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The microbiota regulate neuronal function and fear extinction learning
Open accessAbstract
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota 1. 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 2. 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 3. 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.
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“Without a complex microbiota, both types of mice exhibited altered fear-associated behavior, changes in gene expression in brain cells, and alterations in the firing patterns and rewiring ability of neurons.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [385]
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“In 2019, Artis D.’s group showed that SPF mice treated with a cocktail of broad-spectrum antibiotics, GF mice, GF mice recolonized after weaning age with a simple microbiota or a complex microbiota, have defects in fear extinction learning, compared to SPF mice or GF mice colonized with SPF flora at the time of birth (29).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“Selective colonization revealed a critical developmental period, indicating that microbiota-derived signals were required during early post-natal and adult life for normal learning.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [385]
In the citing paper
“Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]
In the citing paper
“The researchers showed that the microbiota-mediated changes in synapse formation and fear extinction behavior were not the results of the hypothalamic-pituitary-adrenal axis but of the reduced level of potential neuroactive metabolites (phenyl sulfate, pyrocatechol sulfate, 3-(3-sulfooxyphenyl)propanoic acid, and indoxyl sulfate) in the cerebrospinal fluid, serum and in fecal samples of GF mice”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]
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The gut microbiota–brain axis in behaviour and brain disorders
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Alseekh, S., Aharoni, A., Brotman, Y., Contrepois, K., D’Auria, J. C., Ewald, J., Ewald, J. C., Fraser, P. D., Giavalisco, P., Hall, R. D., et al. (2021) · Nature Methods · doi:10.1038/s41592-021-01197-1 · Cited by 1,219
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The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
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Metadata
- Authors
- Chu, C., Murdock, M. H., Jing, D., Won, T. H., Chung, H., Kressel, A. M., Tsaava, T., Addorisio, M. E., Putzel, G. G., Zhou, L., Bessman, N. J., Yang, R., Moriyama, S., Parkhurst, C. N., Li, A., Meyer, H. C., Teng, F., Chavan, S. S., Tracey, K. J., Regev, A., Schroeder, F. C., Lee, F. S., Liston, C., & Artis, D.
- Affiliations
- Cornell University (US)
- Broad Institute (US)
- Northwell Health (US)
- Corresponding author
- Liston, Conor
- Artis, David
- ORCID
- Venue
- Nature
- Published
- 2019-10-23
- Volume
- 574
- Issue
- 7779
- Pages
- 543-548
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6818753
- OpenAlex
- W2981552290
- Cited by
- 421
- References
- 78
- Citations by year
- 2026: 27 · 2025: 49 · 2024: 57 · 2023: 72 · 2022: 77 · 2021: 64 · 2020: 69 · 2019: 3
- FWCI
- 30.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH109685, R01MH118451)
- National Institute of General Medical Sciences (R35GM118182, R01GM132672)
- National Institute of Allergy and Infectious Diseases (R01AI095466, R21AI142213, R01AI102942, R01AI151599, F32AI124517, P01AI102852, R01AI074878, U01AI095608)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126871)
- National Institute of Neurological Disorders and Stroke (R01NS052819)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- gut microbiota, fear extinction learning, germ-free mice, antibiotic-treated mice, medial prefrontal cortex, neuroplasticity, single-nucleus RNA sequencing, metabolomics, neuropsychiatric disorders, anxiety-like behavior
- MeSH terms
- Animals, Anti-Bacterial Agents, Autistic Disorder, Blood, Calcium, Cerebrospinal Fluid, Cues, Extinction, Psychological, Fear, Feces, Germ-Free Life, Indican, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neural Inhibition, Neuroglia, Neurons, Phenylpropionates, Schizophrenia, Vagus Nerve, Prefrontal Cortex, Dendritic Spines, Mice, Metabolomics, Transcriptome, Microbiota
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