The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
Louisana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, 2400 Canal Street, New Orleans, LA 70119, USA.
Prog Neurobiol. 2021 Apr;199:101952. doi: 10.1016/j.pneurobio.2020.101952. Epub 2020 Nov 13.
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.
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。虽然促炎介质会引发和驱动神经免疫反应，但抗炎介质提供了一种重要的动态平衡机制，以限制炎症和防止病理性损伤。然而，我们对抗炎信号在关键成瘾相关脑区神经元生理学中的作用以及病理性酒精依赖诱导的行为的理解有限，这限制了我们识别有前途的治疗靶点的能力。在这里，我们假设慢性酒精暴露会损害中央杏仁核中的抗炎信号，中央杏仁核是一个与焦虑和成瘾有关的脑区，从而持续产生促炎状态，驱动病理性行为下异常的神经元活动。我们发现，酒精依赖会改变大脑的整体免疫景观，增加产生 IL-10 的小胶质细胞和 T 调节细胞，但降低局部杏仁核中的 IL-10 水平。杏仁核中 IL-10 的过表达会减少焦虑样行为，这表明其在调节杏仁核介导的行为方面具有局部作用。从机制上讲，杏仁核中通过 PI3K 和 p38 MAPK 传递的 IL-10 信号调节 GABA 传递，直接作用于突触前末端，间接作用于自发放电的改变。酒精依赖会导致 IL-10 信号的神经适应性改变，导致 GABA 传递的整体 IL-10 诱导减少，从而使依赖诱导的杏仁核 GABA 传递正常化。值得注意的是，杏仁核中 IL-10 的过表达消除了依赖小鼠中酒精摄入量增加的现象，而酒精摄入量增加是 AUD 的一个诊断标准。这凸显了杏仁核 IL-10 信号在调节神经元活动以及焦虑样行为和异常酒精摄入中的重要性，为治疗干预提供了一个新的框架。
