Early Life Adversity Research Articles

Systemic histone deacetylase inhibition ameliorates the aberrant responses to acute stress in socially isolated male mice.

Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group-housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.

Understanding the paradox: anhedonia and the unexpected divergence from reward seeking during adolescence - A commentary on Gupta etal. (2024).

Anhedonia is a symptom encompassing reduced or absence of motivation and pleasure that often emerges in adolescence and conveys risk for different mental illnesses and other difficulties. In their review, Gupta, Eckstrand, and Forbes (Journal of Child Psychology and Psychiatry, 2024) present an empirically-based conceptual neurodevelopmental model of anhedonia whereby brain development and pubertal maturation create openness to vulnerability to anhedonia that is influenced by early life adversity and chronic inflammation. This commentary considers anhedonia as a paradox of adolescence given its juxtaposition to the expected developmental milestones of adolescence. It highlights the need to consider anhedonia in terms of both variability and universality of children's experiences and biological development, missed opportunities for social relationships and experiences, and forms and functions of rewards and anhedonia.

Disease exposure in infancy affects women's reproductive outcomes and offspring health in southern Sweden 1905–2000

Ample evidence demonstrates that early-life adversity negatively affects morbidity and survival in late life. We show that disease exposure in infancy also has a continuous impact on reproduction and health across the female life course and even affects early-life health of the next generation. Using Swedish administrative data, obstetric records, and local infant mortality rates as a measure of disease exposure, we follow women's reproductive careers and offspring health 1905–2000, examining a comprehensive set of outcomes. Women exposed to disease in infancy give birth to a lower proportion of boys, consistent with notions that male fetuses are more vulnerable to adverse conditions and are more often miscarried. Sons of exposed mothers are also more likely to be born preterm and have higher birthweight suggesting in utero out-selection. Exposed women have a greater risk of miscarriage and of male stillbirth, but their overall likelihood of giving birth is not affected.

Early-life influenza A (H1N1) infection independently programs brain connectivity, HPA AXIS and tissue-specific gene expression profiles

Early-life adversity covers a range of physical, social and environmental stressors. Acute viral infections in early life are a major source of such adversity and have been associated with a broad spectrum of later-life effects outside the immune system or “off-target”. These include an altered hypothalamus–pituitary–adrenal (HPA) axis and metabolic reactions. Here, we used a murine post-natal day 14 (PND 14) Influenza A (H1N1) infection model and applied a semi-holistic approach including phenotypic measurements, gene expression arrays and diffusion neuroimaging techniques to investigate HPA axis dysregulation, energy metabolism and brain connectivity. By PND 56 the H1N1 infection had been resolved, and there was no residual gene expression signature of immune cell infiltration into the liver, adrenal gland or brain tissues examined nor of immune-related signalling. A resolved early-life H1N1 infection had sex-specific effects. We observed retarded growth of males and altered pre-stress (baseline) blood glucose and corticosterone levels at PND42 after the infection was resolved. Cerebral MRI scans identified reduced connectivity in the cortex, midbrain and cerebellum that were accompanied by tissue-specific gene expression signatures. Gene set enrichment analysis confirmed that these were tissue-specific changes with few common pathways. Early-life infection independently affected each of the systems and this was independent of HPA axis or immune perturbations.

Older mothers and their difficult adult children: a life course exploration

ABSTRACT Adult child to parent violence is a growing international social problem that needs to be better understood to develop clinical interventions. An exploratory study on the antecedents of early life adversity on adult child to parent violence/elder mistreatment was carried out using secondary analysis. Directed content analysis was used based on life course theory with a data set of older mothers all > 57 years old (J. R. Smith 2021, 2022). Measurement of instances of child abuse, domestic violence, and birth trauma among abused older mothers was conducted. All the older women had reported being negatively affected by their adult children’s problems and 56% reported being physically attacked. A case example is presented to illustrate how repeated incidents of abuse or neglect in early life might explain an older woman’s inability to take actions for her own safety.

