Perched in the corner of Ulrike Heberlein’s office is a four-foot-tall glass column crisscrossed with slanted platforms. It’s a fruit fly inebriometer. Although a relic now, Heberlein used it to gauge how long it takes flies to get drunk. Flies are introduced into the top of the column, which is perfused with ethanol vapor. As the flies become inebriated, they slip from the first platform to the one below, and then the one below that, and so on, until they pass out and tumble to the bottom.
Heberlein, who became a lab head at HHMI’s Janelia Farm Research Campus in 2012, developed the fruit fly Drosophila melanogaster as a model to study alcoholism. Her experiments are providing insights into the genetics of addiction and connections between environmental factors, such as rejection and stress, and alcohol abuse.
The fruit fly is a surprisingly good model for human alcohol addiction. In nature, flies live on rotting, fermented fruit and have done so for millions of years. “They live, court, mate, and lay their eggs around alcohol,” Heberlein says. “Their progeny grow in this fermenting fruit that can contain up to 5 percent alcohol.” And, more importantly, the tiny creatures exhibit many of the same behaviors after ingesting alcohol that people might display after a few strong drinks. First they become hyperactive, and then they lose coordination and fall over; eventually, they pass out.
Heberlein recently showed that, very much like humans, flies exhibit gender-specific responses to ethanol intoxication. That is, to put it bluntly, female flies get drunk faster than male flies. Part of this is because female flies metabolize ethanol more slowly than males. But another component, as Heberlein and her student Anita Devineni reported December 2012 in the Proceedings of the National Academy of Sciences, involves sex differences in the brain, some of which are controlled by a fly gene named fruitless.
In a typical experiment in her lab, Heberlein’s team creates fruit flies with random genetic mutations and then runs them through a series of tests using tools like the inebriometer and the booz-o-mat to see how they react to alcohol. Heberlein created the booz-o-mat, a series of horizontal glass tubes that measure how fast and straight—or slow and crooked—inebriated flies can walk.
Over the past two decades, Heberlein and her colleagues have identified some 30 genes involved in the fruit fly’s response to alcohol. One mutant gene produced an extremely alcohol-sensitive fly her lab christened cheapdate, and, at the other end of the spectrum, another gene was responsible for a mutant called happyhour, with a higher than average tolerance for alcohol.
Studies detailed in a February 2013 paper in The Journal of Neuroscience showed that a gene called apontic (apt) plays a role in the sedative effects of alcohol. The Apt protein acts on a small subset of neurons that express Corazonin (Crz), a neuropeptide likely involved in the body’s response to stress. The Crz neurons also contain receptors for proteins similar to the mammalian corticotropin-releasing factor (CRF), which has been implicated in stress and drug responses in mammals. CRF is being tested as a potential pharmacologic target in treatment for alcohol dependence.
While teasing out the relevant genes, Heberlein is also exploring environmental factors that play into alcohol abuse. About 50 percent of the risk of alcoholism comes from genetics and the other 50 percent is environmental, experiential, and psychosocial. “We’ve been focusing on this gene part, and in humans it’s very complex, involving various combinations of genes in different people,” she explains. So she decided to look at how experiences affect the fly’s behavior and its genome.
In March 2012, she published a paper in Science showing that male flies whose sexual advances were spurned by females chose alcohol-spiked food in response to their rejection. Heberlein and her colleagues determined that a signaling molecule called neuropeptide F (NPF) was responsible for linking the experience—rejection—to the behavior—drinking. NPF has a homolog in humans called neuropeptide Y, which other labs are now studying as a target for alcoholism therapy.
|Watch male fruit flies turn to alcohol after failed courtship advances.|
Heberlein also plans to investigate the effects of aggression, social isolation, and sleep deprivation on alcohol intake. “I think with flies we can probe these mechanisms more deeply [than in other animal models],” she says. “We can do the molecular biology, biochemistry, anatomy, and genetics to actually prove that a certain gene is changed by experience in particular neurons, which ultimately changes the behavior of the fly.”