Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines 作者：Peng Cao, Changmao Chen, An Liu, Qinghong Shan, Xia Zhu, Chunhui Jia, Xiaoqi Peng, Mingjun Zhang, Zahra Farzinpour, Wenjie Zhou, Haitao Wang, Jiang-Ning Zhou, Xiaoyuan Song, Liecheng Wang, Wenjuan Tao, Changjian Zheng, Yan Zhang, Yu-Qiang Ding, Zhi Zhang
期刊：Neuron 发表时间：2021/07/06
Early-life inflammation increases the risk for depression in later life. Here, we demonstrate how early-life inflammation causes adolescent depressive-like symptoms: by altering the long-term neuronal spine engulfment capacity of microglia. For mice exposed to lipopolysaccharide (LPS)-induced inflammation via the Toll-like receptor 4/NF-κB signaling pathway at postnatal day (P) 14, ongoing longitudinal imaging of the living brain revealed that later stress (delivered during adolescence on P45) increases the extent of microglial engulfment around anterior cingulate cortex (ACC) glutamatergic neuronal (ACCGlu) spines. When the ACC microglia of LPS-treated mice were deleted or chemically inhibited, the mice did not exhibit depressive-like behaviors during adolescence. Moreover, we show that the fractalkine receptor CX3CR1 mediates stress-induced engulfment of ACCGlu neuronal spines. Together, our findings establish that early-life inflammation causes dysregulation of microglial engulfment capacity, which encodes long-lasting maladaptation of ACCGlu neurons to stress, thus promoting development of depression-like symptoms during adolescence.
科学家们过去就注意到，出生前或儿童时期经历过创伤或病毒感染，会大大增加青春期或成年后出现情绪障碍的可能性，比如患上抑郁症或焦虑症。近日，中国科学家在神经科学领域权威期刊Neuron上发表了一篇研究论文，揭示了背后的发生机制。中国科学技术大学张智教授、晋艳教授与中国科学院徐林教授合作，通过小鼠实验表明，小时候发生炎症为何会促使青少年阶段出现抑郁症状。
研究人员指出，在幼年大脑发育的关键时间如果发生炎症，对脑中的小胶质细胞会产生深远影响，导致其往后在青春期发育过程中更容易被应激事件随机激活。实验中，小鼠出生后不久因为腹腔注射脂多糖（模拟细菌感染）而产生炎症，尽管很快恢复，但当它们到了青春期，一旦遇到压力事件（比如断奶、分笼、噪音、打架等），大脑前扣带皮层（ACC）中的小胶质细胞都会很容易转变为活化状态。小胶质细胞是常驻在脑中的免疫细胞，作用就像清除故障的清洁工。但研究人员发现，当青春期持续出现各种应激事件，ACC的小胶质细胞如果被频繁激活，会过度清除附近谷氨酸能神经元的树突棘，也就是神经细胞用来接收神经信号的装置。于是，小胶质细胞的活化模式改变进一步导致了神经活动的调控，让这些神经元对应激长期适应不良。最终，由于身体应对压力的能力受损，促进了青春期抑郁症状的发生。
研究人员指出，过去对于神经环路的研究主要集中在神经元-神经元之间的作用，然而，大脑中存在巨量的小胶质细胞，这些细胞在病理环境下介导的神经环路可塑性有什么作用及功能，是当前神经科学领域研究的前沿和热点。随着人们对小胶质细胞与抑郁症发生发展的关系有越来越清楚的了解，未来有望带来相应的诊断和治疗方法，让青少年和成年人摆脱抑郁症的困扰。参考资料 [1] Peng Cao et al., (2021) Early-lifeinflammation promotes depressive symptoms in adolescence via microglialengulfment of dendritic spines. Neuron. Doi: https:///10.1016/j.neuron.2021.06.012 [2] Early-life inflammation inducesdepression in adolescence. Retrieved July 19, 2021 from https://www./pub_releases/2021-07/uosa-eii071521.php [3] Neuron | 张智/徐林/晋艳团队在早期炎症诱发青春期抑郁情绪研究领域取得进展Retrieved July19, 2021 from https://biox.ustc.edu.cn/2021/0709/c635a516958/page.htm
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