Early life stress

Impact of environmental stress upon pathophysiology of the metabolic syndrome (MetS) has been substantiated by epidemiological, psychophysiological, and endocrinological studies. This review discusses recent advances in the understanding of causative roles of nutritional factors, sympathomedullo-adrenal (SMA) and hypothalamic-pituitary adrenocortical (HPA) axes, and adipose tissue chronic low-grade inflammation processes in MetS. Disturbances in the neuroendocrine systems for leptin, melanocortin, and neuropeptide Y (NPY)/agouti-related protein systems have been found resulting directly in MetS-like conditions. The review identifies candidate risk genes from factors shown critical for the functioning of each of these neuroendocrine signaling cascades. In its meta-analytic part, recent studies in epigenetic modification (histone methylation, acetylation, phosphorylation, ubiquitination) and posttranscriptional gene regulation by microRNAs are evaluated. Several studies suggest modification mechanisms of early life stress (ELS) and diet-induced obesity (DIO) programming in the hypothalamic regions with populations of POMC-expressing neurons. Epigenetic modifications were found in cortisol (here HSD11B1 expression), melanocortin, leptin, NPY, and adiponectin genes. With respect to adiposity genes, epigenetic modifications were documented for fat mass gene cluster APOA1/C3/A4/A5, and the lipolysis gene LIPE.With regard to inflammatory, immune and subcellular metabolism, PPARG, NKBF1, TNFA, TCF7C2, and those genes expressing cytochrome P450 family enzymes involved in steroidogenesis and in hepatic lipoproteins were documented for epigenetic modifications.

Objective: To identify modifiable, social factors that moderate the relationship between early-life stress (ELS) and health outcomes as measured by depressive symptoms and inflammation. Methods: Data were from 3,416 adults (58.28% female), ages 36 - 97 (Mage = 68.41; SDage = 10.24) who participated in the 2006 wave of the Health and Retirement Study, a nationally representative sample of older adults in the United States. This study used hierarchical regression analyses to first test the main effects of ELS on depressive symptoms and inflammation (high-sensitivity C-reactive protein). Four social factors (perceived support, frequency of social contact, network size, and volunteer activity) were assessed as moderators of the ELS depression and ELS-inflammation relationships. Results: There was a small, positive association between ELS and depressive symptoms (B = 0.17, SE = 0.05, p = .002), which was moderated by social contact and perceived support. Specifically, ELS was only associated with elevated depressive symptoms for participants with limited social contact (B = 0.24, SE = 0.07, p < .001) and low perceived support (B = 0.24, SE = 0.07, p < .001). These associations remained after accounting for potential confounds (age, body-mass index, adulthood stress, and marital status). Conclusions: Increased social contact and perceived support may be protective for individuals at a higher risk of developing depressive symptoms as a result of ELS. Future interventions may benefit from leveraging these social factors to improve quality of life in adults with ELS.

Internationally adopted postinstitutionalized (PI) children are at risk for lower levels of emotion understanding. This study examined how postadoption parenting influences emotion understanding and whether lower levels of emotion understanding are associated with behavior problems. Emotion understanding and parent mental state language were assessed in 3-year-old internationally adopted PI children (N ¼ 25), and comparison groups of children internationally adopted from foster care (N ¼ 25) and nonadopted (NA) children (N ¼ 36). At 5.5-year follow-up, PI children had lower levels of emotion understanding than NA children, a group difference not explained by language. In the total sample, parent mental state language at age 3 years predicted 5.5-year emotion understanding after controlling for child language ability. The association of parent mental state language and 5.5-year emotion understanding was moderated by adoption status, such that parent mental state language predicted 5.5-year emotion understanding for the internationally adopted children, but not for the NA children. While postadoption experience does not erase negative effects of early deprivation on emotion understanding, results suggest that parents can promote emotion understanding development through mental state talk. At 5.5 years, PI children had more internalizing and externalizing problems than NA children, and these behavioral problems related to lower levels of emotion understanding.

