Genetics of Alcohol Abuse – from Flies to Humans

In an unbiased screen, the lab directed by Adrian Rothenfluh, PhD, isolated flies lacking a certain gene (Rsu1) that produces a strong liking for alcohol, even before repeated exposure. Their investigations in Drosophila showed that Rsu1 and downstream signaling molecules regulate actin dynamics; genetic manipulations that increase actin filament turnover lead to accelerated development of alcohol preference, while manipulations that increase actin filament stability abolish the development of preference. Continue reading → Genetics of Alcohol Abuse – from Flies to Humans

Research Statement

Modeling Addiction and other Neuropsychiatric Illnesses in Drosophila

Alcohol Aversion and Preference 

People at risk for abuse are more sensitive to the rewarding effects of alcohol, and/or less sensitive to its aversive, intoxicating effects. How these opposing responses are mediated at the molecular and circuit level is not well understood. We use the vinegar fly, Drosophilamelanogaster, to elucidate these mechanisms. Just like mammals, naïve flies avoid drinking alcohol, but with prior experience, such as a defined alcohol pre-exposure, this aversion turns into experience-dependent preference. We have isolated numerous genes and neural circuits, which mediate alcohol aversion and preference. Many mechanisms we investigate are centered around signaling mechanisms involving small GTPases, like the ones mediating dynamic regulation of the actin cytoskeleton (Rho-family), or membrane trafficking (Arf6, Rab). For some of these, we have found significant associations between their human variants and alcohol drinking. Our insights thus illuminate the molecular mechanism of human addiction too.

Other Behaviors

We also investigate other behaviors, using novel behavioral assays, neurogenetic approaches, and hi-throughput analysis. We complement these with experiments in cell biology, biochemistry, and molecular biology, including genome editing using CRISPR mutagenesis and recombineering. Some of the questions we are asking are: Does being under the influence affect decision making? How can we get Drosophila to like cocaine? And what are the interactions of drugs with sleep and arousal?