:56:24>> this is where gene therapy is going to
1:56:25be a huge boon to medicine. I'm curious
1:56:28about the regulation of brain function,
1:56:31changes in brain circuitry
1:56:33as female hormones change
1:56:36during say the menstrual cycle.
1:56:39What is known about that? How different
1:56:41is the brain at one stage of the cycle
1:56:43versus another?
1:56:44>> Okay, stepping back in rodents where a
1:56:47lot of this work has been done, we know
1:56:49that the estro cycle, it's not, you
1:56:51know, rats or mstone menstruate, but
1:56:53they still have the ovulatory cycle.
1:56:54They ovulate once every four to five
1:56:56days and their hormones estrogen
1:56:58progesterone do change correspondingly
1:57:00just like they would in in non-human
1:57:02primates or in women. So you have the
1:57:05same hormonal cycle roughly and you have
1:57:07the periodic ovulation.
1:57:08>> So it's just compressed into five days
1:57:10>> into five days.
1:57:10>> Okay.
1:57:11>> And in rats has been known for a while
1:57:13for about 20 to 30 years now that there
1:57:15are very specific sets of neurons that
1:57:18are responsive to estrogen that change
1:57:20the number of um dendritic spine. So
1:57:23these are sort of processes on these are
1:57:26processes on neurons that receive
1:57:29information from other neurons. As as we
1:57:31know neurons act in circuits. So neurons
1:57:33are listening to neurons upstream of
1:57:35them and then transmitting information
1:57:37to other neurons downstream of them. So
1:57:38some of these connections the
1:57:39presinaptic connections that are
1:57:40receiving information from other neurons
1:57:43those spines seem to increase wax and
1:57:46wayne across the estra cycle.
1:57:49Right? And we showed in a different
1:57:51finding more recently that neurons that
1:57:53transmit information, you know, when
1:57:54they are transmitting information
1:57:56downstream to other neurons,
1:57:58those pathways also change pretty
1:58:00dramatically. We saw about a three-fold
1:58:02increase or decrease every 5 days in the
1:58:05adult female brain of the circuit.
1:58:08>> Wow. That's huge.
1:58:09>> That's huge. And this seemed to be
1:58:11functionally relevant because if you
1:58:13when the circuit was fully on or was
1:58:14fully mature when she was ovulating, if
1:58:17we inhibited this pathway, she stopped
1:58:19mating.
1:58:22And coming back to sort of going back to
1:58:23an earlier part of the discussion, this
1:58:25circuit seems to be very dimorphic. This
1:58:27pathway essentially doesn't exist in the
1:58:29male brain,
1:58:30>> which makes sense.
1:58:30>> Which makes sense.
1:58:31>> They don't they don't ovulate,
1:58:32>> right?
1:58:33>> Are there hormonal fluctuations in males
1:58:37across the day or the week? I mean we
1:58:39assume that uh you know testosterone is
1:58:42highest in the morning. That's right. Um
1:58:44my read of the literature is that
1:58:46there's a subset of men for which
1:58:47testosterone is actually higher in the
1:58:49afternoon but in most men it's going to
1:58:50be highest in the morning. But we don't
1:58:52think of hormones as fluctuating in in
1:58:54men very much. Cortisol yes but what
1:58:56testosterone not so much. Is there any
1:58:58evidence of hormonal fluctuations in
1:59:00males that are meaningful or is it just
1:59:02pretty much a you know
1:59:04>> in the experiment that we've done in
1:59:05mice it doesn't seem to be the case. So
1:59:07you can just give testosterone to, you
1:59:09know, a male mouse if you've castrated
1:59:11him. You can basically inject it at any
1:59:14given time of day and it'll have the
1:59:16same effect, right? But in females, if
1:59:19you give estrogen and progesterone, it
1:59:20has to be at a very specific uh time
1:59:23point for you to see the effects of that
1:59:25hormone.
1:59:26>> So during the menstrual cycle, it sounds
1:59:27like there's profound changes in neural
1:59:30circuitry in the female brain.
1:59:31>> That's right. So it's very dynamic.
