Activation of the kynurenine pathway and mitochondrial respiration to face allostatic load in a double-hit model of stress.

Allostasis is the process by which the body's physiological systems adapt to environmental changes. Chronic stress increases the allostatic load to the body, producing wear and tear that could, over time, become pathological. In this study, young adult male Wistar Kyoto rats were exposed to an unpredictable chronic mild stress (uCMS) protocol to increase allostatic load. First, physiological systems which may be affected by extended uCMS exposure were assessed. Secondly, 5 weeks of uCMS were used to investigate early adaptations in the previously selected systems. Adverse experiences during developmentally sensitive periods like adolescence are known to severely alter the individual stress vulnerability with long-lasting effects. To elucidate how early life adversity impacts stress reactivity in adulthood, an additional group with juvenile single-housing (JSH) prior to uCMS was included in the second cohort. The aim of this work was to assess the impact of chronic stress with or without adversity during adolescence on two domains known to be impacted in numerous stress-related disorders: mitochondrial energy metabolism and the immune system. Both, uCMS and adolescence stress increased kynurenine and kynurenic acid in plasma, suggesting a protective, anti-oxidant response from the kynurenine pathway. Furthermore, uCMS resulted in a down-regulation of immediate early gene expression in the prefrontal cortex and hippocampus, while only rats with the double-hit of adolescent stress and uCMS demonstrated increased mitochondrial activity in the hippocampus. These results suggest that early life adversity may impact on allostatic load by increasing energetic requirements in the brain.

Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment.

BACKGROUND: Child maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring's endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns' hair. METHODS: CM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn's cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models. RESULTS: Higher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns' hair. CONCLUSIONS: Results suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus.

Childhood maltreatment, postnatal distress and the protective role of social support.

The postpartum period is a vulnerable period for women with a history of childhood maltreatment. This study investigated the association between childhood maltreatment and postnatal distress three months postpartum and examined the role of social support provided by different sources (intimate partner, parents, parents-in-law, and friends). Analyses are based on N=66 women, who were screened for maltreatment experiences shortly after parturition with the Childhood Trauma Questionnaire. Their levels of postnatal distress (symptoms of depression, anxiety, and stress; assessed with the Hospital Anxiety and Depression Scale and the 4-Item version of the Perceived Stress Scale) and postpartum social support (measured with the Postpartum Social Support Questionnaire) were assessed three months postpartum. Adjusting for educational level and the experience of a recent stressful event, childhood maltreatment was directly associated with higher levels of postnatal distress. Social support provided by friends moderated this association in a heteroscedastic regression analysis. No moderating effect was observed for support provided by the own parents, the intimate partner, or parents-in-law. The association between childhood maltreatment and postnatal distress was not mediated by social support. Additional analyses revealed no main, moderating, or mediating effects of satisfaction with support. Results suggest that support provided by friends may promote resilience during the postpartum period in women with a history of childhood maltreatment. Efforts to better understand the role of postpartum support and mechanisms that may enhance a mother's ability to develop and maintain supportive friendships may be promising for guiding preventive interventions.

Psychosocial Risk Factors for Child Welfare among Postpartum Mothers with a History of Childhood Maltreatment and Neglect.

Background: Childhood maltreatment (CM) can increase the risk of psychosocial risk factors in adulthood (e. g. intimate partner violence, financial problems, substance abuse or medical problems). The transition to parenthood presents those affected by CM with particular challenges, in addition to usual birth-related stressors. Methods: In this cross-sectional study a total of 240 women were interviewed in the puerperium with respect to CM experiences, using the German version of the Childhood Trauma Questionnaire (CTQ). Current psychosocial risk factors (e. g. financial concerns, maternal mental illness, single parent) were assessed using the Constance Index (KINDEX) for early childhood risk factors. Associations between CM experience and psychosocial risk factors were calculated using simple correlation. Results: The average age of participants was 33 years. On the CTQ 13.8 % of participants reported emotional abuse, 6.7 % physical abuse and 12.5 % sexual abuse, while 32.1 % reported emotional neglect and 7.5 % physical neglect during childhood. With rising severity of CM, more psychosocial risk factors (KINDEX) were present. Conclusions: This study shows a clear association between experiences of maltreatment during childhood and the presence of psychosocial stressors among women in the puerperium. Regular screening for a history of CM and parental psychosocial stressors should be conducted early, i.e. during pregnancy, to avoid negative consequences for the child.

The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder.

Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.

Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression.

Mitochondrial dysfunction might have a central role in the pathophysiology of depression. Phenotypically, depression is characterized by lack of energy, concentration problems and fatigue. These symptoms might be partially explained by reduced availability of adenosine triphosphate (ATP) as a consequence of impaired mitochondrial functioning. This study investigated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), an established model to investigate the pathophysiology of depression. Mitochondrial respiration was assessed in intact PBMCs in 22 individuals with a diagnosis of major depression (MD) compared with 22 healthy age-matched controls using high-resolution respirometry. Individuals with MD showed significantly impaired mitochondrial functioning: routine and uncoupled respiration as well as spare respiratory capacity, coupling efficiency and ATP turnover-related respiration were significantly lower in the MD compared with the control group. Furthermore, mitochondrial respiration was significantly negatively correlated with the severity of depressive symptoms, in particular, with loss of energy, difficulties concentrating and fatigue. The results suggest that mitochondrial dysfunction contributes to the biomolecular pathophysiology of depressive symptoms. The decreased immune capability observed in MD leading to a higher risk of comorbidities could be attributable to impaired energy supply due to mitochondrial dysfunction. Thus mitochondrial respiration in PBMCs and its functional consequences might be an interesting target for new therapeutical approaches in the treatment of MD and immune-related comorbidities.

N-glycosylation profiling of plasma provides evidence for accelerated physiological aging in post-traumatic stress disorder.

The prevalence of age-related diseases is increased in individuals with post-traumatic stress disorder (PTSD). However, the underlying biological mechanisms are still unclear. N-glycosylation is an age-dependent process, identified as a biomarker for physiological aging (GlycoAge Test). To investigate whether traumatic stress accelerates the aging process, we analyzed the N-glycosylation profile in n=13 individuals with PTSD, n=9 trauma-exposed individuals and in n=10 low-stress control subjects. Individuals with PTSD and trauma-exposed individuals presented an upward shift in the GlycoAge Test, equivalent to an advancement of the aging process by 15 additional years. Trauma-exposed individuals presented an intermediate N-glycosylation profile positioned between severely traumatized individuals with PTSD and low-stress control subjects. In conclusion, our data suggest that cumulative exposure to traumatic stressors accelerates the process of physiological aging.