Effects of corticosterone on mild auditory fear conditioning and extinction; role of sex and training paradigm

Abstract

Multiple lines of evidence suggest that glucocorticoid hormones enhance memory consolidation of fearful events. However, most of these studies involve male individuals. Since anxiety, fear, and fear-associated disorders present differently in male and female subjects we investigated in mice whether male and female mice perform differently in a mild, auditory fear conditioning task and tested the modulatory role of glucocorticoid hormones. Using an auditory fear conditioning paradigm with different footshock intensities (0.1, 0.2, and 0.4 mA) and frequencies (1× or 3×), we find that intraperitoneal injections with corticosterone (2 mg/kg) immediately after training, altered freezing behavior when repeated footshocks were applied, and that the direction of the effects were opposite in male and female mice. Effects were independent of footshock intensity. In male mice, corticosterone consistently increased freezing behavior in response to the tone, whereas in female mice, corticosterone reduced freezing behavior 24 h after training. These effects were not related to the phase of the oestrous cycle. In addition, corticosterone enhanced extinction learning for all tones, in both male and female mice. These results emphasize that glucocorticoid hormones influence memory consolidation and retrieval, and underscore sex-specific effects of glucocorticoid hormones in modulating conditioned fear responses.

Glucocorticoids Promote Fear Generalization by Increasing the Size of a Dentate Gyrus Engram Cell Population

“…Selectively suppressing this neuronal ensemble restores memory specificity. Given that stress-related disorders are often sexdependent and that glucocorticoids regulate fear memory formation in a sex-dependent manner (22), further investigation is warranted regarding the role of these hormones on memory generalization in females.…”

“…Fear training involved placing mice into a conditioning chamber, and, 3 min later, presenting three co-terminating presentations of a tone conditioned stimulus (CS) (30s, 20.8 kHz, 82 dB) and a foot shock unconditioned stimulus (US) (2s, 0.2 mA). This mild conditioning paradigm was selected to avoid potential ceiling effects on behavior after corticosterone injections (22,23). During testing mice were place in the same (context A) and/or a novel context (context B) and freezing was assessed.…”

“…immediately following conditioning. The corresponding vehicle solution was administered to control group accordingly (22).…”

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning

“…Similarly, in response to high-dose injections of corticosterone, eyeblink conditioning acquisition was facilitated in male Long-Evans rats, but there was no impact on acquisition in female rats (Wentworth-Eidsaune, Hennessy, and Claflin 2016). Corticosterone treatment also enhanced learning in male rats on an auditory fear conditioning task, but impaired learning in female rats (Lesuis et al 2018). These sexually dimorphic behavioral responses to stress suggest that stress may underlie the behavioral differences initially observed in chronically implanted animals.…”

Cerebellar modulation of fear behaviour and memory encoding in the PAG

“…(iii) In relation to anxiety, Oksztel et al (2002) found that systemic administration of muscimol in rats causes a general decrease in motility but has no effect on anxiety levels. And in terms of stress, previous studies (Brinks et al, 2009;Uwaya et al, 2016;Pietersen et al, 2016;Lesuis et al, 2018) have reported a correlation between the amount of freezing and corticosterone levels. Given that the amount of conditioned freezing behaviour was unaffected in our experiments, this suggests that stress is also unlikely to fully explain our findings.…”