1. Neuroscience

Orphan receptor GPR158 controls stress-induced depression

  1. Laurie P Sutton
  2. Cesare Orlandi
  3. Chenghui Song
  4. Won Chan Oh
  5. Brian S Muntean
  6. Keqiang Xie
  7. Alice Filippini
  8. Xiangyang Xie
  9. Rachel Satterfield
  10. Jazmine D W Yaeger
  11. Kenneth J Renner
  12. Samuel M Young
  13. Baoji Xu
  14. Hyungbae Kwon
  15. Kirill A Martemyanov  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. Max Planck Florida Institute for Neuroscience, United States
  3. University of Brescia, Italy
  4. University of South Dakota, United States
https://doi.org/10.7554/eLife.33273
Share this article
Cite this article
  1. Laurie P Sutton
  2. Cesare Orlandi
  3. Chenghui Song
  4. Won Chan Oh
  5. Brian S Muntean
  6. Keqiang Xie
  7. Alice Filippini
  8. Xiangyang Xie
  9. Rachel Satterfield
  10. Jazmine D W Yaeger
  11. Kenneth J Renner
  12. Samuel M Young
  13. Baoji Xu
  14. Hyungbae Kwon
  15. Kirill A Martemyanov
(2018)
Orphan receptor GPR158 controls stress-induced depression
eLife 7:e33273.
https://doi.org/10.7554/eLife.33273
  2. Download BibTeX
  3. Download .RIS

Abstract

Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.

Article and author information

Author details

  1. Laurie P Sutton

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Cesare Orlandi

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Chenghui Song

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3289-809X

  4. Won Chan Oh

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Brian S Muntean

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Keqiang Xie

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Alice Filippini

    Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
    Competing interests
    The authors declare that no competing interests exist.

  8. Xiangyang Xie

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Rachel Satterfield

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Jazmine D W Yaeger

    Department of Biology, University of South Dakota, Vermillion, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Kenneth J Renner

    Department of Biology, University of South Dakota, Vermillion, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Samuel M Young

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7589-7612

  13. Baoji Xu

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Hyungbae Kwon

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Kirill A Martemyanov

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    For correspondence
    kirill@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9925-7599

Funding

National Institute of Mental Health (MH105482)

  • Kirill A Martemyanov

National Heart, Lung, and Blood Institute (HL105550)

  • Kirill A Martemyanov

National Institute of Mental Health (MH107460)

  • Hyungbae Kwon

National Institute on Drug Abuse (DA019921)

  • Kenneth J Renner

National Institute on Deafness and Other Communication Disorders (DC014093)

  • Samuel M Young

University of Iowa

  • Samuel M Young

Max Planck Society

  • Samuel M Young

Canadian Institutes of Health Research

  • Laurie P Sutton

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

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 procedures were approved by the Institutional Animal Care and Use Committee (IACUC) protocol (#16-032) at The Scripps Research Institute.

Copyright

© 2018, Sutton 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

  • 9,673
    views
  • 1,286
    downloads
  • 60
    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. Laurie P Sutton
  2. Cesare Orlandi
  3. Chenghui Song
  4. Won Chan Oh
  5. Brian S Muntean
  6. Keqiang Xie
  7. Alice Filippini
  8. Xiangyang Xie
  9. Rachel Satterfield
  10. Jazmine D W Yaeger
  11. Kenneth J Renner
  12. Samuel M Young
  13. Baoji Xu
  14. Hyungbae Kwon
  15. Kirill A Martemyanov
(2018)
Orphan receptor GPR158 controls stress-induced depression
eLife 7:e33273.
https://doi.org/10.7554/eLife.33273

Share this article

https://doi.org/10.7554/eLife.33273

Categories and tags

Research organisms

Further reading

    1. Neuroscience

    The neural correlates of novelty and variability in human decision-making under an active inference framework

    Shuo Zhang, Yan Tian ... Haiyan Wu
    Research Article

    Active inference integrates perception, decision-making, and learning into a united theoretical framework, providing an efficient way to trade off exploration and exploitation by minimizing (expected) free energy. In this study, we asked how the brain represents values and uncertainties (novelty and variability), and resolves these uncertainties under the active inference framework in the exploration-exploitation trade-off. Twenty-five participants performed a contextual two-armed bandit task, with electroencephalogram (EEG) recordings. By comparing the model evidence for active inference and reinforcement learning models of choice behavior, we show that active inference better explains human decision-making under novelty and variability, which entails exploration or information seeking. The EEG sensor-level results show that the activity in the frontal, central, and parietal regions is associated with novelty, while the activity in the frontal and central brain regions is associated with variability. The EEG source-level results indicate that the expected free energy is encoded in the frontal pole and middle frontal gyrus and uncertainties are encoded in different brain regions but with overlap. Our study dissociates the expected free energy and uncertainties in active inference theory and their neural correlates, speaking to the construct validity of active inference in characterizing cognitive processes of human decisions. It provides behavioral and neural evidence of active inference in decision processes and insights into the neural mechanism of human decisions under uncertainties.

    1. Genetics and Genomics
    2. Neuroscience

    Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus

    Akanksha Bafna, Gareth Banks ... Patrick M Nolan
    Research Article

    The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light–12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.

    1. Neuroscience

    Mesoscale functional organization and connectivity of color, disparity, and naturalistic texture in human second visual area

    Hailin Ai, Weiru Lin ... Peng Zhang
    Research Article

    Although parallel processing has been extensively studied in the low-level geniculostriate pathway and the high-level dorsal and ventral visual streams, less is known at the intermediate-level visual areas. In this study, we employed high-resolution fMRI at 7T to investigate the columnar and laminar organizations for color, disparity, and naturalistic texture in the human secondary visual cortex (V2), and their informational connectivity with lower- and higher-order visual areas. Although fMRI activations in V2 showed reproducible interdigitated color-selective thin and disparity-selective thick ‘stripe’ columns, we found no clear evidence of columnar organization for naturalistic textures. Cortical depth-dependent analyses revealed the strongest color-selectivity in the superficial layers of V2, along with both feedforward and feedback informational connectivity with V1 and V4. Disparity selectivity was similar across different cortical depths of V2, which showed significant feedforward and feedback connectivity with V1 and V3ab. Interestingly, the selectivity for naturalistic texture was strongest in the deep layers of V2, with significant feedback connectivity from V4. Thus, while local circuitry within cortical columns is crucial for processing color and disparity information, feedback signals from V4 are involved in generating the selectivity for naturalistic textures in area V2.