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High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3-6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (βs ≥ 0.16, ps ≤.007). The relationship between childhood unpredictability and subsequent depression at acute post-deployment was partially mediated by lower social support (b = 0.07, 95% CI [0.03, 0.15]) while depression at chronic post-deployment was fully mediated by a combination of lower social support (b = 0.14, 95% CI [0.07, 0.23]) and higher perceived stress (b = 0.09, 95% CI [0.05, 0.15]). These findings implicate childhood unpredictability as a potential risk factor for depression in adulthood and suggest that increasing the structure and predictability of childhood routines and developing social support interventions after life stressors could be helpful for preventing adult depression.

Protecting populations contending with co‐occurring stressors requires a better understanding of how multiple early‐life stressors affect the fitness of natural systems. However, the complexity of such research has limited its advancement and prevented us from answering new questions. In human studies, cumulative risk models predict adult health risk based on early adversity exposure. We apply a similar framework in wild yellow‐bellied marmots (Marmota flaviventer). We tested cumulative adversity indices (CAIs) across different adversity types and time windows. All CAIs were associated with decreased pup survival and were well supported. Moderate and acute, but not standardized CAIs were associated with decreased lifespan, supporting the cumulative stress hypothesis and the endurance of early adversity. Multivariate models showed that differences in lifespan were driven by weaning date, precipitation, and maternal loss, but they performed poorly compared with CAI models. We highlight the development, utility, and insights of CAI approaches for ecology and conservation. [ABSTRACT FROM AUTHOR]

Exposure to early-life adversity (ELA) and iron deficiency early in life are known risk factors for suboptimal brain and socioemotional development. Iron deficiency may arise from and co-occur with ELA, which could negatively affect development. In the present study, we investigated whether ELA is associated with iron deficiency in infants receiving no iron supplementation. This study is a secondary analysis of extant data collected in the 1990s; participants were healthy infants from working-class communities in Santiago, Chile (N = 534, 45.5% female). We measured stressful life events, maternal depression, and low home support for child development during infancy and assessed iron status when the infant was 12 months old. Slightly more than half of the infants were iron-deficient (51%), and 25.8% were iron-deficient anemic at 12 months. Results indicated that ELA was associated with lower iron levels and iron deficiency at 12 months. The findings are consistent with animal and human prenatal models of stress and iron status and provide evidence of the association between postnatal ELA and iron status in humans. The findings also highlight a nutritional pathway by which ELA may impact development and present a nutritionally-focused avenue for future research on ELA and psychopathology.

BACKGROUND AND AIMS: Social determinants of health (SDoHs) impact the development and course of schizophrenia-spectrum psychotic disorders (SSPDs). Yet, we found no published scholarly reviews of psychometric properties and pragmatic utility of SDoH assessments among people with SSPDs. We aim to review those aspects of SDoH assessments. STUDY DESIGN: PsychInfo, PubMed, and Google Scholar databases were examined to obtain data on reliability, validity, administration process, strengths, and limitations of the measures for SDoHs identified in a paired scoping review. STUDY RESULTS: SDoHs were assessed using different approaches including self-reports, interviews, rating scales, and review of public databases. Of the major SDoHs, early-life adversities, social disconnection, racism, social fragmentation, and food insecurity had measures with satisfactory psychometric properties. Internal consistency reliabilities-evaluated in the general population for 13 measures of early-life adversities, social disconnection, racism, social fragmentation, and food insecurity-ranged from poor to excellent (0.68-0.96). The number of items varied from 1 to more than 100 and administration time ranged from less than 5 minutes to over an hour. Measures of urbanicity, low socioeconomic status, immigration status, homelessness/housing instability, and incarceration were based on public records or targeted sampling. CONCLUSIONS: Although the reported assessments of SDoHs show promise, there is a need to develop and test brief but validated screening measures suitable for clinical application. Novel assessment tools, including objective assessments at individual and community levels utilizing new technology, and sophisticated psychometric evaluations for reliability, validity, and sensitivity to change with effective interventions are recommended, and suggestions for training curricula are offered.

