Abstract
A history of exposure to stressors may be a predisposing factor for developing posttraumatic stress disorder (PTSD) after trauma. Extinction of conditioned fear appears to be impaired in PTSD, but the consequences of prior stress or excess glucocorticoid exposure for extinction learning are not known. We report that prior chronic exposure to the stress hormone, corticosterone (CORT), decreases endogenous CORT secretion upon context reexposure and impairs extinction after contextual fear conditioning in rats, while leaving fear memory acquisition and expression intact. Posttraining administration of the glucocorticoid receptor (GR) antagonist, RU38486, partially mimicked prior CORT exposure effects on freezing during fear extinction training. Extinction of conditioned fear is an active learning process thought to involve glutamatergic targets—including specific NMDA and AMPA receptor subunits—in the ventromedial prefrontal cortex (vmPFC), which includes the prelimbic, infralimbic, and medial orbitofrontal cortices. After CORT exposure, decreases in the NMDA receptor NR2B subunit and AMPA receptor subunits, GluR2/3, as well as brain-derived neurotrophic factor, were detected in cortical regions, but not dorsal hippocampus (CA1). Receptor subunit expression levels in the vmPFC correlated with freezing during training. In addition, prior CORT selectively decreased sucrose preference, consistent with established models of anhedonia and with blunted affect in PTSD. Together, these data suggest a cellular mechanism by which chronically elevated glucocorticoid exposure—as may be experienced during repeated exposure to stressors—interferes with the neural systems that modulate behavioral flexibility and may thereby contribute to psychopathological fear states.
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Acknowledgements
We thank Drew D Kiraly and Drs Jennifer Quinn and Natalie Tronson for excellent technical support and advice. This study was supported by PHS MH 25642 and 66172 (JRT) and 79680 (SLG) and the State of Connecticut Department of Mental Health and Addiction Services.
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SL Gourley, AT Kedves, P Olausson, and JR Taylor declare they have no competing financial interests regarding the methods, results, clinical implications, or any other aspect of this paper, and no personal financial holdings that could be perceived as constituting a potential conflict of interest. Further, the authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service.
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Gourley, S., Kedves, A., Olausson, P. et al. A History of Corticosterone Exposure Regulates Fear Extinction and Cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacol 34, 707–716 (2009). https://doi.org/10.1038/npp.2008.123
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DOI: https://doi.org/10.1038/npp.2008.123
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