College of Medicine, Ajman University, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
Division of Biochemistry, Department of Medicine, University of Fribourg, CH-1700, Fribourg, Switzerland.
Physiol Behav. 2022 Oct 1;254:113894. doi: 10.1016/j.physbeh.2022.113894. Epub 2022 Jun 25.
CD81, a member of the tetraspanin family, plays important roles in many physiological processes, such as cell motility, attachment, and entry. Yet, CD81 functions in the brain remain unclear. In this study, we investigated the effects of CD81 knockdown, using lentiviral vectors (LV), on anxiety- and ethanol-related behaviors. For this purpose, mice were stereotaxically injected with CD81 shRNA-expressing LV into the nucleus accumbens (Nacc) and were assessed for anxiety-like behavior using the elevated plus maze (EPM) and open field (OF) tests. Alcohol's sedative effects were studied using loss-of-righting-reflex (LORR) and voluntary ethanol intake was assessed using a two-bottle choice (TBC) procedure. Results showed that mice depleted of CD81 exhibited an anxiolytic-like response in the EPM and OF tests with no effect on locomotor activity. In addition, genetic reduction of CD81 in the Nacc increased mice' sensitivity to alcohol's sedative effects in the LORR test, although plasma alcohol concentrations were unaffected. Interestingly, CD81 loss-of-function-induced anxiolysis was accompanied by a significant decrease in ethanol, but not saccharin nor quinine, intake in the TBC procedure. Finally, and following CD81 mRNA quantification, Pearson's correlations showed a significant positive relationship between accumbal CD81 mRNA with anxiety and ethanol-related behaviors. Our data indicate that CD81 is implicated in the pathogenesis of anxiety and alcoholism. Indeed the targeted disruption of CD81, with the resultant decrease in CD81 mRNA in the Nacc, converted ethanol-"preferring" mice into ethanol "non-preferring" mice. Collectively, these findings demonstrate that future CD81-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.
CD81 是四跨膜蛋白家族的成员，在许多生理过程中发挥着重要作用，如细胞运动、附着和进入。然而，CD81 在大脑中的功能尚不清楚。在这项研究中，我们使用慢病毒载体（LV）研究了 CD81 敲低对焦虑和乙醇相关行为的影响。为此，我们通过立体定位向伏隔核（Nacc）注射 CD81 shRNA 表达的 LV，并用高架十字迷宫（EPM）和旷场（OF）测试评估焦虑样行为。使用翻正反射丧失（LORR）研究酒精的镇静作用，使用双瓶选择（TBC）程序评估自愿性乙醇摄入。结果表明，CD81 耗竭的小鼠在 EPM 和 OF 测试中表现出抗焦虑样反应，而对运动活动没有影响。此外，Nacc 中 CD81 的遗传减少增加了小鼠对 LORR 测试中酒精镇静作用的敏感性，尽管血浆酒精浓度不受影响。有趣的是，CD81 功能丧失诱导的焦虑缓解伴随着 TBC 程序中乙醇但不是糖精或奎宁摄入的显著减少。最后，进行 CD81 mRNA 定量后，Pearson 相关性分析显示，伏隔核 CD81 mRNA 与焦虑和乙醇相关行为之间存在显著正相关。我们的数据表明，CD81 参与了焦虑症和酒精中毒的发病机制。事实上，CD81 的靶向破坏，导致 Nacc 中 CD81 mRNA 的减少，将乙醇“偏好”小鼠转化为乙醇“非偏好”小鼠。总之，这些发现表明，未来针对 CD81 的药物治疗可能有益于焦虑症和酒精中毒的治疗。
