Effects of early life adversity on immediate early gene expression: Systematic review and 3-level meta-analysis of rodent studies

Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of psychopathologies later in life. Immediate-early genes (IEGs) provide a potential marker for the observed alterations, bridging the gap between activity-regulated transcription and long-lasting effects on brain structure and function. Several heterogeneous studies have used IEGs to identify differences in cellular activity after ELA; systematically investigating the literature is therefore crucial for comprehensive conclusions. Here, we performed a systematic review on 39 pre-clinical studies in rodents to study the effects of ELA (alteration of maternal care) on IEG expression. Females and IEGs other than cFos were investigated in only a handful of publications. We meta-analyzed publications investigating specifically cFos expression. ELA increased cFos expression after an acute stressor only if the animals (control and ELA) had experienced additional hits. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naïve, acutely stressed animals. We present a conceptual theoretical framework to interpret the unexpected results. Overall, ELA likely alters IEG expression across the brain, especially in interaction with other negative life events. The present review highlights current knowledge gaps and provides guidance to aid the design of future studies.

Developmental Alterations of Intestinal SGLT1 and GLUT2 Induced by Early Weaning Coincides with Persistent Low-Grade Metabolic Inflammation in Female Pigs

Early life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters SGLT1 and GLUT2 are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. Jejunum and ileum of 90 d old pigs previously exposed to EW (16 d wean age), exhibited reduced SGLT1 activity (by ~ 30%, P<0.05), compared with late weaned (LW, 26 d wean age) controls . In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs compared with LW pigs. Reciprocal changes in SGLT1 and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush border membranes (BBM) that were observed at 90 d and 150 d of age. Ileal SGLT1-mediated glucose transport and BBM expression were Inhibited by the β-adrenergic receptor (βAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P=0.015) and BBMV abundance (P=0.035) LW pigs, but not EW pigs. Early weaned pigs exhibited chronic elevated blood glucose and C-Reactive Protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.

Prenatal Exposure to Early Life Adversity and Neonatal Brain Volumes at Birth

Importance: Exposure to early life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The extent that prenatal exposure to life adversity alters structure at birth remains poorly understood. Objective: To determine if prenatal exposure to maternal social advantage and psychosocial distress alters global and regional brain volumes and cortical folding in the first weeks of life. Design: A prospective, longitudinal study of sociodemographically-diverse mothers recruited in the first trimester of pregnancy and their infants who underwent brain magnetic resonance imaging scan in the first weeks of life. Setting: Mothers were recruited from local obstetric clinics from 2017-2020. Participants: Of 399 mother-infant dyads prospectively recruited into the parent study, 280 healthy, term-born infants (47% female, mean postmenstrual age at scan 42 weeks) were eligible for inclusion. Exposures: Maternal social advantage and psychosocial distress in pregnancy. Main Measures and Outcomes: Two measures of latent constructs were created using Confirmatory Factor Analyses spanning Maternal Social Advantage (Income to Needs ratio, Area Deprivation Index, Healthy Eating Index, education level, insurance status) and Psychosocial Stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellar, hippocampus, and amygdala volumes were generated using semi-automated age-specific segmentation pipelines. Results: After covariate adjustment and multiple comparisons correction, greater social disadvantage (i.e., lower Advantage values) was associated with reduced cortical gray matter (p=.03), subcortical gray matter (p=.008), and white matter (p=.004) volumes and cortical folding (p=.001). Psychosocial Stress was not related to neonatal brain metrics. While social disadvantage was associated with smaller absolute volumes of the bilateral hippocampi and amygdalae, after correcting for total brain volume, there were no regional effects. Conclusions and Relevance: Prenatal exposure to social disadvantage is associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that the deleterious effects of poverty begin in utero and are evident in the first weeks of life. These findings emphasize that preventative interventions to support fetal brain development should address socioeconomic hardships for expectant parents.

