Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China.
Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230022, China.
Neuron. 2021 Aug 18;109(16):2573-2589.e9. doi: 10.1016/j.neuron.2021.06.012. Epub 2021 Jul 6.
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 (ACC) 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 ACC neuronal spines. Together, our findings establish that early-life inflammation causes dysregulation of microglial engulfment capacity, which encodes long-lasting maladaptation of ACC neurons to stress, thus promoting development of depression-like symptoms during adolescence.
早期生活中的炎症会增加晚年患抑郁症的风险。在这里，我们展示了早期生活中的炎症如何导致青少年抑郁样症状：通过改变小胶质细胞长期吞噬神经元棘突的能力。对于在出生后第 14 天（P）通过 Toll 样受体 4/NF-κB 信号通路暴露于脂多糖（LPS）诱导的炎症的小鼠，对活体大脑进行的持续纵向成像显示，随后的应激（在 P45 期间的青春期施加）会增加前扣带皮层（ACC）谷氨酸能神经元（ACC）棘突周围小胶质细胞吞噬的程度。当 LPS 处理的小鼠的 ACC 小胶质细胞被删除或化学抑制时，这些小鼠在青春期不会表现出抑郁样行为。此外，我们表明，趋化因子受体 CX3CR1 介导了应激诱导的 ACC 神经元棘突的吞噬作用。总之，我们的研究结果表明，早期生活中的炎症会导致小胶质细胞吞噬能力的失调，从而导致 ACC 神经元对压力的适应不良，从而促进青春期抑郁样症状的发展。
