A History of Corticosterone Exposure Regulates Fear Extinction and Cortical NR2B, GluR2/3, and BDNF

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.

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

“…Previous reports from the clinical literature have shown that methylation of the Fkbp5 gene (at the promoter region of exon 1) did not predict treatment response, but decreased in association with recovery (Yehuda et al, 2013). A study using a chronic corticosterone administration paradigm, that had been previously shown to result in a phenotype similar to chronic stress exposure (Gourley et al, 2009), induced an increase in Fkbp5 mRNA expression in the hippocampus, hypothalamus, and blood of mice with a correspondent decrease in DNA methylation at Fkbp5 intron 5 (Lee et al, 2010).…”

“…We obviously cannot discount the contribution of other neurobiological pathways on HPA axis activity and subsequent behavioral effects in fear EXT learning. Other candidate systems include, but are not limited to, brainderived neurotrophic factor (Gourley et al, 2009), pituitary adenylate cyclase activating polypeptide (Stroth et al, 2011), the endogenous cannabinoid system (Hill and Tasker, 2012), and Nociceptin-Nociceptin receptor (Andero, 2015).…”

The STRONG STAR Multidisciplinary PTSD Research Consortium

“…By contrast, injections of GR agonist into the hippocampus immediately before retention testing in a Morris water maze impaired spatial memory , and both of these effects were dependent on convergent noradrenergic signaling. Further, either chronic low-dose CORT or acute GR antagonists given after the first extinction exposure impaired extinction (Gourley et al, 2009). Thus, chronically elevated CORT, together with GR down-regulation and reduced NE release capacity in PFC may have all contributed to impaired extinction after PNS/CAPS.…”

“…We also showed that CAPS treatment resulted in a downregulation of glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) (Green et al, 2011). This could have contributed to the impairments observed during extinction testing, as glucocorticoids are known to be involved in learning and memory, including fear and extinction learning (Gourley et al, 2009;de Quervain et al, 2009;. The mPFC, particularly the infralimbic cortex, is a key region involved in extinction learning (Milad and Quirk, 2002;Quirk et al, 2000;.…”

“…Moreover, in the context of stress, both the brain noradrenergic system and the HPA axis are involved in regulation and dysregulation of cognitive processes such as learning and memory (de Quervain et al, 2009), including specifically conditioned fear and extinction learning (McIntyre et al, 2002;Mueller et al, 2008;Gourley et al, 2009). Impaired cognition, maladaptive fear responses, and impaired extinction of learned fear are primary symptoms of a number of affective disorders, with these fear-related symptoms being most relevant to anxiety disorders such as panic disorder, phobias, obsessivecompulsive disorder, and PTSD Fossati et al, 1999;Koenen et al, 2001;Moritz et al, 2002;Kangaratnam and Asbjørnsen, 2007;.…”