1:59:32>> Circuits are growing, circuits are
1:59:34disappearing, circuits are growing,
1:59:35circuit
1:59:35>> and people have seen in women also
1:59:37people women on the pill for example or
1:59:39not on the pill across the menstrual
1:59:40cycle you do see changes in MRI imaging
1:59:44in in women as well.
1:59:46>> So what's known about that in terms of
1:59:48blocking ovulation with oral
1:59:49contraception?
1:59:50>> No. So I think what I'm just saying is
1:59:51that the brain is seems to be also
1:59:53dynamic as visualized by imaging in
1:59:56women. So it's not just a rodent sort of
1:59:58phenomenon. It seems to be there's
2:00:00dynamic processes going on in humans as
2:00:02well across the menstrual cycle.
2:00:06>> What about during pregnancy?
2:00:08>> We don't know.
2:00:09>> We don't know.
2:00:10>> There are a couple of reports that say
2:00:11there are circuits that are changing in
2:00:13the adult in the mouse brain when she's
2:00:15pregnant when mice are pregnant.
2:00:17>> Hippocampus grows.
2:00:18>> I don't know that. Maybe you do.
2:00:20>> I I recall um there was a guy who did a
2:00:23sbatical in our colleague Leech and
2:00:25Lowe's lab. I forget now. Um he was from
2:00:27Larry Katz's lab. Well, factory guy
2:00:29>> Adi Misrai.
2:00:30>> Adi Mizrai. That's right.
2:00:32>> He showed that the cir the auditory
2:00:34cortex the circuit and the auditory
2:00:36cortex changes. I think mothers so
2:00:38they're more attuned to pup
2:00:40vocalizations.
2:00:41>> That's right. Their auditory cortex
2:00:43changed so they could hear their pups
2:00:44better. And that's
2:00:45>> that's the mothers though. Yeah.
2:00:46>> That wasn't during pregnancy. That was
2:00:48in
2:00:49>> the study might have started in
2:00:50pregnancy, but I'm pretty sure the
2:00:51experiments, the assays were done when
2:00:54she was nursing. I definitely need more
2:00:56science on how the brain changes uh
2:00:58during pregnancy, how the mother's brain
2:01:00changes during pregnancy. What about
2:01:02menopause? You know, these days there is
2:01:05appropriately, I think, uh increasing
2:01:07attention on pmenopause and menopause as
2:01:11very important stages of human
2:01:13development that have not been entirely
2:01:15ignored, but that were largely ignored
2:01:17for a long time. Now, there's a lot of
2:01:18attention about it. um what's known in
2:01:21terms of brain circuitry changing during
2:01:23menopause because my understanding is
2:01:26one of the most market changes
2:01:28hormonally is a reduction in estrogen.
2:01:30So again these studies are just being
2:01:32done in mice just starting to be done in
2:01:35a sort of very careful molecular way in
2:01:37the mouse and I think the jury is still
2:01:40out but it's clear that cognitive
2:01:42changes happen with menopause. So the
2:01:45estrogen going down is definitely
2:01:47affecting cognitive performance and this
2:01:48is sort of you know reported by women
2:01:51too is their mood changing the appetite
2:01:53changing and also the steep increase in
2:01:55Alzheimer's incidents in women in mice I
2:01:59think there's going to be a lot of focus
2:02:01on hypocampus which is involved in
2:02:02learning and memory and the frontal
2:02:04cortex where in the non-agged mouse
2:02:07female mouse people have seen these
2:02:09dendritic spines waxing and waning
2:02:11across the estro cycle. So what happens
2:02:13there and what happens to those circuits
2:02:15and you know the downstream behaviors is
2:02:18something that's still being
2:02:18investigated.
2:02:20>> Yeah. I think we often hear about
2:02:23estrogen and we think only in terms of
2:02:26ovarian function and ovulation and and
2:02:28you know that you know tucks right in
2:02:30with menopause. But when we hear about
2:02:33the effect of estrogen in preserving
2:02:34brain function my understanding is it's
2:02:37also true for men. and that one of the
2:02:39ways that it helps preserve brain
2:02:41function is that it helps keep the the
2:02:42blood vessels and capillaries very
2:02:44pliable. It's like very good for the
2:02:46cardiovascular system. Do we know if any
2:02:49of the reductions in estrogen that occur
2:02:51during menopause are acting directly on
2:02:54neurons or is this all like downstream
2:02:55of reduced blood flow for instance?
