Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status.

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention. A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples. Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group. These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Using unconditioned responses to predict fear acquisition, fear extinction learning, and extinction retention patterns: Sex hormone status matters.

Following a traumatic event, fear dysregulation can increase the likelihood of developing post-traumatic stress disorder (PTSD). This psychopathology is twice as prevalent in women than in men. High physiological reactivity following trauma may be an early risk indicator for the development of PTSD. Elevated physiological reactivity and low estradiol levels have individually been associated with higher fear acquisition and/or lower extinction retention. Thus, sex hormone status may also modulate fear regulation abilities. However, it is unknown whether these two vulnerability factors interact to modulate fear learning and regulation. Using a fear conditioning and extinction protocol, we examined whether physiological reactivity to the aversive stimulus during fear acquisition training predicted fear responses during fear learning, extinction learning, and extinction retention. We verified whether these associations differed according to sex hormone status. Seventy-seven non-clinical participants were recruited including oral contraceptive users (n = 18), early follicular women (n = 20, [low estradiol]), mid-cycle women (n = 20, [high estradiol]), and men (n = 19). Participants underwent a three-day fear conditioning and extinction protocol (day 1: fear acquisition training; day 2: extinction training; day 3: retention test). Skin conductance responses were recorded. In early follicular women, physiological reactivity predicted conditioned and extinguished stimulus fear responses during all phases. For the remaining women, this effect was only present during fear learning and extinction learning. These findings highlight the importance of considering physiological reactivity and sex hormone status following a traumatic event. This knowledge could aid in the early identification of those at higher risk of developing PTSD.

A review on how stress modulates fear conditioning: Let's not forget the role of sex and sex hormones.

Stress and fear are two fields of research that have evolved simultaneously. It was not until the eighties that these domains converged in order to better characterize the impact of stress on fear memory formation. Here, we reviewed the effects of stress occurring before fear acquisition on the main phases of fear conditioning protocols (acquisition training, extinction training, extinction retention test), with a specific focus on sex and sex hormones. We also paid close attention to methodological aspects in order to better understand and characterize discrepant findings across studies. In men, stress appears to potentiate fear acquisition at a physiological level but induces lower activations of fear-related brain regions. In women, results are inconsistent. Although some studies have shown that stress lowers physiological fear responses and heightens brain activations in women during fear acquisition, many studies report no significant effects. Irrespective of sex, pre-acquisition stress seems to induce fear extinction learning resistance. Overall, few studies have taken into account sex hormones, despite their impact on both the fear and stress brain networks. As methodological variability makes it complex to draw strong conclusions, several methodological aspects are discussed with the aim of orienting future research.