ABSTRACT
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.
Subject(s)
Kynurenine/metabolism , Mitochondria/metabolism , Stress, Physiological/physiology , Adaptation, Physiological/physiology , Allostasis/physiology , Animals , Brain/metabolism , Cell Respiration/physiology , Energy Metabolism/physiology , Hippocampus/metabolism , Immunity/physiology , Kynurenine/physiology , Male , Prefrontal Cortex/metabolism , Rats , Rats, Inbred WF , Stress, Psychological/metabolismABSTRACT
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.
Subject(s)
Adult Survivors of Child Abuse/psychology , Dehydroepiandrosterone/analysis , Hair/chemistry , Hydrocortisone/analysis , Mothers/psychology , Pregnancy Complications/metabolism , Adult , Child Development , Female , Humans , Hypothalamo-Hypophyseal System , Infant, Newborn , Parturition/metabolism , Pituitary-Adrenal System , Pregnancy , Pregnancy Complications/psychology , Pregnancy Trimester, Third/metabolism , Surveys and QuestionnairesABSTRACT
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.