Stress effects on human fear conditioning and the role of female sex hormones

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Title: Stress effects on human fear conditioning and the role of female sex hormones
Authors: Antov, Martin I.
Thesis advisor: Prof. Dr. Ursula Stockhorst
Thesis referee: Prof. Dr. Rudolf Stark
Abstract: Classical fear conditioning – including acquisition and extinction – is a model for fear learning and memory in health and disease. Moreover, trauma-related disorders can be viewed as comprising fear acquisition under severe stress. Yet, in humans, we know comparatively little about how acute stress affects fear conditioning. Therefore, the first aim of this thesis was to investigate the effect of stress on fear acquisition or extinction. Stress induces multiple hormonal and neurotransmitter changes dynamically developing over time, including a fast first-wave and a slower second-wave stress response. Models derived from avoidance learning and declarative memory studies suggest that stress effects on memory depend on the temporal proximity between learning and stressor: encoding close to the stressor will be enhanced, but encoding and recall later in time (during the second-wave) will be suppressed (e.g., Schwabe, Joëls, Roozendaal, Wolf, & Oitzl, 2012). So far, these predictions were not related to fear conditioning. Therefore, we investigated if the model-based predictions are also valid in human fear conditioning. We used two stressors to investigate first-wave and second-wave stress effects: the cold pressor test (CPT) inducing a strong first-wave but little second-wave activation and a psychosocial stressor, reliably inducing both, first- and second-wave stress responses. Conditioning was measured via skin conductance responses (SCRs). Investigating the first-wave (Experiment 2), we placed fear acquisition and immediate extinction directly after the CPT (n = 20) or after the control treatment (n = 20). We found no group difference in acquisition performance, but significantly increased extinction resistance in the stressed CPT group. In Experiment 3, CPT (n = 20) or control (n = 20) was placed after acquisition but directly prior to extinction training. Here, we found improved extinction and 24h-delayed extinction recall after CPT. Investigating the second-wave (Experiment 1), we placed fear acquisition and immediate extinction 45 min after the psychosocial stressor (i.e., at the peak of salivary cortisol, n = 12) or after control (n = 12). Here, we found no significant stress effects. Sex and female sex hormones also influence fear conditioning: Women are at a higher risk to develop anxiety and stressor-related disorders than men. Interestingly, patients with these disorders show impaired fear extinction and extinction recall, and low levels of the sex hormone 17β-estradiol (E2) are linked to impaired extinction in both, healthy and patient female samples. So far, there is little data on how acute stress and circulating E2-levels might interact in fear acquisition and especially in fear extinction. Therefore, the second aim of this thesis was to explore this possible interaction in healthy women in different cycle phases compared to men. Thus, in Experiment 4, we included hormone status as a quasi-experimental variable and compared free cycling women in the midcycle phase (high E2, low progesterone, n = 24), women in the early follicular phase of the menstrual cycle (low E2, low progesterone, n = 24), and men (n = 24). We placed fear acquisition and extinction 45 min after the psychosocial stressor (n = 36) or control (n = 36), and tested extinction recall after 24 h. In line with Experiment 1, the second-wave stressor did not affect fear acquisition and immediate extinction. However, we found a stress by hormone status interaction within women at the 24h-delayed extinction recall test: in the stressed group, early follicular women showed impaired extinction recall and a higher return of fear compared to midcycle women, whereas there was no difference between early follicular and midcycle women after control treatment. Collectively our results support a different role for the first- and second-wave stress response in human fear conditioning. Fear acquisition near the first-wave stress response results in enhanced fear memory, which is resistant to extinction. Extinction training near the first-wave enhances extinction learning. In contrast, fear conditioning at the peak of the peripheral second-wave cortisol response had no effect on acquisition or extinction performance. However, second-wave stress interacted with the hormone status of women, where only women in a low E2 state were vulnerable to negative stress effects in extinction recall. The last result will encourage further investigation of the interplay between E2 and stress in fear extinction. Enhancement of extinction by the CPT could – if replicated – be translated into strategies for optimizing exposure therapy.
Subject Keywords: Fear conditioning; Fear acquisition; Fear extinction; Stress; Estradiol
Issue Date: 18-Dec-2015
License name: Namensnennung-NichtKommerziell-KeineBearbeitung 3.0 Unported
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Type of publication: Dissertation oder Habilitation [doctoralThesis]
Appears in Collections:FB08 - E-Dissertationen

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