Search

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behaviour. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene.

Lasting changes in the hypothalamic-pituitary-adrenal (HPA) axis are a potential indication of the biological embedding of early life adversity, yet, prospective and repeatedly collected data are needed to confirm this relation. Likewise, integrating information from multiple biological systems, such as the HPA axis and the epigenome, has the potential to identify individuals with enhanced embedding of early life adversity. The current study reports results from the Female Growth and Development Study, a 30-year prospective cohort study of childhood sexual abuse (CSA). Females exposed to substantiated CSA and a demographically-similar comparison condition were enrolled and resting state cortisol concentrations were sampled on seven subsequent occasions across childhood, adolescence, and adulthood. Differences in participants’ cortisol trajectories were examined in relation to prior CSA exposure and DNA methylation-derived epigenetic age acceleration at midlife. Bilinear spline growth models revealed a trajectory where cortisol secretion increased until approximately age twenty and then declined into mid-life, consistent with normative trends. However, cortisol concentrations peaked at a lower level and transitioned to the decline phase at an earlier age for females in the CSA condition with increased epigenetic age acceleration. Robustness tests across three independent measures of epigenetic age acceleration demonstrated similar results for lower peak cortisol levels and earlier ages at transition. Results suggest that CSA is associated with significant changes in HPA-axis activity over extended periods of time with these changes most pronounced in females with accelerated epigenetic aging in mid-life. Implications for biological embedding models of early life adversity and adulthood health are discussed.

Maternal behavior (MB) is observable across mammals and represents an important feature of environmental variation during early postnatal development. Oxytocin (OT) plays a crucial role in MB. Even prior to childbirth, pregnancy induces epigenetic and other downstream changes in the maternal OT-system, likely mediated by the actions of steroid hormones. However, little is known about the nature and consequences of epigenetic modifications in the maternal OT-encoding gene (OXT) during pregnancy. Our study aims to investigate temporal dynamics of OXT promoter DNA methylation (DNAm) throughout pregnancy in predicting MB in humans. In 107 mother-child dyads, maternal OXT DNAm was serially analyzed in whole blood in early, mid and late pregnancy. MB was coded based on standardized mother-child interactions at six months postpartum. After controlling for cellular heterogeneity, race/ethnicity, age, and socioeconomic status, OXT-promoter DNAm exhibited a dynamic profile during pregnancy (b = 0.026, t=−3.37, p < .001), with decreases in DNAm from early to mid-pregnancy and no further change until late pregnancy. Moreover, dynamic DNAm trajectories of the OXT-promoter region predicted MB (intrusiveness) at six months postpartum (b = 0.006, t = 2.0, p < 0.05), with 6% higher OXT DNAm in late pregnancy in intrusive compared to non-intrusive mothers. We here demonstrate that OXT promoter DNAm changes significantly throughout gestation in peripheral blood and that these changes are associated with variability in MB, providing a novel potential biomarker predicting postnatal MB.

Overexposure of the developing fetus to glucocorticoids is a key mechanism linking early development with later life disease. In humans low birthweight, a marker of an adverse in utero environment, associates with increased fasting cortisol, increased hypothalamic-pituitary-adrenal (HPA) axis reactivity and with cardiovascular risk factors, cardiovascular disease and poorer cognitive function. Animal models suggest the HPA axis of female offspring is more susceptible to programming insults. We hypothesised that there would be similar sex differences in humans. We carried out a systematic review, searching Embase, Medline and Web of Science up to June 2014. Two independent researchers screenedarticles for eligibility. The29 includedstudies investigated the consequences of maternal stressors of asthma, psychosocial stress and glucocorticoid medications on HPA axis outcomes of placental glucocorticoid biology, and HPA axis function in earlyand later-life. Overall, the studies reported sex differences such that female offspring were more responsive to stress both in earlyand later-life: females had lower birthweight, increased therapeutic responsiveness to glucocorticoids, increased diurnal cortisol secretion and HPA axis reactivity, compared to males. Further, in comparison to males, the female placenta increased its permeability to maternal glucocorticoids following maternal stress with downregulation of the enzyme 11-beta-hydroxysteroid dehydrogenase (which converts active cortisol to inactive cortisone) in response to maternal glucocorticoid exposure or maternal asthma. Theobservationsof increasedprogrammedvulnerabilityof theHPA axis in females is consistentwith data fromanimalmodels andmay be a mechanism underlying sex differences in later life diseases including depression and cardiometabolic disease.

