Fruit Fly Fight Club

Sarah Certel says that tiny fruit flies could provide the key to understanding how brains are capable of producing aggression.

Wired for aggression, fly brains may lead to improved drugs

A still frame from a fruit fly battle videoPeople seem hard-wired for anger, joy and other human emotions. For UM neurobiology professor Sarah Certel, finding out how behavior is wired into the nervous system is the guiding question for her research.

The star of the Certel lab is the simple fruit fly, Drosophila melanogaster. With only about 100,000 neurons in its brain – compared to the human brain that dazzles with as many as 100 billion neurons – the fruit fly offers a surprisingly comparable brain to all vertebrates.

Neurons are the cells that process and transmit chemical and electrical signals in the brain. While the numbers of neurons in the fruit fly are far fewer than ours, their neurons transmit the same chemical signals and function in the same manner as our neurons.

Certel and her team combine watching the behavior of fruit flies with sophisticated manipulation of genes or neurons to visualize how circuits function. The flies multiply rapidly. The behavioral patterns are reproducible. The data is prodigious.

“There are two lessons we hope to learn from our work,” Certel says. “We want to understand the fundamental process by which environmental information gets transferred to the brain, and how we can target second-order neurons to alter one behavior and not another.”

Results from the team’s research will contribute to future studies focused on improving therapeutic drugs for conditions in which aggression is manifested, including schizophrenia, Alzheimer’s disease, attention-deficit disorder, post-traumatic stress disorder,

Parkinson’s disease and depression.Currently, drugs affect an entire category of neurons that regulate many behaviors, including sleep, appetite, mood, movement and aggression. While these drugs may help quell aggressive behavior, they also have side effects like sleepiness or weight gain.

However, if drugs can be designed that only target the neurons within this category that are responsible for aggression, therapies could avoid undesirable side effects.

Certel, who is soft-spoken, serious and measured in her choice of words, is passionate about genetics linked to human behavior. After completing a genetics doctorate at the University of Iowa in 1999, she worked a postdoctoral position at Harvard Medical School in the laboratory of Dr. Edward Kravitz. The Kravitz lab had turned to analyzing the genetic control of aggression in Drosophila at that time. Certel joined the UM faculty in 2010.

The fluorescent colors in this fruit fly image reveal neurotransmitters studied in Sarah Certel’s UM lab. (Image by David Hess-Homeier)Aggression evolved for a purpose in males and females – fighting over turf, mates, food or defending progeny. While that concept is easy to understand, what triggers the behavioral response is difficult to pinpoint, especially if neurobiologists could only study the complex human brain.

The Certel lab’s recent findings, published in the journal PLOS Genetics (May 2014), demonstrate that a specific type of neuron located in the leg of a male fruit fly receives a pheromonal (chemical) signal from another male and sends it to a second group of neurons in the brain called octopamine neurons. The neurons on a fly are critical, as the insect explores its world first with its legs, capturing minute and delicate signals to transmit to the brain. The male identification chemicals signal the circuits to produce aggression.

The role of octopamine neurons is significant. Neurons responsible for aggression reside in this group, along with other neurons that affect other behaviors, from sleep to hunger. Fruit flies have just 100 octopamine neurons. Studying the smaller number of neurons in fruit flies allows the Certel lab to differentiate their behavioral roles more easily.

In the fly lab, Certel and her graduate students, undergraduates and research assistants perform sophisticated, high-tech manipulations of genes and neurons on thousands of flies. The lab brims with boxes of labeled vials of genetically modified flies and bottles of live flies. Incubators keep live flies at the right temperatures and humidity for survival, with a light and dark cycle as well. Fruit flies grow from egg to larvae to pupae and then to adult in about two weeks. An adult fly can live for several weeks.

Members of the lab study videos of daily boxing matches held in a fly-sized arena. The action takes place in a closet-sized “behavior” room, where two video cameras point down at two shallow cups covered with a favorite fruit fly food, which looks like white chocolate but is a yeast substance. In each cup, two males compete over a larger female, as well as for food and space.
The resulting 30-minute videos are analyzed for aggressive and courtship actions. When a male identifies another male, he uses several aggressive behavioral patterns to respond. One such pattern is a lunge, where a male rises up on its back legs, lunges and snaps down on the competitor. He also can raise or elevate his wings to look menacing. Pairs will box, wrestle and strike each other until ones pushes the other off the edge of the cup.

To find out which neurons are important for aggression, “We genetically remove the neurons or silence the neurons we want to test and then analyze the aggression behavior of these male flies by placing the flies in the chamber,” Certel explains. “For each experiment, there are two sets of controls with unaltered flies. The results tell us if the specific neurons we changed are indeed important for male behavior.”

To examine specific neurons and neuronal circuits, members of the Certel lab dissect the tiny fly brains and identify individual or small sets of neurons by illuminating them with a green, florescent jellyfish protein that enables visualization of a neuron’s cell body and elaborate branches. The resulting images show beautiful cobalt-blue colored fly brains with the neurons of interest highlighted in green. Lab members spend hours analyzing images of the brain to determine how neurons in an aggression circuit develop and connect with each other.

To share the remarkable complexity of these tiny insects, Certel helped UM’s spectrUM Discovery Area set up an interactive demonstration area where kids can see what happens when, say, a blind male fruit fly meets a seeing male. They don’t fight, because every cue is important, from visual to touch, taste and sound.

Fruit flies, it turns out, are more than annoying insects that magically appear around rotting fruit in your kitchen, or ho-hum subjects of science classes on basic genetics. Certel hopes that once people appreciate that a fruit fly’s behavior is far from simple, random or boring, they will appreciate that every species – no matter how inconspicuous – is marvelous in its own right and just may contain the answer to big questions.

In this case, the fruit fly may hold the secret to more peace and less fighting in the world.

— By Deborah Richie

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