Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model

Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined a priori as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders.

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Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

Proceedings of The Nutrition Society ◽

10.1017/s0029665119000958 ◽

2019 ◽

Vol 79 (1) ◽

pp. 113-132 ◽

Cited By ~ 3

Author(s):

Marion Rincel ◽

Muriel Darnaudéry

Keyword(s):

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Human Subjects ◽

Early Life Stress ◽

Long Term Effects ◽

Early Life Adversity ◽

Critical Window ◽

Beneficial Impact ◽

The Impact

The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut–brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut–brain axis. Further research is required to understand the complex mechanisms underlying gut–brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.

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Repeated Three-Hour Maternal Separation Induces Depression-Like Behavior and Affects the Expression of Hippocampal Plasticity-Related Proteins in C57BL/6N Mice

Neural Plasticity ◽

10.1155/2015/627837 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 21

Author(s):

Yaoyao Bian ◽

Lili Yang ◽

Zhongli Wang ◽

Qing Wang ◽

Li Zeng ◽

...

Keyword(s):

Early Life ◽

Maternal Separation ◽

Forced Swimming Test ◽

Life Experiences ◽

Tail Suspension Test ◽

Early Life Stages ◽

Early Life Adversity ◽

Swimming Test ◽

Related Proteins ◽

The Brain

Adverse early life experiences can negatively affect behaviors later in life. Maternal separation (MS) has been extensively investigated in animal models in the adult phase of MS. The study aimed to explore the mechanism by which MS negatively affects C57BL/6N mice, especially the effects caused by MS in the early phase. Early life adversity especially can alter plasticity functions. To determine whether adverse early life experiences induce changes in plasticity in the brain hippocampus, we established an MS paradigm. In this research, the mice were treated with mild (15 min, MS15) or prolonged (180 min, MS180) maternal separation from postnatal day 2 to postnatal day 21. The mice underwent a forced swimming test, a tail suspension test, and an open field test, respectively. Afterward, the mice were sacrificed on postnatal day 31 to determine the effects of MS on early life stages. Results implied that MS induces depression-like behavior and the effects may be mediated partly by interfering with the hippocampal GSK-3β-CREB signaling pathway and by reducing the levels of some plasticity-related proteins.

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Early life adversity alters normal sex-dependent developmental dynamics of DNA methylation

Development and Psychopathology ◽

10.1017/s0954579416000833 ◽

2016 ◽

Vol 28 (4pt2) ◽

pp. 1259-1272 ◽

Cited By ~ 18

Author(s):

Renaud Massart ◽

Zsofia Nemoda ◽

Matthew J. Suderman ◽

Sheila Sutti ◽

Angela M. Ruggiero ◽

...

Keyword(s):

Dna Methylation ◽

Early Life ◽

Maternal Separation ◽

Methylation Profile ◽

Early Life Adversity ◽

Developmental Evolution ◽

Dna Methylation Profile ◽

Males And Females ◽

The Difference ◽

The Impact

AbstractStudies in rodents, nonhuman primates, and humans suggest that epigenetic processes mediate between early life experiences and adult phenotype. However, the normal evolution of epigenetic programs during child development, the effect of sex, and the impact of early life adversity on these trajectories are not well understood. This study mapped the genome-wide DNA methylation changes in CD3+ T lymphocytes from rhesus monkeys from postnatal day 14 through 2 years of age in both males and females and determined the impact of maternal deprivation on the DNA methylation profile. We show here that DNA methylation profiles evolve from birth to adolescence and are sex dependent. DNA methylation changes accompany imposed weaning, attenuating the difference between males and females. Maternal separation at birth alters the normal evolution of DNA methylation profiles and targets genes that are also affected by a later stage maternal separation, that is, weaning. Our results suggest that early life events dynamically interfere with the normal developmental evolution of the DNA methylation profile and that these changes are highly effected by sex.

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Trajectories of Mother-Infant Communication: An Experiential Measure of the Impacts of Early Life Adversity

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.632702 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lauren Granata ◽

Alissa Valentine ◽

Jason L. Hirsch ◽

Jennifer Honeycutt ◽

Heather Brenhouse

Keyword(s):

