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Background: Maternal stress can have short and long term adverse (mental) health effects for the mother and her child. Previous evidence suggests that the gut microbiota may be a potential mediator and moderator for the effects of stress via various pathways. This study explored the maternal microbiota trajectory during pregnancy as well as the association between pre- and postnatal maternal stress and features of the maternal and infant gut microbiota during and after pregnancy. In line with previous research, we hypothesized that maternal stress would be positively related to maternal and infant microbiota volatility and that infants of highly stressed mothers would show a relative increase in Proteobacteria and a relative decrease in Bifidobacterium., Methods: We collected maternal stool samples at 18 and 32 weeks of pregnancy and 8 months postpartum. Infant stools samples were obtained at 2, 6 and 12 weeks and 8 months postpartum. All samples were analyzed using shotgun metagenome sequencing. We also collected several measures of maternal stress (self-reported depression, anxiety, and stress, and hair cortisol and cortisone), most at the same time points as the microbiota samples., Results: Our data indicated that the maternal microbiota does not undergo drastic changes from the second to the third trimester of pregnancy but that the postpartum microbiota differs significantly from the prenatal microbiota. Furthermore, we identified associations between several stress measures and maternal and infant gut microbiota features at different time points including positive and negative associations with alpha diversity, beta diversity and individual microbial phyla and species relative abundances. Also, the maternal stress composite score, the perceived stress score and the log-ratio of hair cortisol and cortisone were all positively associated with infant microbiota volatility., Conclusion: Our study provides evidence that maternal prenatal and postnatal stress is related to both the maternal and the infant microbiota. Collectively, this and previous studies indicate that maternal stress does not uniformly associate with most gut microbial features. Instead, the associations are highly time point specific. Regarding infant microbiota volatility, we have consistently found a positive association between stress and infant microbiota volatility. This warrants future research investigating this link in more depth., Competing Interests: Declaration of Competing Interest The author Carolina de Weerth is an Editorial Board Member for Psychneuroendocrinology and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests: this work was supported by the Dutch National Science Organisation (NWO) VICI grant (016.Vici. 185.038) received by C.dW. The funder had no role in study design, data collection, analysis, interpretation of data, writing of the report or the decision to submit the manuscript for publication., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prenatal maternal psychological distress and physiological stress (hypothalamic-pituitary-adrenal [HPA] activity) can negative impact early child development. Research rarely examines the combined or interactive role of prenatal perceived stress and HPA activity on child outcomes. The current longitudinal study examined how prenatal distress and HPA activity impacted child socioemotional functioning from age 1-3. This sample (n=148) was followed from pregnancy, 15-, 24- and 35-months postpartum. During pregnancy, mothers reported their levels of perceived stress and hair samples were collected, reflecting cortisol secretion in the past 3 months. At each postpartum timepoint, mothers reported toddler socioemotional functioning using the Brief Infant-Toddler Social and Emotional Assessment. Multivariate regression results indicated that higher maternal perceived stress interacted with higher hair cortisol levels in association with greater socioemotional problems at 15 and 24 months. In addition, there was a main effect of higher prenatal perceived stress in relation to greater socioemotional problems at 36 months. Exploratory sex-specific moderation analyses indicated that sex interacted with hair cortisol, such that higher levels of prenatal cortisol were associated greater behaviour problems and lower socioemotional competence for females compared to males at 24-months. Findings indicated the importance of examining both physiological stress and psychological stress in pregnancy, as they interact to impact child socioemotional development. Findings also highlight sex-specific prenatal effects., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maternal body mass index (BMI) influences pregnancy and birth outcomes along with child metabolic and neurodevelopmental health and fetal sex may be a moderating factor in these effects. Alternations in autonomic nervous system (ANS) functioning, identified in heart rate (HR) measurements, could present early markers of these prenatal programming effects in both the mother and the