Fitness Costs of Early Life Adversity in Primates

As arguably the most critical period of mammalian development, early life can be defined as the period from conception to reproductive maturity (Tung et al., 2016). The importance of adequate nutrition and proper maternal care for maximizing the survival and development of offspring has been demonstrated through research findings in various species (Lu et al., 2018). However, these ideal growth conditions are difficult to achieve for wild offspring, who often have to overcome various energetically or socially challenging conditions that limit their development in early life. This paper will focus on the effect that environmental and social adversities have on the fitness of wild and captive non-human primates as measured by lifespan and reproductive success. Current research suggests that early life adversity in non-human primates reduces individual fitness by decreasing lifespan, fertility, and offspring survival. This paper will explore and discuss the various factors that contribute to this fitness reduction. These factors include but are not limited to: increased risk of physical illness and behavioral disorders, social isolation, maternal death, intergenerational effects, reduced female fertility, maternal stress, delayed sexual maturation, and lower adult body size.

Independent effects of early life adversity on social cognitive function in patients with schizophrenia.

The aim of this study was to investigate the impact of early life adversity on cognitive function in patients with schizophrenia, with a focus on social cognition (SC). Two groups of patients with schizophrenia were recruited and matched on sociodemographic and clinical characteristics. One group consisted of 32 patients with a history of childhood trauma (SCZ-ct), and the other group consisted of 30 patients without a history of childhood trauma (SCZ-nct). In addition, 39 healthy controls without a history of childhood trauma (HC-nct) were also recruited. The intelligence of the three groups was assessed using the Wechsler Abbreviated Scale of Intelligence (WAIS-RC) short version. The cognitive function evaluation was conducted using the MATRICS Consensus Cognitive Battery (MCCB), and early life adversity was measured using the Childhood Trauma Questionnaire-Short Form (CTQ) and Bullying Scale for Adults (BSA). Patients with schizophrenia endosed significantly higher scores on the CTQ (F=67.61, p<0.001) and BSA (F=9.84, p<0.001) compared to the HC-nct. Analysis of covariance (ANCOVA) and post-hoc analyses revealed that SCZ-ct (F=11.20, p<0.001) exhibited the most pronounced cognitive impairment among the three groups, as indicated in MCCB total scores and in the domain score of SC. CTQ exhibited a negative correlation with MCCB (r=-0.405, p< 0.001); SC was negatively correlated with physical abuse (PA) of CTQ (r=-0.271, p=0.030) and emotional abuse (EA) of BSA (r=-0.265, p=0.034) in the whole patient sample. Higher SC performance was significantly predicted by CT_total (Beta =-0.582, p<0.001, 95% CI -0.96-0.46), and years of education (Beta=0.260, p =0.014, 95% CI 0.20-1.75) in schizophrenia. Besides familial trauma, schizophrenia patients appear to have a higher likelihood of experiencing bullying in their early life. These experiences seem to contribute significantly to their severe impairments in SC.

DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons

The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.

Commentary on the power of predictability: patterns of signals in early life shape neurodevelopment and mental health trajectories.

As Davis and Glynn observe in the introduction to their review, early life adversity is a significant impediment to healthy child development. Whereas some theoretical accounts emphasize the sheer number of physical and psychosocial risk factors children experience (Evans, Li, & Whipple, Psychological Bulletin, 2013, 139, 1342), Davis and Glynn review a program of research that is aligned with models highlighting the types of adversity children encounter. They expand on accounts that differentiate threat from deprivation (McLaughlin & Sheridan, Current Directions in Psychological Science, 2016, 25, 239) to draw attention to the role of unpredictability in children's development.

Abstract 1974 Exploring the Link Between Early Life Adversity, Sleep Patterns, and Eating Using Automated High-Throughput Behavioral Recognition Software

Abstract 1974 Exploring the Link Between Early Life Adversity, Sleep Patterns, and Eating Using Automated High-Throughput Behavioral Recognition Software

Leveraging multivariate approaches to advance the science of early-life adversity

Since the landmark Adverse Childhood Experiences (ACEs) study, adversity research has expanded to more precisely account for the multifaceted nature of adverse experiences. The complex data structures and interrelated nature of adversity data require robust multivariate statistical methods, and recent methodological and statistical innovations have facilitated advancements in research on childhood adversity. Here, we provide an overview of a subset of multivariate methods that we believe hold particular promise for advancing the field's understanding of early-life adversity, and discuss how these approaches can be practically applied to explore different research questions. This review covers data-driven or unsupervised approaches (including dimensionality reduction and person-centered clustering/subtype identification) as well as supervised/prediction-based approaches (including linear and tree-based models and neural networks). For each, we highlight studies that have effectively applied the method to provide novel insight into early-life adversity. Taken together, we hope this review serves as a resource to adversity researchers looking to expand upon the cumulative approach described in the original ACEs study, thereby advancing the field's understanding of the complexity of adversity and related developmental consequences.

