Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress
Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress
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慢性不可预测应激引起的抑郁小鼠模型中小胶质细胞刺激的抗抑郁特性
DOI：
10.1016/j.pnpbp.2020.109931
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发表时间：
2020-07-13
影响因子：
5.6
通讯作者：
Huang, Chao
中科院分区：
文献类型：
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作者：
Cai, Zixuan;Ye, Ting;Huang, Chao
海马小胶质细胞减少是抑郁症发病的一个新机制。抑制这种降低可以改善啮齿动物中应激诱导的抑郁样行为。然而，这种治疗策略的性质仍不清楚。我们通过设计一系列行为实验来解决这个问题。结果表明，单次注射脂多糖（LPS）75和100 μg/kg，在给药后5 h对慢性不可预知应激（CUS）小鼠产生明显的抗抑郁作用，而30和50 μg/kg则无此作用。在时间依赖性实验中，单次注射LPS（100 μg/kg）在给药后5和8 h改善了小鼠的抑郁样行为，但在给药后3 h没有改善。单次注射LPS的抗抑郁作用持续至少10天，并在给药后14天消失。第一次注射后14天，第二次注射LPS（100 μg/kg）仍然在慢性应激小鼠中产生抗抑郁作用，这些小鼠在给药后5 h再次显示抑郁样行为。LPS的抗抑郁作用似乎依赖于小胶质细胞，在LPS给药（100 μg/kg）后5 h，海马中小胶质细胞数量和Iba-1 mRNA水平的减少明显逆转，米诺环素（40 mg/kg）或PLX 33297（290 mg/kg）抑制小胶质细胞可阻止LPS在CUS小鼠中的抗抑郁作用。这些结果表明，单次LPS注射在慢性应激小鼠中显示快速和持续的抗抑郁作用，可能是通过刺激海马小胶质细胞。
The decrease of microglia in the hippocampus is a novel mechanism for depression onset. Reversal of this decrease can ameliorate stress-induced depression-like behaviors in rodents. However, the property of this therapeutic strategy remains unclear. We addressed this issue by designing a series of behavioral experiments. Results showed that a single lipopolysaccharide (LPS) injection at the dose of 75 and 100 μg/kg, but not at 30 or 50 μg/kg, produced obvious antidepressant effects in chronic unpredictable stress (CUS) mice at 5 h after the drug administration. In the time-dependent experiment, a single LPS injection (100 μg/kg) ameliorated the CUS-induced depression-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug administration. The antidepressant effect of a single LPS injection persisted at least 10 days and disappeared at 14 days after the drug administration. 14 days after the first injection, a second LPS injection (100 μg/kg) still produced antidepressant effects in chronically-stressed mice who re-displayed depression-like behaviors at 5 h after the drug administration. The antidepressant effect of LPS appears to be dependent on microglia, as at 5 h after LPS administration (100 μg/kg), the CUS-induced decrease in microglial numbers and Iba-1 mRNA levels in the hippocampus was reversed markedly, and inhibition of microglia by minocycline (40 mg/kg) or PLX33297 (290 mg/kg) prevented the antidepressant effect of LPS in CUS mice. These results indicate that a single LPS injection displays rapid and sustained antidepressant effects in chronically stressed mice likely through stimulating hippocampal microglia.