β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.
β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.
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DOI：
10.1523/jneurosci.0450-11.2011
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发表时间：
2011-04-27
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影响因子：
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通讯作者：
Sheridan JF
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作者：
Wohleb ES;Hanke ML;Corona AW;Powell ND;Stiner LM;Bailey MT;Nelson RJ;Godbout JP;Sheridan JF
心理社会压力与免疫功能改变和包括焦虑和抑郁在内的心理障碍的发展有关。在这里，我们发现，小鼠反复的社交失败增加了与恐惧和威胁评估相关的大脑区域的c-Fos染色，并以β-肾上腺素能受体依赖的方式促进了焦虑样行为。反复的社交失败也显著增加了贩运到大脑的CD 11b +/CD 45 high/Ly 6Chigh巨噬细胞的数量。此外，社交失败后，小胶质细胞（CD 14、CD 86和TLR 4）和巨噬细胞（CD 14和CD 86）表面的几种炎症标志物增加。反复的社交失败也增加了内侧杏仁核、前额叶皮层和海马体中去分支小胶质细胞的存在。此外，小胶质细胞的mRNA分析表明，反复的社会失败增加了白细胞介素（IL）-1β的水平，降低了糖皮质激素反应基因（GILZ和FKBP 51）的水平。β-肾上腺素能受体拮抗剂普萘洛尔可抑制小胶质细胞和巨噬细胞的应激反应。从社交失败的小鼠中分离并离体培养的小胶质细胞在脂多糖（LPS）刺激后产生显著高于对照小鼠的小胶质细胞的IL-6、肿瘤坏死因子（TNF）-α和单核细胞趋化蛋白-1（MCP-1）水平。最后，反复的社交失败增加了IL-1受体1型缺陷（IL-1 r1-/-）小鼠中的c-Fos激活，但在缺乏功能性IL-1受体1型的情况下并没有促进焦虑样行为或小胶质细胞激活。这些发现表明，反复社交失败诱导的焦虑样行为和小胶质细胞反应性的增强依赖于β-肾上腺素能受体和IL-1受体的激活。
Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chigh macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of de-ramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes (GILZ and FKBP51). The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1) after stimulation with lipopolysaccharide (LPS) compared to microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1 deficient (IL-1r1-/-) mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.