Early life stress perturbs the maturation of microglia in the developing hippocampus.
Early life stress perturbs the maturation of microglia in the developing hippocampus.
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DOI：
10.1016/j.bbi.2016.06.006
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发表时间：
2016-10
影响因子：
15.1
通讯作者：
Kaffman, Arie
中科院分区：
文献类型：
--
作者：
Delpech, Jean-Christophe;Wei, Lan;Hao, Jin;Yu, Xiaoqing;Madore, Charlotte;Butovsky, Oleg;Kaffman, Arie
暴露于虐待或忽视的儿童表现出异常的海马发育，在啮齿动物模型中也有类似的发现。使用短暂的每日分离（BDS），早期生活压力的小鼠模型，我们以前表明，暴露于BDS损害海马功能在成年期和干扰突触成熟，突触修剪，轴突生长和髓鞘在发育中的海马。鉴于小胶质细胞参与这些发育过程，我们测试了BDS是否会损害14天（BDS期间）和28天（BDS后一周）小鼠海马中的小胶质细胞活性。我们发现，BDS的密度增加，改变了14天大的幼崽海马体中的小胶质细胞的形态，这种影响在出生后第28天（PND）不再存在。尽管在PND 28时观察到正常的细胞数量和形态，但使用NanoString免疫小组评估的海马小胶质细胞的分子特征在两个年龄段都发生了改变。我们发现，在正常海马发育期间，小胶质细胞在PND 14和PND 28之间发生了显著变化，包括细胞密度降低，体外吞噬活性降低，以及参与炎症和细胞迁移的基因表达增加。然而，从28天大的BDS小鼠海马收获的小胶质细胞显示出吞噬活性的增加和通常在发育过程中增加的基因表达的减少。启动子分析表明，PU.1，Creb1，Sp1和RelA的转录活性的改变占了正常小胶质细胞发育过程中观察到的大部分转录变化，以及PND 14和PND 28时BDS诱导的大部分变化。这些发现首次证明了早期生活压力使发育中的海马体中的小胶质细胞功能失调，并确定了可能介导这些变化的关键转录因子。
Children exposed to abuse or neglect show abnormal hippocampal development and similar findings have been reported in rodent models. Using brief daily separation (BDS), a mouse model of early life stress, we previously showed that exposure to BDS impairs hippocampal function in adulthood and perturbs synaptic maturation, synaptic pruning, axonal growth and myelination in the developing hippocampus. Given that microglia are involved in these developmental processes, we tested whether BDS impairs microglial activity in the hippocampus of 14 (during BDS) and 28-day old mice (one week after BDS). We found that BDS increased the density and altered the morphology of microglia in the hippocampus of 14-day old pups, effects that were no longer present on postnatal day (PND) 28. Despite the normal cell number and morphology seen at PND28, the molecular signature of hippocampal microglia, assessed using the NanoString immune panel, was altered at both ages. We showed that during normal hippocampal development, microglia undergo significant changes between PND14 and PND28, including reduced cell density, decreased ex vivo phagocytic activity, and an increase in the expression of genes involved in inflammation and cell migration. However, microglia harvested from the hippocampus of 28-day old BDS mice showed an increase in phagocytic activity and reduced expression of genes that normally increase across development. Promoter analysis indicated that alteration in the transcriptional activity of PU.1, Creb1, Sp1, and RelA accounted for most of the transcriptional changes seen during normal microglia development and for most of the BDS-induced changes at PND14 and PND28. These findings are the first to demonstrate that early life stress dysregulates microglial function in the developing hippocampus and to identify key transcription factors that are likely to mediate these changes.
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影响因子：
3.6
作者：
Carrion, Victor G.;Haas, Brian W.;Reiss, Allan L.
通讯作者：
Reiss, Allan L.
影响因子：
5.1
作者：
Garofalo, Roberto
通讯作者：
Garofalo, Roberto
影响因子：
15.1
作者：
Diz-Chaves, Yolanda;Astiz, Mariana;Garcia-Segura, Luis M.
通讯作者：
Garcia-Segura, Luis M.
DOI：
10.1073/pnas.0711961105
发表时间：
2008-04-22
影响因子：
11.1
作者：
Feng, Ru;Desbordes, Sabrina C.;Graf, Thomas
通讯作者：
Graf, Thomas
影响因子：
7.3
作者：
Bellavance MA;Rivest S
通讯作者：
Rivest S