Effects Of Early Adversity Research Articles

The impact of early adversity on later life health, lifestyle, and cognition

BackgroundEarly life adversity has been shown to have long-lasting detrimental effects on a variety of biopsychosocial outcomes. Early adversity and its consequences may directly or indirectly affect cognitive aging and increase the risk of developing dementia in older age. Investigating the biopsychosocial outcomes associated with early adverse experiences is essential to inform health policies and promote healthy cognitive development across the life course.MethodsThe aim of this study is to investigate the effect of early adversity (i.e., abuse and deprivation) on selected outcomes (i.e., physical and mental health, lifestyle, and cognition) in two UK cohorts (the English Longitudinal Study of Ageing (ELSA), N = 12,653, Mdnage = 66, SDage = 9.58; UK Biobank, N = 502,360, Mdnage = 58, SDage = 8.09). In both cohorts, adversities were self-reported retrospectively, and only those adversity types assessed in both cohorts were utilized. A post-hoc analysis was performed to examine the role of education as a mediator of the association between early adversity and the selected outcomes.ResultsMost of the results show that early adversity is negatively associated with health (both physical and mental), lifestyle, and cognition while also highlighting the important mediating role of education. However, differences exist according to the specific adversity experienced and the cohort studied.ConclusionsThe results found bring into attention the complex associations between early adversity and multiple later life outcomes, and suggest that various mechanisms might be at play. Furthermore, the findings highlight the importance of multi-cohort comparisons for the generalization of the results.

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Cardiometabolic and psychiatric disorders often co-exist and share common early life risk factors, such as low birth weight. However, the biological pathways linking early adversity to adult cardiometabolic/psychiatric comorbidity remain unknown. Dopamine (DA) neurotransmission in the striatum is sensitive to early adversity and influences the development of both cardiometabolic and psychiatric diseases. Here we show that a co-expression based polygenic score (ePGS) reflecting individual variations in the expression of the striatal dopamine transporter gene (SLC6A3) network significantly interacts with birth weight to predict psychiatric and cardiometabolic comorbidities in both adults (UK Biobank, N = 225,972) and adolescents (ALSPAC, N = 1188). Decreased birth weight is associated with an increased risk for psychiatric and cardiometabolic comorbidities, but the effect is dependent on a striatal SLC6A3 ePGS, that reflects individual variation in gene expression of genes coexpressed with the SLC6A3 gene in the striatum. Neuroanatomical analyses revealed that SNPs from the striatum SLC6A3 ePGS were significantly associated with prefrontal cortex gray matter density, suggesting a neuroanatomical basis for the link between early adversity and psychiatric and cardiometabolic comorbidity. Our study reveals that psychiatric and cardiometabolic diseases share common developmental pathways and underlying neurobiological mechanisms that includes dopamine signaling in the striatum.

Early life adversity has sex-dependent effects on survival across the lifespan in rhesus macaques.

Exposure to early life adversity is linked to detrimental fitness outcomes across taxa. Owing to the challenges of collecting longitudinal data, direct evidence for long-term fitness effects of early life adversity from long-lived species remains relatively scarce. Here, we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico. We leveraged six decades of data to quantify the relative importance of 10 forms of early life adversity for 6599 macaques. Individuals that experienced more early life adversity died earlier than those that experienced less adversity. Mortality risk was highest during early life, defined as birth to 4 years old, but heightened mortality risk was also present in macaques that survived to adulthood. Females and males were affected differently by some forms of adversity, and these differences might be driven by varying energetic demands and dispersal patterns. Our results show that the fitness consequences of early life adversity are not uniform across individuals but vary as a function of the type of adversity, timing and social context, and thus contribute to our limited but growing understanding of the evolution of early life sensitivities.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.

