Ojelade Shamsideen A, Jia Tianye, Rodan Aylin R, Chenyang Tao, Kadrmas Julie L, Cattrell Anna, Ruggeri Barbara, Charoen Pimphen, Lemaitre Hervé, Banaschewski Tobias, Büchel Christian, Bokde Arun L W, Carvalho Fabiana, Conrod Patricia J, Flor Herta, Frouin Vincent, Gallinat Jürgen, Garavan Hugh, Gowland Penny A, Heinz Andreas, Ittermann Bernd, Lathrop Mark, Lubbe Steven, Martinot Jean-Luc, Paus Tomás, Smolka Michael N, Spanagel Rainer, O'Reilly Paul F, Laitinen Jaana, Veijola Juha M, Feng Jianfeng, Desrivières Sylvane, Jarvelin Marjo-Riitta, Schumann Gunter, Rothenfluh Adrian
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Program in Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390;
Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; Medical Research Council (MRC) Social, Genetic and Developmental Psychiatry Centre, London SE5 8AF, United Kingdom;
Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4085-93. doi: 10.1073/pnas.1417222112. Epub 2015 Jul 13.
Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.
酒精滥用非常普遍，但对其分子成因却知之甚少。在此，我们报告称Ras抑制因子1（Rsu1）会影响果蝇和人类的乙醇摄入量。缺乏Rsu1的果蝇对乙醇诱导的镇静作用敏感性降低。我们发现，成体神经系统中的Rsu1对于正常敏感性是必需的，并且它在整合素细胞粘附分子下游以及Ras相关的C3肉毒杆菌毒素底物1（Rac1）GTP酶上游发挥作用，以调节肌动蛋白细胞骨架。在乙醇偏好试验中，Rsu1的整体缺失会导致较高的初始偏好。相比之下，仅在大脑蘑菇体中缺乏Rsu1的果蝇表现出正常的初始偏好，但随后无法像正常果蝇那样获得乙醇偏好。因此，Rsu1在不同神经元中是调节初始和获得性乙醇偏好所必需的。在人类中，我们发现RSU1的多态性与青少年奖励预期期间腹侧纹状体的大脑激活以及青少年和成年人的酒精消费有关。总之，这些数据表明整合素/Rsu1/Rac1/肌动蛋白信号在调节跨门类与奖励相关的表型（包括乙醇消费）中具有保守作用。
