Glucocorticoids are required for extinction of predator stress-induced hyperarousal

Abstract

Extinction of fearful behavior induced by severe stress was studied using predator stress. Predator stress involves a ten minute unprotected exposure of a rodent to a cat which induces long-lasting changes in anxiety-like behaviours and hyperarousal (increased acoustic startle response) (Adamec & Shallow, 1993; Adamec et al., 200 I;Cohen et al., 2004). In the present set of experiments, three questions were addressed using predator stressed mice. First, can predator stress-induced fear memories be extinguished? Second, is the extinction of predator stress-induced fear memories glucocorticoid-dependent? Finally, is re-exposure to the predator stress context necessary to see glucocorticoid's effects on predator stress-induced fear memories?Extinction was induced by re-exposing mice to the predator stress room in the absence of the cat. This repeated re-exposure to predator stress context increased activity in the predator stress context implying extinction of predator stress-induced immobility, a context-dependent fear memory. Repeated re-exposures to the predator stress context also decreased subsequent hyperarousal (acoustic startle response) and generalized anxiety-like behaviour. These fearful behaviors were predator stress context independent, having been tested in environments different from the cat exposure room. Furthermore, blocking glucocorticoid synthesis with metyrapone during repeated exposures to the predator stress context had no effect on activity. Therefore, reducing corticosterone levels did not affect extinction of the predator stress-induced, context-dependent fear memory.However, metyrapone given during repeated exposures to the predator stress context prevented extinction of predator stress-induced hyperarousal. These results suggest that extinction of predator stress-induced, context-independent fear memory is dependent on Ill the presence of endogenous corticosterone during the extinction trial . Finally, reexposure to the predator stress context was found to be necessary to see glucocorticoid's effects on predator stress-induced fear memories. This was determined by repeated injection of metyrapone over days without re-exposure to the predator stre s context.

Predator odor stress alters corticotropin-releasing factor-1 receptor (CRF1R)-dependent behaviors in rats

“…We report that predator odor produced hyperarousal 24–48 hrs post odor-exposure, in agreement with previous reports that predator stress produces lasting increases in startle reactivity in rats (Adamec et al, 2010) and mice (Clay et al, 2011). Other modalities of stress (e.g., footshock or restraint) also produce increases in arousal in rodents as measured by the acoustic startle test (Chester et al, 2008; Jiang et al, 2011; Rasmussen et al, 2008).…”

A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: Potential extinction enhancers

“…Several studies have also demonstrated the role of the glucocorticoid system in fear memory extinction (Barrett and GonzalezLima, 2004;Blundell et al, 2011;Clay et al, 2011;Yang et al, 2006Yang et al, , 2007 (see Table 2). For instance, Barrett and Gonzales-Lima showed that the release of corticosterone is fundamental for the extinction of conditioned fear, since extinction can be impaired by inhibition of corticosterone synthesis with metyrapone (Barrett and Gonzalez-Lima, 2004) or by adrenalectomy (Bohus et al, 1982).…”

“…The answer is still not obvious, but here we propose a tentative model. We have seen that both eCB (Chhatwal et al, 2005;Marsicano et al, 2002) and glucocorticoids Clay et al, 2011;Yang et al, 2006Yang et al, , 2007 are essential to the extinction of aversive memories. Additionally, we have also seen that glucocorticoids can increase eCB levels (Di et al, 2003;Hill et al, 2005Hill et al, , 2011Patel et al, 2005).…”

“…administration of corticosterone normalizes the behavioral response, even in the absence of the endogenous hormone (Bohus et al, 1982). Metyrapone also prevents contextual fear extinction in a way that is reversible by exogenous administration of corticosterone Clay et al, 2011). Additionally, several studies have shown the capacity of the synthetic glucocorticoid dexamethasone to promote the facilitation of extinction of aversive memories in different behavioral tasks Ninomiya et al, 2010;Yang et al, 2006Yang et al, , 2007.…”

Cannabinoids Modulation of Emotional and Non-Emotional Memory Processes After Stress

“…On the basis of the data suggesting that endocannabinoids [14][15] and glucocorticoids [91][92] mediate the extinction of aversive memories and that glucocorticoids can increase endocannabinoids levels [93][94][95], they suggested that endocannabinoids are recruited by glucocorticoids in the process of extinction of aversive memories. As endocannabinoids are released in the basolateral amygdala during fear extinction [15], and glucocorticoids can trigger endocannabinoids release at this location, they hypothesized that an endocannabinoid-mediated feedback of the hypothalamic-pituitary-adrenal axis, which is dependent on glucocorticoid release, is an important component of the mechanism of fear memory extinction.…”