Effects Of Early Life Adversity Research Articles

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

BackgroundBrain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder.MethodsBrain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined.ResultsSubjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity.ConclusionsThis study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Consequences of early life stress on genomic landscape of H3K4me3 in prefrontal cortex of adult mice

BackgroundMaternal separation models in rodents are widely used to establish molecular mechanisms underlying prolonged effects of early life adversity on neurobiological and behavioral outcomes in adulthood. However, global epigenetic signatures following early life stress in these models remain unclear.ResultsIn this study, we carried out a ChIP-seq analysis of H3K4 trimethylation profile in the prefrontal cortex of adult male mice with a history of early life stress. Two types of stress were used: prolonged separation of pups from their mothers (for 3 h once a day, maternal separation, MS) and brief separation (for 15 min once a day, handling, HD). Adult offspring in the MS group demonstrated reduced locomotor activity in the open field test accompanied by reduced exploratory activity, while the HD group showed decreased anxiety-like behavior only. In a group of maternal separation, we have found a small number (45) of slightly up-regulated peaks, corresponding to promoters of 70 genes, while no changes were observed in a group of handling. Among the genes whose promoters have differential enrichment of H3K4me3, the most relevant ones participate in gene expression regulation, modulation of chromatin structure and mRNA processing. For two genes, Ddias and Pip4k2a, increased H3K4me3 levels were associated with the increased mRNA expression in MS group.ConclusionThe distribution of H3K4me3 in prefrontal cortex showed relatively low variability across all individuals, and only some subtle changes were revealed in mice with a history of early life stress. It is possible that the observed long-lasting behavioral alterations induced by maternal separation are mediated by other epigenetic mechanisms, or other brain structures are responsible for these effects.

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life.

10.0 Behavioral, Biological, and Epigenetic Consequences of Early Life Adversity in Children, Adolescents, and Monkeys

10.0 Behavioral, Biological, and Epigenetic Consequences of Early Life Adversity in Children, Adolescents, and Monkeys

Early life adversity potentiates expression of addiction-related traits

Many individuals sporadically and circumstantially sample addictive drugs, yet few become addicted. The individual vulnerabilities underlying the development of addiction are not well understood. Correlational findings show that early life adversity is associated with a greater propensity to develop drug addiction. However, the mechanisms by which early life adversity increases addiction vulnerability are unknown. Separate lines of research have found that several traits are associated with addiction. Here, we examined the effects of early life adversity on addiction-related traits in adulthood. We weaned male and female Sprague-Dawley rats (postnatal day – PND21) and randomly assigned them to either a non-adversity group (N-ADV) or an adversity group (ADV). ADV rats experienced adversity from PND 21-35, they were: a) singly housed, b) food restricted for 12h/day, c) subjected to forced-swim sessions, and d) restrained and exposed to predator odour (1h). As adults, rats were tested for impulsivity, anxiety-like behaviour, novelty preference, and attribution of incentive salience to a reward cue. ADV rats showed enhanced novelty preference and attributed greater incentive value to a reward cue. Compared to N-ADV rats, a greater proportion of ADV rats expressed multiple addiction risk traits. Furthermore, fewer ADV rats expressed no addiction risk traits. This effect was most evident in female ADV rats.

Prevent, Screen, Heal: Collective Action to Fight the Toxic Effects of Early Life Adversity

Prevent, Screen, Heal: Collective Action to Fight the Toxic Effects of Early Life Adversity

Impact of early life adversity and tryptophan depletion on functional connectivity in menopausal women: A double-blind, placebo-controlled crossover study