2:02:57>> Yeah, I don't know the answer to that to
2:02:59be honest. I suspect there's going to be
2:03:01both. There's certainly going to be
2:03:02direct effects on neurons because
2:03:03neurons express the receptor for
2:03:04estrogen. Many neurons, not all, express
2:03:07receptors for estrogen. So estrogen
2:03:09going down is certainly going to affect
2:03:10their function.
2:03:11>> Every MD that I've had on this podcast
2:03:14who has a specialization in in endocrine
2:03:17stuff will say the goal is to keep your
2:03:20estrogen as high as possible without
2:03:22running into side effects. That's good
2:03:24for your brain. So, and that when people
2:03:26quash estrogen or when you get uh males
2:03:30that have for instance very high DHT
2:03:32levels and T levels and their and their
2:03:34estrogen is very low, uh it's not a good
2:03:38picture cognitively. Certainly not in
2:03:40terms of cognitive longevity. So,
2:03:42estrogen is pretty interesting, I think,
2:03:43from the standpoint of its effects on
2:03:45the body, but also as a as a
2:03:47neuroprotective agent,
2:03:48>> right,
2:03:49>> in men and women. I have all sorts of
2:03:51questions about why that might be.
2:03:54I solicited for some questions from the
2:03:57internet.
2:03:57>> Okay.
2:03:58>> Always a dangerous thing to do, but a
2:04:00lot of fun. And so I'll ask you some of
2:04:03the more frequent questions. Feel free
2:04:05to pass on any of these. Um, if you
2:04:08don't feel like you have an answer or
2:04:10want answer, um, one was whether or not
2:04:13men's hormones cycle throughout the day.
2:04:15And we talked about an early morning
2:04:17peak in testosterone, which by the way
2:04:19is very correlated with the amount of
2:04:20REM sleep that people get. Seems like
2:04:22that if you don't get enough REM sleep
2:04:24that that might blunt some of that
2:04:26testosterone increase. Okay, here's a
2:04:29speculative question.
2:04:31If male and female brains are wired so
2:04:33differently, does that mean they
2:04:36experience reality in fundamentally
2:04:37different ways? Like maybe we're not uh
2:04:41at all having the same experience of
2:04:43life.
2:04:44>> Let me answer that from our studies in
2:04:46the mouse.
2:04:48Right. So a fundamental
2:04:50feature of social interactions is the
2:04:52ability to recognize potential mates
2:04:55from potential competitors. Recognize
2:04:58sex of other individuals. Female, male.
2:05:01You know, we do that subconsciously. You
2:05:03walk into a bar, you're subconsciously
2:05:05processing female, male, female, male.
2:05:07We all do that automatically. Mice also
2:05:10seem to do that. And we identified a
2:05:12region of the brain, a set of neurons of
2:05:14the brain that if we record from these
2:05:17cells, you and I, if you're just looking
2:05:19looking at the activity of these cells,
2:05:21we can say he's thinking that's a female
2:05:23or a male.
2:05:24>> So there's sex recognition going on in
2:05:27the male mouse brain.
2:05:30If you record from the same cells in the
2:05:32female brain, those cells to be seem to
2:05:34be quent.
2:05:36So it seems that male mice and female
2:05:38mice are using different circuits for
2:05:41recognizing females and males within
2:05:43their species.
2:05:46So they're wired differently and they're
2:05:48recognizing
2:05:49females and males using different
2:05:52pathways. So that's
2:05:54in in one sense having a very different
2:05:58intake of reality.
2:06:02If that makes sense.
