小柯机器人

美国约翰霍普金斯大学Akira Sawa团队发现，产前免疫应激会削弱小胶质细胞的反应性并损害神经环路。这一研究成果于2022年9月28日在线发表在国际学术期刊《自然》上。

研究人员表明，在小鼠的母体免疫激活（MIA）后，子代的小胶质细胞在整个发育轨迹中具有长期的免疫反应性下降（钝化）。免疫反应迟钝伴随着染色质可及性的变化和开放染色质的转录因子占用率的降低。单细胞RNA测序分析显示，MIA并不诱导一个独特的亚群，而是减少了对炎症小胶质细胞状态的贡献。产前用生理性浸润的初始小胶质细胞替代MIA后代的小胶质细胞，改善了免疫钝化，并恢复了突触前囊泡释放到多巴胺受体二型中棘神经元上的概率下降，从而表明产前不良环境导致的小胶质细胞异常形成影响了小胶质细胞的长期反应性和纹状体回路的正常发育。

据了解，最近的研究表明，小胶质细胞是主要的大脑免疫细胞，可以影响回路连接和神经元功能。小胶质细胞在胚胎发育早期渗入神经上皮细胞，并在整个成年时期维持在大脑中。一些母体环境因素，如异常的微生物组、免疫激活和营养不良，可以影响产前的大脑发育。然而，产前环境的变化如何指示浸润小胶质细胞的发育轨迹，进而影响大脑的发育和功能，这一点尚不清楚。

附：英文原文

Title: Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry

Author: Hayes, Lindsay N., An, Kyongman, Carloni, Elisa, Li, Fangze, Vincent, Elizabeth, Trippaers, Chlo, Paranjpe, Manish, Dlen, Gl, Goff, Loyal A., Ramos, Adriana, Kano, Shin-ichi, Sawa, Akira

Issue&Volume: 2022-09-28

Abstract: Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors—such as an aberrant microbiome, immune activation and poor nutrition—can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.

DOI: 10.1038/s41586-022-05274-z

Source: https://www.nature.com/articles/s41586-022-05274-z

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