Friend or foe? Early life adversity to improve farmed animal welfare

Early life experiences can have lasting impacts on an animal’s development. Extensive research evidence aligns across both human and non-human rodent and primate laboratory animals showing negative impacts of early life adversity such as impairments in neurological and behavioural development. Farmed animals experience a range of adversities across their production lifetimes, often early in life, including species atypical social groupings, invasive husbandry procedures, and transport. Correspondingly, farmed animals also demonstrate a wide range of impairments such as stereotypic, injurious, and other abnormal behaviours. An individual, however, needs to experience adversity to be able to develop resilience and coping mechanisms that facilitate dealing with challenges later in life. Not all individuals will experience stress vulnerability following adversity, with some individuals instead developing stress resilience. This mini review collates evidence on the positive effects of early life adversity on improving adaptability in farmed species, both terrestrial and aquatic. While evidence across farmed animal species is currently much less than for humans, laboratory rodents or non-human primates, similar patterns emerge where mild adversity early in life, can improve the adaptability of the animal in the face of future stressors. Many views of optimised welfare posit that farmed animals should be housed in as natural environments as possible to limit many of the typical adversities they face. However, strategic mild exposure to early life adversity may facilitate improved animal welfare under intensive commercial farming conditions. Future research into this area could provide management tools to better predict and promote stress resilience over stress vulnerability.

Childhood Maltreatment and Electrodermal Reactivity to Stress Among Pregnant Women.

There are competing theoretical hypotheses regarding the consequences of early adversity, such as childhood maltreatment, for individuals' autonomic nervous system activity. Research examining potential implications of child maltreatment for sympathetic nervous system activity, specifically, is scarce. In this preregistered study, we examined whether childhood maltreatment history is associated with pregnant adults' sympathetic responses to different stressors. This population is particularly relevant, given potential intergenerational consequences of pregnant individuals' physiological responses to stress. Pregnant women's (N=162) electrodermal levels were recorded while completing the Trier Social Stress Test (TSST), which elicits social-evaluative threat, and while watching a video of an unfamiliar infant crying, which was intended to activate the attachment system. Pregnant women's retrospective reports of childhood maltreatment were negatively associated with their electrodermal reactivity to the TSST and to the video of the infant crying. Follow-up analyses indicated that these associations were specific to reported experiences of childhood abuse and not childhood neglect. Altogether, these findings indicate that self-reported childhood maltreatment experiences, and childhood abuse in particular, may result in blunted activity of the sympathetic nervous system in response to multiple types of stressors.

Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT1A autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT1A autoreceptors as potential targets to prevent these enduring effects of ELA.

Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

Early Life Adversity, Microbiome, and Inflammatory Responses.

Early life adversity has a profound impact on physical and mental health. Because the central nervous and immune systems are not fully mature at birth and continue to mature during the postnatal period, a bidirectional interaction between the central nervous system and the immune system has been hypothesized, with traumatic stressors during childhood being pivotal in priming individuals for later adult psychopathology. Similarly, the microbiome, which regulates both neurodevelopment and immune function, also matures during childhood, rendering this interaction between the brain and the immune system even more complex. In this review, we provide evidence for the role of the immune response and the microbiome in the deleterious effects of early life adversity, both in humans and rodent models.

Effects of early life adversity and adolescent basolateral amygdala activity on corticolimbic connectivity and anxiety behaviors.

Early postnatal development of corticolimbic circuitry is shaped by the environment and is vulnerable to early life challenges. Prior work has shown that early life adversity (ELA) leads to hyperinnervation of glutamatergic basolateral amygdala (BLA) projections to the prefrontal cortex (PFC) in adolescence. While hyperinnervation is associated with later-life anxiety behaviors, the physiological changes underpinning corticolimbic and behavioral impacts of ELA are not understood. We tested whether postsynaptic BLA-driven PFC activity is enhanced in ELA-exposed animals, using the maternal separation (MS) model of ELA. PFC local-field potential following BLA stimulation was facilitated in MS-exposed adolescents. Since ELA increases activity of the early-developing BLA, while the PFC exhibits protracted development, we further examined impacts of glutamatergic BLA activity during early adolescence on later-life PFC innervation and heightened anxiety. In early adolescence, MS-exposed animals exhibited decreased anxiety-like behavior, and acute adolescent BLA inhibition induced behaviors that resembled those of MS animals. To examine long-lasting impacts of adolescent BLA activity on innervation, BLA-originating axonal boutons in the PFC were quantified in late adolescence after early adolescent BLA inhibition. We further tested whether late adolescent BLA-PFC changes were associated with anxious reactivity expressed as heightened acoustic startle responses. MS rearing increased BLA-PFC innervation and threat reactivity in late adolescence, however early adolescent BLA inhibition was insufficient to prevent MS effects, suggesting that earlier BLA activity or post-synaptic receptor rearrangement in the PFC drives altered innervation. Taken together, these findings highlight both pre- and postsynaptic changes in the adolescent BLA-PFC circuit following ELA.