Exposure to early-life adversity and long-term trajectories of multimorbidity among older adults in China: analysis of longitudinal data from the China Health and Retirement Longitudinal Study

ObjectivesThis study aimed to identify long-term distinct trajectories of multimorbidity with ageing from 50 to 85 years among Chinese older adults and examine the relationship between exposure to early-life adversity...

DNA methylation-environment interactions in the human genome

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures—one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

DNA methylation-environment interactions in the human genome.

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures-one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

Annual Research Review: The power of predictability - patterns of signals in early life shape neurodevelopment and mental health trajectories.

The global burden of early life adversity (ELA) is profound. The World Health Organization has estimated that ELA accounts for almost 30% of all psychiatric cases. Yet, our ability to identify which individuals exposed to ELA will develop mental illness remains poor and there is a critical need to identify underlying pathways and mechanisms. This review proposes unpredictability as an understudied aspect of ELA that is tractable and presents a conceptual model that includes biologically plausible mechanistic pathways by which unpredictability impacts the developing brain. The model is supported by a synthesis of published and new data illustrating the significant impacts of patterns of signals on child development. We begin with an overview of the existing unpredictability literature, which has focused primarily on longer patterns of unpredictability (e.g. years, months, and days). We then describe our work testing the impact of patterns of parental signals on a moment-to-moment timescale, providing evidence that patterns of these signals during sensitive windows of development influence neurocircuit formation across species and thus may be an evolutionarily conserved process that shapes the developing brain. Next, attention is drawn to emerging themes which provide a framework for future directions of research including the evaluation of functions, such as effortful control, that may be particularly vulnerable to unpredictability, sensitive periods, sex differences, cross-cultural investigations, addressing causality, and unpredictability as a pathway by which other forms of ELA impact development. Finally, we provide suggestions for prevention and intervention, including the introduction of a screening instrument for the identification of children exposed to unpredictable experiences.

Family of Origin Stress, Posttraumatic Stress Symptoms, and Resource Loss for Couples During COVID-19: A Longitudinal Analysis

Few studies have addressed the influence of mass stressors in the context of couple relationships; therefore, understanding how unique constraints and stressors related to the COVID-19 pandemic influenced mental health distress and, in turn, loss in couple relationships is valuable. Because resource loss has been defined as the primary agent of stress, examining factors that may have shaped the degree of resource loss incurred during the pandemic will be vital. Previous research implies that early life adversity may be a form of resource loss and is linked to poorer mental health and relational outcomes in adulthood. Additionally, the stress sensitization hypothesis posits that childhood adversity may prime individuals to have a lower threshold for later life stress. As such, this study was designed to examine how family of origin stress (reported at the outset of pandemic related shutdowns in the US in April 2020) associated with posttraumatic stress (PTSS) 3 months later (July 2020) to, in turn, predict variation in resource losses associated with the COVID-19 pandemic reported 3 months later (October 2020) in 535 cisgender, heterosexual couples. Findings showed that individual’s higher family of origin stress predicted higher levels of their own PTSS at wave 2, and higher PTSS at wave 2 predicted higher levels of couples’ shared resource loss at wave 3. Additionally, family of origin stress is associated with higher levels of couples’ shared experience of loss via higher levels of their own PTSS.

Antecedents of maternal pregnancy-related anxiety trajectories: The FinnBrain birth cohort study.

