Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model

Single prolonged stress (SPS) is a rodent model of post traumatic stress disorder that is comprised of serial application of restraint (r), forced swim (fs), and ether (eth) followed by a 7-day quiescent period. SPS induces extinction retention deficits and it is believed that these deficits are caused by the combined stressful effect of serial exposure to r, fs, and eth. However, this hypothesis remains untested. Neurobiological mechanisms by which SPS induces extinction retention deficits are unknown, but SPS enhances glucocorticoid receptor (GR) expression in the hippocampus, which is critical for contextual modulation of extinction retrieval. Upregulation of GRs in extinction circuits may be a mechanism by which SPS induces extinction retention deficits, but this hypothesis has not been examined. In this study, we systematically altered the stressors that constitute SPS (i.e. r, fs, eth), generating a number of partial SPS (p-SPS) groups, and observed the effects SPS and p-SPSs had on extinction retention and GR levels in the hippocampus and prefrontal cortex (PFC). PFC GRs were assayed, because regions of the PFC are critical for maintaining extinction. We predicted that only exposure to full SPS would result in extinction retention deficits and enhance hippocampal and PFC GR levels. Only exposure to full SPS induced extinction retention deficits. Hippocampal and PFC GR expression was enhanced by SPS and most p-SPSs, however hippocampal GR expression was significantly larger following the full SPS exposure than all other conditions. Our findings suggest that the combined stressful effect of serial exposure to r, fs, and eth results in extinction retention deficits. The results also suggest that simple enhancements in GR expression in the hippocampus and PFC are insufficient to result in extinction retention deficits, but raise the possibility that a threshold-enhancement in hippocampal GR expression contributes to SPS-induced extinction retention deficits.

► Exposure to the full SPS protocol induces extinction retention (ER) deficits.
► Exposure to partial SPS protocols do not induce ER deficits.
► Exposure to full and partial SPS protocols enhance hippocampal and PFC GR levels.
► Exposure to full SPS induces maximal hippocampal GR enhancement.
► A threshold-enhancement in hippocampal GRs contributes to ER deficits in SPS.