Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction

Abstract

BackgroundFindings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps.MethodsWe recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC).ResultsSignificant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations.ConclusionsOur data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation.

Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014–2017)

“…These studies present evidence for significantly higher activations in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus, among high-estrogen females compared to males, but not low-estrogen females, during conditioning, extinction, and recall. However, during the unconditioned response, a different pattern was observed, with males showing significantly higher brain activations [112]. This suggests that long-term impact of threat exposure in females may be mediated by estrogens and is in line with findings of PTSD-specific menstrual phase differences in threat processing among females as compared to trauma-exposed counterparts [113].…”

Absence of conditioned responding in humans: A bad measure or individual differences?

“…Selected shock levels ranged from 0.6-4.0 mA. Following the procedure described by Milad and colleagues (Hwang et al, 2015;Linnman et al, 2012;Marin et al, 2016Marin et al, , 2017Milad et al, 2009Milad et al, , 2007, the fear conditioning phase consisted of 32 trials. For each trial, a depicted context (e.g., an office) first appeared for 3 s, during which the imbedded conditioned stimulus (CS; a lamp) was not lit.…”

What Does Sex Have to Do with It? The Role of Sex as a Biological Variable in the Development of Posttraumatic Stress Disorder

“…That higher levels of estradiol are associated with increased activation of brain structures responsible for learning and memory (different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus) during fear conditioning suggests that the sex differences in the activity of these structures may be partially attributed to female gonadal hormones [91•]. Relevant to the development of PTSD, elevated activation of the circuitry responsible for arousal (hypothalamus, amygdala, and cingulate cortex) is also associated with elevated estradiol in response to emotional stimuli [55].…”