2:06:03>> That makes sense. I'm remembering an
2:06:05early discussion that you and I had,
2:06:07meaning many years ago, where for
2:06:10whatever reason, you said exactly what
2:06:12you said here, minus the difference
2:06:14between males and females, where you
2:06:16said, you know, as you walk down the
2:06:18street, there's a process happening
2:06:21beneath your conscious awareness where
2:06:23you're going male, female, male, female,
2:06:26male, female. you're you're you're
2:06:27batching people into these two
2:06:29compartments based on maleness or
2:06:33femaleeness and and it in the mind it's
2:06:36just happening.
2:06:38And
2:06:39you said it's because you need to know
2:06:41whether or not someone's a potential
2:06:42mate or a potential foe or a potential
2:06:44collaborator.
2:06:46Based on what you just told us that
2:06:48females aren't necessarily making the
2:06:50same calculation the same way, I have to
2:06:54speculate a bit. One, they have to know
2:06:56male versus female, right? Because males
2:06:59could be a threat. Females could be a
2:07:00threat, too, but males are more often a
2:07:02threat to females than than other other
2:07:04females. Females can be a collaborator,
2:07:07a friend or a threat, maybe a physical
2:07:10threat, but could be a sociological
2:07:13threat. Um, I've observed this. Okay.
2:07:17Um, and so it it makes sense that one of
2:07:22the most fundamental calculations we
2:07:23make as we move through life is batching
2:07:26people into these different
2:07:27compartments. How plastic do you think
2:07:30that process is? Like this sounds like a
2:07:32pretty hardwired thing that is difficult
2:07:34to get people's minds around. I mean,
2:07:36now it would never air, but in the old
2:07:39Saturday Night Live, they had this
2:07:40character Pat, right, which was you was
2:07:43supposed to be neither male nor female
2:07:45or you weren't supposed to be clear on
2:07:47what what Pat was. And that was the
2:07:50whole basis of the the skit. That was
2:07:52the whole basis of the character that
2:07:54was a repeated character on Saturday
2:07:55Night Live. I don't think they're going
2:07:56to reintroduce Pat, but um that
2:08:01character was an interesting experiment
2:08:03at the time because it introduced this
2:08:06kind of um circuit confusion where
2:08:08people didn't quite know where to place
2:08:10Pad that the whole basis of the the
2:08:12script for it was exactly that. So, how
2:08:14do you think about these things? I mean,
2:08:16most circuits in the brain are push
2:08:18pull. They're binary. Mate or fight,
2:08:21right? Eat or don't eat. There isn't a
2:08:24whole lot of middle ground.
2:08:25>> I think it is more nuanced. It is female
2:08:28male but as you pointed out in humans
2:08:30you're going to say okay potential mate
2:08:32potential foe collaborator friend
2:08:34unknown person. So there are other
2:08:37recognitive pathways feeding into your
2:08:40initial binary classification of female
2:08:42or male.
2:08:44>> So it's not a simple go no-go decision
2:08:47in humans. In the mouse world it's
2:08:49simpler at least in the assays that we
2:08:52design. So in the same in the instance I
2:08:54was telling you about if you take the
2:08:56male mouse
2:08:58the sex recognition happens in the first
2:09:0010 15 five to 10 seconds
2:09:02>> just like in humans
2:09:03>> just like in humans it just instantly
2:09:04knows
2:09:05>> if you can make the distinction your
2:09:06brain makes it automatically
2:09:07>> right so first five to 10 seconds right
2:09:10and and that signal of female or male
2:09:12persists for about 90 seconds and it's
2:09:14much larger fecing a female than a male
2:09:18so if we artificially optogenetically
2:09:20activate these cells in the male brain
2:09:22only for 90 seconds
2:09:25and then give him a male.
2:09:27For the next 15 to 20 minutes, he thinks
2:09:29it's a female and he'll try and mate
2:09:31with him. So that
2:09:34recognitive process has induced a state
2:09:36in the male that says it's a female.
2:09:39Although the sensory input that's coming
2:09:41in, the pherommones that are coming in,
2:09:42the size, the way the animal's walking
2:09:44around, all screams male, he thinks it's
2:09:47a female. He tries to mate with him.
2:09:48>> So he's different even though the
2:09:50outside world isn't.
