Scientists Tinker with Neurons to Turn Lovers into Fighters

It would be nice to know how and why aggression occurs. It would give us better insight into everything from international war to schoolyard bullying. New research in mice suggests that estrogen may be more important than testosterone in modulating aggressive behavior, and that sex and aggression may be intimately connected.

A Caltech research group led by David J. Anderson (who also studies aggression in fruit flies) started by identifying a set of neurons in the hypothalamus of mouse brains that are active during social behaviors. Specifically, those neurons are found in the ventromedial hypothalamus, which means they're near the bottom (ventral) and interior (medial) surfaces of the hypothalamus.

The hypothalamus, which is contained in the brains of all vertebrate species, is involved in a wide variety of functions, from regulating circadian rhythms and thirst to modulating anti-predator defense and parenting behaviors. It's therefore not surprising that the mouse hypothalamus is active during social encounters, both between two males and between males and females.

But rather than be content that this cluster of neurons was affiliated with social behavior the researchers, led by research fellow Hyosang Lee, wanted to see whether there was a direct causal relationship between those brain cells and visible social behavior. After all, one important "unsolved problem in neuroscience," according to Anderson, is how the selection of overt behaviors is encoded in the brain.

Using a technique called optogenetics, the group used pulses of light directed through an electrode implanted in the brains of the mice to activate or inhibit those particular neurons. Indeed, they found that when they artificially activated hypothalamic brain cells, the male mice became more aggressive, even attacking females and toy mice. On the other hand, if they temporarily stopped the activity of those neurons, they could eliminate all aggression, even in the middle of a fight.

When they tried to activate those same cells in the brains of female mice, they weren't able to induce attack-related behaviors, but they did increase "social investigation." It isn't that female mice aren't capable of aggression, or that those cells aren't used for social behaviors in females, just that other cells must be somehow more important for female aggression.

What the researchers identified a cluster of cells directly responsible for aggression in males is interesting to be sure, but what's more interesting is just how those cells work.

For one thing, the neurons – which initiate attack behaviors in males but not females – have specialized receptors for binding to estrogen. While the nuances of the relationship between the hormone estrogen and the neurobiology of those cells are still not entirely understood, the finding adds to a growing pile of evidence that estrogen plays a key role in guiding male aggression.

If that wasn't enough to make you sit up and take notice, the estrogen-sensitive neurons of the male hypothalamus have another curious feature. It's not as if these cells act as an on-off switch, such that when activated they promote aggression, and when inhibited they stop attacks from occurring. Instead, they're more like volume control knobs.

When the researchers used their optogenetic techniques to create a high level of activation, as if they were turning the volume all the way up to 11, the mice launched their attack behaviors. But when they activated those cells only weakly, if the volume knob was set to just 1 or 2 or 3, the males instead initiated mating-related behaviors. By fiddling with the knobs, the researchers could provoke their male mice to mount not just females, but also males, both intact and castrated.

By slowly increasing the strength of neural stimulation, the researchers were even able to switch the behavior of individual mice from sexual mounting to attack! Kissing becomes killing, humping becomes homicide (well, muricide, technically).

There were two important differences between the way these neurons responded to artificial stimulation for aggression and for mating. First, even though the researchers could invoke the males to attempt to mate with other males, the pair never actually proceeded to pelvic thrusting or ejaculation. Second, if the researchers inhibited those cells while male and female mice were already having sex, they didn't stop. That's contrary to the findings for aggression, since the researchers were able to artificially disrupt a fight.

What does it all mean? At the neurobiological level, it tells us that the level of activity in those neurons determines, at least in part, just what sort of social behavior is elicited.

It's easy to run away with endless speculations based on these findings, but it's worth taking a step back. For one thing, this work was done in mice, and there are plenty of reasons to suspect that mice are fairly unreliable as a model species when it comes to gaining better insight into our own. For another, the brain is perhaps the most complicated system in the known universe, and even the simplest behavior is the consequence of dizzying complexity.

Still, the finding further erodes the common views that aggression is controlled primarily by testosterone, and that estrogen is associated with more stereotypically feminine behaviors. Rather, estrogen is important both for males and for females, and is implicated in different types of social behavior. Could the same be true for humans? At least one thing is for certain: neurobiology is simply more complicated than the prevailing assumptions would lead you to believe.

Header image: Rama/Wikimedia Commons.