Neuronal correlates of extinction learning are modulated by sex hormones

Abstract

In emotional learning tasks, sex differences, stress effects and an interaction of these two moderators have often been observed. The sex hormones estradiol (E2) and progesterone (P4) vary over the menstrual cycle. We tested groups with different sex hormone status: 39 men, 30 women in the luteal phase (LU, high E2+P4) and 29 women taking oral contraceptives (OC, low E2+P4). They received either 30 mg cortisol or placebo prior to instructed differential fear conditioning consisting of neutral conditioned stimuli (CS) and an electrical stimulation (unconditioned stimulus; UCS). One figure (CS+) was paired with the UCS, the other figure (CS-) never. During extinction, no electrical stimulation was administered. Regarding fear acquisition, results showed higher skin conductance and higher brain responses to the CS+ compared to the CS- in several structures that were not modulated by cortisol or sex hormones. However, OC women exhibited higher CS+/CS- differentiations than men and LU women in the amygdala, thalamus, anterior cingulate and ventromedial prefrontal cortex during extinction. The suppression of endogenous sex hormones by OC seems to alter neuronal correlates of extinction. The observation that extinction is influenced by the current sex hormone availability is relevant for future studies and might also be clinically important.

Fig. 1

Mean differential SCRs (CS+ minus CS− in the SIR) in (A) the fear acquisition and (B) the fear extinction phase separated for men, LU and OC women. A moving average over three trials is illustrated to enhance temporal smoothness. Error bars are standard errors of the mean.

Fig. 2

Neuronal activation in the extinction for the main effect of sex hormone status on conditioned responses (CS+ minus CS−). Data are illustrated with F ≥ 5.0 (see color bar for exact F-values). The depicted slices were selected according to the reported activations in the left (y = −21) and right thalamus (y = −15), the right amygdala (y = 0), the right anterior cingulate cortex (ACC; y = 54), as well as in the left (y = 48) and right ventromedial prefrontal cortex (vmPFC; y = 57). Additionally, mean contrast estimates as well as the respective standard errors of the mean to CS+ minus CS− for men, LU and OC women in the respective peak voxels are displayed in the bar graphs. L = left, R = right.

Fig. 3

Extinction learning curves for the contrast CS+ minus CS− for the three sex hormone status groups (men, LU women and OC women) in the peak voxels of the group statistics (cf. Table 3 and Figure 2). A moving average over three trials is illustrated to enhance temporal smoothness. Error bars are standard errors of the mean. L = left, R = right.