Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

  1. Mar Gacias  Is a corresponding author
  2. Sevasti Gaspari
  3. Patricia Mae-Santos
  4. Sabrina Tamburini
  5. Monica Andrade
  6. Fan Zang
  7. Nan Shen
  8. Vladimir Tolstikov
  9. Michael A Kiebish
  10. Jeffrey L Dupree
  11. Venetia Zachariou
  12. Jose C Clemente
  13. Patrizia Casaccia
  1. Icahn School of Medicine at Mount Sinai, United States
  2. Icahn School of Medicine at Mount Sinaii, United States
  3. BERG, United States
  4. Virginia Commonwealth University, United States

Abstract

Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of saline in non-obese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.

Article and author information

Author details

  1. Mar Gacias

    Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    mar.gacias-monserrat@mssm.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Sevasti Gaspari

    Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Patricia Mae-Santos

    Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sabrina Tamburini

    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Monica Andrade

    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Fan Zang

    Department of Neuroscience, Icahn School of Medicine at Mount Sinaii, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nan Shen

    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Vladimir Tolstikov

    BERG, Framingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael A Kiebish

    BERG, Framingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jeffrey L Dupree

    Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Venetia Zachariou

    Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jose C Clemente

    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Patrizia Casaccia

    Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Icahn School of Medicine at Mount Sinai (#08-0676, #08-0675; LA10-00398; LA12-00193; LA12-00146).

Reviewing Editor

  1. Peggy Mason, University of Chicago, United States

Publication history

  1. Received: December 3, 2015
  2. Accepted: April 7, 2016
  3. Accepted Manuscript published: April 20, 2016 (version 1)
  4. Accepted Manuscript updated: May 3, 2016 (version 2)
  5. Version of Record published: May 16, 2016 (version 3)

Copyright

© 2016, Gacias et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mar Gacias
  2. Sevasti Gaspari
  3. Patricia Mae-Santos
  4. Sabrina Tamburini
  5. Monica Andrade
  6. Fan Zang
  7. Nan Shen
  8. Vladimir Tolstikov
  9. Michael A Kiebish
  10. Jeffrey L Dupree
  11. Venetia Zachariou
  12. Jose C Clemente
  13. Patrizia Casaccia
(2016)
Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior
eLife 5:e13442.
https://doi.org/10.7554/eLife.13442
  1. Further reading

Further reading

  1. Microbes in the gut influence the social behaviour of mice.

    1. Neuroscience
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    Research Article

    Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as the latter state is thought to allow for more efficient storage, retrieval and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation-inhibition (E-I) ratio towards inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in mice mimicking the etiology of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.