Merrill, C. B. | bioRxiv Science

bioRxiv2019

Dopaminergic learning and arousal circuits mediate opposing effects on alcohol consumption in Drosophila

The response to drugs of abuse is a combination of aversive and reinforcing reactions. While much is known about the role of dopamine in mammalian drug reinforcement, we know little about the brain circuits mediating drug aversion. Here we show that two distinct dopaminergic circuits mediate reinforcing and acute aversive responses to alcohol consumption in Drosophila. Protocerebral anterior medial dopamine neurons projecting to the mushroom bodies are required for flies to acquire alcohol preference. Conversely, a bilateral pair of dopamine neurons projecting to the dorsal fan-shaped body (dFSB) mediates acute alcohol avoidance. Alcohol consumption can be reduced by decreasing the activity of the appetitive reinforcement-circuit to the mushroom bodies, or by increasing activity in the dopamine neurons projecting to the dFSB. Thus, distinct dopaminergic pathways can be targeted to reduce the intake of harmful drugs.

neuroscience↗

bioRxiv2019

Altered actin filament dynamics in the Drosophila mushroom bodies lead to fast acquisition of alcohol consumption preference.

Alcohol use is highly prevalent in the United States and across the world, and every year millions of people suffer from alcohol use disorders (AUDs). While the genetic contribution to developing AUDs is estimated to be 50-60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our lab revealed that Drosophila lacking RhoGAP18B and Ras Suppressor 1 (Rsu1) display reduced sensitivity to ethanol-induced sedation. Both Rsu1 and RhoGAP18B are negative regulators of the small Rho-family GTPase, Rac1, a modulator of actin dynamics. Here we investigate the role of Rac1 and its downstream target, the actin-severing protein cofilin, in alcohol consumption preference. We show that these two regulators of actin dynamics can alter experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MB) abolishes experience-dependent alcohol preference. Conversely, dominant-negative Rac1 or activated cofilin MB expression lead to faster acquisition of alcohol preference. Our data show that Rac1 and cofilin activity are key to determining the rate of acquisition of alcohol preference, revealing a critical role of actin dynamics regulation in the development of voluntary self-administration in Drosophila.\n\nSignificance StatementThe risks for developing an alcohol use disorder (AUD) are strongly determined by genetic factors. Understanding the genes and molecular mechanisms that contribute to that risk is therefore a necessary first step for the development of targeted therapeutic intervention. Here we show that regulators of actin cytoskeleton dynamics can bidirectionally determine the acquisition rate of alcohol self-administration, highlighting this process as a key mechanism contributing to the risk of AUD development.

neuroscience↗