During the menopause transition, women are at increased risk of subjective symptoms of executive dysfunction. Evidence from animal and human participant studies suggests adverse childhood experiences (ACE) may be a risk factor for executive complaints during this hormonal transition. Preclinical literature indicates early life adversity effects on serotonin function may play a role in this increased susceptibility. However, the mechanisms underlying this increase in vulnerability in human participants remain relatively unknown. Here we examined the impact of ACE and tryptophan depletion (TD), a paradigm used to lower central serotonin levels, on functional network connectivity in discovery and replication datasets. We hypothesized that ACE would be associated with decreased within-network connectivity. We predicted that TD would further lower connectivity in women with high levels of early adversity, but have no effect in women with low levels of early adversity. Forty women underwent two functional imaging sequences at two time points (141 total scans) in a double-blind, placebo controlled, crossover study. The effects of ACE and TD were evaluated using generalized estimating equations (GEE). As predicted, ACE was associated with lower within-network connectivity. While TD had no effect on connectivity in the low ACE group, TD increased connectivity in the high ACE group. The robust effect of ACE remained significant in the replication dataset, though the ACE×TD interaction did not. Together, these results suggest that early life adversity has lasting impacts on large-scale functional networks underlying executive function. Alterations in functional network connectivity may be one mechanism by which early life adversity increases the risk of cognitive disorders during menopause.

Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure

The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8-12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein – CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health.

Enduring Neural and Behavioral Effects of Early Life Adversity in Infancy: Consequences of Maternal Abuse and Neglect, Trauma and Fear

Early life experiences have long-lasting influence on a child. For an infant, the quality of caregiving is one of the most critical factors supporting growth and development. Adverse social events in infancy have the potency to alter the child’s developmental trajectory and elevate the lifetime risk for a range of psychiatric disorders. Although clinical studies associate early childhood adversities with lifetime risk for mental disorders, the knowledge of underlying neural and molecular alterations leading to these disorders comes mostly from animal studies. In this article, we overview selected animal models of early life social adversity, including maternal abuse and neglect, and maternal trauma and fear. We first characterize the major behavioral and neural changes normally occurring in early life. We then present several animal models of maternally mediated early life adversity that contribute to reorient the developmental changes toward pathological outcomes. These models yielded to recently identified neurobiological mechanisms, including epigenetic alterations, through which these adversities lead to a lasting dysregulation of the stress response system, aberrant fear learning and memory, and increased anxiety or depression-like behaviors. We conclude by emphasizing the unique role of the caregiver’s influences on the developing brain in infancy. Understanding of the infant’s mechanisms of vulnerability and resilience to maltreatment is essential for the advancement of novel therapeutic and preventive approaches.

Effects of early life adversity and sex on dominance in European starlings

Dominance in socially foraging animals may be related to sex and to variation in individual quality. Individual quality may in turn reflect conditions during early development. We studied dominance in a cohort of adult European starlings, Sturnus vulgaris, that had been subject to experimental manipulations of food supply and begging effort when they were nestlings. We measured dominance in two different contexts, contests over a food resource and relative position on a sloping perch, over the course of 3 weeks. Dominance in food contests was extremely stable over the 3 weeks and relative perch position somewhat stable. Males were dominant over females in contests over food and perched in higher positions. These sex differences were not explained by males' greater size or body weight. Food dominance and perch position were uncorrelated. Neither early life food supply nor early life begging effort affected food dominance; nor did an alternative measure of developmental stress, developmental telomere attrition. Birds that had been made to beg more as nestlings perched in higher positions than those that had begged less. Our results did not support the hypothesis that early life adversity leads to lower adult dominance rank in the context of feeding, and we suggest that relative perch position may have measured individual preference rather than competitive ability.

Impact of Tryptophan Depletion on Executive System Function during Menopause is Moderated by Childhood Adversity.

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.

Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period

BackgroundMounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR.MethodsWistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2–21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-κB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17 of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation.ResultsMS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-κB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-κB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF-κB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia.ConclusionsEarly life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses.

Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions.

The science behind psychotherapy has garnered considerable interest, as objective measures are being developed to map the patient's subjective change over the course of treatment. Prenatal and early life influences have a lasting impact on how genes are expressed and the manner in which neural circuits are consolidated. Transgenerationally transmitted epigenetic markers as well as templates of enhanced thought flexibility versus evasion can be passed down from parent to child. This influences gene expression/repression (impacting neuroplasticity) and kindling of neurocircuitry which can perpetuate maladaptive cognitive processing seen in a number of psychiatric conditions. Importantly, genetic factors and the compounding effects of early life adversity do not inexorably lead to certain fated outcomes. The concepts of vulnerability and resilience are becoming more integrated into the framework of “differential susceptibility,” speaking to how corrective environmental factors may promote epigenetic change and reconfigure neural templates, allowing for symptomatic improvement. Psychotherapy is one such factor, and this review will focus on our current knowledge of its epigenetic and neurocircuitry impact.