The epigenetics of early life adversity and trauma inheritance: an interview with Moshe Szyf

In this interview, Professor Moshe Szyf speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work to date in the field of social epigenetics. Szyf received his PhD from the Hebrew University and did his postdoctoral fellowship in genetics at Harvard Medical School, joined the Department of Pharmacology and Therapeutics at McGill University in Montreal in 1989 and is a fellow of the Royal Society of Canada and the Academy of Health Sciences of Canada. He is the founding codirector of the Sackler Institute for Epigenetics and Psychobiology at McGill and is a Fellow of the Canadian Institute for Advanced Research Experience-Based Brain and Biological Development program. Szyf was the founder of the first pharma to develop epigenetic pharmacology, Methylgene Inc., and the journal Epigenetics. The Szyf lab proposed two decades ago that DNA methylation is a prime therapeutic target in cancer and other diseases and postulated and provided the first set of evidence that the social environment early in life can alter DNA methylation, launching the emerging field of social epigenetics.

Early Life Adversity and Clinical Intimate Partner Violence in Adulthood: The Mediating Role of Interpersonal Conflict in Adolescence

Intimate partner violence (IPV) is associated with adverse outcomes for both victims and perpetrators, though there is significant heterogeneity in manifestations of relationship violence. A growing amount of research has focused on elucidating predictors of clinical IPV—defined as severe violence involving institutional or medical intervention due to actual or potential injury—so as to better understand potential prevention and intervention targets. Early life adversity (ELA) is associated with IPV in adulthood, yet this literature focuses on discrete, retrospectively reported adversities (e.g., physical abuse and neglect) and has yet to consider clinical IPV as an outcome. Little is known about if and how broadly adverse early environments may confer risk for this specific form of relationship violence. We investigated associations between exposure to ELA prior to age five and clinical IPV victimization and perpetration by age 20 in a longitudinal, community-based sample of men and women in Australia ( N = 588). Early life adversity was prospectively indexed by maternal reports of financial hardship, child chronic illness, maternal stressful life events, maternal depressive symptoms, parental discord, and parental separation. Youth interpersonal conflict life events at age 15—an interviewer-rated assessment of episodic stressors involving conflict across relationships in mid-adolescence—was tested as a potential mediator for both victims and perpetrators. Among women, ELA predicted IPV victimization and perpetration, and interpersonal conflict life events partially mediated the link between ELA and victimization, but not perpetration. Neither ELA nor interpersonal conflict life events predicted victimization or perpetration among men. Women exposed to ELA are at-risk for conflictual interpersonal relationships later in life, including violent intimate relationships, and deficits in conflict resolution skills may be one mechanism through which ELA leads to IPV victimization among this subgroup. Violence prevention and intervention efforts should target interpersonal skills, including conflict resolution, among women and girls exposed to adverse early environments.

Adverse childhood experiences (ACEs) associated with reduced cognitive flexibility in both college and community samples

The prefrontal cortex is sensitive to stress experiences and significantly impacted by early life adversity. Cognitive flexibility is an executive function that is associated with positive outcomes in adulthood and implicated in activity in the prefrontal cortex. The relationship between early life adversity and cognitive flexibility is underreported. Using the cumulative risk model, we conducted two studies to examine the association between early life adversity and cognitive flexibility in college students and adults (cumulative N = 510). Exposure to early life adversity was assessed using the adverse childhood experiences scale (ACEs). Cognitive flexibility was assessed using the Wisconsin Card Sorting Test (WCST). Additionally, as perceived chronic stress is associated with impaired prefrontal cortex function, we measured that as well. Higher number of ACEs was correlated with lower number of completed categories on the WCST in both college students and adults. Perceived chronic stress was not associated with cognitive flexibility, but did correlate positively with ACEs. Individuals with a higher number of ACEs were also more likely to report higher levels of perceived chronic stress. Hierarchical regression analyses indicated that exposure to adverse childhood experiences predicted lower scores on completed categories. Our findings provide further evidence that individuals with early life adversity exhibit reduced cognitive flexibility in adulthood.

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.