Adverse childhood experiences (ACEs) significantly impact lifelong health and well‐being. Despite extensive research, a comprehensive understanding of ACEs' multifaceted impacts continues to be challenging to achieve. This study synthesizes meta‐analytic evidence to provide a comprehensive view of ACEs' effects, addressing various approaches to conceptualizing ACEs and their diverse outcomes. Employing an umbrella synthesis methodology, this review integrated findings from 99 meta‐analyses involving 592 effect sizes. We examined ACEs through specificity, lumping, dimensional, and child maltreatment‐centric approaches, assessing their impact across six domains: biological system dysregulation, neuropsychological impairments, physical health complications, mental health conditions, social and behavioral challenges, and criminal justice involvement. The findings reveal a small to moderate overall effect size of ACEs across outcome domains. Specific ACE approaches exhibited varying impact levels, with notable differences in effects on mental health, social/behavioral issues, and criminal justice involvement. When ACEs were aggregated without distinguishing between different types, but with consideration of their cumulative effects, adverse outcomes were significantly exacerbated. The child maltreatment‐centric approach consistently demonstrated substantial effects across all evaluated domains. This review underscores the heterogeneity in ACEs' impacts, influenced by the type of ACE and specific outcomes considered. It highlights the necessity for comprehensive approaches to understanding, preventing, and mitigating the effects of ACEs. These insights are vital for developing targeted interventions and informing policy‐making, emphasizing the complexity and varied nature of ACEs' influence on individual development and societal well‐being. [ABSTRACT FROM AUTHOR]

Existing evidence indicates genetic and non-genetic influences on sexual orientation; however, the possibility of gene-environment interplay has not been previously formally tested despite theories indicating this. Using a Finnish twin cohort, this study investigated whether childhood gender nonconformity and early-life adversities independently moderated individual differences in sexual orientation and childhood gender nonconformity, the relationship between them, and the etiological bases of the proposed moderation effects. Sexual orientation, childhood gender nonconformity, and early-life adversities were assessed using standard questionnaires. Structural equation twin model fitting was carried out using OpenMx. Childhood gender nonconformity was significantly associated with reduced phenotypic variance in sexual orientation (β = − 0.14, 95% CI − 0.27, − 0.01). A breakdown of the underlying influences of this moderation effect showed that this was mostly due to moderation of individual-specific environmental influences which significantly decreased as childhood gender nonconformity increased (βE = − 0.38; 95% CI − 0.52, − 0.001) while additive genetic influences were not significantly moderated (βA = 0.05; 95% CI − 0.30, 0.27). We also observed that the relationship between sexual orientation and childhood gender nonconformity was stronger at higher levels of childhood gender nonconformity (β = 0.10, 95% CI 0.05, 0.14); however, significance of the underlying genetic and environmental influences on this relationship could not be established in this sample. The findings indicate that beyond a correlation of their genetic and individual-specific environmental influences, childhood gender nonconformity is further significantly associated with reduced individual-specific influences on sexual orientation. [ABSTRACT FROM AUTHOR]

Early-life adversity, even when transient, can have lasting effects on individual phenotypes and reduce lifespan across species. If these effects can be mitigated by a high-quality later-life environment, then differences in future resources may explain variable resilience to early-life adversity. Using data from over 1000 wild North American red squirrels, we tested the hypothesis that the costs of early-life adversity for adult lifespan could be offset by later-life food abundance. We identified six adversities that reduced juvenile survival in the first year of life, though only one—birth date—had continued independent effects on adult lifespan. We then built a weighted early-life adversity (wELA) index integrating the sum of adversities and their effect sizes. Greater weighted early-life adversity predicted shorter adult lifespans in males and females, but a naturally occurring food boom in the second year of life ameliorated this effect. Experimental food supplementation did not replicate this pattern, despite increasing lifespan, indicating that the buffering effect of a future food boom may hinge on more than an increase in available calories. Our results suggest a non-deterministic role of early-life conditions for later-life phenotype, highlighting the importance of evaluating the consequences of early-life adversity in the context of an animal's entire life course. [ABSTRACT FROM AUTHOR]

Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal–child relationships modeling early‐life adversity (ELA) in laboratory rats and mice have a strong long‐term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother–infant relationship, with a focus on the regulation of hypothalamic–pituitary–adrenal axis and brain‐derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research. [ABSTRACT FROM AUTHOR]

BackgroundEarly-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis.MethodsParents reported their child's exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers.ResultsRelative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1-3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA.ConclusionsResults are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.

