This thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two... Show moreThis thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two major stress systems (i.e. the ANS and the HPA-axis), and their relation with psychological and psychiatric characteristics. Show less
During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory... Show more During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory processes. To investigate this further we aimed to answer the question:""What are the primary genomic binding sites of the by stress and thus cortisol stimulated protein receptors MR and GR in the hippocampus?" To answer this question, new methods have been applied to determine where exactly MR and GR bind to the DNA, to find out which genes are potentially involved during stress management. As a result we have identified thousands of GR-binding sites at the DNA of which we have analyzed a selection in further detail. One of the identified pathways that have been found to be sensitive for activated GR and corticosteroids is the mTOR pathway. This pathway is involved in neuronal plasticity, which is the fundament for resilience. We have found that expression of the mTOR protein is decreased after exposure to acute stress when the organism has a history of chronic stress. Our results indicate that the reduced resilience after experiencing chronic stress is likely to be mediated by mTOR. Show less
The overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study,... Show moreThe overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study, was to expand our knowledge of homeostatic mechanisms at old age, thus trying to unravel underlying mechanisms of healthy human longevity. The focus of this thesis will be on analysis of the HPT-axis and HPA-axis in participants who have the propensity to reach old age in good health compared to age-matched controls. In humans, we are able to assess the 'function' of the HPT- and HPA- axes by measuring the key hormones involved as well as physiological parameters that are affected by these systems (heart rate, metabolism) under different conditions (in rest and during stress). Show less
Dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have... Show moreDysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relation between trauma exposure, stress regulation, and psychopathology. Mentally healthy trauma-exposed subjects were compared with non-trauma-exposed healthy controls. To distinguish between the potential effects of childhood trauma as opposed to adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role. Show less
In this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common... Show moreIn this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common psychiatric disorders. We found evidence of the involvement of serotonin, dopamine, and noradrenaline/the autonomic nervous system, but not the hypothalamic-pituitary-adrenal-axis, in the neurobiology of gSAD. As a result of our studies, we hypothesize that serotonin and dopamine function is decreased in gSAD, that there is hyperfunctioning of the autonomic nervous system, and that the other part of the stress system, the hypothalamic-pituitary-adrenal-axis function is not concordant with autonomic nervous system activation, as we saw in basal conditions, and in stress conditions following manipulation of the serotonergic system. We also think that there are indications that the female gonadal hormones also have a modulatory role in gSAD in a subgroup of women. This exploration of the neurobiology of gSAD leads to the conclusion that a variety of brain systems are involved in gSAD in a complex way.involvement of several neurotransmitter and hormonal systems in gSAD. Show less
We investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear... Show moreWe investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear and avoidance of social situations. Previous studies in animals and children showed a relation between increased fearfulness and avoidance and elevated cortisol levels, but the causal role of cortisol in these processes is not known. We found that, only in high socially anxious participants, cortisol administration or stress induction increased avoidance of social threat on an affect-evaluation computer task. Concurrent event-related potentials (brain activity measured with electrodes on the scalp) showed an associated increase in early processing of social threat. Another experiment indicated that the effects of cortisol on early threat processing are task dependent. We conclude that cortisol increases avoidance and facilitates or inhibits early processing of social threat in an adaptive manner, in line with the task goal. This effect is strongest in high anxious individuals, which are particularly sensitive to these threat signals. This knowledge can be relevant for the treatment of SAD, as cortisol levels may increase during exposure therapy, and also because cortisol administration has recently been proposed as a treatment for this disorder. Show less
Not everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have... Show moreNot everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse life events (stress) as risk factors. The objective of this thesis is to investigate the contribution of the adrenal stress hormones glucocorticoids and epinephrine to the psychostimulant effects of cocaine in the inbred DBA/2 and C57BL/6 mouse strains. Behavioural sensitisation, measured as an enhanced locomotor response to repeated cocaine exposure, was used as a model for the long-term neural adaptations underlying aspects of drug addiction. The results demonstrate that adrenal hormones play a critical role in cocaine sensitivity, which depends on genetic background because surgical removal of the adrenals (__adrenalectomy__) prevented cocaine sensitisation in DBA/2, but not C57BL/6 mice. The impact of genetic background was further emphasised by strain-specific changes in the midbrain dopamine system that mediates the rewarding effects of drugs. The effects of adrenalectomy could only be fully reversed by co-administration of glucocorticoids and epinephrine. These findings show that, depending on genetic background, adrenal stress hormones are important risk factors for vulnerability to cocaine, suggesting that pharmacological intervention in stress hormone action has therapeutic potential in drug addiction. Show less
