With a pulse of light, Dayu Lin from New York University can turn docile mice into violent fighters – it’s Dr Jekyll’s potion, delivered via fibre optic cable. The light activates a group of neurons in the mouse’s brain that are involved in aggressive behaviour. As a result, the mouse attacks other males, females, and even inanimate objects.
Lin focused on a primitive part of the brain called the hypothalamus that keeps our basic bodily functions ticking over. It lords over body temperature, hunger, thirst, sleep and more. In particular, Lin found that a small part of this area – the ventrolateral ventromedial hypothalamus (VMHvl) – acts as a hub for both sex and violence.
Many of the neurons in the VMHvl fire only when male mice act belligerently, while others fire during sex. The two groups of neurons even compete with one another – some of the violence cells are suppressed while the sexual ones are busy.
Lin’s work follows on the back of many studies going back to the 1920s. For example, in 1955, Walter Rudolf Hess and Konrad Akert managed to make cats more aggressive at the flick of a switch, by stimulating their hypothalamus with electricity. Until now, no one had managed to do the same in rats. However, some scientists had shown that the VMHvl was clearly involved, since it lit up with active genes during aggressive encounters.
A mouse’s VMHvl is much smaller than a cat’s and it’s very difficult to stimulate it accurately using electrodes. Instead, Lin turned to a more sophisticated technique that uses beams of light to control the behaviour of cells and animals. It’s called optogenetics and it is already revolutionising the world of biology. Last year, Nature rightly named it as the Method of the Year.
Lin loaded neurons the VMHvl with a light-sensitive protein called channelrhodopsin-2 (Chr2), taken from algae. When light hits the transplanted proteins, they allow ions to stream into the neurons, which makes them fire. Lin loaded a virus with Chr2 proteins, which it would transfer into any cell it infected. By injecting the virus directly into the VMHvl, she ensured that only neurons in this tight area would fire on demand.
If the mice were alone, nothing happened when Lin shone a light onto their brains. But if they had company, it was a different story. A flash of light, and the mice transformed from Jekylls into Hydes. They rapidly attacked other mice, whether male, female or anaesthetised. They would even assail an inflated glove.
There was only one way of preventing these violent urges – sex. If the males were actually mounting a female, the bursts of light had little effect. Once they had ejaculated, they went back to being easily provoked. These experiments clearly showed that the act of sex suppresses neurons in the brains of mice that trigger aggression.
Lin backed up his optogenetic results with several other experiments. She managed to track active neurons in the brains of mice by watching the activity of a gene called c-fos, which is switched on when neurons fire. By exposed male mice to other males and females, Lin found an overlap between the fighter and lover parts their brains. Some cells were active during bouts of violence and others during sex. Around a quarter of the cells in the VMHvl were active during both.
Lin also recorded the activity of individual neurons in the VMHvl, and found that half the cells initially responded to both male and female mice. But many of these only continued firing during either fighting or sex. Around 40% of the VMHvl neurons fired when in the presence of another male, and half of these really started buzzing when the mouse attacked. And most of these violence neurons were actively silenced during sex (the opposite wasn’t true; Lin found several sex-specific neurons that weren’t switched off during fights).
Finally, Lin showed that she could curb the rodents’ violent streaks by silencing their VMHvl. She infected mice with a virus carrying a different protein, one that stops neurons from firing instead of encouraging them. With their VMHvl gagged in this way, a quarter of the mice that normally attack other males stayed calm and peaceful.
Lin’s results show that a small cluster of neurons within the VMHvl act as a nexus for aggression. They’re necessary – stimulate them and mice turn on their neighbours. And they’re sufficient – gag them, and hostility never happens.
In a related editorial, Clifford Saper from Harvard Medical School takes Lin’s discovery into an evocative flight of fancy. He wonders if, in the future, you could load the VMHvl of sex offenders and violent criminals with proteins that can be triggered by light or drugs. But such applications (and the ethical issues that surround them) are a long way off. For the moment, there are plenty of unanswered questions.
For a start, what happens in the brains of female mice? This study only looked at males, but Lin’s busily working on the opposite sex too. She notes that there are differences in the size and shape of the VMHvl in male and female mice. Do the same circuits govern aggressive behaviour in males and females? If males are more aggressive than females (as is the case for humans), is this difference to do with the strength of the VMHvl circuits, or does it lie in entirely different connections? Lin’s experiments could provide us with an answer, literally shining a light onto the seat of aggressive behaviour.
PS Some readers might be a bit squeamish about the thought of inducing aggressive behaviour with a cable to the brain. It’s worth pointing out that nature isn’t particularly kind on this front either. Tomorrow, you’ll see an example of a Jekyll-and-Hyde potion that’s entirely natural…
Reference: Lin, Boyle, Dollar, Lee, Lein, Perona & Anderson. 2011. Functional identification of an aggression locus in the mouse hypothalamus. http://dx.doi.org/10.1038/nature09736