developing fetus. This study examines the associations between pre-pregnancy BMI and maternal and fetal ANS functioning and infant postnatal behavioral outcomes stratified by fetal sex. Pregnant women (N=176) were recruited at gestational week (GW) T1: 12-22 and categorized into Normal (BMI< 25) or High BMI (BMI > 25). Women attended laboratory sessions at T2: GW 23-28, and T3: GW 34-36 to assess maternal and fetal HR and HR variability (HRV) at baseline and after a stressor at T3. Infant behavior was assessed at 4 months using the Infant Behavior Questionnaire-Revised. Women with high BMI bearing female fetuses had higher HR and lower HRV at both gestational time points. Later in the third trimester, female fetuses of high BMI women exhibited lower HRV when challenged with a stressor. At 4 months, female infants were rated as having lower scores on the Orienting/Regulatory scale. Our findings provide evidence of female sex-specific programming of maternal pre-pregnancy BMI on maternal ANS regulation and neurodevelopment identified in-utero and continuing into early infancy., Competing Interests: Declaration of Competing Interest EW is a consultant for the medical company Philips for an application about pregnancy called Pregnancy + and has received payment from Philips. We confirm that there are no other known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome for other authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic exposure to prenatal stress can impair neurogenesis and lead to irreversible cognitive and neuropsychiatric abnormalities in offspring. The retina is part of the nervous system; however, the impacts of prenatal stress on retinal neurogenesis and visual function remain unclear. This study examined how elevated prenatal glucocorticoid levels differentially affect retinal development in the offspring of pregnant mice exposed to chronic unpredictable mild stress (CUMS). Offspring were classified into control, stress-resilient, and stress-susceptible groups based on behavioral tests assessing spatial memory and depression-like behaviors. The stress-susceptible group exhibited significantly altered synaptogenesis, reduced ganglion cell development, decreased retinal thickness, and visiual impairment. These mice also showed a pervasive transformation of retinal astrocytes into a proinflammatory A1-like reactive state, evidenced by increased GFAP and decreased STAT3 expression levels. This astrocyte phenotype shift coincided with disruptions in neurogenesis and synaptic formation. Furthermore, prenatal exposure to exogenous corticosterone confirmed that the effects of prenatal stress are mediated by glucocorticoid-induced retinal neurodegeneration. Our findings suggest that elevated prenatal glucocorticoid levels trigger a series of neurodevelopmental disturbances leading to retinal neurodegeneration and vision impairment. This research highlights the impact of prenatal stress on retinal development and visual health, suggesting new avenues for understanding and potentially mitigating the negative effects of early-life stress on neurodevelopment., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health., Competing Interests: Declarations. Ethics Approval and Consent to Participate: All animal experiments were carried out in accordance with the Laboratory Animal Management Regulations with approval of the Research Ethics Committee of the First Affiliated Hospital of Soochow University. Consent for Publication: All authors have approved for publication. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Few longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence., Methods: This study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models., Results: Prenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression., Conclusions: Prenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy., Competing Interests: Declaration of Competing Interest No conflict, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maternal major depressive disorder with peripartum onset presents health risks to the mother and the developing fetus. Using a rat model of chronic mild stress, we previously reported on the neurodevelopmental impact of maternal perinatal stress on their offspring. This study examined the cardiovascular impact of maternal perinatal stress on their offspring. The cardiovascular impact was assessed in terms of blood pressure and echocardiographic parameters. The results examined by a three-way ANOVA showed a significant association of cardiovascular parameters with maternal perinatal stress and offspring sex and age. Increased blood pressure was observed in adolescent female and adult male offspring of stress-exposed dams. Echocardiography showed an increase in left atrial dimension and a reduction in left ventricular systolic function in adolescent stress-exposed female offspring. Increased interventricular septum thickness at end-diastole and left ventricular diastolic dysfunction were observed in adult stress-exposed male offspring. The underlying mechanisms of cardiovascular impact were examined