Mineralocorticoid receptors in the ventral hippocampus are involved in extinction memory in rats

Abstract

Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for posttraumatic stress disorder (PTSD). However, knowledge about the neurobiology of extinction is insufficient. The present study investigated changes in the protein expression of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the dorsal hippocampus (DH)and ventral hippocampus (VH), induced by extinction and return of conditioned fear responses to an auditory signal. Western blot analysis indicated that shock stress enhanced the expression of MRs in only the DH, whereas extinction selectively increased the expression of MRs in the VH. The infusion of MRs antagonist spironolactone in the VH indicated that MRs in the VH did not affect the retrieval of fear and extinction memories, but facilitated the formation of extinction memory. However, no changes in GRs in either the DH or VH were observed in each phase of auditory fear conditioning. These results suggest that MRs in the DH and VH have differential functions in the extinction of auditory fear conditioning. MRs in the DH appear to be related to only stressful experiences, whereas MRs in the VH are involved in extinction formation. The enhancement of MRs in the VH might be necessary to improve PTSD.

Differential Phosphorylation of the Glucocorticoid Receptor in Hippocampal Subregions Induced by Contextual Fear Conditioning Training

“…Semi-quantification of total GR by Western blotting and by immunohistochemical techniques showed that levels of this protein were not affected 60 min after training in CFC in any of the hippocampal subregions. Several studies have also reported that the optical density (OD) of the total GR protein does not change, either in vitro after incubation of U2OS and HEK 293 cell lines with the GR agonist dexamethasone (Wang et al, 2002;Lambert et al, 2013), nor in vivo after training animals in fear conditioning (Xing et al, 2014). However, increasing this interval would be likely to induce a decrease in GR concentration in certain subregions of the hippocampus, since GR is a transcription factor that negatively self-regulates in certain brain areas after binding its hormone ligand (Sapolsky et al, 1986).…”

Spatial object recognition memory formation under acute stress

“…The MR antagonist spironolactone (spiro, 75 ng/μL) and GR antagonist mifepristone (mife, 20 ng/ μL) was dissolved in DMSO and diluted in saline for a final concentration of DMSO 5%. The doses were determined from published studies (Korte, Boer, Kloet, & Bohus, 1995;Moncada et al, 2011;Xing et al, 2014) and pilots experiments in our lab. The function-blocking anti-BDNF antibodies (Chemicon, Temecula, CA; AB1513P) were diluted to working concentration (0.5 μg/0.8 μL) with saline (Slipczuk et al, 2009).…”

Blunted glucocorticoid responsiveness to stress causes behavioral and biological alterations that lead to posttraumatic stress disorder vulnerability

“…Accordingly, these findings may underlie-at least to some extent-the blunted glucocorticoid responsiveness in these animals. Importantly, several studies have suggested that fear extinction may rely on forebrain MRs during periods of low circulating CORT levels at the time of extinction training (88,89). Moreover, the balance between MR and GR activation seems to be crucial for adequately processing aversive memories (90).…”