2:09:50>> Right? And if we inactivate these cells,
2:09:52if we silence these cells or if we kill
2:09:54the cells, and again, we're talking of,
2:09:56you know, maybe 2,000 cells. If we kill
2:09:59the cells, he cannot recognize females
2:10:01from males. Typically, he prefers the
2:10:04smell of a female. That preference is
2:10:05gone. And because he can't say that's a
2:10:08male or a female, he neither mates with
2:10:11females nor attacks other males. He will
2:10:14interact with them. He'll hang out with
2:10:15them. He'll be pretty chill. He simply
2:10:17won't mate or fight with them. Right? So
2:10:20that that says that there are some
2:10:23hardwired things
2:10:26in the mouse brain at least right where
2:10:28you can sort of convert those with
2:10:31experiments into yes go no go signals
2:10:34but I imagine if you set up more
2:10:36complicated assays where if the other
2:10:38male is a sibling
2:10:40then you won't attack the male but you
2:10:43won't mate with them either as long as
2:10:44you don't sort of touch the neurons
2:10:47right so right now we're just trying to
2:10:49understand the basic decision decisions
2:10:50these cells are making the basic sort of
2:10:52information they're processing and that
2:10:55seems to be you know go no-go mate don't
2:10:57mate fight
2:11:00seems you want context to matter but not
2:11:04when survival and reproduction are
2:11:07critical I like watching nature shows
2:11:09for a variety of reasons but there's an
2:11:11incredible one where these hyenas are
2:11:13attacking a lion and they're trying to
2:11:14rip off its testicles it's pretty
2:11:16convenient way to limit lion numbers
2:11:20as long as they're going to kill this
2:11:21lion and eat it. But even if they don't
2:11:24succeed in that, they try and castrate
2:11:26the animal. And another male lion shows
2:11:29up. And it's really interesting because
2:11:30typically those lions would fight. But
2:11:33in this case, the second male lion is
2:11:35willing to risk his fertility and his
2:11:39life in order to protect the other. So
2:11:40there's this higher order calling,
2:11:42right? It's like suddenly he has a
2:11:44mission that overrides his desire to be
2:11:46the dominant lion. And it's just about
2:11:49preserving lions more generally. That's
2:11:50right.
2:11:51>> Pretty incredible that, you know, as
2:11:53unsophisticated as a lion brain may be,
2:11:57it's able to just completely switch
2:11:59over. And I I raised this because what
2:12:02you're describing and what this nature
2:12:05show
2:12:06reveals is that it's almost like
2:12:10hormones activate circuits activate
2:12:12repertoires of behaviors. that we're
2:12:15sort of a we're sort of a like a
2:12:17repertoire machine as opposed to like
2:12:20just having like switches in the brain
2:12:21which is how we were talking about them
2:12:23earlier.
2:12:23>> It's tempting to think about them as
2:12:24switches but but there that context
2:12:27really matters. context matters and you
2:12:30know people have tinergen for example
2:12:31has proposed that there's a hierarchy of
2:12:33behaviors right so you have mating
2:12:36aggression protection of young or
2:12:38defense from predation so all of those
2:12:40are sort of have nested regulatory
2:12:42structures one imagines as you pointed
2:12:44out with this lion that if you have a
2:12:46different context then a different set
2:12:48of behaviors is sort of you know
2:12:50activated and the same thing's true for
2:12:53you know even aggression right if you
2:12:55take these VMH cells that we've talked
2:12:56about before If you activate them, the
2:12:59animals will attack other males or
2:13:01females for that matter or a glove for
2:13:02that matter. But if you change the
2:13:04context that the animals in, your
2:13:06experimental animals in, and you
2:13:07activate these cells, he may not attack.
2:13:10Because in this case, the context is
2:13:13overriding activation of these cells,
2:13:14and telling him, "No, it might be too
2:13:16dangerous. Do not attack." So if you put
2:13:18him in another resident's cage, in a
2:13:20different animal's cage, so it's no
2:13:21longer his turf, and you activate the
2:13:23cells, he's much less likely to attack
2:13:25now. And then there are these
2:13:27experiments, right, that um females will
2:13:30kill the offspring of other females.
