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

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.

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.

Metrics

  • 2,983
    views
  • 297
    downloads
  • 28
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jordon D White
  2. Tanzil M Arefin
  3. Alexa Pugliese
  4. Choong H Lee
  5. Jeff Gassen
  6. Jiangyang Zhang
  7. Arie Kaffman
(2020)
Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning
eLife 9:e58301.
https://doi.org/10.7554/eLife.58301

Share this article

https://doi.org/10.7554/eLife.58301

Further reading

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.