Let's talk about sex … differences in human fear conditioning
Introduction
Anxiety and stress-related disorders occur twice as likely and with a higher severity in women compared to men [1•, 2, 3]. Fear conditioning represents an important model for the development, maintenance and treatment of these disorders [4, 5, 6]. However, surprisingly few fear conditioning studies have been conducted in females questioning the generalizability of the obtained results [1•, 7]. Proper research in females faces some methodological challenges such as the fluctuation of sex hormones over the menstrual cycle or the intake of hormonal contraceptives [cf. 8], which requires multiplying the sample sizes per experiment when compared to a study conducted in men only. For this reason, such a strategy has not been pursued systematically as evident by a substantially reduced number of fear conditioning studies investigating female compared to male brains [9].
In this review, we will selectively focus on the available literature reporting sex differences in human fear conditioning. We present evidence for sex and sex hormone effects on the different phases of fear conditioning, separated into fear acquisition, extinction and the return of fear. After that, current trends will be highlighted and an outlook will be given before coming to concluding remarks.
Section snippets
Sex differences in fear acquisition
During fear acquisition training, the paired presentation of a stimulus (conditioned stimulus, CS+) with an innately aversive event (unconditioned stimulus, UCS, e.g. an electrical stimulation) leads to fear learning as indexed by conditioned fear responses to the CS+ on different outcome measures [for methodological details, see 10]. Most human studies employ differential fear conditioning designs, in which a second CS (CS−) is added without coupling with the UCS, usually acting as a safety
Sex differences in extinction and the return of fear
During extinction training, repeated presentations of the CS without further pairings with the UCS lead to decreasing conditioned fear responses (cf. Figure 1). Extinction learning is considered to mediate exposure-based treatments in cognitive-behavioral therapy [24, 25].
However, even after successful extinction, conditioned responding may reoccur (cf. Figure 1) as a function of time (spontaneous recovery), after a contextual change (renewal) or unsignalled presentations of the UCS or other
Methodological considerations
Important methodological considerations need to be taken into account when trying to draw a conclusive picture of the presented results. First, we provided a selective overview of recent fear conditioning studies reporting sex differences. However, while available data are still limited due to the overrepresentation of results derived from research including males only [1•], the existing literature including both sexes with null or not reported results concerning sex differences is hard to
Sex differences in fear conditioning: current trends and outlook
Stress is another important risk factor for the development, maintenance and relapse of anxiety disorders [38, 39]. In response to stress, the adrenal cortex releases glucocorticoids (GCs), which typically enhance memory consolidation but impair memory retrieval [40, 41]. These effects might explain why stress is often associated with symptom relapse [38]. At the same time, GCs appear to be able to boost the success of exposure based therapy presumably by impairing the retrieval of previously
Conclusion
The present review highlights sex hormones as an important modulator of different fear conditioning processes. Whereas high estrogen levels are associated with enhanced extinction and extinction memory recall, they also seem to facilitate initial fear acquisition. Thus, it might be assumed that high estrogens play an essential role in emotional learning processes in general, ultimately leading to unfavorable effects during fear acquisition, whereas being beneficial during extinction processes.
Role of the funding source
This work was supported by a grant from the German Research Foundation (DFG; SFB 1280 Extinction Learning; project A09 to CJM and OTW). The DFG had no further role in interpretation of data, in the writing of the report and in the decision to submit the paper for publication.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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