The role of stress in the biological embedding of experience - ISPNE 2023 Dirk Hellhammer Award.

in Psychoneuroendocrinology (2023), 156

Exposure to early adversity is one of the most important and pervasive risk factors for the development of nearly all major mental disorders across the lifespan. In the search for the mediating mechanisms ... [more ▼]

Exposure to early adversity is one of the most important and pervasive risk factors for the development of nearly all major mental disorders across the lifespan. In the search for the mediating mechanisms and processes that underlie long-term stability of these effects, changes to stress-associated hormonal and cellular signalling have emerged as prime candidates. This review summarises evidence showing that experience of early adversity in the form of childhood abuse or neglect and exposure to severe institutional deprivation influences multiple interconnected bio-behavioural, physiological and cellular processes. This paper focusses on dysregulations of hormonal stress regulation, altered DNA methylation pattern, changes to transcriptomic profiles in the context of stress-immune interplay, and mitochondrial biology. Consistent findings that have emerged include a relative cortisol hypoactivity and hyporeactivity in response to challenge, increased activity of pro-inflammatory genes, and altered mitochondrial function. The majority of investigations have focussed on single outcomes, but there is a clear rationale of conceiving the implicated physiological processes as interconnected parts of a wider stress-associated regulatory network, which in turn is connected to behaviour and mental disorders. This calls for integrated and longitudinal investigations to come to a more comprehensive understanding of the role of stress in the biological embedding of experience. The review concludes with considerations of how stress research can contribute to translational efforts through characterising subtypes of mental disorders which arise as a function of early adversity, and have distinct features of behavioral and biological stress processing. [less ▲]

Mitochondrial DNA as a marker for treatment-response in post-traumatic stress disorder.

in Psychoneuroendocrinology (2022), 148

Post-traumatic stress disorder (PTSD) is a serious mental health condition thought to be mediated by a dysregulated stress response system. Stress, especially chronic stress, affects mitochondrial ... [more ▼]

Post-traumatic stress disorder (PTSD) is a serious mental health condition thought to be mediated by a dysregulated stress response system. Stress, especially chronic stress, affects mitochondrial activity and their efficiency in duplicating their genomes. Human cells contain numerous mitochondria that harbor multiple copies of their own genome, which consist of a mixture of wild type and variant mtDNA - a condition known as mitochondrial heteroplasmy. Number of mitochondrial genomes in a cell and the degree of heteroplasmy may serve as an indicator of mitochondrial allostatic load. Changes in mtDNA copy number and the proportion of variant mtDNA may be related to mental disorders and symptom severity, suggesting an involvement of mitochondrial dysfunction also in PTSD. Therefore, we examined number and composition of mitochondrial DNA before and after six weeks of inpatient psychotherapy treatment in a cohort of 60 female PTSD patients. We extracted DNA from isolated monocytes before and after inpatient treatment and quantified cellular mtDNA using multiplex qPCR. We hypothesized that treatment would lead to changes in cellular mtDNA levels and that change in mtDNA level would be associated with PTSD symptom severity and treatment response. It could be shown that mtDNA copy number and the ratio of variant mtDNA decreased during therapy, however, this change did not correlate with treatment response. Our results suggest that inpatient treatment can reduce signs of mitochondrial allostatic load, which could have beneficial effects on mental health. The quantification of mtDNA and the determination of cellular heteroplasmy could represent valuable biomarkers for the molecular characterization of mental disorders in the future. [less ▲]

The mediating role of KITLG DNA methylation in the association between childhood adversity and cortisol stress reactivity does not replicate in monocytes

in Psychoneuroendocrinology (2020), 116

Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans

in Psychoneuroendocrinology (2019), 102

Cortisol modulates the engagement of multiple memory systems: Exploration of a common NR3C2 polymorphism

in Psychoneuroendocrinology (2019), 107

HPA axis dysregulation in adult adoptees twenty years after severe institutional deprivation in childhood

in Psychoneuroendocrinology (2017), 86

Acute stress influences the discrimination of complex scenes and complex faces in young healthy men

in Psychoneuroendocrinology (2016), 66

The stress-induced release of glucocorticoids has been demonstrated to influence hippocampal functions via the modulation of specific receptors. At the behavioral level stress is known to influence ... [more ▼]

The stress-induced release of glucocorticoids has been demonstrated to influence hippocampal functions via the modulation of specific receptors. At the behavioral level stress is known to influence hippocampus dependent long-term memory. In recent years, studies have consistently associated the hippocampus with the non-mnemonic perception of scenes, while adjacent regions in the medial temporal lobe were associated with the perception of objects, and faces. So far it is not known whether and how stress influences non-mnemonic perceptual processes. In a behavioral study, fifty male participants were subjected either to the stressful socially evaluated cold-pressor test or to a non-stressful control procedure, before they completed a visual discrimination task, comprising scenes and faces. The complexity of the face and scene stimuli was manipulated in easy and difficult conditions. A significant three way interaction between stress, stimulus type and complexity was found. Stressed participants tended to commit more errors in the complex scenes condition. For complex faces a descriptive tendency in the opposite direction (fewer errors under stress) was observed. As a result the difference between the number of errors for scenes and errors for faces was significantly larger in the stress group. These results indicate that, beyond the effects of stress on long-term memory, stress influences the discrimination of spatial information, especially when the perception is characterized by a high complexity. [less ▲]

Cortisol rapidly affects amplitudes of heartbeat-evoked brain potentials - Implications for the contribution of stress to an altered perception of physical sensations?

in Psychoneuroendocrinology (2013), 38(11), 2691-2698

Little is known about the impact of stress and stress hormones on the processing of visceral-afferent signals. Clinical data suggest that cortisol may lower the threshold for interoceptive stimuli, while ... [more ▼]

Little is known about the impact of stress and stress hormones on the processing of visceral-afferent signals. Clinical data suggest that cortisol may lower the threshold for interoceptive stimuli, while a pharmacological administration of cortisol decreases the sensitivity for physical symptoms. To clarify the role of cortisol for the processing of interoceptive signals, we investigated 16 healthy men on two occasions, once during the infusion of 4mg of cortisol and once during the infusion of a placebo substance. Heartbeat-evoked potentials (HEP; derived from resting EEG and ECG, during open and closed eyes), which are psychophysiological indicators for the cortical processing of cardioceptive signals, were measured over 6-min periods once before, and four times after the infusion (1-7, 11-17, 21-27 and 31-37min). We found that HEP amplitudes were higher during open than during closed eyes between 1 and 17min after cortisol infusion. There was no effect of cortisol on heart rate. We conclude that cortisol may rapidly modulate the cortical processing of cardioceptive neural signals. These results may have relevance for the effects of stress on the development and maintenance of psychosomatic symptoms. [less ▲]

Stress response and humoral immune system alterations related to chronic hypergravity in mice

in Psychoneuroendocrinology (2012), 37(1), 137-147

Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The ... [more ▼]

Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNγ and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level. [less ▲]

Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone

in Psychoneuroendocrinology (2010), 35(3), 339-349