BackgroundMental health and vulnerabilities to neuropsychiatric disorders involve the interplay of genes and environment, particularly during sensitive developmental periods. Early-life adversity (ELA) and stress promote vulnerabilities to stress-related affective disorders, yet it is unknown how transient ELA dictates lifelong neuroendocrine and behavioral reactions to stress. The population of hypothalamic corticotropin-releasing factor (CRF)-expressing neurons that regulate stress responses is a promising candidate to mediate the long-lasting influences of ELA on stress-related behavioral and hormonal responses via enduring transcriptional and epigenetic mechanisms.MethodsCapitalizing on a well-characterized model of ELA, we examined ELA-induced changes in gene expression profiles of CRF-expressing neurons in the hypothalamic paraventricular nucleus of developing male mice. We used single-cell RNA sequencing on isolated CRF-expressing neurons. We determined the enduring functional consequences of transcriptional changes on stress reactivity in adult ELA mice, including hormonal responses to acute stress, adrenal weights as a measure of chronic stress, and behaviors in the looming shadow threat task.ResultsSingle-cell transcriptomics identified distinct and novel CRF-expressing neuronal populations, characterized by both their gene expression repertoire and their neurotransmitter profiles. ELA-provoked expression changes were selective to specific subpopulations and affected genes involved in neuronal differentiation, synapse formation, energy metabolism, and cellular responses to stress and injury. Importantly, these expression changes were impactful, apparent from adrenal hypertrophy and augmented behavioral responses to stress in adulthood.ConclusionsWe uncover a novel repertoire of stress-regulating CRF cell types differentially affected by ELA and resulting in augmented stress vulnerability, with relevance to the origins of stress-related affective disorders.

Abstract Background Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence.

Background: Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by early-life adversity, animal models have been developed to capture critical features of early-life stress and the behavioral deficits that such stressors induce. We have previously shown that rats exposed to the limited bedding and nesting protocol exhibited blunted reward responsivity in the probabilistic reward task, a touchscreen-based task reverse translated from human studies. Methods: To test the quantitative limits of this translational platform, we examined the ability of Bayesian computational modeling and probability analyses identical to those optimized in previous human studies to quantify the putative mechanisms that underlie these deficits with precision. Specifically, 2 parameters that have been shown to independently contribute to probabilistic reward task outcomes in patient populations, reward sensitivity and learning rate, were extracted, as were trial-by-trial probability analyses of choices as a function of the preceding trial. Results: Significant deficits in reward sensitivity, but not learning rate, contributed to the anhedonic phenotypes in rats exposed to early-life adversity. Conclusions: The current findings confirm and extend the translational value of these rodent models by verifying the effectiveness of computational modeling in distinguishing independent features of reward sensitivity and learning rate that complement the probabilistic reward task’s signal detection end points. Together, these metrics serve to objectively quantify reinforcement learning deficits associated with anhedonic phenotypes.

BackgroundRecent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early-life adversity. Early-life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self-reported early-life unpredictability is associated with psychiatric symptoms in adult clinical populations.MethodsUsing the newly validated Questionnaire of Unpredictability in Childhood, we assessed early-life unpredictability in 156 trauma-exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early-life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6-month period were determined.ResultsEarly-life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early-life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms.ConclusionsEarly-life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology.

Rodent model systems using lipopolysaccharide (LPS) administration have been developed to examine the effect of postnatal inflammation on neuropsychiatric behaviors. In this study, we investigated the effect of 250 μg/kg of LPS administration in male and female Wistar rats at three different postnatal periods. Rats were divided into four groups: a control group which received an intraperitoneal (IP) injection of phosphate buffer saline (PBS) on postnatal day 1 and three experimental groups which received an IP injection of LPS (250 μg/kg) at three different postnatal periods: day 1, day 3 and day 5. Each group consisted of 12 rats and had an equal gender distribution. At three months, rats were subjected to neurobehavioral assessments and biochemical oxidative and inflammatory assays. As a trend, LPS administration generates uniform anxiogenic behaviors, a depressive response, and increased central oxidative and inflammatory stress across all groups as compared to controls. Males receiving an LPS injection at postnatal days 1 and 3 and females receiving it at days 3 and 5 displayed more anxiogenic and depressive responses than their gender counterparts. Females had higher biomarker levels, with results being more pronounced in the group receiving injection on day 3. Postnatal LPS induces emotional disturbances along with oxidative stress and inflammation in brain tissues. Response to LPS injection seems to be gender-dependent and modulated by several variables, including its time of administration. Further investigations that take into consideration these variables, among others, are needed. [ABSTRACT FROM AUTHOR]

The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in earlylife stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes. [ABSTRACT FROM AUTHOR]

Background: Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results: None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions: Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence. [ABSTRACT FROM AUTHOR]

High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3–6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (βs > 0.16, ps

Addiction is a chronic relapsing disorder with devastating personal, societal, and economic consequences. In humans, early-life adversity (ELA) such as trauma, neglect, and resource scarcity are linked with increased risk of later-life addiction, but the brain mechanisms underlying this link are still poorly understood. Here, we focus on data from rodent models of ELA and addiction, in which causal effects of ELA on later-life responses to drugs and the neurodevelopmental mechanisms by which ELA increases vulnerability to addiction can be determined. We first summarize evidence for a link between ELA and addiction in humans, then describe how ELA is commonly modeled in rodents. Since addiction is a heterogeneous disease with many individually varying behavioral aspects that may be impacted by ELA, we next discuss common rodent assays of addiction-like behaviors. We then summarize the specific addiction-relevant behavioral phenotypes caused by ELA in male and female rodents and discuss some of the underlying changes in brain reward and stress circuits that are likely responsible. By better understanding the behavioral and neural mechanisms by which ELA promotes addiction vulnerability, we hope to facilitate development of new approaches for preventing or treating addiction in those with a history of ELA.

