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Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress × sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders.
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BACKGROUND: Gene by environment (G×E) interaction between genetic variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) and stressful life events (SLEs) has been extensively studied in the context of depression. Recent findings suggest increased neural and endocrine stress sensitivity as a possible mechanism conveying elevated vulnerability to psychopathology. Furthermore, these G×E mediated alterations very likely reflect interrelated biological processes. METHODS: In the present functional magnetic resonance imaging study, amygdala reactivity to fearful stimuli was assessed in healthy male adults (n = 44), who were previously found to differ with regard to endocrine stress reactivity as a function of 5-HTTLPR × SLEs. Furthermore, functional connectivity between the amygdala and the hypothalamus was measured as a potential mechanism linking elevated neural and endocrine responses during stressful/threatening situations. The study sample was carefully preselected regarding 5-HTTLPR genotype and SLEs. RESULTS: We report significant G×E interaction on neural response patterns and functional amygdala-hypothalamus connectivity. Specifically, homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs (S'S'/high SLEs group) displayed elevated bilateral amygdala activation in response to fearful faces. Within the same sample, a comparable G×E interaction effect has previously been demonstrated regarding increased cortisol reactivity, indicating a cross-validation of heightened biological stress sensitivity. Furthermore, S'S'/high SLEs subjects were characterized by an increased functional coupling between the right amygdala and the hypothalamus, thus indicating a potential link between neural and endocrine hyperreactivity. CONCLUSIONS: The present findings contribute to the ongoing debate on 5-HTTLPR × SLEs interaction and are discussed with respect to clinical implications.
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- Vaitl (2)
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Thema
- Hydrocortisone/metabolism
- Adult (2)
- alpha-Amylases/metabolism (1)
- Amygdala (1)
- Amygdala/*metabolism (1)
- Anterior cingulate (1)
- Brain Mapping (1)
- Brain Mapping/methods (1)
- Brain/physiology (1)
- Conditioning, Classical/*physiology (1)
- Cortisol (1)
- Facial Expression (1)
- Fear (1)
- Fear learning (1)
- Fear/*physiology/*psychology (1)
- Female (1)
- fMRI (1)
- Galvanic Skin Response/physiology (1)
- *Gene-Environment Interaction (1)
- Humans (2)
- Hypothalamus/*metabolism (1)
- Life Change Events (1)
- Magnetic Resonance Imaging/methods (1)
- Male (2)
- Neural Pathways/metabolism (1)
- Nucleus accumbens (1)
- Oral contraceptives (1)
- Polymorphism, Genetic/*genetics (1)
- Reference Values (1)
- Saliva/metabolism (1)
- Serotonin Plasma Membrane Transport Proteins/*genetics/metabolism (1)
- *Sex Characteristics (1)
- Sex differences (1)
- Stress hormones (1)
- Stress, Psychological/*genetics/metabolism (1)
- Stress, Psychological/*physiopathology/*psychology (1)
- TSST (1)