IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake

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作   者：

Patel, Reesha R.;  Wolfe, Sarah A.;  Bajo, Michal;  Abeynaike, Shawn;  Pahng, Amanda;  Borgonetti, Vittoria;  D'Ambrosio, Shannon;  Nikzad, Rana;  Edwards, Scott;  Paust, Silke;  Roberts, Amanda J.;  Roberto, Marisa; 

作者机构：

Hlth Sci Ctr;  10550 N Torrey Pines Rd;  1901 Perdido St;  Scripps Res Inst;  La Jolla;  Louisana State Univ;  LA 70112 USA;  New Orleans;  CA 92037 USA; 

关键词：

Amygdala;  Alcohol;  Anxiety;  Alcohol drinking;  GABA transmission;  IL-10; 

期刊名称：

Progress in Neurobiology: An International Review Journal

i s s n：

0301-0082

年卷期：

2021 年 199 卷

页   码：

摘   要：

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, antiinflammatory 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 amygdalamediated 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.