Early‐life conditions impact fitness, but whether the combined effect of extrinsic stressors is additive or synergistic is not well known. This is a major knowledge gap because exposure to multiple stressors is frequent. Telomere dynamics may be instrumental when testing how stressors interact because many factors affect telomere shortening, and telomere shortening predicts survival. We evaluated the effect of manipulated brood size and natural infestation by the carnid fly Carnus hemapterus on nestling growth and telomere shortening of wild jackdaws (Corvus monedula). Telomere length, measured in blood using TRF, shortened on average by 264 bp, and on average, Carnus infection induced more telomere shortening. Further analyses showed that in enlarged broods, nestlings' telomeres shortened more when parasitized, while in reduced broods there was no effect of infection on telomere shortening. We conclude that there is a synergistic effect of number of siblings and Carnus infection on telomere shortening rate: blood‐sucking parasites may negatively impact telomeres by increasing cell proliferation and/or physiological stress, and coping with infection may be less successful in enlarged broods with increased sibling competition. Larger nestlings had shorter telomeres independent of age, brood manipulation or infection. Growth was independent of infestation but in enlarged broods, nestlings were lighter at fledging. Our findings indicate that (i) evaluating consequences of early‐life environmental conditions in isolation may not yield a full picture due to synergistic effects, and (ii) effects of environmental conditions may be cryptic, for example, on telomeres, with fitness consequences expressed beyond the temporal framework of the study. [ABSTRACT FROM AUTHOR]

Epigenetic biomarkers of accelerated aging have been widely used to predict disease risk and may enhance our understanding of biological mechanisms between early-life adversity and disparities in aging. With respect to childhood adversity, most studies have used parental education or childhood disadvantage and/or have not examined the role played by socioemotional or physical abuse and trauma in epigenetic profiles at older ages. This study leveraged data from the Multi-Ethnic Study of Atherosclerosis (MESA) on experiences of threat and deprivation in participants' early lives (i.e. before the age of 18 years) to examine whether exposure to specific dimensions of early-life adversity is associated with epigenetic profiles at older ages that are indicative of accelerated biological aging. The sample included 842 MESA respondents with DNA methylation data collected between 2010 and 2012 who answered questions on early-life adversities in a 2018–2019 telephone follow-up. We found that experiences of deprivation, but not threat, were associated with later-life GrimAge epigenetic aging signatures that were developed to predict mortality risk. Results indicated that smoking behavior partially mediates this association, which suggests that lifestyle behaviors may act as downstream mechanisms between parental deprivation in early life and accelerated epigenetic aging in later life. [ABSTRACT FROM AUTHOR]

Objectives: In many taxa, adverse early‐life environments are associated with reduced growth and smaller body size in adulthood. However, in wild primates, we know very little about whether, where, and to what degree trajectories are influenced by early adversity, or which types of early adversity matter most. Here, we use parallel‐laser photogrammetry to assess inter‐individual predictors of three measures of body size (leg length, forearm length, and shoulder‐rump length) in a population of wild female baboons studied since birth. Materials and Methods: Using >2000 photogrammetric measurements of 127 females, we present a cross‐sectional growth curve of wild female baboons (Papio cynocephalus) from juvenescence through adulthood. We then test whether females exposed to several important sources of early‐life adversity—drought, maternal loss, low maternal rank, or a cumulative measure of adversity—were smaller for their age than females who experienced less adversity. Using the "animal model," we also test whether body size is heritable in this study population. Results: Prolonged early‐life drought predicted shorter limbs but not shorter torsos (i.e., shoulder‐rump lengths). Our other measures of early‐life adversity did not predict variation in body size. Heritability estimates for body size measures were 36%–67%. Maternal effects accounted for 13%–17% of the variance in leg and forearm length, but no variance in torso length. Discussion: Our results suggest that baboon limbs, but not torsos, grow plastically in response to maternal effects and energetic early‐life stress. Our results also reveal considerable heritability for all three body size measures in this study population. [ABSTRACT FROM AUTHOR]

