Apoptosis-triggered decline in hippocampal microglia mediates adolescent intermittent alcohol exposure-induced depression-like behaviors in mice
Apoptosis-triggered decline in hippocampal microglia mediates adolescent intermittent alcohol exposure-induced depression-like behaviors in mice
复制标题
细胞凋亡引发的海马小胶质细胞下降介导小鼠青少年间歇性酒精暴露诱发的抑郁样行为
DOI：
10.1016/j.neuropharm.2020.108054
复制
发表时间：
2020-06-15
影响因子：
4.7
通讯作者：
Huang, Chao
中科院分区：
文献类型：
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作者：
Hu, Peili;Wang, Dan;Huang, Chao
抑郁-酒精成瘾合并症是一种常见的临床现象。研究表明，青春期接触酒精会诱发啮齿类动物出现类似抑郁的行为。然而，此类抑郁症的作用机制仍不清楚。先前的研究报道，几种不同类型的压力，例如慢性不可预测的压力和早期的社会孤立，通过诱导海马小胶质细胞衰退而引发小鼠的抑郁样症状，这是由小胶质细胞的初始激活介导的。由于酒精也会激活小胶质细胞，因此我们评估了接受青少年间歇性酒精暴露（AIE）的小鼠海马小胶质细胞的动态变化。我们的结果表明，14 天的 AIE 治疗以及随后 21 天的不治疗期会导致小鼠行为异常以及海马小胶质细胞的显着丧失和营养不良。我们发现，这种 AIE 诱导的海马小胶质细胞下降是由小胶质细胞活化和细胞凋亡介导的，因为（i）酒精暴露 1 天诱导海马小胶质细胞明显活化，随后发生凋亡；（ii）通过米诺环素预处理阻断海马小胶质细胞的初始活化，抑制了 AIE 诱导的海马小胶质细胞凋亡和丧失以及 AIE 诱导的抑郁样症状。脂多糖 (LPS) 是一种经典的小胶质细胞激活剂，通过逆转海马小胶质细胞的衰退来改善 AIE 诱发的抑郁样症状。这些结果揭示了 AIE 诱发抑郁症的可能机制，并证明海马小胶质细胞稳态的恢复可能是治疗酒精摄入和戒酒诱发抑郁症的策略。
Depression-alcohol addiction comorbidity is a common clinical phenomenon. Alcohol exposure in adolescence has been shown to induce depression-like behaviors in rodents. However, the mechanism of action for this type of depression remains unclear. Previous studies have reported that several different types of stress, such as chronic unpredictable stress and early social isolation, trigger depression-like symptoms in mice by inducing hippocampal microglial decline, which is mediated by the initial activation of the microglial cells. Since alcohol also activates microglia, we evaluated the dynamic changes in hippocampal microglia in mice receiving adolescent intermittent alcohol exposure (AIE). Our results showed that 14 days of AIE, followed by 21 days period of no treatment, induced behavioral abnormalities as well as a significant loss and dystrophy of hippocampal microglia in mice. We found that this AIE-induced decline in hippocampal microglia was mediated by both microglial activation and apoptosis, as (i) 1 day of alcohol exposure induced a distinct activation of hippocampal microglia followed by their apoptosis, and (ii) blocking the initial activation of hippocampal microglia by pretreatment with minocycline suppressed the AIE-induced apoptosis and loss of hippocampal microglia as well as the AIE-induced depression-like symptoms. Lipopolysaccharide (LPS), a classical activator of microglia, ameliorated the AIE-induced depression-like symptoms by reversing the decline in the hippocampal microglia. These results reveal a possible mechanism for AIE-induced depression and demonstrate that the restoration of hippocampal microglial homeostasis may be a therapeutic strategy for depression induced by alcohol intake and withdrawal.