2:13:33Females will kill the offspring of other
2:13:35females,
2:13:36>> right?
2:13:37>> Unless certain conditions are met, like
2:13:39they've already had a litter of their
2:13:41own. They've happily raised that litter
2:13:43>> or they've been hanging out with the
2:13:44other female and her pups for a while.
2:13:47It's worth mentioning because, you know,
2:13:48I'm not trying to equally distribute
2:13:50violence here, but so often we think
2:13:51about, you know, males and violence, but
2:13:54maternal aggression is one of the most
2:13:56robust things one will ever observe.
2:13:59>> But female female aggression does exist
2:14:01and it usually exists in the context of
2:14:03of who gets to have and raise successful
2:14:05offspring.
2:14:06>> That's when you see real nastiness
2:14:09emerge. Yeah. Which is, you know, in in
2:14:12the context of sexual behavior. um we're
2:14:15yet to get this guest on here, but
2:14:16there's someone out there that studies
2:14:18female sexual behavior in an interesting
2:14:20way in terms somewhat evolutionary
2:14:21terms, but was saying that um you know,
2:14:24one of the more pronounced effects that
2:14:27you see is uh depending on whether or
2:14:30not someone has had and raised children,
2:14:33how they behave towards um other women.
2:14:38um or the more salient experiment and I
2:14:40need to verify this is actually true
2:14:42that um when apparently there's a study
2:14:46where um they sort of scale the level of
2:14:49attractiveness of women coming in for
2:14:51their to get a haircut from another
2:14:53heterosexual woman. And the more
2:14:55attractive a woman is who comes in to
2:14:57get her haircut, the more hair the uh
2:15:00the haired stylist, the female hair
2:15:02stylist cuts off. almost as if there's a
2:15:05competition and they're trying to
2:15:06actually damage the competition.
2:15:09>> And then other examples where the whole
2:15:12notion of women shaming other women for
2:15:14being promiscuous, the the notion being,
2:15:17well, if men can get sex without having
2:15:19to invest much, then that will change
2:15:22the standard of what men expect and will
2:15:25make it less likely that they'll be able
2:15:27to find a, you know, a safe, happy mate
2:15:31situation to raise kids. I mean, these
2:15:33are the the ideas that spin in the
2:15:35background and you kind of go, "Okay,
2:15:37well, that's a just so story. I probably
2:15:38could explain those data five different
2:15:40other ways." But then you hear the
2:15:42animal data and you go, "Wow, a lot of
2:15:44this is really about extension and
2:15:46preservation of our species, you know."
2:15:49Um, all right, more questions.
2:15:52This is interesting given our earlier
2:15:54discussion of periqueductal gray and its
2:15:56involvement in sexual behavior and in
2:15:59pain management. Is there a difference
2:16:02in the way that males and females
2:16:05experience and attempt to relieve pain?
2:16:07Do do we know anything about the
2:16:08interaction between hormones and pain
2:16:11management um as it relates to males and
2:16:14females?
2:16:15>> There are a lot of reports saying that
2:16:16males and females have different pain
2:16:18thresholds. But I think it's been really
2:16:20challenging to dissect out where those
2:16:22differences arise from. I mean that's
2:16:24all I have to say. So I don't know much
2:16:26about this
2:16:26>> because people will say because of the
2:16:28pain of childbirth that women have a
2:16:30higher pain threshold and that's been
2:16:32revealed in some studies at least to my
2:16:34knowledge
2:16:35>> but that could also be because they're
2:16:36in a different hormonal state they're
2:16:38having a baby you know so
2:16:41>> a lot of natural endorphins released
2:16:42>> presumably yeah
2:16:44>> there were a lot of questions about
2:16:46environmental toxins in food in water
2:16:50um you know some of this gets to the
2:16:54atris
2:16:55data from Tyrone Hayes from Berkeley
2:16:57years ago said that atrizine present in
2:17:00the water and uh that frogs were being
2:17:03exposed to was um causing an inversion
2:17:06of sexual behavior in these frogs and
2:17:08disrupting sexual differentiation. That
2:17:10was you know taken and run with in a
2:17:12variety of directions. Some accurate,
2:17:13some far from accurate. But I think
2:17:15nowadays people are very concerned about
2:17:18endocrine disruptors
2:17:20>> especially during pregnancy and in early
2:17:22childhood. And a lot of people are
2:17:24speculating as to whether or not this is
2:17:26one reason that there's a fair amount of
2:17:30discussion about confusion about gender
2:17:32identity and and sexual differentiation.
