Sex in the Brain: Genes, Hormones, and Evolution

The fact that men and women tend to behave differently is so widely accepted that it’s become a cliche. The subject of hundreds of relationship books and self-help seminars. The constant butt of lame jokes in second tier Sunday cartoons.

So, what makes men and women behave differently anyway?

Brain-gender-slide

There are about a million of these cartoons on Google image. (credit: U. Habel via Elsevier)

Or perhaps you’re first wondering, are there actually innate, biological differences in the behavior of men and women? Maybe sex differences are merely a product of cultural and societal norms?

Well, for us humans you have a point—it’s super tricky to separate biology from culture. And society certainly does reinforce gender stereotypes that may not have any biological basis.

But for other animals, it’s clear that there are indeed certain biological differences in the behavior of males and females. Let’s start by considering why these differences exist in the first place.

Evolution drives sex differences in behavior

Across most of the animal kingdom, females are the ones who have the babies. Males, on the other hand, usually just contribute their sperm and go along their merry way. This fundamental asymmetry in reproductive biology drives the evolution of sex differences in behavior. Each sex has evolved behavioral responses that maximize its ability to pass on its genes, i.e. to have kids that are healthy enough to survive and reproduce. But because males and females have different roles in reproduction, evolution favors different behaviors in each sex.

Grizzly_Bear maternal behavior

grizzly bear mother guiding her cubs (Denali NPS via Wikimedia Commons)

Let’s first consider females. Females can only pop out so many babies in their lifetime, and each one is a lot of work: it requires carrying a fetus or producing an egg filled with nutrients. Because a female invests so much energy into producing offspring, it makes sense that she’d want to take care of the babies after they’re born to make sure they don’t immediately starve to death or get eaten by a predator. Babies are kind of stupid, you know.

So females of many species have evolved innate behaviors related to caring for their offspring, such as feeding, grooming, and protecting them. Additionally, females are pretty choosy in selecting their mates, which makes sense: they want a baby daddy with good genes (which can be assessed in a variety of ways) to ensure that their precious child will also have good enough genes to survive in this cruel world.

By contrast, males can afford to be less choosy in who they mate with, since they’re not the ones who get stuck with the kid. It’s advantageous for them to maximize quantity over quality: have a bunch of offspring with a bunch of females, and hope that some of the kids do ok. That’s why, across many species, males have evolved to be the sex-crazed ones trying to pick up chicks 24/7, while the gals sit around playing hard to get. Intense competition for females can also promote the evolution of aggressive behavior in males.

Fighting_Hartebeest

2 male hartebeest fighting. Aggression is a common male behavior across many species. (F. Lachowski via Wikimedia Commons)

Now even though some of these behaviors may sound familiar to you, I’m not saying that we humans are relegated to dutifully playing out this script like other animals. Yes, we are a product of evolution, which has certainly written some of these sex differences into our DNA. But we are also a product of culture and history and a highly developed brain capable of higher-order cognition, all of which complicate the relationship between our innate tendencies and our actual behavior. So I’m going to leave the topic of human sex differences for another time, and focus now on animal models whose sex differences we can attribute to specific mechanisms in the brain.

The surprising role of estrogen

Behaviors that are sexually dimorphic (a fancy way of saying “different”) must arise from differences in the brain, since the brain controls our behavior. In mammals, these brain differences are regulated by sex hormones. Estrogen and testosterone are the two sex hormones you’ve probably heard of. We’ve known for a long time that the ovaries produce estrogen and the testes produce testosterone. So obviously estrogen is for the ladies and testosterone is for the guys, right?

Nope! Actually, estrogen is the most important hormone for masculinizing the brain, and thus behavior. People just didn’t realize this for a long time because blood samples from males show that their estrogen levels are basically zero, whereas testosterone levels are super high. So what gives?

estrogen and testosterone structure

It turns out that there’s an enzyme in the male brain that converts testosterone to estrogen. So males don’t have any estrogen coursing through their veins, but they have plenty of it in certain parts of their brain where this particular enzyme is hanging out.

