Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice

Abstract

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

Data availability

All data are available in the main text or the supplementary materials.

Article and author information

Author details

  1. Lara S Hwa

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5197-6201
  2. Sofia Neira

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Meghan E Flanigan

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3185-7459
  4. Christina M Stanhope

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Melanie M Pina

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5638-0474
  6. Dipanwita Pati

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6303-4871
  7. Olivia J Hon

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Waylin Yu

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Emily Kokush

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rachel Calloway

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kristen Boyt

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas L Kash

    Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    tkash@email.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4747-4495

Funding

National Institute on Alcohol Abuse and Alcoholism (K99AA027576)

  • Lara S Hwa

National Institute on Alcohol Abuse and Alcoholism (T32AA007573)

  • Meghan E Flanigan

National Institute on Alcohol Abuse and Alcoholism (F32AA026485)

  • Melanie M Pina

National Institute on Alcohol Abuse and Alcoholism (F31AA027129)

  • Waylin Yu

National Institute on Alcohol Abuse and Alcoholism (R01AA019454)

  • Thomas L Kash

National Institute on Alcohol Abuse and Alcoholism (U01AA020911)

  • Thomas L Kash

National Institute on Alcohol Abuse and Alcoholism (R01AA025582)

  • Thomas L Kash

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

Ethics

Animal experimentation: The UNC School of Medicine Institutional Animal Care and Use Committee approved all experiments (Protocol # 19-078). Procedures were conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals.

Copyright

© 2020, Hwa 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

  • 4,367
    views
  • 440
    downloads
  • 11
    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. Lara S Hwa
  2. Sofia Neira
  3. Meghan E Flanigan
  4. Christina M Stanhope
  5. Melanie M Pina
  6. Dipanwita Pati
  7. Olivia J Hon
  8. Waylin Yu
  9. Emily Kokush
  10. Rachel Calloway
  11. Kristen Boyt
  12. Thomas L Kash
(2020)
Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice
eLife 9:e59709.
https://doi.org/10.7554/eLife.59709

Share this article

https://doi.org/10.7554/eLife.59709

Further reading

    1. Neuroscience
    Andrea Sattin, Chiara Nardin ... Tommaso Fellin
    Research Advance

    Two-photon (2P) fluorescence imaging through gradient index (GRIN) lens-based endoscopes is fundamental to investigate the functional properties of neural populations in deep brain circuits. However, GRIN lenses have intrinsic optical aberrations, which severely degrade their imaging performance. GRIN aberrations decrease the signal-to-noise ratio (SNR) and spatial resolution of fluorescence signals, especially in lateral portions of the field-of-view (FOV), leading to restricted FOV and smaller number of recorded neurons. This is especially relevant for GRIN lenses of several millimeters in length, which are needed to reach the deeper regions of the rodent brain. We have previously demonstrated a novel method to enlarge the FOV and improve the spatial resolution of 2P microendoscopes based on GRIN lenses of length <4.1 mm (Antonini et al., 2020). However, previously developed microendoscopes were too short to reach the most ventral regions of the mouse brain. In this study, we combined optical simulations with fabrication of aspherical polymer microlenses through three-dimensional (3D) microprinting to correct for optical aberrations in long (length >6 mm) GRIN lens-based microendoscopes (diameter, 500 µm). Long corrected microendoscopes had improved spatial resolution, enabling imaging in significantly enlarged FOVs. Moreover, using synthetic calcium data we showed that aberration correction enabled detection of cells with higher SNR of fluorescent signals and decreased cross-contamination between neurons. Finally, we applied long corrected microendoscopes to perform large-scale and high-precision recordings of calcium signals in populations of neurons in the olfactory cortex, a brain region laying approximately 5 mm from the brain surface, of awake head-fixed mice. Long corrected microendoscopes are powerful new tools enabling population imaging with unprecedented large FOV and high spatial resolution in the most ventral regions of the mouse brain.