2:17:34What are your thoughts on this? Is it
2:17:36conceivable that things in food in the
2:17:38environment which act as endocrine
2:17:40disruptors are smearing some of the uh
2:17:45previously clearer outcomes for human
2:17:48fetuses? I think you have to ingest
2:17:51large amounts of these hormones at the
2:17:53right time
2:17:55>> to or these modifiers, these modulators
2:17:57to have an effect. So I don't know what
2:17:59the kinds of exposures there are, you
2:18:02know, with plastic bottles and whatnot.
2:18:04I mean maybe, but it's you'd have to
2:18:06have a large exposure. That's not to say
2:18:08it doesn't happen. There might be
2:18:10species in which it's really sensitive.
2:18:12So it could happen.
2:18:14>> Here's one thing I know for sure. Our
2:18:15former friend and colleague Ben Barers,
2:18:19right, who was born Barbara Baris was an
2:18:22identical twin, has an identical twin
2:18:24sister that is perfectly happy being a
2:18:27woman. Ben was definitely not happy
2:18:30being a woman from an early age.
2:18:32Switched to being Ben.
2:18:35And for a long time, and I know this
2:18:36because he told me directly, but it's
2:18:39been documented, he claimed that his
2:18:42mother was treated with an
2:18:43anti-miscarriage drug that had
2:18:46androgenic protestosterone properties.
2:18:49And he thought that perhaps that had an
2:18:51impact on his um gender preference,
2:18:56which is interesting, right? Because
2:18:57he's speaking to hormonal influence on
2:19:00gender preference. That at least his
2:19:02idea
2:19:03>> gender identity,
2:19:04>> right? Right. And he he can't know, but
2:19:06he was an MD and a PhD and he was
2:19:08thoughtful about the biology of sex
2:19:10differentiation obviously. So it's
2:19:12conceivable, right? He passed away in
2:19:142017. Um so I can't get his thoughts on
2:19:16this now, but you know, he was pretty
2:19:19vocal about the fact that he thought
2:19:20that there were things that medications
2:19:22and other things that could certainly
2:19:25impact um gender identity.
2:19:28>> What you're referring to was a pretty
2:19:29powerful hormonal modulator that he was
2:19:32exposed to. Right. So that is a very
2:19:34different dosage
2:19:36>> than you know you might presumably get
2:19:38from these days from environmental you
2:19:40know plastics with modulators that could
2:19:43impact hormone signaling. That's a
2:19:46pharmacological dose
2:19:47>> he was presumably exposed to
2:19:49>> right and I think that's a big question
2:19:51nowadays to what extent these endocrine
2:19:53disruptors are impacting the fetus. I
2:19:55mean it has been shown that
2:19:56microplastics are present in the first
2:20:00fecal matter that a baby you know
2:20:02excretes.
2:20:03>> Um whether or not those microplastics
2:20:05are effective endocrine disruptors in
2:20:07the sense that they are causing um
2:20:09androgen disruption or estrogen
2:20:11disruption um isn't clear. Um lots to
2:20:15consider. I mean that there are so many
2:20:17conflicting data. You know it's it's
2:20:19easy to paint a picture where it's all
2:20:20about endocrine disruptors pushing
2:20:21things one way or the other. Our
2:20:23colleague Mike Eisenberg has done
2:20:24studies showing that indeed testosterone
2:20:26levels and sperm counts are dropping,
2:20:28but according to data from his lab,
2:20:30penis sizes are going up. So, you know,
2:20:33it's the data don't always fall squarely
2:20:35into a like a a news article type
2:20:39>> um framework, you know, and and
2:20:42typically news articles on the stuff
2:20:44pick one or the other side to push for.
