Understanding Which Chemicals Promote Aggressive Behavior

It’s rush hour. The subway platform is crowded with commuters anxious to get home.  The train rolls to a stop, the doors open and people start moving toward the cars--only to get shoved aside by others apparently in a bigger hurry, and indifferent to their own rude behavior.  

Scientists don’t understand yet what prompts this kind of aggression in humans. But they may be closer, having recently figured it out in flies. Male flies, specifically Drosophila melanogaster, also known as the vinegar fly, act pretty much the same way toward their fellow flies, the result of an aggression-promoting pheromone, a chemical used to communicate and control behavior.

Scientists at the California Institute of Technology (Caltech) recently identified the pheromone, and they also directly linked it to specific neurons in the fly’s antenna that respond by sending a message to the brain to encourage aggression.

“We know very little about how brains control aggression in humans,” said David Anderson, Caltech’s Seymour Benzer Professor of Biology and a Howard Hughes Medical Institute investigator. “This is a first step in understanding the circuitry in the brain that controls aggressive behavior. The hope is that, possibly, some general principles will emerge on how aggression is hardwired to the brain, and how animals control it.”

This was not the first aggression pheromone to be identified, but it was the first time scientists have identified both the pheromone and the receptor neuron that detects it--and to show that animals use it to control each other’s aggression, the researchers said.

Humans produce some pheromones. Studies, for example, have linked pheromones to how desirable women find men during various times in their menstrual cycle.  But there is no evidence yet of a human aggression pheromone.

“Pheromones should be thought of as private lines of communication between members of a species, without allowing other members of the species to listen in on the conversation,” Anderson said. “Is there a pheromone for aggression in humans? We have no idea. We simply don’t know.”

Liming Wang, a graduate student in Anderson’s lab, discovered that 11-cis-vaccenylacetate (cVA), a pheromone present in the male fly’s cuticle, “robustly promotes aggression in pairs of male flies,” Anderson said.

Aggressive behavior in Drosophila is characterized by brief lunges, when one fly rears up on its hind legs and snaps down with its forelegs on its opponent. When Wang and Anderson added synthetic cVA to an “arena,” the frequency of these lunges increased dramatically.

Building upon earlier work from other laboratories that had identified the receptors for this pheromone, Wang showed that silencing the neurons in the fly’s antenna that contain these specific receptors blocks the ability of synthetic cVA to promote aggression.

The researchers then further tested whether the flies actually could detect the release of this pheromone from other flies--and whether such detection promotes aggression--using two sets of flies.

First, they trapped between 20 and 100 “donor” male flies--so called because they “donated” the volatile pheromones into the surrounding environment--in a tiny cage surrounded by a fine mesh screen. The screen allowed pheromones to escape, but kept the donor flies inside.

The researchers then placed a pair of male “tester” flies on top of the cage and measured the effect the donors had upon them. The testers were close enough to sense the pheromone, but couldn’t reach the donors through the screen.

“The presence of the caged donor flies strongly increased aggression between the tester flies, and this aggression-promoting effect increased with a higher number of donor male flies,” Anderson said.

Furthermore, researchers were able to block the effect of the donor flies on the aggressiveness of the tester flies by inactivating-- in the tester flies’ antennae--the neurons that sense the aggression pheromone. “These experiments suggested that the presence of high densities of male flies in a local environment can indeed promote aggression through their release of cVA and its detection by other flies,” Wang said.

The researchers don’t know if flies produce varying levels of the chemical. This would require measuring levels within individual insects, a test the researchers did not perform. They also didn’t examine whether the donors exhibited aggression among themselves. “They were packed densely together, and there was no easy way to quantify the level of aggression,” Anderson said. “But the donor flies were surely duking it out.”

The researchers suspect the pheromone helps control the population density of male flies in a given environment, such as food. Typically, male flies are drawn to food both to feed and to mate with feeding female flies. If there are too many male flies on the food, the competition could become intense--enough to endanger feeding and mating. Since aggressive flies tend to chase away their competitors, an aggression-promoting pheromone could help manage the fly population on the food. 

The scientists tested this by allowing a small number of flies to compete for a limited supply of food, while genetically manipulating their cVA-receptor neurons, making them hyperactive. The flies with the hyperactive neurons quickly departed, leaving the food behind.

“They fought one another until a dominant fly became ‘king of the hill’ and drove the other flies away,” Anderson said. “In contrast, flies whose genes weren’t manipulated in this way ate happily together, like cows grazing placidly on an alpine meadow.”

The results suggest that the concentration of cVA rises to a level that promotes aggression when there are too many flies, forcing some of them to leave. Their departure then prompts the pheromone to decrease, resulting in less aggression.

“If too many flies get in each other’s way, they start pushing and shoving and fighting, all the time pumping out this pheromone, and some get driven off,” Anderson said. “As they leave, the number of flies goes down, and so does the level of the pheromone. Then there is less pushing and shoving. The population will stabilize. Then the cycle will repeat itself. It’s a universal kind of problem.”

Researchers like using Drosophila for studies because their genes are so similar to human genes, including those that affect nervous system functions. “Molecularly, the flies’ nervous system is very close to us, although it is anatomically much simpler than ours,” Anderson said. “The human brain has 10 million times more neurons than the fly brain does.”

He added:  “Lots of insects show aggression. But Drosophila has something other insects don’t--powerful genetic tools that can turn genes on and off and cells on and off in the brain. That’s what allowed us to detect the pheromone, and see how the flies actually use it to communicate with each other.”

The study, recently published in the online edition of the journal Nature, was funded by the National Science Foundation and the Howard Hughes Medical Institute.

--By Marlene Cimons, NSF

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