Sex differences in fear conditioning: a role of the forebrain mineralocorticoid receptor

Abstract

Rationale : A recent study showed that a mineralocorticoid receptor (MR) gene variant, MR haplotype 2, was associated with higher levels of dispositional optimism, less thoughts of hopelessness, and lower risk of depression in women but not in men. Mice lacking the MR in the forebrain, MRCaMKCre mice, were generated to further investigate behavioral sex differences with and without the MR. Here, the hypothesis that sex differences would disappear after deletion of the MR was tested. Methods : We used male (n=8–9) and female (n=9–14) MRCaMKCre mice and control littermates to study fear conditioning, memory performance, and extinction. The fear-conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. Results : At the end of the conditioning, all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MRCaMKCre mice remembered and feared the context more than the control mice. Furthermore, female MRCaMKCre mice were not able to extinguish this memory even on the second day of memory testing. The female mutants could also not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MRCaMKCre and control mice showed extinction and were capable to discriminate, although extinction of the MRCaMKCre mice started slower. Conclusion : The loss of forebrain MR does not eliminate sex differences but rather results in large differences in emotional and cognitive behaviors between female and male mice. This finding suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders.

Keywords

• fear conditioning
• sex differences
• mineralocorticoid receptor