2:20:47What do you want to know most going
2:20:49forward about how uh sex differences in
2:20:52the brain come about? Like what are you
2:20:54most excited about lately?
2:20:56>> There are many questions, right? One is
2:20:59we still don't have the identity of all
2:21:02the different social behaviors that
2:21:03animals engage in that mice engage in
2:21:05the innate behaviors, right? So we what
2:21:08what are these circuits? How do they
2:21:10interact with each other? So if you're
2:21:11mating, how do you assess threats and
2:21:15stop mating for example? Right? So
2:21:17that's one level of questions. What are
2:21:18the circuits and how do they interact
2:21:20with each other? And at the same time,
2:21:23how are they interacting with higher
2:21:26order circuits that you know let you
2:21:29navigate, let you make decisions? What
2:21:31is interaction between cortical cells
2:21:33and hypothalamic cells? So that's a big
2:21:34question. I think the other is this
2:21:37thing this plasticity this adult dynamic
2:21:40circuit feature that we and others have
2:21:42run into in the female brain. How
2:21:43widespread is it in the brain? Do males
2:21:46also have such dynamic plasticity in the
2:21:49adult animal? We don't know. And if so,
2:21:52what what are the conditions in which
2:21:54the male brain rewires?
2:21:57And you know females undergo different
2:21:59as we've talked about undergo many
2:22:01different life stages that are pretty
2:22:04unique to females right lactation's one
2:22:05of them menopause is another pregnancy
2:22:07is another ovulation's another so how
2:22:09are these circuits different across
2:22:12these stages compared to say the female
2:22:14who's not gone through any of those yet?
2:22:16>> Those are very interesting questions
2:22:18especially given the divergence of uh of
2:22:21life choices that you see out there now.
2:22:23Not everyone is getting married, having
2:22:25kids, and um and doing that. I mean,
2:22:28many people still are, but I my
2:22:29understanding is birth rates are going
2:22:31way down. Um so certainly some people
2:22:33are opting out or for whatever reason
2:22:35aren't having kids.
2:22:38Nural, thank you so much for coming here
2:22:41today, for sharing with us all your
2:22:43incredible knowledge and experiments. Uh
2:22:46for me it was especially um gratifying
2:22:49because I think these topics are not
2:22:51just timely but they're it's fundamental
2:22:54to who we are. I mean as you pointed out
2:22:58perhaps one of the most important
2:22:59distinctions that we make in life is
2:23:01determining like who we are and who
2:23:02others are as we and the male female
2:23:05distinction is uh is a critical one that
2:23:08you know arises at least as early as
2:23:12conception in terms of the the the
2:23:14chromosomes are involved and then the
2:23:17hormones are acting on that of course.
2:23:18So want to thank you for the the work
2:23:20you're doing. You do really hard
2:23:22experiments. You do beautiful
2:23:24experiments. They're super clean
2:23:26>> and you get really incredible outcomes
2:23:29uh which you've shared with us today.
2:23:31And
2:23:32>> it's also wonderful that you took the
2:23:33time to be a public educator, come here
2:23:36and share with us on this uh set of not
2:23:39trivial topics when it comes to
2:23:41navigating the landscape of sex and
2:23:44gender and hormones and all this stuff.
2:23:46So, you're brave and we appreciate your
2:23:48bravery and uh and then the way you you
2:23:51approach these questions.
2:23:52>> Thanks, Andrew. It's a pleasure being
2:23:53here. Thanks for having me on the show.
2:23:54>> Yeah. Well, we'll have you back again
2:23:56and uh thanks for also being a bulldog
2:23:59owner. I love that you uh bring Cooper
2:24:02>> got that you got Cooper and uh next time
2:24:04bring him. He's an amazing French
2:24:07bulldog and uh you know just makes me
2:24:10appreciate you that much more.
2:24:11>> Thank you, Andrew.
2:24:13>> Thank you for joining me for today's
2:24:14discussion with Dr. Nural Shaw. To learn
2:24:16more about his work, please see the
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2:24:55that haven't heard, I have a new book
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2:24:59It's entitled Protocols, an operating
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2:26:41[Music]

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