Adverse conditions early in life have been identified as risk factors for the susceptibility for psychopathology during adolescence and adulthood. A change in the regulation of stress response systems has been discussed as potential mechanism linking early life stress to later psychopathology. Over the past several years, we have gathered data from several independent studies assessing the regulation of the hypothalamic–pituitary–adrenal (hpa) axis, the sympathetic and parasympathetic nervous system, and the volume of key brain structures involved in the regulation of these systems, to investigate the effects of various forms of early life adversity. All studies consistently show effects of early life adversity on the regulation of the stress response systems. However, the directionality of the effect appears to be variable. For cortisol as a marker of the hpa axis, subjects with low early life parental care show signs of changed cortisol awakening response, afternoon cortisol output, and cortisol stress responses, when compared to subjects with average parental care scores. For sympathetic and parasympathetic nervous system, results point to a systematic cross-talk with the hpa axis, depending on specific aspects of early-life adversity. The changes in the regulation of these systems map on to the changes of distinct areas in the central nervous system believed to be involved in the regulation of the stress response systems. Together, the differential regulation of these systems suggest that specific stress response endophenotypes emerge as a consequence of experiences during critical development periods early in life.

Interest in the mechanisms whereby stressors can influence behavior and physiological functioning has involved the use of a variety of methods to prevent the stress-induced release of glucocorticoids, an important and commonly studied stress hormone. We examined the effect of intracerebral ventricular dexamethasone (ICV DEX) on the stress-induced release of adrenocorticotropic hormone (ACTH), corticosterone, plasma epinephrine (E), and plasma norepinephrine (NE). Male Sprague-Dawley rats were stereotaxically implanted with third ventricle ICV cannulae, administered DEX or vehicle, and exposed to 100 1.6-mA tail shocks. Stress hormones were assessed from blood taken during and after the cessation the shock. We report an ICV DEX injection protocol (10 microgram given four times) that results in blocking the stress-induced release of ACTH and corticosterone, and attenuating the stress-induced release of plasma E and NE. We hypothesize that ICV DEX reduces hypothalamic corticotropin releasing hormone (CRH) synthesis and/or release. This method would be especially useful for those studying the effect of pituitary-adrenal hormones on steroid sensitive peripheral targets, such as the immune system.

Several years ago Levine, Denenberg, Weininger, Ader, and others described the effects of postnatal “handling” on the development of behavioral and endocrine responses to stress. The handling procedure usually involved removing rat pups from their cages, placing the animals together in small containers, and 15–20 min later, returning the animals to their cages and their mothers. The manipulation was performed daily for the first 21 days of life. As adults, handled (H) rats exhibited attenuated fearfulness (e.g., decreased freezing, increased exploration) in novel environments and a less pronounced increase in the secretion of adrenal glucocorticoids in response to a variety of stressors. These findings clearly demonstrated that the development of rudimentary, adaptive responses to stress could be modified by environmental events. We have followed on these earlier handling studies, convinced that this paradigm provides a marvelous opportunity to examine how subtle variations in the early environment alter the development of specific biochemical systems in the brain, leading to stable individual differences in biological responses to stimuli that threaten homeostasis. In this work we have shown how early handling influences the neurochemical development of certain brain regions that regulate the adrenocortical response to stress. Neonatal handling increases the efficiency of this endocrine response to stress, preventing excessive exposure to the highly catabolic adrenal steroids. In later life, this effect appears to protect the animal from potentially damaging effects of these steroids, ensuring the anatomical integrity of brain structures involved in cognitive functioning.

Repeated periods of maternal separation in the early life of rats decreased dopamine transporter expression and significantly increased dopamine responses to stress, and behavioral responses to either stress or cocaine. As adults, maternal separation animals showed increased sensitivity to the effects of cocaine on locomotor activity and greater sensitivity to stress-induced sensitization to the effects of amphetamine on locomotor activity. These findings raise the possibility that in addition to effects on stress reactivity, early life events might dispose individuals to illness in later life through effects on very specific neurotransmitter systems.