This chapter discusses how the complex concept of anhedonia can be operationalized and studied in preclinical models. It provides information about the development of anhedonia in the context of early-life adversity, and the power of preclinical models to tease out the diverse molecular, epigenetic, and network mechanisms that are responsible for anhedonia-like behaviors.Specifically, we first discuss the term anhedonia, reviewing the conceptual components underlying reward-related behaviors and distinguish anhedonia pertaining to deficits in motivational versus consummatory behaviors. We then describe the repertoire of experimental approaches employed to study anhedonia-like behaviors in preclinical models, and the progressive refinement over the past decade of both experimental instruments (e.g., chemogenetics, optogenetics) and conceptual constructs (salience, valence, conflict). We follow with an overview of the state of current knowledge of brain circuits, nodes, and projections that execute distinct aspects of hedonic-like behaviors, as well as neurotransmitters, modulators, and receptors involved in the generation of anhedonia-like behaviors. Finally, we discuss the special case of anhedonia that arises following early-life adversity as an eloquent example enabling the study of causality, mechanisms, and sex dependence of anhedonia.Together, this chapter highlights the power, potential, and limitations of using preclinical models to advance our understanding of the origin and mechanisms of anhedonia and to discover potential targets for its prevention and mitigation.

Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been proposed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.

Background: Early-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis. Methods: Parents reported their child’s exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers. Results: Relative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1−3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA. Conclusions: Results are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.

Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements. Abbreviations: DNAm – DNA methylation, CpG − 5’-cytosine-phosphate-guanine-3,’ ICC – Interclass correlation coefficient, ELA – Early-life adversity, PBMCs – Peripheral blood mononuclear cells, mQTL – Methylation quantitative trait loci, TSS – Transcription start site, GSR – Glutathione-disulfide reductase gene, TSST – Trier social stress test, PC – Principal component.

Stressful life experiences are associated with the development of neuropsychiatric disorders like depression. Emerging evidence indicates that microglia, the specialized resident macrophages of the brain, may be a key mediator of the relationship between psychosocial stressor exposure and adaptive or maladaptive responses at the level of synaptic, circuit, and neuroimmune alterations. Here, we review current literature regarding how psychosocial stressor exposure changes microglial structure and function, thereby altering behavioral and brain outcomes, with a particular focus on age- and sex-dependent effects. We argue that additional emphasis should be placed in future research on investigating sex differences and the impacts of stressor exposure during sensitive periods of development, as well as going beyond traditional morphological measurements to interrogate microglial function. The bidirectional relationship between microglia and the stress response, particularly the role of microglia in the neuroendocrine control of stress-related circuits, is also an important area for future investigation. Finally, we discuss emerging themes and future directions that point to the possibility of the development of novel therapeutics for stress-related neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Early-life adversity (ELA) exposure (e.g., trauma, abuse, neglect, or institutional care) is a precursor to poor physical and mental health outcomes and is implicated in 30% of adult mental illness. In recent decades, ELA research has increasingly focused on characterizing factors that confer resilience to ELA and on identifying opportunities for intervention. In this review, we describe recent behavioral and neurobiological resilience work that suggests that adolescence (a period marked by heightened plasticity, development of key neurobiological circuitry, and sensitivity to the social environment) may be a particularly opportune moment for ELA intervention. We review intrapersonal factors associated with resilience that become increasingly important during adolescence (specifically, reward processing, affective learning, and self-regulation) and describe the contextual factors (family, peers, and broader social environment) that modulate them. In addition, we describe how the onset of puberty interacts with each of these factors, and we explore recent findings that point to possible "pubertal recalibration" of ELA exposure as an opportunity for intervention. We conclude by describing considerations and future directions for resilience research in adolescents, with a focus on understanding developmental trajectories using dimensional and holistic models of resilience.

Background: Mental health and vulnerabilities to neuropsychiatric disorders involve the interplay of genes and environment, particularly during sensitive developmental periods. Early-life adversity (ELA) and stress promote vulnerabilities to stress-related affective disorders, yet it is unknown how transient ELA dictates lifelong neuroendocrine and behavioral reactions to stress. The population of hypothalamic corticotropin-releasing factor (CRF)–expressing neurons that regulate stress responses is a promising candidate to mediate the long-lasting influences of ELA on stress-related behavioral and hormonal responses via enduring transcriptional and epigenetic mechanisms. Methods: Capitalizing on a well-characterized model of ELA, we examined ELA-induced changes in gene expression profiles of CRF-expressing neurons in the hypothalamic paraventricular nucleus of developing male mice. We used single-cell RNA sequencing on isolated CRF-expressing neurons. We determined the enduring functional consequences of transcriptional changes on stress reactivity in adult ELA mice, including hormonal responses to acute stress, adrenal weights as a measure of chronic stress, and behaviors in the looming shadow threat task. Results: Single-cell transcriptomics identified distinct and novel CRF-expressing neuronal populations, characterized by both their gene expression repertoire and their neurotransmitter profiles. ELA-provoked expression changes were selective to specific subpopulations and affected genes involved in neuronal differentiation, synapse formation, energy metabolism, and cellular responses to stress and injury. Importantly, these expression changes were impactful, apparent from adrenal hypertrophy and augmented behavioral responses to stress in adulthood. Conclusions: We uncover a novel repertoire of stress-regulating CRF cell types differentially affected by ELA and resulting in augmented stress vulnerability, with relevance to the origins of stress-related affective disorders.

