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.
Reviewing Editor
- Matthew N Hill, University of Calgary, Canada
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.
Version 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
Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are often assumed to feed pools that are mobilized more quickly, in a series. However, electrophysiological studies of synaptic transmission have suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool. Here, we use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses and a parallel organization that prevents intermixing between the pools, even when stimulation is intense enough to drive exocytosis at the maximum rate. The experiments additionally demonstrate extensive heterogeneity among synapses in the relative sizes of the slowly and quickly mobilized reserve pools, which suggests equivalent heterogeneity in the numbers of reluctant and fast-releasing readily releasable vesicles that may be relevant for understanding information processing and storage.