The importance of decomposing periodic and aperiodic EEG signals for assessment of brain function in a global context.

Measures of early neuro-cognitive development that are suitable for use in low-resource settings are needed to enable studies of the effects of early adversity on the developing brain in a global context. These measures should have high acquisition rates and good face and construct validity. Here, we investigated the feasibility of a naturalistic electroencephalography (EEG) paradigm in a low-resource context during childhood. Additionally, we examined the sensitivity of periodic and aperiodic EEG metrics to social and non-social stimuli. We recorded simultaneous 20-channel EEG and eye-tracking in 72 children aged 4-12 years (45 females) while they watched videos of women singing nursery rhymes and moving toys, selected to represent familiar childhood experiences. These measures were part of a feasibility study that assessed the feasibility and acceptability of a follow-up data collection of the South African Safe Passage Study, which tracks environmental adversity and brain and cognitive development from before birth up until childhood. We examined whether data quantity and quality varied with child characteristics and the sensitivity of varying EEG metrics (canonical band power in the theta and alpha band and periodic and aperiodic features of the power spectra). We found that children who completed the EEG and eye-tracking assessment were, in general, representative of the full cohort. Data quantity was higher in children with greater visual attention to the stimuli. Out of the tested EEG metrics, periodic measures in the theta frequency range were most sensitive to condition differences, compared to alpha range measures and canonical and aperiodic EEG measures. Our results show that measuring EEG during ecologically valid social and non-social stimuli is feasible in low-resource settings, is feasible for most children, and produces robust indices of social brain function. This work provides preliminary support for testing longitudinal links between social brain function, environmental factors, and emerging behaviors.

The growing interdisciplinarity of developmental psychopathology: Implications for science and training.

The field of developmental psychopathology has grown exponentially over the past decades, and has become increasingly multifaceted. The initial focus on understanding abnormal child psychology has broadened to the study of the origins of psychopathology, with the goals of preventing and alleviating disorder and promoting healthy development. In this paper, we discuss how technological advances and global events have expanded the questions that researchers in developmental psychopathology can address. We do so by describing a longitudinal study that we have been conducting for the past dozen years. We originally planned to examine the effects of early adversity on trajectories of brain development, endocrine function, and depressive symptoms across puberty; it has since become an interdisciplinary study encompassing diverse domains like inflammation, sleep, biological aging, the environment, and child functioning post-pandemic, that we believe will advance our understanding of neurobehavioral development. This increase in the breadth in our study emerged from an expansion of the field; we encourage researchers to embrace these dynamic changes. In this context, we discuss challenges, opportunities, and institutional changes related to the growing interdisciplinarity of the field with respect to training the next generation of investigators to mitigate the burden of mental illness in youth.

A sex-specific pathway linking early life maltreatment, vagal activity, and depressive symptoms