ObjectiveWhile early-life adversity can have negative effects on health and wellbeing that persist across the lifespan, some individuals show indications of resilience. Resilience can be understood as a dynamic coping process involving the mobilization of resources in response to adversity exposure. Sense of coherence—revised (SOC-R), an ability linked to health maintenance in the face of adversity, may be influential in this process. However, research is lacking on the mechanisms underpinning SOC-R and resilience-related resources and their impact on the (mental) health of individuals exposed to early-life adversity. Therefore, this study examined the role of SOC-R and selected resilience-related resources in the relationship between early-life adversity and later-life health and wellbeing.MethodParticipants were N = 531 Irish (older) adults (58.2% female, mean age = 59.5 years, range = 50–86 years). Standardized questionnaires assessed retrospective reports of early-life adversity, as well as current physical and mental health, satisfaction with life, SOC-R, and resilience-related resources (self-efficacy, optimism, social support). A multiple mediation analysis tested the indirect effects of the resources and a moderated mediation tested for conditional dependence on SOC-R.ResultsFor mental health and satisfaction with life, significant partial mediations were found for all three resources. Only optimism showed a significant partial mediation for physical health. In the moderated mediation, SOC-R significantly moderated the associations between early-life adversity and self-efficacy (b = .06, t = 3.65, p = .001), optimism (b = .04, t = 2.60, p = .009), and social support (b = .08, t = 3.75, p

Background: Early‐life adversity is associated with adverse mental health outcomes and poorer cognitive functioning in later development. However, little is known about how early‐life adversity, mental health, and cognition affect one another or how the effects unfold over time. Here, we test the hypothesis that early‐life adversity may lead to mental health challenges which in turn have adverse consequences for the development of cognitive abilities. Methods: In a large (N = 13,287) longitudinal (5 wave) sample assessed at ages 3, 5, 7, 11 and 14, we use both path analysis approach and latent growth curve mediation model to study whether poorer mental health in childhood may mediate the effects of early‐life adversity on later working memory and vocabulary outcomes. Results: We found a significant total association between early‐life adversity and poorer performance on working memory (β =.123, p <.001, [95% CI 0.106, 0.141]) and vocabulary scores (β = −.111, p <.001, [95% CI −0.129, −0.093]). Notably, current and previous mental health mediated a substantial proportion (working memory: 59%; vocabulary: 70%) of these effects. Further longitudinal modeling showed that early‐life adversity has an enduring adverse effect on mental health, and that poorer mental health is associated with poorer cognitive performance later on in development. In a complementary analysis using latent growth curve mediation model, we found indirect associations between early‐life adversity and working memory through baseline mental health at age 3 (intercept: β =.083, p <.001, [95% CI 0.072, 0.094]) and change in mental health across ages 3–11 (slope: β = −.012, p =.001, [95% CI −0.019, −0.005]). Likewise, baseline mental health at age 3 (intercept: β = −.095, p <.001, [95% CI −0.107, −0.083]) and change in mental health across ages 3–14 (slope: β =.007, p =.001, [95% CI 0.003, 0.011]) significantly and completely mediated the relation between early‐life adversity and vocabulary outcome. Conclusions: These findings have important potential clinical and educational implications, because they suggest that academic and cognitive resilience may be supported through early mental health interventions in vulnerable children. [ABSTRACT FROM AUTHOR]

Early-life adversity is a major risk factor for psychopathology, but not all who experience adversity develop psychopathology. The current study evaluated whether the links between child and adolescent adversity and depression and anxiety were described by general benefits and / or buffering effects of interpersonal support. Data from 456 adolescents oversampled on neuroticism over a 5-year period were examined in a series of discrete-time survival analyses to predict subsequent disorder onsets. Models examined linear, quadratic, and interactive effects of interpersonal support over time, as measured by chronic interpersonal stress interview ratings. Results did not support buffering effects of interpersonal support against either child or adolescent adversity in predicting depression or anxiety. However, there was support for the general benefits model of interpersonal support as evidenced by follow-up analyses of significant quadratic effects of interpersonal support, demonstrating that higher interpersonal support led to decreased likelihood of depression and anxiety onsets. Secondary analyses demonstrated that effects of interpersonal support remained after accounting for baseline depression and anxiety diagnoses. Further, quadratic effects were driven by social domains as opposed to familial domains when considering child adversity. Implications for interventions and randomized controlled prevention trials regarding interpersonal relationships are discussed. [ABSTRACT FROM AUTHOR]

Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a withinperson between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements. Abbreviations: DNAm - DNA methylation, CpG - 5'-cytosine-phosphate-guanine-3,' ICC - Interclass correlation coefficient, ELA - Early-life adversity, PBMCs - Peripheral blood mononuclear cells, mQTL - Methylation quantitative trait loci, TSS - Transcription start site, GSR - Glutathione-disulfide reductase gene, TSST - Trier social stress test, PC - Principal component. [ABSTRACT FROM AUTHOR]

Early-life adversity has profound consequences for youth neurodevelopment and adjustment; however, experiences of adversity are heterogeneous and interrelated in complex ways that can be difficult to operationalize and organize in developmental research. We sought to characterize the underlying dimensional structure of co-occurring adverse experiences among a subset of youth (ages 9–10) from the Adolescent Brain Cognitive Development (ABCD) Study (N = 7115), a community sample of youth in the United States. We identified 60 environmental and experiential variables that reflect adverse experiences. Exploratory factor analysis identified 10 robust dimensions of early-life adversity co-occurrence, corresponding to conceptual domains such as caregiver substance use and biological caregiver separation, caregiver psychopathology, caregiver lack of support, and socioeconomic disadvantage / neighborhood lack of safety. These dimensions demonstrated distinct associations with internalizing problems, externalizing problems, cognitive flexibility, and inhibitory control. Non-metric multidimensional scaling characterized qualitative similarity among the 10 identified dimensions. Results supported a nonlinear three-dimensional structure representing early-life adversity, including continuous gradients of “perspective”, “environmental uncertainty”, and “acts of omission/commission”. Our findings suggest that there are distinct dimensions of early-life adversity co-occurrence in the ABCD sample at baseline, and the resulting dimensions may have unique implications for neurodevelopment and youth behavior.

Background: Early-life adversities during development (e.g., child abuse and neglect) are linked to multiple behavioral and cognitive dysfunctions, such as attention deficit/hyperactivity disorder (ADHD) and anxiety disorders, which have high comorbidity. However, the impact of adversities during adolescence, a crucial period in early life for these disorders, is understudied. Using a chronic unpredictable stress (CUS) model in rats, we investigated whether adversities in adolescence could lead to increased anxiety and ADHD-like symptoms in adulthood. Methods: Mid- to late-adolescent (5–7-week-old) male and female Sprague–Dawley rats underwent a mild CUS procedure for 2 weeks. Various stressors were applied in an unpredictable way. Rats of both sexes were then trained with a 2-choice reaction time (2-CRT) task during adulthood, which are designed to detect ADHD-like symptoms, including increased impulsivity and lapse of attention. In addition, an open field test was conducted to examine if CUS resulted in a persistent increase in anxiety-like behavior during adulthood. Results: Both male and female rats with CUS exposure travelled shorter distances in the open field and spent less time in the center zone, indicating increased anxiety. In the 2-CRT task, rats of both sexes with CUS exposure showed increased impulsivity. Augmented lapses of attention were observed in female but not male rats. Conclusion: Chronic unpredictable stress during adolescence increases anxiety and leads to ADHD-like symptoms in both male and female rats in adulthood. The deficits are more severe in females than in males. These observations support that adversities during adolescence persistently increase anxiety, which is comorbid with attention deficits. [ABSTRACT FROM AUTHOR]

Early-life adversity (ELA) is known to alter brain circuit maturation as well as increase vulnerability to cognitive and emotional disorders. However, the importance of examining sex as a biological variable when researching the effects of ELA has not been considered until recently. This perspective discusses the sex-specific behavioral outcomes of ELA in both humans and animal models, then proposes microglia-mediated mechanisms as a potential underlying cause. Recent work in rodent models suggests that ELA provokes cognitive deficits, anhedonia, and alcohol abuse primarily in males, whereas females exhibit greater risk-taking and opioid addiction-related behaviors. In addition, emerging evidence identifies microglia as a key target of ELA. For example, we have recently shown that ELA inhibits microglial synapse engulfment and process dynamics in male mice, leading to an increase in excitatory synapse number onto corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) and aberrant stress responses later in life. However, ELA-induced synaptic rewiring of neural circuits differs in females during development, resulting in divergent behavioral outcomes. Thus, examining the role of microglia in the sex-specific mechanisms underlying ELA-induced neuropsychiatric disorders is an important topic for future research. [ABSTRACT FROM AUTHOR]

