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

    Theta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze whether brain oscillations are related to co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (~20-30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings suggest that neural oscillations play a role for the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories.