The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.

in Translational psychiatry (2023), 13(1), 265

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG ... [more ▼]

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites. [less ▲]

Proteome analysis of monocytes implicates altered mitochondrial biology in adults reporting adverse childhood experiences.

in Translational psychiatry (2023), 13(1), 31

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations ... [more ▼]

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14(+) monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology. [less ▲]

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 ▲]

A matter of habit? Stressful life events and cognitive flexibility in 15-month-olds

in Infant Behavior and Development (2023), 71 file://localhost/Users/robert.kumsta/Documents/Papers%20Library/Tisborn-A%20matter%20of%20habit-%20Stressful%20life%20events%20and%20cognitive%20flexibility%20in%2015-month-olds-2023-Infant%20Behavior%20and%20Development.pdf

Exposure to chronic stress is associated with habitual learning in adults. We studied the origins of this association by examining the link between stressful life events and infant cognitive flexibility ... [more ▼]

Exposure to chronic stress is associated with habitual learning in adults. We studied the origins of this association by examining the link between stressful life events and infant cognitive flexibility. The final sample consisted of N = 72 fifteen-month-old infants and their mothers. Mothers completed a survey on pre- and postnatal negative life events. To assess chronic stress physiologically, infant and maternal hair cortisol concentrations were determined for cortisol accumulation during the past 3 months. Each infant participated in two cognitive tasks in the laboratory. An instrumental learning task tested infants’ ability to disengage from a habituated action when this action became ineffective (Seehagen et al., 2015). An age-adequate version of the A-not-B task tested infants’ ability to find a toy at location B after repeatedly finding it at location A. Correlations between cortisol concentrations and postnatal negative life events (number, perceived impact) did not yield significance. Infant and maternal hair cortisol concentrations were not correlated. Infants’ ability to shift to a new action in either task, controlled for acute stress, correlated neither with pre- and postnatal negative life events nor with cortisol concentrations. Taken together, these results indicate that the potential link between long-term stress exposure and cognitive flexibility might not be present in samples with low levels of psychosocial stress. [less ▲]

Investigating subjective well-being and mental health of children in out-of-home care during the COVID-19 pandemic

Scientific Conference (2022, September 15)

No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder.

in Scientific reports (2022), 12(1), 17347

DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent ... [more ▼]

DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD. [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 ▲]

Less efficient cognitive pain modulation in healthy older adults – the impact of executive functions, chronic stress, and physical activity

in Heinrichs, Markus; Schönauer, Monika (Eds.) 47. Jahrestagung Psychologie und Gehirn (2022)

Demographic change and the associated increasing prevalence of chronic pain have contributed to increased research interest in the field of aging. Aging has been associated with less efficient pain ... [more ▼]

Demographic change and the associated increasing prevalence of chronic pain have contributed to increased research interest in the field of aging. Aging has been associated with less efficient pain inhibition through cognitive distraction. As pain modulation and executive functioning mainly involve the prefrontal cortical network, which shows age-related atrophy, we hypothesized an association between deteriorating cognitive modulation of pain in healthy older adults and reduced executive functions. As chronic stress can decrease executive functioning through prefrontal cortical impairment, we expected a negative impact on distraction from pain. In contrast, physical activity can have a stress-buffering effect and positively influences executive functions in older age. Therefore, increased physical activity should lead to better distraction from pain. Healthy young (18 -30 years) and older adults (65+ years) took part in a pain distraction paradigm (N-back) while receiving non-painful and moderately painful electric stimuli. Before, we examined executive functions, including response inhibition (Go/No-Go-task), inhibitory control (Stroop task), and working memory (Sternberg task). Additionally, chronic stress and physical activity were assessed using self-report questionnaires, supported by physiological measurements (heart rate variability). Preliminary results indicate a negative impact of chronic stress on distraction from pain particular in young participants, while physical fitness was related to more successful pain modulation in older adults. Our final results will contribute to a more differentiated view on executive functioning and pain modulation in aging, thereby leading to a better understanding of the impact of aging on non-pharmacological pain treatment and to better adapted pain therapies in this population. [less ▲]

Polygenic scores for handedness and their association with asymmetries in brain structure

in Brain Structure and Function (2021)

The brain under stress—A systematic review and activation likelihood estimation meta-analysis of changes in BOLD signal associated with acute stress exposure

in Neuroscience and Biobehavioral Reviews (2021), 124