1. Neuroscience
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Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning

  1. Jordon D White
  2. Tanzil M Arefin
  3. Alexa Pugliese
  4. Choong H Lee
  5. Jeff Gassen
  6. Jiangyang Zhang
  7. Arie Kaffman  Is a corresponding author
  1. Yale University, United States
  2. New York University School of Medicine, United States
  3. Texas Christian University, United States
  4. Yale University School of Medicine, United States
Research Article
  • Cited 5
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Cite this article as: eLife 2020;9:e58301 doi: 10.7554/eLife.58301

Abstract

It is currently unclear whether early life stress (ELS) affects males and females differently. However, a growing body of work has shown that sex moderates responses to stress and injury, with important insights into sex-specific mechanisms provided by work in rodents. Unfortunately, most of the ELS studies in rodents were conducted only in males, a bias that is particularly notable in translational work that has used human imaging. Here we examine the effects of unpredictable postnatal stress (UPS), a mouse model of complex ELS, using high resolution diffusion magnetic resonance imaging. We show that UPS induces several neuroanatomical alterations that were seen in both sexes and resemble those reported in humans. In contrast, exposure to UPS induced fronto-limbic hyper-connectivity in males, but either no change or hypoconnectivity in females. Moderated-mediation analysis found that these sex-specific changes are likely to alter contextual freezing behavior in males but not in females.

Data availability

All imaging data were despited at https://doi.org/10.35092/yhjc.12367658

Article and author information

Author details

  1. Jordon D White

    Psychiatry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tanzil M Arefin

    Radiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexa Pugliese

    Psychiatry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Choong H Lee

    Radiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeff Gassen

    Psychology, Texas Christian University, Fort Worth, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiangyang Zhang

    Radiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Arie Kaffman

    Psychiatry, Yale University School of Medicine, New Haven, United States
    For correspondence
    arie.kaffman@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7028-8869

Funding

National Institute of Mental Health (R01MH119164)

  • Jiangyang Zhang
  • Arie Kaffman

National Institute of Mental Health (R01MH118332)

  • Jiangyang Zhang
  • Arie Kaffman

National Center for Advancing Translational Sciences (TL1 TR001864)

  • Jordon D White

National Institute of Neurological Disorders and Stroke (R01NS102904)

  • Jiangyang Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All studies were approved by the Institutional Animal Care and Use Committee (IACUC) at Yale University, protocol #2020-10981, and were conducted in accordance with the recommendations of the NIH Guide for the Care and the Use of Laboratory Animals.

Reviewing Editor

  1. Jason P Lerch, The Hospital for Sick Children, Canada

Publication history

  1. Received: April 27, 2020
  2. Accepted: November 30, 2020
  3. Accepted Manuscript published: December 1, 2020 (version 1)
  4. Version of Record published: December 9, 2020 (version 2)

Copyright

© 2020, White 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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