Kindling of Life Stress in Bipolar Disorder: Effects of Early Adversity

Most theoretical frameworks regarding the role of life stress in bipolar disorders (BD) do not incorporate the possibility of a changing relationship between psychosocial context and episode initiation across the course of the disorder. The kindling hypothesis theorizes that over the longitudinal course of recurrent affective disorders, the relationship between major life stressors and episode initiation declines (Post, 1992). The present study aimed to test an extension of the kindling hypothesis in BD by examining the effect of early life adversity on the relationship between proximal life events and prospectively assessed mood episodes. Data from 145 bipolar participants (59.3% female, 75.2% Caucasian, and mean age of 20.19 years; SD = 1.75 years) were collected as part of the Temple-Wisconsin Longitudinal Investigation of Bipolar Spectrum Project (112 Bipolar II; 33 Cyclothymic disorder). Participants completed a self-report measure of early adversity at baseline and interview-assessed mood episodes and life events at regular 4-month follow-ups. Results indicate that early childhood adversity sensitized bipolar participants to the effects of recent stressors only for depressive episodes and not hypomanic episodes within BD. This was particularly the case with minor negative events. The current study extends prior research examining the kindling model in BD using a methodologically rigorous assessment of life stressors and mood episode occurrence. Clinicians should assess experiences of early adversity in individuals with BD as it may impact reactivity to developing depressive episodes in response to future stressors.

The effects of early life adversity on responses to the Montreal Imaging Stress Task

The effects of early life adversity on responses to the Montreal Imaging Stress Task

Mgat5 modulates the effect of early life stress on adult behavior and physical health in mice

Psychosocial adversity in early life increases the likelihood of mental and physical illness, but the underlying mechanisms are poorly understood. Mgat5 is an N-acetylglucosaminyltransferase in the Golgi pathway that remodels the N-glycans of glycoproteins at the cell surface. Mice lacking Mgat5 display conditional phenotypes in behaviour, immunity, metabolism, aging and cancer susceptibility. Here we investigated potential gene-environment interactions between Mgat5 and early life adversity on behaviour and physiological measures of physical health. Mgat5−/− mutant and Mgat5+/+ wild-type C57Bl/6 littermates were subject to maternal separation or foster rearing as an early life stressor, in comparison to control mice reared normally. We found an interaction between Mgat5 genotype and maternal rearing condition in which Mgat5−/− mice subjected to early life stress had lower glucose levels and higher bone density. Mgat5−/− genotype was also associated with less immobility in the forced swim test and greater sucrose consumption, consistent with a less depression-like phenotype. Cortical neuron dendrite spine density and branching was altered by Mgat5 deletion as well. In general, Mgat5 genotype affects both behaviour and physical outcomes in response to early life stress, suggesting some shared pathways for both in this model. These results provide a starting point for studying the mechanisms by which protein N-glycosylation mediates the effects of early life adversity.

Effects of early life adversity on cortisol/salivary alpha-amylase symmetry in free-ranging juvenile rhesus macaques

Early life adversity (ELA) affects physiological and behavioral development. One key component is the relationship between the developing Hypothalamic-Pituitary-Adrenal (HPA) axis and the Sympathetic Nervous System (SNS). Recent studies suggest a relationship between early life adversity and asymmetry in cortisol (a measure of HPA activation) and salivary alpha-amylase (sAA: a correlate of SNS activation) responses to stress among human children, but to our knowledge there have been no comparable studies in nonhumans. Here, we investigate the responses of these two analytes in “low stress” and “high stress” situations in free-ranging juvenile rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico. Behavioral data on maternal maltreatment were collected during the first 3months of life to determine individual rates of ELA, and saliva samples were collected from subjects noninvasively during juvenility. Irrespective of ELA, salivary alpha-amylase levels were lower in low stress situations and higher in high stress situations. For cortisol however, high ELA subjects exhibited higher low stress concentrations and blunted acute responses during high stress situations compared to moderate and low ELA subjects. Cortisol and sAA values were positively correlated among low ELA subjects, suggesting symmetry, but were uncorrelated or negatively correlated among moderate and high ELA subjects, suggesting asymmetry in these individuals. These findings indicate dysregulation of the stress response among juveniles maltreated during infancy: specifically, attenuated cortisol reactivity coupled with typical sAA reactivity characterize the stress response profiles of juveniles exposed to higher rates of ELA during the first 3months of life.

