Altered Actin Filament Dynamics in the Drosophila Mushroom Bodies Lead to Fast Acquisition of Alcohol Consumption Preference
Altered Actin Filament Dynamics in the Drosophila Mushroom Bodies Lead to Fast Acquisition of Alcohol Consumption Preference
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DOI：
10.1523/jneurosci.0973-19.2019
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发表时间：
2019-11-06
影响因子：
5.3
通讯作者：
Rothenfluh, Adrian
中科院分区：
文献类型：
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作者：
Butts, Andrew R.;Ojelade, Shamsideen;Rothenfluh, Adrian
酒精使用在美国乃至全世界都极为普遍，每年有数百万人患有酒精使用障碍（AUDs）。尽管据估计遗传因素对酒精使用障碍形成的贡献率为50 - 60%，但许多潜在的分子机制仍不清楚。我们实验室先前的研究表明，缺乏RhoGAP18B和Ras抑制因子1（Rsu1）的黑腹果蝇对乙醇诱导的镇静作用敏感性降低。Rsu1和RhoGAP18B都是小Rho家族GTP酶Rac1的负调节因子，Rac1是肌动蛋白动力学的调节因子。在此我们研究了Rac1及其下游靶点——肌动蛋白切割蛋白丝切蛋白在酒精摄入偏好中的作用。我们发现这两种肌动蛋白动力学调节因子能够以双向方式改变雄性果蝇依赖经验的酒精偏好：在蘑菇体中表达激活的Rac1或显性负性丝切蛋白会消除依赖经验的酒精偏好。相反，显性负性Rac1或激活的丝切蛋白在蘑菇体中的表达会导致更快地形成酒精偏好。我们的数据表明，Rac1和丝切蛋白的活性是决定酒精偏好获得速率的关键，揭示了肌动蛋白动力学调节在果蝇自主自我给药行为发展中的关键作用。
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). Although the genetic contribution to developing AUDs is estimated to be 50-60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our laboratory revealed that Drosophila melanogaster 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 male experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MBs) 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.