Previous studies have shown that socio-demographic factors, childhood socioeconomic status (CSES), childhood traumatic experiences (CTEs), social support and behavioral factors are associated with health and well-being in adulthood. However, the relative importance of these factors for mental health, health, and well-being has not been studied. Moreover, the mechanisms by which CTEs affect mental health, health, and well-being in adulthood are not clear. Using data from a representative sample (n = 12,981) of the adult population in Tromsø, Norway, this study examines (i) the relative contribution of structural conditions (gender, age, CSES, psychological abuse, physical abuse, and substance abuse distress) to social support and behavioral factors in adulthood; (ii) the relative contribution of socio-demographic factors, CSES, CTEs, social support, and behavioral factors to three multi-item instruments of mental health (SCL-10), health (EQ-5D), and subjective well-being (SWLS) in adulthood; (iii) the impact of CTEs on mental health, health, and well-being in adulthood, and; (iv) the mediating role of adult social support and behavioral factors in these associations. Instrumental support (24.16%, p < 0.001) explained most of the variation in mental health, while gender (21.32%, p < 0.001) explained most of the variation in health, and emotional support (23.34%, p < 0.001) explained most of the variation in well-being. Psychological abuse was relatively more important for mental health (12.13%), health (7.01%), and well-being (9.09%), as compared to physical abuse, and substance abuse distress. The subjective assessment of childhood financial conditions was relatively more important for mental health (6.02%), health (10.60%), and well-being (20.60%), as compared to mother's and father's education. CTEs were relatively more important for mental health, while, CSES was relatively more important for health and well-being. Respondents exposed to all three types of CTEs had a more than two-fold increased risk of being mentally unhealthy (RR Total Effect = 2.75, 95% CI: 2.19–3.10), an 89% increased risk of being unhealthy (RR Total Effect = 1.89, 95% CI: 1.47–1.99), and a 42% increased risk of having a low level of well-being in adulthood (RR Total Effect = 1.42, 95% CI: 1.29–1.52). Social support and behavioral factors mediate 11–18% (p < 0.01) of these effects. The study advances the theoretical understanding of how CTEs influence adult mental health, health, and well-being.

Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the patho-genesis of depression, being well established as acute triggers of psychiatric illness. The vulnerability for developing depression is associated to changes in neurobiological systems related to stress regulation. The hypothalamic-pituitary-adrenal (HPA) axis responds to external and internal stimuli. Reported results indicate that stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to depression. These abnormalities appear to be related to the HPA axis deregulation in depression, partially due to an imbalance between glucocorticoid receptors (GR) and mineral ocorticoid receptors (MR). While most studies have consistently demonstrated that GR function is impaired in major depression (reduced GR-mediated feedback in HPA axis), data about the MR role in depression are still limited and controversial. Thus, in this review article we summarize the main reported findings about the consequences of ELS in HPA axis functioning and in the responsivity of MR/GR receptors in depression.

Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.

Exposure to early life stress (ELS) is strongly associated with poor treatment outcomes, particularly for trauma-associated disorders such as depression. Little research to date, however, has examined the potential effects of ELS on outcomes with newer treatments, such as repetitive transcranial magnetic stimulation (rTMS). This study evaluated whether ELS exposure impacts resting state functional connectivity associated with brain regions targeted by rTMS. Twenty-seven medication-free adults without psychiatric or medical illness (14 with a history of at least moderate ELS) were scanned using a 3T magnetic resonance imaging (MRI) scanner during two 4-minute rest periods. The primary targets of rTMS, the left and right dorsolateral prefrontal cortex (DLPFC), were utilized as seed regions in connectivity analyses. Relative to controls, when seeding the left DLPFC, ELS subjects demonstrated significantly increased local connectivity with the left middle frontal gyrus and negative connectivity with the left precuneus. ELS status was also associated with negative connectivity from the right DLPFC to the left precuneus and left inferior parietal lobule. These findings demonstrate greater dissociation between the executive and default mode networks in individuals with a history of ELS, and these results may inform neuroimaging assessments in future rTMS studies of ELS-related conditions.

Early life experiences program lifelong responses to stress. In agreement, resilience and vulnerability to psychopathologies, such as posttraumatic stress disorder (PTSD), have been suggested to depend on the early background. New therapies have targeted memory reconsolidation as a strategy to modify the emotional valence of traumatic memories. Here, we used animal models to study the molecular mechanism through which early experiences may later affect aversive memory reconsolidation. Handling (H)-separation of pups from dams for 10 minor maternal separation (MS)-3-h separation-were performed from PDN1-10, using non-handled (NH) litters as controls. Adult males were trained in a contextual fear conditioning (CFC) task; 24 h later, a short reactivation session was conducted in the conditioned or in a novel context, followed by administration of midazolam 3 mg/kg i.p. (mdz), known to disturb reconsolidation, or vehicle; a test session was performed 24 h after. The immunocontent of relevant proteins was studied 15 and 60 min after memory reactivation in the dorsal hippocampus (dHc) and basolateral amygdala complex (BLA). Mdz-treated controls (NH) showed decreased freezing to the conditioned context, consistent with reconsolidation impairment, but H and MS were resistant to labilization. Additionally, MS males showed increased freezing to the novel context, suggesting fear generalization; H rats showed lower freezing than the other groups, in accordance with previous suggestions of reduced emotionality facing adversities. Increased levels of Zif268, GluN2B, β-actin and polyubiquitination found in the BLA of all groups suggest that memory reconsolidation was triggered. In the dHc, only NH showed increased Zif268 levels after memory retrieval; also, a delay in ERK1/2 activation was found in H and MS animals. We showed here that reconsolidation of a contextual fear memory is insensitive to interference by a GABAergic drug in adult male rats exposed to different neonatal experiences; surprisingly, we found Frontiers in Molecular Neuroscience | www.frontiersin.org 1 May 2019 | Volume 12 | Article 134