Early life stressful experiences and neuropsychiatric vulnerability: evidences from human and animal models

The human newborn is highly dependent on parental care for its survival but also for the healthy development of its brain. A large body of literature demonstrates the impact of early life adversity, even during the prenatal period, on the adult's health. The susceptibility to neuropsychiatric diseases is often potentiated by early stress. If there is an agreement that a critical developmental period exists, the mechanisms underlying the long term effects of early life adversity are still poorly understood. Recent studies in animals highlight the involvement of epigenetic processes in the transmission of such vulnerabilities, notably via modifications in germ cells, which can be transmitted in the next generations.

Entangled lives: Implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course.

Epidemiological research since the 1980s has highlighted the consequences of early life adversity, particularly during gestation and early infancy, for adult health (the "Barker hypothesis"). The fast-evolving field of molecular epigenetics is providing explanatory mechanisms concerning phenotypic plasticity in response to developmental stressors and the accumulation of disease risk throughout life. In addition, there is now evidence for the heritability of poor health across generations via epigenetic modifications. This research has the potential to invoke a paradigmatic shift in how we interpret factors such as growth insults and immune response in past skeletal remains. It demonstrates that health cannot be understood in terms of immediate environmental circumstances alone. Furthermore, it requires both a theoretical and practical re-evaluation of disease biographies and the life course more generally. Individual life courses can no longer be regarded as discrete, bounded, life histories, with clearly defined beginning and end points. If socioeconomic circumstances can have intergenerational effects, including disease susceptibility and growth stunting, then individual biographies should be viewed as nested or "embedded" within the lives of others. This commingling of life courses may prove problematic to unravel; nevertheless, this review aims to consider the potential consequences for bioarchaeological interpretations. These include a greater consideration of: the temporal power of human skeletons and a life course approach to past health; infant health and the implications for maternal well-being; and the impact of non-proximate stressors (e.g., early life and ancestral environments) on the presence of health indicators.

A groundwork for allostatic neuro-education.

We propose to enliven educational practice by marrying a conception of education as guided human development, to an advanced scientific understanding of the brain known as allostasis (stability through change). The result is a groundwork for allostatic neuro-education (GANE). Education as development encompasses practices including the organic (homeschooling and related traditions), cognitive acquisition (emphasis on standards and testing), and the constructivist (aimed to support adaptive creativity for both learner and society). Allostasis views change to be the norm in biology, defines success in contexts of complex natural environments rather than controlled settings, and identifies the brain as the organ of central command. Allostatic neuro-education contrasts with education focused dominantly on testing, or neuroscience based on homeostasis (stability through constancy). The GANE perspective is to view learners in terms of their neurodevelopmental trajectories; its objective is to support authentic freedom, mediated by competent, integrated, and expansive executive functionality (concordant with the philosophy of freedom of Rudolf Steiner); and its strategy is to be attuned to rhythms in various forms (including those of autonomic arousal described in polyvagal theory) so as to enable experiential excitement for learning. The GANE presents a variety of testable hypotheses, and studies that explore prevention or mitigation of the effects of early life adversity or toxic stress on learning and development may be of particular importance. Case studies are presented illustrating use of allostatic neurotechnology by an adolescent male carrying diagnoses of Asperger’s syndrome and attention-deficit hyperactivity disorder, and a grade school girl with reading difficulties. The GANE is intended as a re-visioning of education that may serve both learners and society to be better prepared for the accelerating changes of the 21st century.