Early life stress impairs synaptic pruning in the developing hippocampus.
Early life stress impairs synaptic pruning in the developing hippocampus.
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DOI：
10.1016/j.bbi.2022.09.014
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发表时间：
2023-01
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--
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在包括人类和啮齿动物在内的多种哺乳动物中，早期生活中的逆境会损害正常的海马功能和连通性。根据“累积模型”，早期逆境的数量可以总结出来，以确定以后发展为精神病理的风险。相反，“维度模型”认为“剥夺”和“威胁”影响不同的发展过程，这些过程不应该被添加到决定临床结果中。在这里，我们在暴露于单一逆境（有限床上（LB））的雄性和雌性小鼠与暴露于多种逆境（不可预测的产后应激（UPS））的小鼠中研究了这些预测，重点关注小胶质细胞介导的发育中的海马突触修剪。暴露于LB和UPS都减少了小胶质细胞的分支，损害了它们在体内和体外吞噬突触物质的能力，并降低了TREM2的表达。异常吞噬活动与CA1锥体神经元脊柱密度增加有关，这在17日龄组中可见，并在29日龄LB和UPS小鼠中持续存在。与UPS相比，LB对小胶质分支和突触吞噬的损害更严重，结果伴随着UPS特异性的与突触修剪相关的几个基因表达的增加。我们认为，尽管LB是一个单一的应激源，但它代表了一种更严重的早期剥夺形式，并且在生命的第二和第三周适当水平的海马刺激是支持正常小胶质分支和突触修剪所必需的。此外，在海马发育的这一关键时期突触修剪受损会导致UPS和LB在以后的生活中出现的海马功能和连通性异常。
Early life adversity impairs normal hippocampal function and connectivity in various mammalian species, including humans and rodents. According to the ‘cumulative model’ the number of early adversities can be summed up to determine the risk for developing psychopathology later in life. In contrast, the ‘dimensional model’ argues that ‘Deprivation’ and ‘Threat’ impact different developmental processes that should not be added in determining clinical outcomes. Here we examine these predictions in male and female mice exposed to a single adversity — limited bedding (LB) — versus mice exposed to multiple adversities — unpredictable postnatal stress (UPS) — focusing on microglia-mediated synaptic pruning in the developing hippocampus. Exposure to both LB and UPS reduced the ramification of microglia, impaired their ability to phagocytose synaptic material in vivo and ex vivo, and decreased expression of TREM2. Abnormal phagocytic activity was associated with increased spine density in CA1 pyramidal neurons that was seen in 17-day-old groups and persisted in peri-pubescent 29-day-old LB and UPS mice. Exposure to LB caused more severe impairment in microglial ramification and synaptic engulfment compared to UPS, outcomes that were accompanied by a UPS-specific increase in the expression of several genes implicated in synaptic pruning. We propose that despite being a single stressor, LB represents a more severe form of early deprivation, and that appropriate levels of hippocampal stimulation during the second and third weeks of life are necessary to support normal microglial ramification and synaptic pruning. Further, impaired synaptic pruning during this critical period of hippocampal development contributes to the abnormal hippocampal function and connectivity seen in UPS and LB later in life.
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影响因子：
32.4
作者：
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通讯作者：
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