Maternal Care ◽

Early Life ◽

Maternal Separation ◽

Developmental Trajectories ◽

Later Life ◽

Developmental Trajectory ◽

Acoustic Properties ◽

Emission Rates ◽

Acoustic Parameters ◽

Early Life Adversity

Caretaking stability in the early life environment supports neurobehavioral development, while instability and neglect constitute adverse environments that can alter maturational processes. Research in humans suggests that different types of early life adversity (ELA) can have differential effects on caretaker relationships and later cognitive and social development; however, identifying mechanistic underpinnings will require animal models with translational validity. Two common rodent models, maternal separation (MS) and limited bedding (LB), influence the mother-infant relationship during a critical window of development. We hypothesized that these paradigms may affect the development of communication strategies on the part of the pup. Ultrasonic vocalizations (USVs) are a care-eliciting mechanism and ethologically relevant response to stressors in the rat pup. USV emission rates and acoustic parameters change throughout early development, presenting the opportunity to define developmental milestones in USVs that would reflect neurobehavioral aberrations if disrupted. This study investigated the effects of MS or LB on the dam-pup relationship by quantifying pup USVs, maternal behavior, and the relationship between the two. First, we used a generalized additive model approach to establish typical developmental trajectories of USV acoustic properties and determine windows of change in MS or LB rearing. Additionally, we quantified maternal behaviors and the predictability of maternal care sequences using an entropy rate calculation. MS and LB each shifted the developmental trajectories of USV acoustic parameters and call types in a sex-specific manner. MS more often impacted male USVs, while LB impacted female USVs. MS dams spent more time passive nursing, and LB dams spent more time on the nest. The predictability of maternal care was associated with the rate of USV emissions exclusively in females. Taken together, findings demonstrate sex- and model-specific effects of rearing environments on a novel developmental trajectory involving the mother-infant relationship, facilitating the translation of animal ELA paradigms to assess later-life consequences.

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

10.1101/2021.12.20.21268125 ◽

2021 ◽

Author(s):

Regina L Triplett ◽

Rachel E Lean ◽

Amisha Parikh ◽

J Philip Miller ◽

Dimitrios Alexopoulos ◽

...

Keyword(s):

White Matter ◽

Prenatal Exposure ◽

Gray Matter ◽

Early Life ◽

Psychosocial Stress ◽

Social Disadvantage ◽

Cortical Folding ◽

Neonatal Brain ◽

Early Life Adversity ◽

Brain Volumes

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

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Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress

10.20944/preprints202104.0024.v1 ◽

2021 ◽

Author(s):

Sara B. Fernandes ◽

Neha D. Patil ◽

Sophie B. Meriaux ◽

Maud Theresine ◽

Fleur A.D. Leenen ◽

...

Keyword(s):

Immune System ◽

Immune Responses ◽

Nk Cells ◽

Early Life ◽

Social Stress ◽

Maternal Separation ◽

Economic Status ◽

Childhood Adversity ◽

Early Life Adversity ◽

Human Situation

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD), the closest animal model available to the human situation, is known to similarly induce long lasting behavioural effects, to cause changes in the HPA axis and to have an impact in the immune system. Even though the immune responses to potential pathogens after early stress have been somehow documented, the mechanisms by which they occur are still not fully understood. Here, we have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after childhood adversity. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. Altogether, these results lead us to conclude that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

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Psychiatric symptoms in adolescents: FKBP5 genotype—early life adversity interaction effects

European Child & Adolescent Psychiatry ◽

10.1007/s00787-015-0768-3 ◽

2015 ◽

Vol 24 (12) ◽

pp. 1473-1483 ◽

Cited By ~ 18

Author(s):

Erika Comasco ◽

Per A. Gustafsson ◽

Gunilla Sydsjö ◽

Sara Agnafors ◽

Nikolas Aho ◽

...

Keyword(s):

Early Life ◽

Psychiatric Symptoms ◽

Interaction Effects ◽

Early Life Adversity

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Adversity in preschool-aged children: Effects on salivary interleukin-1β

Development and Psychopathology ◽

10.1017/s0954579415000164 ◽

2015 ◽

Vol 27 (2) ◽

pp. 567-576 ◽

Cited By ~ 19

Author(s):

Audrey R. Tyrka ◽

Stephanie H. Parade ◽

Thomas R. Valentine ◽

Nicole M. Eslinger ◽

Ronald Seifer

Keyword(s):