in stress-exposed adult offspring by assessing the levels of neurotransmitters and their metabolites in the medulla oblongata using high-performance liquid chromatography. A significant decrease in homovanillic acid, a dopamine metabolite and indicator of dopaminergic activity, was observed in adult stress-exposed female offspring. These results suggest a significant sex- and age-dependent impact of maternal stress during the peripartum period on the cardiovascular system in the offspring that extends to adulthood and suggests a multigenerational effect. The presented data urgently need follow-up to confirm their potential clinical and public health relevance. NEW & NOTEWORTHY We demonstrate that maternal perinatal stress is associated with sex- and age-dependent impact on the cardiovascular system in their offspring. The effect was most significant in adolescent female and adult male offspring. Observed changes in hemodynamic parameters and dopaminergic activity of the medulla oblongata are novel results relevant to understanding the cardiovascular impact of maternal perinatal stress on the offspring. The cardiovascular changes observed in adult offspring suggest a potential long-term, multigenerational impact of maternal perinatal stress.

Background: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up., Methods: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m 2 ) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns., Results: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation., Conclusion: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding., Competing Interests: Declaration of Competing Interest None of the findings described in this manuscript were influenced by any financial source or sponsor. None of the authors have potential conflicts of interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exposure to prolonged stress in pregnancy and/or lactation can lead to the future development of diseases. We aimed to study the effects of maternal stress on the biometry, metabolism, and penile morphology of young Wistar rats. Animals were divided into two experimental groups: Control Group (C) - pups from control mothers, without any intervention (n=5); and Chronic Stress Group (S) - pups from mothers who suffered variable stress in the third week of pregnancy (14th to 21st day; n=5). Food intake and body mass of the pups (n=10, in the C group and n=9 in the S group) were checked; at euthanasia (three months old), fat deposits and penis were removed. At birth and weaning, S animals were lighter than C animals, [-33.72% ( p =0.0422) and -17.07% ( p =0.0018)], respectively. However, the final body mass and body mass delta showed no differences. Food intake and fat deposits also did not differ. However, the S group was hyperglycemic at 30 and 60 days of life [+20.59% ( p =0.0042) and +14.56% ( p =0.0079), respectively], despite the glycemia measured at 90 days showing no difference between groups. Penile areas and surface densities of the corpora cavernosa components were similar between groups. The results indicate that maternal stress is an important metabolic programmer, which generates low birth weight and accelerated recovery of body mass after birth (catch-up). However, in an early analysis (90 days of life), exposure to gestational stress did not change the morphology of the offspring's penis in adulthood., (©The Author(s) 2023. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Stress during pregnancy is often linked with increased incidents of neurodevelopmental disorders, including cognitive impairment. Here, we report that stress during pregnancy leads to alterations in the intestinal flora, which negatively affects the cognitive function of offspring. Cognitive impairment in stressed offspring can be reproduced by transplantation of cecal contents of stressed pregnant rats (ST) to normal pregnant rats. In addition, gut microbial dysbiosis results in an increase of β-guanidinopropionic acid in the blood, which leads to an activation of the adenosine monophosphate-activated protein kinase (AMPK) and signal transducer and activator of transcription 3 (STAT3) in the fetal brain. Moreover, β-guanidinopropionic acid supplementation in pregnant rats can reproduce pregnancy stress-induced enhanced glial differentiation of the fetal brain, resulting in impaired neural development. Using probiotics to reconstruct maternal microbiota can correct the cognitive impairment in the offspring of pregnant stressed rats. These findings suggest that microbial reconstitution reverses gestational stress-induced cognitive impairment and synaptic deficits in male rat offspring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The placenta acts as a buffer to regulate the degree of fetal exposure to maternal cortisol through the 11-Beta Hydroxysteroid Dehydrogenase isoenzyme type 2 (11-β HSD2) enzyme. We conducted a systematic review and meta-analysis to assess the effect of prenatal psychological distress (PPD) on placental 11-β HSD2 gene expression and explore the related mechanistic pathways involved in fetal