Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice
- University of North Carolina at Chapel Hill, United States
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
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
- Matthew N Hill, University of Calgary, Canada
Publication history
- Received: June 5, 2020
- Accepted: July 20, 2020
- Accepted Manuscript published: July 21, 2020 (version 1)
- 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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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
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- Neuroscience
Previously, we developed a novel model for anxiety during motivated behavior by training rats to perform a task where actions executed to obtain a reward were probabilistically punished and observed that after learning, neuronal activity in the ventral tegmental area (VTA) and dorsomedial prefrontal cortex (dmPFC) represent the relationship between action and punishment risk (Park and Moghaddam, 2017). Here, we used male and female rats to expand on the previous work by focusing on neural changes in the dmPFC and VTA that were associated with the learning of probabilistic punishment, and anxiolytic treatment with diazepam after learning. We find that adaptive neural responses of dmPFC and VTA during the learning of anxiogenic contingencies are independent from the punisher experience and occur primarily during the peri-action and reward period. Our results also identify peri-action ramping of VTA neural calcium activity, and VTA-dmPFC correlated activity, as potential markers for the anxiolytic properties of diazepam.
