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Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

多细胞生物与复杂的病毒、细菌、真菌和寄生虫共生体共同进化，这些共生体统称为微生物组。在哺乳动物中，微生物组的组成变化可以影响许多生理过程（包括发育、代谢和免疫细胞功能），并与多种疾病的易感性有关。微生物组的改变也可以调节宿主行为，如社交活动、压力和与多种神经精神障碍相关的焦虑反应。然而，微生物组影响神经元活动和宿主行为的机制仍不清楚。

在这里，我们表明，在抗生素处理或无菌成年小鼠中操纵微生物组会导致恐惧消退学习显著缺陷。大脑中前额叶皮质的单细胞 RNA 测序显示，兴奋性神经元、神经胶质和其他细胞类型的基因表达发生了显著改变。颅透双光子成像显示，在成年小鼠操纵微生物组后，恐惧消退学习的缺陷与微生物组相关的学习相关的突触后树突棘重塑缺陷和前额叶皮质中线索编码神经元活动减少有关。此外，选择性重建微生物组表明，在新生儿发育过程中有一个有限的窗口期，在此期间，微生物组衍生的信号可以恢复成年期的正常消退学习。最后，无偏代谢组学分析确定了在无菌小鼠中显著下调的四种代谢物，这些代谢物已被报道与人类和小鼠模型中的神经精神障碍有关，这表明微生物组衍生的化合物可能直接影响大脑功能和行为。

综上所述，这些数据表明，恐惧消退学习需要微生物组衍生的信号，无论是在早期产后神经发育期间还是在成年小鼠中，这对我们理解饮食、感染和生活方式如何影响大脑健康以及随后对神经精神障碍的易感性具有重要意义。