Early-life adversity is associated with increased vulnerability to depression in humans, and depression-like phenotypes in animals. However, different types of adverse experience may leave different signatures in adulthood. We experimentally manipulated the Amount of food delivered to European starling nestlings and the begging Effort required to obtain food during early development. Here, we report behavioural data in adulthood from a task that assessed sensitivity to shifts in reward magnitude characteristic of depression-like low mood. Birds that had experienced Hard Effort were more food motivated than birds that had experienced Easy Effort. Both Effort and Amount affected sensitivity to shifts in reward magnitude: Hard Effort birds showed an enhanced negative contrast effect following loss of reward ('disappointment'), and Lean Amount birds failed to show a normal positive contrast effect following gain in reward (a lack of 'elation'). Therefore, the feeding schedule experienced for just 10 days in early life caused enduring effects on feeding motivation and sensitivity to reward loss/gain consistent with human depression. Furthermore, the contrast effects were specific to different types of adversity. These results highlight the importance of early-life feeding schedules in the development of depression-like phenotypes. In humans, various types of early-life adversity including physical and emotional neglect, abuse and trauma are associated with increased vulnerability to mood disorders in later life 1–3. We propose two possible models of the association between early-life adversity and an adult depressive phenotype. According to a 'common pathway' model (Fig. 1a), different types of adversity all feed into a common mechanism that in turn influences the adult phenotype in a range of different ways (e.g. calibration of the developing HPA axis or disruption of hippocampal structure 4,5). Alternatively, according to a 'specific effects' model (Fig. 1b), specific types of early-life adversity cause specific phenotypic outcomes via a range of different mechanisms 6,7. Recent evidence hints that the type and timing of childhood exposure to adversity could be critical in determining its subsequent consequences for the development of mood disorders 8. However, due to the fact that different types of adversity tend to be correlated in humans 6,9 , it is challenging to conclusively identify specific effects using epidemiological human data. Animal studies in which different sources of adversity are experimentally manipulated are necessary to conclusively test causal hypotheses. Substantial effort has been devoted to the creation and study of experimental animal models of the effects of early-life adversity in laboratory rodents 10,11. Many of these models involve manipulations in which pups are temporarily separated from the mother for varying periods in the first two weeks after birth 10. In the light of the discussion above, one criticism of these rodent paradigms is that, like the human epidemiological studies, they typically confound different sources of adversity (e.g. malnutrition, hypothermia, lack of grooming, physical contact and protection). Few rodent studies have attempted to experimentally dissociate the effects of different developmental adversities on subsequent phenotypes. In one exception, Crnic et al. 12 tested the moderating effects of providing rat pups removed from their mother and deprived of food for 12 hours a day with a non-lactating aunt. While some differences in behaviour and in brain biochemistry were found between the isolated pups and those

Psychiatric disorders are multifactorial diseases with etiology that may involve genetic factors, early life environment and stressful life events. The neurodevelopmental hypothesis of schizophrenia is based on a wealth of data on increased vulnerability in individuals exposed to insults during the perinatal period. Maternal deprivation (MD) disinhibits the adrenocortical response to stress in neonatal rats and has been used as an animal model of schizophrenia. To test if long-term affective consequences of early life stress were influenced by maternal presence, we submitted 10-day old rats, either deprived (for 22 h) or not from their dams, to a stress challenge (i.p. saline injection). Corticosterone plasma levels were measured 2 h after the challenge, whereas another subgroup was assessed for behavior in the open field, elevated plus maze (EPM), social investigation and the negative contrast sucrose consumption test in adolescence (postnatal day 45). Maternally deprived rats exhibited increased plasma corticosterone (CORT) levels which were higher in maternally deprived and stress challenged pups. Social investigation was impaired in maternally deprived rats only, while saline injection, independently of MD, was associated with increased anxiety-like behavior in the EPM and an impaired intake decrement in the negative sucrose contrast. In the open field, center exploration was reduced in all maternally-deprived adolescents and in control rats challenged with saline injection. The most striking finding was that exposure to a stressful stimulus per se, regardless of MD, was linked to differential emotional consequences. We therefore propose that besides being a well-known and validated model of schizophrenia in adult rats, the MD paradigm could be extended to model early signs of psychiatric dysfunction, and would particularly be a useful tool to detect early signs that resemble schizophrenia.