Altered actin filament dynamics in theDrosophilamushroom bodies lead to fast acquisition of alcohol consumption preference
| Autor: | Adrian Rothenfluh, Shamsideen A. Ojelade, Collin B. Merrill, Andrew R. Butts, Aylin R. Rodan, Alexandra Seguin |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Mechanism (biology) RAC1 macromolecular substances Alcohol use disorder GTPase Cofilin Biology medicine.disease Actin cytoskeleton Cell biology 03 medical and health sciences 0302 clinical medicine Mushroom bodies medicine 030217 neurology & neurosurgery Actin 030304 developmental biology |
| DOI: | 10.1101/623991 |
| Popis: | 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 thatDrosophilalacking 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 inDrosophila.Significance 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. |
| Databáze: | OpenAIRE |
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