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.

中文翻译：

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海马小胶质细胞凋亡触发的下降介导了青春期间歇性酒精暴露引起的小鼠抑郁样行为。

抑郁症-酒精成瘾合并症是一种常见的临床现象。青春期的酒精暴露已显示出可在啮齿动物中诱发抑郁样行为。但是，这种抑郁症的作用机理仍不清楚。先前的研究报道了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下降而触发了抑郁症样症状，这是由小胶质细胞的初始激活介导的。由于酒精还会激活小胶质细胞，因此我们评估了接受青春期间歇性酒精暴露（AIE）的小鼠海马小胶质细胞的动态变化。我们的结果显示，AIE为14天，其后为21天不接受治疗，引起的行为异常，以及小鼠海马小胶质细胞的明显丢失和营养不良。我们发现，这种由AIE诱导的海马小胶质细胞下降是由小胶质细胞激活和凋亡共同介导的，因为（i）酒精暴露1天会诱导海马小胶质细胞明显激活，然后凋亡，并且（ii）阻止海马小胶质细胞的初始激活用美满霉素预处理海马小胶质细胞可抑制AIE诱导的细胞凋亡和海马小胶质细胞丢失以及AIE诱导的抑郁样症状。脂多糖（LPS）是小胶质细胞的经典激活剂，它通过逆转海马小胶质细胞的下降，改善了AIE诱发的抑郁样症状。