Faculty Opinions recommendation of The microbiota regulate neuronal function and fear extinction learning.

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 a wide range of 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 behaviors such as social activity, stress, and anxiety-related responses that are linked to diverse neuropsychiatric disorders.However, the mechanisms through which the microbiota influence neuronal activity and host behavior remain poorly defined.Here we demonstrate that manipulation of the microbiota in either antibiotictreated 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 multiple cell types including excitatory neurons and glial cells.Transcranial two-photon imaging following deliberate manipulation of the microbiota demonstrated that extinction learning deficits were associated with defective learning-related remodeling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex.In addition to effects of manipulating the microbiota on behavior in adult mice, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood.Lastly, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and were previous reported to be related to human and mouse models of neuropsychiatric disorders, suggesting that microbiota-derived compounds may directly affect brain function and behavior.Together, these data indicate that fear extinction learning requires microbiota-derived signals during both 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.