Many of the masculinizing effects that scientists originally attributed to testosterone are actually due to estrogen. It’s estrogen that produces permanent changes in the developing male brain to ensure that once they’re grown up, adult males will display male-typical behaviors such as aggression.1

Importantly, estrogen only has these potent effects during a specific period of development. So even though female ovaries also produce estrogen, they don’t start producing much of it until later in development, when it no longer has this masculinizing effect on the brain. But by simply injecting female mice with estrogen during that critical developmental period, you can masculinize their brain and cause them to act like males when they’re older.

Estrogen isn’t just important in the developing brain; it’s also required in adults to directly activate male behaviors. So estrogen promotes male behavior in two ways: by creating masculinized neural circuits during development as well as acting upon those circuits in adulthood.

But wait, adult females have estrogen too! Adult estrogen doesn’t induce male behaviors in females, though. In fact, it’s actually responsible for activating female-related behaviors in females. How is it possible that one molecule can do two totally opposite things?

The difference is whether adult estrogen is acting on a brain that’s been previously masculinized during development. If so, then adult estrogen activates male behaviors; if not, then it activates female behaviors. So the exact same molecule can induce either male or female behaviors depending on what happened months or years in the past. Cool, right?

What about testosterone?

So what’s the deal with testosterone? Is its only purpose in life to be converted into estrogen, or does it actually do anything on its own?

Adult testosterone does turn out to be important for controlling the intensity of male behaviors. Testosterone may not be strictly necessary to get males to fight each other or woo females, but it’s required for amping up these behaviors to a normal level.2 So even if it’s not as important as estrogen for inducing male behaviors, it might be a way for males to control their level of maleness—perhaps amping up male behaviors like aggression at certain times in their life when they need it the most.

Hormone signaling in the brain

Okay, so we’ve talked about how important sex hormones are in controlling male- and female-typical behaviors. But how do these hormones actually work?

Like other signaling molecules, sex hormones like estrogen and testosterone influence the way that cells function (in this case we’re talking about brain cells, called neurons). But sex hormones work in a different way from most other signaling molecules. Most signaling molecules bind to receptors attached to the outside of cells and indirectly affect what’s going on inside the cell. Sex hormones, however, are able to sneak across the cell membrane (the wall that separates the inside from the outside of a cell) and directly influence what’s going on inside.

Not only that, sex hormones can sneak all the way into a cell’s nucleus and mess around with its DNA. It’s thought that these hormones activate certain genes to change how neurons function, which changes how the brain functions, which ultimately determines an animal’s behavior.

A recent study suggests that different genes activated by sex hormones control different aspects of sexually dimorphic behavior, which is pretty cool.3 But in general, we know very little about the genes that are activated by sex hormones and how they actually act in the brain to control behavior.

sex hormones gene modules

Depiction of how sex hormones activate different genes to control different aspects of sexually dimorphic behavior. (from Yang and Shah, 20144)

Sex doesn’t end there

There’s a lot more interesting science about sexually dimorphic behavior that I haven’t talked about, which I’ll try to address in the future. Which neural circuits in the brain control sexually dimorphic behaviors? How do sensory systems determine when an animal should display these behaviors? Why is it that surgically removing part of a mouse’s nose can make females suddenly behave like males?! Yup, sex in the brain is almost as messy—and cool—as the act itself.

 

References:

1. Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda S, Harada N, Shah NM. Estrogen masculinizes neural pathways and sex-specific behaviors. Cell 139:61-72 (2009).

2. Juntti SA, Tollkuhn J, Wu MV, Fraser EJ, Soderborg T, Tan S, Honda S, Harada N, Shah NM. The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors. Neuron 66:260-272 (2010).

3. Xu X, Coats JK, Yang CF, Wang A, Ahmed OM, Alvarado M, Izumi T, Shah NM. Modular genetic control of sexually dimorphic behaviors. Cell 148:596-607 (2012).

4. For further reading, here’s a comprehensive review on how the brain controls sexually dimorphic behavior. It also cites a lot of the older, foundational studies that I didn’t cite here:

Yang CF, Shah NM. Representing sex in the brain, one module at a time. Neuron 82:261-278 (2014).


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