Sex differences in the immediate extinction deficit and renewal of extinguished fear in rats

Abstract

Extinction learning is central to exposure-based behavioral therapies for reducing fear and anxiety in humans. However, patients with fear and anxiety disorders are often resistant to extinction. Moreover, trauma and stress-related disorders are highly prone to relapse and are twice as likely to occur in females compared to males, suggesting that females may be more susceptible to extinction deficits and fear relapse phenomena. In this report, we tested this hypothesis by examining sex differences in a stress-induced extinction learning impairment, the immediate extinction deficit (IED), and renewal, a common form of fear relapse. In contrast to our hypothesis, there were no sex differences in the magnitude of the immediate extinction deficit in two different rat strains (Long-Evans and Wistar). However, we did observe a sex difference in the renewal of fear when the extinguished conditioned stimulus was presented outside the extinction context. Male Wistar rats exhibited significantly greater renewal than female rats, a sex difference that has previously been reported after appetitive extinction. Collectively, these data reveal that stress-induced extinction impairments are similar in male and female rats, though the context-dependence of extinction is more pronounced in males.

Fig 1. Male () and female () Long-Evans rats exhibit the IED.

(A) Behavioral timeline for the different experimental groups. (B) Freezing data show that Long-Evans rats acquired equivalent levels of conditional fear to the auditory CS (Conditioning). Both Immediate and Delayed groups showed a marked reduction in fear to the CS throughout fear extinction, with Delayed animals showing lower levels of fear at the end of extinction training (Extinction). Although all groups of animals showed equivalent levels of fear early in the retrieval test (Block 1), immediately extinguished animals demonstrated a reduced rate of re-extinction compared to Delayed animals, indicative of impaired extinction memory (Retrieval). This IED was similar between male and females, though, females showed faster rate of re-extinction compared to males in both groups. All error bars represent ± SEM.

Fig 2. Male () and female () Wistar rats exhibit an IED.

(A) Behavioral timeline for the different experimental groups. (B) All groups acquired similar levels of conditioned freezing prior to extinction. (C) Wistar rats that underwent extinction training showed a reduction in fear across extinction trials with immediately extinguished rats reaching lower levels of freezing than delayed animals. Despite this, immediate extinction animals still showed impaired extinction during retrieval testing as indicated by reduced rate of re-extinction. This effect was similar in both males and females. (D) Comparatively, No-Extinction animals exhibited high levels of conditioned freezing during retrieval testing that was similar among all groups. All error bars represent ± SEM.

Fig 3. Male () but not female () Wistar rats exhibit renewal of extinguished fear.

Freezing data showing that male and female Wistar rats displayed similar levels of fear during a second extinction session after the prior extinction retrieval test (left). However, only male rats displayed fear renewal the following day when presented the extinguished CS in a novel context (DIFF, right) relative to animals tested in the extinction context (SAME). This was particularly evident during the first two trials of testing. All error bars represent ± SEM.