Format

Send to

Choose Destination
Neuropsychopharmacology. 2009 Feb;34(3):707-16. doi: 10.1038/npp.2008.123. Epub 2008 Aug 20.

A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF.

Author information

1
Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.

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.

PMID:
18719621
PMCID:
PMC3679657
DOI:
10.1038/npp.2008.123
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center