Little is known about the normative courses of pregnancy-related anxiety throughout pregnancy and their antecedents. We examined in a large scale pregnancy cohort which potentially distinct trajectories of pregnancy-related anxiety across pregnancy can be identified, and which factors predict these trajectories. A general sample of pregnant women (n = 2928) from the FinnBrain Birth Cohort participated in this study. Several questionnaires were filled in at 14, 24, and 34 weeks of gestation, including the pregnancy-related anxiety questionnaire-revised as main outcome. Latent Growth Mixture Modeling was applied to identify the trajectories of pregnancy-related anxiety across pregnancy, and t-tests and chi-quare tests were conducted to find antecedents of these trajectories. Two distinct trajectories were identified: (1) a low symptoms group, N = 2594 (88.6%), with lower and slightly increasing levels of pregnancy-related anxiety (2) a moderately-high symptoms group, N = 334 (11.4%) reported higher and slightly decreasing levels of anxiety. Correlates of the moderately-high anxious group included a lower monthly income, drinking alcohol or smoking in early pregnancy, more daily hassles and less joy, more early life adversities, younger age, primiparity, single parenthood, using depression medication, and having higher scores on depression and general anxiety. Although the majority of pregnant women fall within a low risk trajectory of pregnancy-related anxiety, another group with consistently higher levels of pregnancy anxiety throughout pregnancy may need more clinical attention, as their high pregnancy-related anxiety scores may indicate a risk profile that includes a variety of general and more pregnancy-specific risk factors, which together can negatively affect fetal and infant development and behavior.

How do family adversity and youth stressful experiences lead to adult economic adversity? An integration of multiple life course mechanisms

ABSTRACT The primary objective of the present study was to apply multiple life course mechanisms, drawn from the life course epidemiological perspective, to explain the long-term influence of family socioeconomic adversity and adolescent stressful life events on adult economic adversity. The study used prospective data over 13 years from 11,075 adolescents from the Adolescent to Adult Health Study (Add Health). First, we developed a comprehensive life course model by integrating causal and temporal relationships among different life course processes and pathways discussed in previous research. Specifically, the findings provided evidence for the long-term influence of family socioeconomic adversity on adult economic adversity through life-stage specific stressful life events and depressive symptoms. This connection occurred through various risk pathways such as the clustering of risk, risk cascading, and cumulative exposure. Such integrated models are well suited to investigate life course stressors and can be used as broad analytical frameworks for life course developmental studies. Thus, the present study has served substantive, illustrative, and methodological purposes. The study findings suggest that to improve adult wellbeing, programmes and policies focusing on early life adversities and stressors are important.

Impact of poverty and adversity on perceived family support in adolescence: findings from the UK Millennium Cohort Study

Emotional support from family members may have an important effect on adolescent health outcomes, and has been identified as a target for policy to protect against the impacts of poverty and other early life adversities. However, few studies have assessed the extent to which poverty and adversity themselves influence the nature of emotional support that parents can provide to adolescents. We, therefore, aimed to investigate the impact of trajectories of income poverty and family adversities, including parental mental ill health, alcohol misuse and domestic violence across childhood developmental stages on young people’s relationships with their families and perceived emotional support received. We analysed longitudinal data on 10,976 children from the nationally representative UK Millennium Cohort study. Exposure trajectories of poverty and family adversities were characterised using group-based multi-trajectory models (age 9 months–14 years). The outcomes were perceived emotional support and quality of family relationships, measured by the three-item Short Social Provisions Scale (SPS-3) and levels of parent–adolescent closeness and conflict, measured at age 14. ORs and 95% CIs were estimated using multivariable logistic regression models, adjusting for potential confounding factors. At age 14, the overall prevalence of low perceived emotional support was 13% (95% CI: 12, 14). Children of mothers with lower socioeconomic status (SES) were more likely to report low emotional support, with a clear social gradient (education—degree plus: 10.3% vs. no qualifications: 15.4%). Compared with children exposed to low levels of poverty and adversity, children in the persistent adversity trajectory groups experienced higher odds of low emotional support and low-quality parent–adolescent relationship; those exposed to both persistent poverty and poor parental mental health were particularly at increased risk of experiencing poor family relationships and low perceived emotional support (adjusted odds ratio 2·2; 95% CI 1·7–2·9). Low perceived emotional support and poor family relationships in adolescence are more prevalent among socially disadvantaged children and adolescents and those experiencing social adversity. Policies to improve levels of family support for UK adolescents should focus on improving modifiable determinants such as child poverty and family mental health.

Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring.

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.