Childhood Maltreatment ◽

Early Life ◽

Stress Exposure ◽

Early Life Adversity ◽

Reactive Protein ◽

Markers Of Inflammation ◽

Traumatic Life Events ◽

Cytokine Levels ◽

Main Effect ◽

Before And After

AbstractExposure to early life adversity is linked to impaired affective, cognitive, and behavioral functioning and increases risk for various psychiatric and medical conditions. Stress-induced increases in pro-inflammatory cytokines may be a biological mechanism of these effects. Few studies have examined cytokine levels in children experiencing early life adversity, and very little research has investigated cytokines or other markers of inflammation in saliva. In the present study, we examined salivary interleukin (IL)-1β and C-reactive protein (CRP) levels in relation to stress exposure in 40 children aged 3 to 5 years who were enrolled in a larger study of early life adversity. Childhood maltreatment status was assessed via review of child welfare records. Contextual stress exposure, traumatic life event history, and symptoms of psychopathology were assessed via caregiver interviews at a home visit. In a subsequent visit, salivary IL-1β and CRP were obtained before and after participation in four emotion-eliciting tasks. The number of past-month contextual stressors, lifetime contextual stressors, and traumatic life events each demonstrated a significant main effect on IL-1β. Baseline IL-1β was positively associated with each of the significant main-effect adversities. Postchallenge IL-1β displayed positive associations with each adversity variable, but these were not significant. CRP was not significantly associated with any of the adversity variables. Given the evidence suggesting the involvement of IL-1β in the neuropathology of psychiatric conditions, these results may have important implications for developmental outcomes.

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Early life experiences and social cognition in major psychiatric disorders: A systematic review

European Psychiatry ◽

10.1016/j.eurpsy.2018.06.006 ◽

2018 ◽

Vol 53 ◽

pp. 123-133 ◽

Cited By ~ 19

Author(s):

Karolina I. Rokita ◽

Maria R. Dauvermann ◽

Gary Donohoe

Keyword(s):

Systematic Review ◽

Social Cognition ◽

Quality Assessment ◽

Psychiatric Disorders ◽

Childhood Maltreatment ◽

Early Life ◽

Parental Attachment ◽

Social Cognitive ◽

Self Regulation ◽

Early Life Adversity

AbstractObjective:To present a systematic review of the literature on the associations between early social environment, early life adversity, and social cognition in major psychiatric disorders, including schizophrenia, bipolar disorder, borderline personality disorder, major depressive disorder and posttraumatic stress disorder.Method:Relevant studies were identified via electronic and manual searches of the literature and included articles written in English and published in peer-reviewed journals up to May 2018. Quality assessment was performed using the quality evaluation scale employed in previous systematic reviews.Results:A total of 25 studies were included in the systematic review with the quality assessment scores ranging from 3 to 6 (out of 6). The vast majority of the studies reviewed showed a significant association between early childhood social experience, including both insecure attachment and adversity relating to neglect or abuse, and poorer social cognitive performance.Conclusion:We discuss these findings in the context of an attachment model, suggesting that childhood social adversity may result in poor internal working models, selective attention toward emotional stimuli and greater difficulties with emotional self-regulation. We outline some of the steps required to translate this understanding of social cognitive dysfunction in major psychiatric disorders into a target for interventions that mitigate the adverse effects of childhood maltreatment and poor parental attachment on social cognition.

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The 5-HTTLPR genotype, early life adversity and cortisol responsivity to psychosocial stress in women

BJPsych Open ◽

10.1192/bjo.2018.23 ◽

2018 ◽

Vol 4 (4) ◽

pp. 180-185 ◽

Cited By ~ 2

Author(s):

Jurate Aleknaviciute ◽

Joke H. M. Tulen ◽

Yolanda B. de Rijke ◽

Mark van der Kroeg ◽

Cornelis G. Kooiman ◽

...

Keyword(s):

Childhood Maltreatment ◽

Life Stress ◽

Early Life ◽

Psychosocial Stress ◽

Social Stress ◽

Stress Test ◽

Early Life Stress ◽

Trier Social Stress Test ◽

Early Life Adversity ◽

Personality Psychopathology

BackgroundThe serotonin transporter gene-linked polymorphic region (5-HTTLPR) has previously been associated with hypothalamus–pituitary–adrenal axis function. Moreover, it has been suggested that this association is moderated by an interaction with stressful life experiences.AimsTo investigate the moderation of cortisol response to psychosocial stress by 5-HTTLPR genotype, either directly or through an interaction with early life stress.MethodA total of 151 women, 85 of which had personality psychopathology, performed the Trier Social Stress Test while cortisol responsivity was assessed.ResultsThe results demonstrate a main effect of genotype on cortisol responsivity. Women carrying two copies of the long version of 5-HTTLPR exhibited stronger cortisol responses to psychosocial stress than women with at least one copy of the short allele (P = 0.03). However, the proportion of the variance of stress-induced cortisol responsivity explained by 5-HTTLPR genotype was not further strengthened by including early life adversity as a moderating factor (P = 0.52).ConclusionsOur results highlight the need to clarify gender-specific biological factors influencing the serotonergic system. Furthermore, our results suggest that childhood maltreatment, specifically during the first 15 years of life, is unlikely to exert a moderating influence of large effect on the relationship between the 5-HTTLPR genotype and cortisol responsivity to psychosocial stress.Declaration of interestNone.

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