Exposure to different environmental factors, social and socioeconomic factors promotes development of the early-life adversity (ELA) phenotype. The persistence of this phenotype across generations is an interesting phenomenon that remains unexplored. Of late many studies have focused on disease-associated outcomes of ELA following exposure during childhood but the persistence of epigenetic imprints transmitted by ELA exposed parents to their offspring remains poorly described. It is possible that both parents are able to transmit ELA-associated genetic imprints to their offspring via transgenerational inheritance mechanisms. Here, we highlight the role of the mother and father in the biological process of conception, from epigenetic reprogramming cycles to later environmental exposures. We explain some of the known determinants of ELA (pollution, socioeconomic challenges, infections, etc.) and their disease-associated outcomes. Finally, we highlight the role of epigenetics, mitochondria and ncRNAs as mechanisms mediating transgenerational inheritance. Whether these transgenerational inheritance mechanisms occur in the human context remains unclear but there is a large body of suggestive evidence in non-human models that points out to its existence. [Display omitted] • ELA phenotype transmission across generations is an underexplored phenomenon, involving parental epigenetic imprints. • Transgenerational inheritance mechanisms remain unclear in man, but substantial evidence exists in non-human models. • Epigenetics, maternal mitochondrial imprinting and non-coding RNAs mechanisms may mediate transgenerational inheritance. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook. • The cornerstone of AD may include the inflammation that accompanies it. • Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation. • Individual metabolic, and lipid profiles can differentially regulate this inflammatory process. • We integrate evidence for the role of aging, obesity, poor diet, early life stress and other inflammatory factors in AD. • We examine the importance of appropriate dietary polyunsaturated fatty acids (PUFA) for AD outlook. [ABSTRACT FROM AUTHOR]

Early-life adversity (ELA) is known to alter brain circuit maturation as well as increase vulnerability to cognitive and emotional disorders. However, the importance of examining sex as a biological variable when researching the effects of ELA has not been considered until recently. This perspective discusses the sex-specific behavioral outcomes of ELA in both humans and animal models, then proposes microglia-mediated mechanisms as a potential underlying cause. Recent work in rodent models suggests that ELA provokes cognitive deficits, anhedonia, and alcohol abuse primarily in males, whereas females exhibit greater risk-taking and opioid addiction-related behaviors. In addition, emerging evidence identifies microglia as a key target of ELA. For example, we have recently shown that ELA inhibits microglial synapse engulfment and process dynamics in male mice, leading to an increase in excitatory synapse number onto corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) and aberrant stress responses later in life. However, ELA-induced synaptic rewiring of neural circuits differs in females during development, resulting in divergent behavioral outcomes. Thus, examining the role of microglia in the sex-specific mechanisms underlying ELA-induced neuropsychiatric disorders is an important topic for future research.

Background: Violence exposure during childhood and adolescence is associated with increased prevalence and severity of psychopathology. Neurobiological correlates suggest that abnormal maturation of emotion-related brain circuitry, such as amygdala-prefrontal cortex (PFC), may underlie the development of psychiatric symptoms after exposure; however, it remains unclear how amygdala-PFC circuit maturation is related to psychiatric risk in the context of violence., Methods: This study analyzed individual differences in amygdala-PFC circuit maturity using data collected from the Philadelphia Neurodevelopmental Cohort (PNC; N=1,133 youth). Neurodevelopment models of amygdala-PFC resting-state functional connectivity were built using deep learning, trained to predict chronological age in typically developing youth (neither violence exposed nor having a psychiatric diagnosis). Using the brain age gap estimate (BrainAGE), an index of relative circuit maturation, patterns of atypical neurodevelopment were interrogated., Results: Violence exposure was associated with delayed maturation of basolateral amygdala (BLA) - PFC circuits, driven by increased BLA - medial orbitofrontal cortex functional connectivity. Increased psychiatric symptoms, on the other hand, was associated with advanced maturation of BLA - PFC functional connectivity, driven by decreased BLA - dorsolateral PFC functional connectivity., Conclusions: Delayed frontoamygdala maturation after exposure to violence suggests atypical, yet adaptive, development of threat appraisal processes, potentially reflecting greater threat generalization characteristic of younger children. Advanced circuit maturation with increasing symptoms suggests divergent neurodevelopmental mechanisms underlying illness after emotion-circuits have adapted to adversity, exacerbated by pre-existing vulnerabilities to early maturation. Disentangling the effects of adversity and psychopathology on neurodevelopment is crucial for helping youth recover from violence and preventing illness from continuing into adulthood., (Copyright © 2024. Published by Elsevier Inc.)