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IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake
Progress in Neurobiology ( IF 6.7 ) Pub Date : 2020-11-13 , DOI: 10.1016/j.pneurobio.2020.101952
Reesha R Patel 1 , Sarah A Wolfe 1 , Michal Bajo 1 , Shawn Abeynaike 1 , Amanda Pahng 2 , Vittoria Borgonetti 3 , Shannon D'Ambrosio 1 , Rana Nikzad 1 , Scott Edwards 4 , Silke Paust 1 , Amanda J Roberts 1 , Marisa Roberto 1
Affiliation  

Alcohol elicits a neuroimmune response in the brain contributing to the development and maintenance of alcohol use disorder (AUD). While pro-inflammatory mediators initiate and drive the neuroimmune response, anti-inflammatory mediators provide an important homeostatic mechanism to limit inflammation and prevent pathological damage. However, our understanding of the role of anti-inflammatory signaling on neuronal physiology in critical addiction-related brain regions and pathological alcohol-dependence induced behaviors is limited, precluding our ability to identify promising therapeutic targets. Here, we hypothesized that chronic alcohol exposure compromises anti-inflammatory signaling in the central amygdala, a brain region implicated in anxiety and addiction, consequently perpetuating a pro-inflammatory state driving aberrant neuronal activity underlying pathological behaviors. We found that alcohol dependence alters the global brain immune landscape increasing IL-10 producing microglia and T-regulatory cells but decreasing local amygdala IL-10 levels. Amygdala IL-10 overexpression decreases anxiety-like behaviors, suggesting its local role in regulating amygdala-mediated behaviors. Mechanistically, amygdala IL-10 signaling through PI3K and p38 MAPK modulates GABA transmission directly at presynaptic terminals and indirectly through alterations in spontaneous firing. Alcohol dependence-induces neuroadaptations in IL-10 signaling leading to an overall IL-10-induced decrease in GABA transmission, which normalizes dependence-induced elevated amygdala GABA transmission. Notably, amygdala IL-10 overexpression abolishes escalation of alcohol intake, a diagnostic criterion of AUD, in dependent mice. This highlights the importance of amygdala IL-10 signaling in modulating neuronal activity and underlying anxiety-like behavior and aberrant alcohol intake, providing a new framework for therapeutic intervention.



中文翻译:

IL-10 使异常杏仁核 GABA 传输正常化并逆转焦虑样行为和依赖引起的酒精摄入量增加

酒精会在大脑中引发神经免疫反应,从而导致酒精使用障碍 (AUD) 的发展和维持。虽然促炎介质启动和驱动神经免疫反应,但抗炎介质提供了一种重要的稳态机制来限制炎症和预防病理损伤。然而,我们对抗炎信号在关键成瘾相关大脑区域和病理性酒精依赖诱导行为中神经元生理学的作用的理解是有限的,这排除了我们识别有希望的治疗靶点的能力。在这里,我们假设慢性酒精暴露会损害中央杏仁核(与焦虑和成瘾有关的大脑区域)的抗炎信号传导,从而使促炎状态持续存在,从而导致病理行为的异常神经元活动。我们发现酒精依赖改变了全球大脑免疫格局,增加了产生 IL-10 的小胶质细胞和 T 调节细胞,但降低了局部杏仁核 IL-10 水平。杏仁核 IL-10 过表达减少了焦虑样行为,表明其在调节杏仁核介导的行为中的局部作用。从机制上讲,杏仁核 IL-10 信号通过 PI3K 和 p38 MAPK 直接在突触前末端调节 GABA 传递,并通过自发放电的改变间接调节。酒精依赖诱导 IL-10 信号传导的神经适应,导致整体 IL-10 诱导的 GABA 传递减少,这使依赖诱导的杏仁核 GABA 传递升高正常化。尤其,杏仁核 IL-10 过表达消除了酒精摄入量的增加,这是 AUD 的诊断标准,在依赖性小鼠中。这突出了杏仁核 IL-10 信号在调节神经元活动和潜在的焦虑样行为和异常酒精摄入中的重要性,为治疗干预提供了新的框架。

更新日期:2020-11-13
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