ABSTRACT Background: Experiences of early life maltreatment (ELM) are alarmingly common and represent a risk factor for the development of psychopathology, particularly depression. Research has focused on alterations in autonomic nervous system (ANS) functioning as a mediator of negative mental health outcomes associated with ELM. Early alterations in autonomic vagal activity (vmHRV) may moderate the relationship between ELM and depression, particularly when considering forms of emotional maltreatment. Recent evidence suggests that the relationships of both ELM and vmHRV with depression may be non-linear, particularly considering females. Objective: Building on and extending theoretical considerations and previous work, the present work aims to further the current understanding of the complex relationships between ELM exposure, vmHRV, and depression. Methods: This study uses an adaptive modelling approach, combining exploratory network-based analyses with linear and quadratic moderation analyses, drawing on a large sample of males and females across adolescence (total N = 213; outpatient at-risk sample and healthy controls) and adulthood (total N = 85; community-based convenience sample). Results: Exploratory network-based analyses reveal that exposure to emotional abuse is particularly central within a network of ELM subtypes, depressive symptoms, and concurrent vmHRV in both adolescents and adults. In adults, emotional neglect shows strong associations with both emotional abuse and vmHRV and is highly central as a network node, which is not observed in adolescents. Moderator analyses reveal significant interactions between emotional maltreatment and vmHRV predicting depressive symptoms in adult females. Significant quadratic relationships of emotional maltreatment and vmHRV with depression are observed in both adolescent and adult females. Conclusions: The present findings contribute to the understanding of the psychological and physiological mechanisms by which ELM acts as a risk factor for the development of depression. Ultimately, this will contribute to the development of targeted and effective intervention strategies to mitigate the detrimental effects of early adversity.

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.

The impact of self‐reported retrospective early adversity on later life biopsychosocial outcomes

AbstractBackgroundEarly adversity has been associated with several biopsychosocial outcomes later in life. Early adversity and its long‐lasting consequences may affect directly or indirectly cognitive aging and increase the risk of developing dementia in older age. Therefore, investigating the biopsychosocial outcomes associated with early adverse experiences is essential to be able to promote good development across the life course (i.e., resilience) and healthy (cognitive) aging.MethodThe goal of this study is to investigate the effect of early adversity (i.e., trauma and deprivation) on various biopsychosocial outcomes (i.e., physical and mental health, lifestyle, and cognition) in two UK cohorts (UK Biobank, N = 500,000; the English Longitudinal Study of Ageing (ELSA), N = 20,000). In both cohorts, adversities are self‐reported retrospectively, and only those adversities assessed in both cohorts were selected.ResultThe preliminary results showed that in both cohorts early adverse experiences have a significant detrimental effect on all the biopsychosocial outcomes investigated (i.e., physical and mental health, lifestyle, and cognition), Ps &lt;.01.ConclusionIn line with the literature, early adverse experiences have long‐lasting detrimental effects on a variety of biopsychosocial outcomes. The results found will be replicated on longitudinal data, to gain more information about the associations found and their underlying mechanisms. The aim of this study is to identify target factors on which to base interventions to promote resilience and healthy (cognitive) aging.

Does early adversity predict aggression among Chinese male violent juvenile offenders? The mediating role of life history strategy and the moderating role of meaning in life

BackgroundAdolescent aggression has long been of interest to researchers. However, few studies have examined the influencing factors and mechanisms of aggression among violent juvenile offenders. This study tests a moderated mediation model with Chinese male violent juvenile offenders as subjects. Specifically, it explores the relationship between early adversity and aggression, as well as the mechanisms of life history strategy and meaning in life in this relationship.MethodsA total of 537 Chinese male violent juvenile offenders completed the Childhood Environment Scale, the Life History Strategy Short Form Scale, the Aggression Questionnaire, and the Meaning in Life Questionnaire. After controlling for socioeconomic status (SES), the current cross-sectional study used structural equation modeling (SEM) to examine a moderated mediation model.ResultsThe results showed that life history strategy mediated the relationship between early adversity and aggression, and early adversity affected individuals’ aggression by accelerating their life history strategies. The results also showed that meaning in life moderated the relationship between early adversity and life history strategy. For individuals with high meaning in life scores, the negative predictive effect of early adversity on life history strategy was stronger than that for individuals with low meaning in life scores.ConclusionThe results of this study can advance the understanding of how early adversity affects aggression among violent juvenile offenders and provide theoretical support for prison staff to develop educational strategies and subsequent interventions.

Differential effects of early life adversity on male and female rhesus macaque lifespan.

