Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province, 226001, China.
Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, China.
Neuropharmacology. 2018 Jun;135:223-233. doi: 10.1016/j.neuropharm.2018.03.023. Epub 2018 Mar 21.
Depression triggered by early-life stress has begun to attract wide attention due to its severe symptoms and poor treatment outcomes. However, the pathophysiological mechanism for this type of depression remains unclear. Recently, we and others reported that different types of chronic stress induce a significant loss of hippocampal microglia, which is mediated by an initial activation of these microglia. Since early-life stress also promotes microglial activation, we investigated the dynamic changes in hippocampal microglia in mice suffering from depression induced by early social isolation (ESI). Results showed that 8 days of ESI induced depressive-like behaviors in a tail suspension test, forced swim test, sucrose preference test, and open field test, and it also induced a loss and dystrophy of hippocampal microglia. We found that this ESI-induced loss of hippocampal microglia was mediated by both microglial activation and apoptosis. This was demonstrated by the following results: (i) 1 day of ESI induced an obvious activation of hippocampal microglia followed by their apoptosis, and (ii) the blockade of the initial activation of hippocampal microglia by minocycline pretreatment suppressed the ESI-induced apoptosis and loss as well as ESI-induced depressive-like behavior. Lipopolysaccharide (LPS) and macrophage colony-stimulating factor (M-CSF), two activators of microglia, almost completely reversed ESI-induced depressive-like behavior by promoting microglial proliferation in the hippocampus. These results reveal an etiological role of hippocampal microglial loss in ESI-induced depression and demonstrate that the restoration of microglial homeostasis in the hippocampus may serve as a therapeutic strategy for depression induced by early-life stress.
由于其严重的症状和较差的治疗效果，由早期生活压力引发的抑郁症开始引起广泛关注。然而，这种类型的抑郁症的病理生理机制仍不清楚。最近，我们和其他人报道称，不同类型的慢性应激会导致海马体小胶质细胞的大量丧失，而这种丧失是由小胶质细胞的初始激活所介导的。由于早期生活压力也会促进小胶质细胞的激活，我们研究了在经历早期社交隔离（ESI）诱导的抑郁的小鼠中海马体小胶质细胞的动态变化。结果表明，8 天的 ESI 在悬尾试验、强迫游泳试验、糖水偏好试验和旷场试验中诱导出抑郁样行为，并诱导出海马体小胶质细胞的丧失和萎缩。我们发现，这种 ESI 诱导的海马体小胶质细胞的丧失是由小胶质细胞的激活和凋亡介导的。这可以通过以下结果证明：（i）1 天的 ESI 诱导了海马体小胶质细胞的明显激活，随后发生凋亡；（ii）米诺环素预处理阻断海马体小胶质细胞的初始激活，抑制了 ESI 诱导的凋亡和丧失以及 ESI 诱导的抑郁样行为。脂多糖（LPS）和巨噬细胞集落刺激因子（M-CSF）是小胶质细胞的两种激活剂，通过促进海马体中小胶质细胞的增殖，几乎完全逆转了 ESI 诱导的抑郁样行为。这些结果揭示了海马体小胶质细胞丧失在 ESI 诱导的抑郁症中的病因作用，并表明海马体中小胶质细胞稳态的恢复可能成为治疗早期生活压力引起的抑郁症的一种策略。
