Abstract
Post-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety and impaired fear extinction. To model the heterogeneity of PTSD behavioral responses, we exposed male Sprague–Dawley rats to predator scent stress once for 10 min and then assessed anxiety-like behavior 7 days later using the elevated plus maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress Susceptible, and rats exhibiting behavior no different from un-exposed Controls were classified as stress Resilient. In Resilient rats, we previously found increased mRNA expression of mGlu5 in the amygdala and prefrontal cortex (PFC) and CB1 in the amygdala. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and cell-type-specific expression of these genes in Resilient rats 3 weeks after TMT exposure. Resilient rats displayed increased mGlu5 mRNA expression in the basolateral amygdala (BLA) and the infralimbic and prelimbic regions of the PFC and increased BLA CB1 mRNA. These increases were limited to glutamatergic cells. To test the necessity of mGlu5 for attenuating TMT-conditioned contextual fear 3 weeks after TMT conditioning, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. In TMT-exposed Resilient rats, but not Controls, MTEP increased freezing on the day of administration, which extinguished over two additional un-drugged sessions. These results suggest that increased mGlu5 expression in BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations.
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Acknowledgements
The authors thank Jason Dee, Stephen Beaudin-Curley and Doug Smith for their assistance with image acquisition and analysis. The fluorescent microscopy images were acquired using Olympus DSU (DU-DBIX) spinning disk confocal microscope located at the Cell & Tissue Analysis Core (CTAC) facility. This facility is funded through user fees and the generous financial support of the McKnight Brain Institute at the University of Florida. This research was supported by the following grants: the subcontract 8738sc and 9250sc from the Institute on Molecular Neuroscience (awarded to LAK). Award Number: W81XWH-12-2-0048. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred; by the pilot grant from the Center for OCD, Anxiety, and Related Disorders (COARD) at the University of Florida (awarded to MS) and by the CTSA Grants TL1TR001428 and UL1TR001427 (awarded to CSW).
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JS, performed all behavioral and in situ hybridization experiments, wrote the first draft of the manuscript, compiled, and edited the figures, and edited successive drafts of the manuscript. LW assisted with behavioral experiments and processed brain tissue for the histological analysis. CW conducted part of Experiment 2 data collection and analysis. LAK and MS co-designed the study, co-directed the research, oversaw all aspects of data analysis, and edited successive drafts of the manuscript. Both LK and MS prepared the final version of the manuscript.
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Shallcross, J., Wu, L., Wilkinson, C.S. et al. Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure. Brain Struct Funct 226, 2279–2293 (2021). https://doi.org/10.1007/s00429-021-02326-4
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DOI: https://doi.org/10.1007/s00429-021-02326-4