Early life adversity predicts shorter adult lifespan in several animal taxa. Yet, work on long-lived primate populations suggests the evolution of mechanisms that contribute to resiliency and long lives despite early life insults. Here, we tested associations between individual and cumulative early life adversity and lifespan on rhesus macaques at the Cayo Santiago Biological Field Station using 50 years of demographic data. We performed sex-specific survival analyses at different life stages to contrast short-term effects of adversity (i.e., infant survival) with long-term effects (i.e., adult survival). Female infants showed vulnerability to multiple adversities at birth, but affected females who survived to adulthood experienced a reduced risk later in life. In contrast, male infants showed vulnerability to a lower number of adversities at birth, but those who survived to adulthood were negatively affected by both early life individual and cumulative adversity. Our study shows profound immediate effects of insults on female infant cohorts and suggests that affected female adults are more robust. In contrast, adult males who experienced harsh conditions early in life showed an increased mortality risk at older ages as expected from hypotheses within the life course perspective. Our analysis suggests sex-specific selection pressures on life histories and highlights the need for studies addressing the effects of early life adversity across multiple life stages.

3 Neuropsychiatric Change and Childhood Adversity Levels in an Opioid Treatment Population

Objective:Early life adversity is strongly correlated with a number of negative health outcomes, with some of the highest risks are related to later illicit drug use and substance use disorders (SUDs). Specifically, it has been found that an ACEs score of &gt;4 confers a 7-10-fold risk of substance abuse. Subsequent research has identified a number of neurobiological effects of childhood trauma, including structural and functional disruptions of the LHPA axis, the brain's primary stress-response system. It has been hypothesized that various trauma-induced neurobiological changes may lead to later physical health, mental health, and psychosocial problems in persons with early life adversity. One area that such changes might affect is a person's ability to stop abusing substances, with factors such as trauma-related mood, self-efficacy, or cognitive functioning as considerations in early treatment success. This study followed a group of participants in a residential substance abuse treatment program across their first month of abstinence, to assess natural change in cognitive performance as well as potential effect of early life adversity on changes in neuropsychiatric outcomes.Participants and Methods:Participants were 37 adults (mean age=33.9 years, SD=6.7) who had completed detoxification and were first assessed during their first week of residential treatment. Follow-up assessment was completed 4 weeks later. Participants were primarily male (62%) and white (62%). They were all in treatment for opioid abuse, with a majority of participants reporting a history of polysubstance abuse. To measure adverse and protective factors, participants completed the Adverse Childhood Experiences scale and Protective And Compensatory Experiences Scale at baseline. Participants also completed the NIH Toolbox cognition battery and a set of self-report measures of cognitive functioning, mood, anxiety, and self-efficacy at baseline and follow up.Results:Results of paired samples t-test comparison between baseline and follow-up testing found a significant improvement in self-reported depression symptoms, anxiety symptoms, and self-efficacy (all p&lt;.001). Interestingly, participants overall reported an increase in cognitive problems between baseline and retest, even though on objective cognitive testing (NIH Toolbox cognition battery) there was significant improvement in cognitive performance. Participants generally had a high level of childhood adversity (mean ACE score of 4.5), with an average level of childhood compensatory experiences. Considering the specific effect for childhood adversity, ACE score was found to be predictive in amount of anxiety and self-reported cognitive change but not for objective cognitive performance or change in other factors.Conclusions:Consistent with previous research, these patients had a high level of past trauma, which interacted with a number of other neuropsychiatric measures and support the importance of assessing for trauma history and integrating trauma-focused treatment into substance abuse treatment programs.

Subcutaneous Mycobacterium vaccae ameliorates the sex-specific effects of early life adversity alone or in combination with chronic stress during adulthood in mice

Subcutaneous Mycobacterium vaccae ameliorates the sex-specific effects of early life adversity alone or in combination with chronic stress during adulthood in mice

Subcutaneous Mycobacterium vaccae ameliorates the effects of early life adversity alone or in combination with chronic stress during adulthood in male and female mice

Chronic psychosocial stress is a burden of modern society and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability.In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females.Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes.Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.

A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females

Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.