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Hypothalamic-pituitary-adrenal (HPA) axis-related genetic variants influence the stress response
(2019)
The physiological stress system includes the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary system (SAM). Parameters representing these systems such as cortisol, blood pressure or heart rate define the physiological reaction in response to a stressor. The main objective of the studies described in this thesis was to understand the role of the HPA-related genetic factors in these two systems. Genetic factors represent one of the components causing individual variations in physiological stress parameters. Five genes involved in the functioning of the HPA axis regarding stress responses are examined in this thesis. They are: corticotropin-releasing hormone (CRH), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the 5-hydroxytryptamine-transporter-linked polymorphic region (5-HTTLPR) in the serotonin transporter (5-HTT) and the brain-derived neurotrophic factor (BDNF) gene. Two hundred thirty-two healthy participants were genotyped. The influence of genetic factors on physiological parameters, such as post-awakening cortisol and blood pressure was assessed, as well as the influence of genetic factors on stress reactivity in response to a socially evaluated cold pressor test (SeCPT). Three studies tested the HPA-related genes each on three different levels. The first study examined the influences of genotypes and haplotypes of these five genes on physiological as well as psychological stress indicators (Chapter 2). The second study examined the effects of GR variants (genotypes and haplotypes) and promoter methylation level on both the SAM system and the HPA axis stress reactivity (Chapter 3). The third study comprised the characterization of CRH promoter haplotypes in an in-vitro study and the association of the CRH promoter with stress indicators in vivo (Chapter 4).
Early life adversity (ELA) poses a high risk for developing major health problems in adulthood including cardiovascular and infectious diseases and mental illness. However, the fact that ELA-associated disorders first become manifest many years after exposure raises questions about the mechanisms underlying their etiology. This thesis focuses on the impact of ELA on startle reflexivity, physiological stress reactivity and immunology in adulthood.
The first experiment investigated the impact of parental divorce on affective processing. A special block design of the affective startle modulation paradigm revealed blunted startle responsiveness during presentation of aversive stimuli in participants with experience of parental divorce. Nurture context potentiated startle in these participants suggesting that visual cues of childhood-related content activates protective behavioral responses. The findings provide evidence for the view that parental divorce leads to altered processing of affective context information in early adulthood.
A second investigation was conducted to examine the link between aging of the immune system and long-term consequences of ELA. In a cohort of healthy young adults, who were institutionalized early in life and subsequently adopted, higher levels of T cell senescence were observed compared to parent-reared controls. Furthermore, the results suggest that ELA increases the risk of cytomegalovirus infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence.
The third study addresses the effect of ELA on stress reactivity. An extended version of the Cold Pressor Test combined with a cognitive challenging task revealed blunted endocrine response in adults with a history of adoption while cardiovascular stress reactivity was similar to control participants. This pattern of response separation may best be explained by selective enhancement of central feedback-sensitivity to glucocorticoids resulting from ELA, in spite of preserved cardiovascular/autonomic stress reactivity.
In order to investigate the psychobiological consequences of acute stress under laboratory conditions, a wide range of methods for socially evaluative stress induction have been developed. The present dissertation is concerned with evaluating a virtual reality (VR)-based adaptation of one of the most widely used of those methods, the Trier Social Stress Test (TSST). In the three empirical studies collected in this dissertation, we aimed to examine the efficacy and possible areas of application of the adaptation of this well-established psychosocial stressor in a virtual environment. We found that the TSST-VR reliably incites the activation of the major stress effector systems in the human body, albeit in a slightly less pronounced way than the original paradigm. Moreover, the experience of presence is discussed as one potential factor of influence in the origin of the psychophysiological stress response. Lastly, we present a use scenario for the TSST-VR in which we employed the method to investigate the effects of acute stress on emotion recognition performance. We conclude that, due to its advantages concerning versatility, standardization and economic administration, the paradigm harbors enormous potential not only for psychobiological research, but other applications such as clinical practice as well. Future studies should further explore the underlying effect mechanisms of stress in the virtual realm and the implementation of VR-based paradigms in different fields of application.