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.

Reviewing Editor

  1. Matthew N Hill, University of Calgary, Canada

Publication history

  1. Received: June 5, 2020
  2. Accepted: July 20, 2020
  3. Accepted Manuscript published: July 21, 2020 (version 1)
  4. Version of Record published: August 20, 2020 (version 2)

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.

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  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

Further reading

    1. Neuroscience
    Payel Chatterjee et al.
    Research Article

    During flight maneuvers, insects exhibit compensatory head movements which are essential for stabilizing the visual field on their retina, reducing motion blur, and supporting visual self-motion estimation. In Diptera, such head movements are mediated via visual feedback from their compound eyes that detect retinal slip, as well as rapid mechanosensory feedback from their halteres - the modified hindwings that sense the angular rates of body rotations. Because non-Dipteran insects lack halteres, it is not known if mechanosensory feedback about body rotations plays any role in their head stabilization response. Diverse non-Dipteran insects are known to rely on visual and antennal mechanosensory feedback for flight control. In hawkmoths, for instance, reduction of antennal mechanosensory feedback severely compromises their ability to control flight. Similarly, when the head movements of freely-flying moths are restricted, their flight ability is also severely impaired. The role of compensatory head movements as well as multimodal feedback in insect flight raises an interesting question: in insects that lack halteres, what sensory cues are required for head stabilization? Here, we show that in the nocturnal hawkmoth Daphnis nerii, compensatory head movements are mediated by combined visual and antennal mechanosensory feedback. We subjected tethered moths to open-loop body roll rotations under different lighting conditions, and measured their ability to maintain head angle in the presence or absence of antennal mechanosensory feedback. Our study suggests that head stabilization in moths is mediated primarily by visual feedback during roll movements at lower frequencies, whereas antennal mechanosensory feedback is required when roll occurs at higher frequency. These findings are consistent with the hypothesis that control of head angle results from a multimodal feedback loop that integrates both visual and antennal mechanosensory feedback, albeit at different latencies. At adequate light levels, visual feedback is sufficient for head stabilization primarily at low frequencies of body roll. However, under dark conditions, antennal mechanosensory feedback is essential for the control of head movements at high of body roll.