neurodevelopment., Methods: We searched PubMed, Embase, Scopus, APA PsycInfo®, and ProQuest Dissertations for observational studies assessing the association between PPD and 11-β HSD2 expression in human placentas. Adjusted regression coefficients (β) and corresponding 95% confidence intervals (CIs) were pooled based on three contextual PPD exposure groups: prenatal depression, anxiety symptoms, and perceived stress., Results: Of 3159 retrieved records, sixteen longitudinal studies involving 1869 participants across seven countries were included. Overall, exposure to PPD disorders showed weak negative associations with the placental 11-β HSD2 gene expression as follows: prenatal depression (β -0.01, 95% CI 0.05-0.02, I2=0%), anxiety symptoms (β -0.02, 95% CI 0.06-0.01, I2=0%), and perceived stress (β -0.01 95% CI 0.06-0.04, I2=62.8%). Third-trimester PPD exposure was more frequently associated with lower placental 11-β HSD2 levels. PPD and placental 11-β HSD2 were associated with changes in cortisol reactivity and the development of adverse health outcomes in mothers and children. Female-offspring were more vulnerable to PPD exposures., Conclusion: The study presents evidence of a modest role of prenatal psychological distress in regulating placental 11-β HSD2 gene expression. Future prospective cohorts utilizing larger sample sizes or advanced statistical methods to enhance the detection of small effect sizes should be planned. Additionally, controlling for key predictors such as the mother's ethnicity, trimester of PPD exposure, mode of delivery, and infant sex is crucial for valid exploration of PPD effects on fetal programming., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prenatal stress increases the risk of neurodevelopmental disorders. NMDA-type glutamate receptor (NMDAR) activity plays an important pathophysiological role in the cortico-hippocampal circuit in these disorders. We tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex (FCx) and hippocampus after exposure to prenatal restraint stress (PRS) in mice. At 10 weeks of age, male PRS offspring (n = 20) and non-stressed controls (NS, n = 20) were treated with haloperidol (1 mg/kg), clozapine (5 mg/kg) or saline twice daily for 5 days, before measuring social approach (SOC). Saline-treated and haloperidol-treated PRS mice had reduced SOC relative to NS (P < 0.01), but clozapine-treated PRS mice had similar SOC to NS mice. These effects of PRS were associated with increased transcription of NMDAR subunits encoded by GRIN2A and GRIN2B genes in the hippocampus but not FCx. GRIN transcription in FCx correlated positively with SOC, but hippocampal GRIN transcription had negative correlation with SOC. The ratio of GRIN2A/GRIN2B transcription is known to increase during development but was lower in PRS mice. These results suggest that GRIN2A and GRIN2B transcript levels are modified in the hippocampus by PRS, leading to life-long deficits in social behavior. These data have some overlap with the molecular pathophysiology of schizophrenia. Similar to PRS in mice, schizophrenia, has been associated with social withdrawal, with increased GRIN2 expression in the hippocampus, and reduced GRIN2A/GRIN2B expression ratios in the hippocampus. These findings suggest that PRS in mice may have construct validity as a preclinical model for antipsychotic drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Adverse environments during pregnancy impact neurodevelopment including cognitive abilities of the developing children. The mediating biological alterations are not fully understood. Maternal stress may impact the neurotrophic regulation of the offspring as early as in utero and at birth. Brain-derived neurotrophic factor (BDNF) is essential for neurodevelopment. Short-term higher levels of BDNF in mice upon stressors associate with lower BDNF later in life, which itself associates with depression in animals and humans. Stress including glucocorticoids may impact BDNF, but there is a lack of data at birth. This study investigated if stress near term associates with fetal BDNF at birth in humans., Methods: Pregnant women near term who underwent primary cesarean sections (at 38.80±0.64 weeks), were included in this study (n=41). Stress at the end of pregnancy was assessed before the cesarean section by determining maternal depressive symptoms (EDPS), maternal state and trait anxiety (STAI-S and STAI-T), maternal prenatal distress (PDQ), stress over the past month (PSS), prenatal attachment to the offspring (PAI), maternal social support (F-Sozu), maternal early life stress (CTQ), socioeconomic status, and the glucocorticoids cortisol and cortisone (n=40) in amniotic fluid at birth. The association with fetal BDNF was analyzed. Cord blood serum of n=34 newborns at birth was analyzed for BDNF and newborn anthropometrics (weight, length and head circumference per gestational age at birth) were assessed. The association of fetal BDNF with anthropometrics at birth was analyzed., Results: After a BDNF-outlier (>3 SD) was removed, higher fetal BDNF associated significantly with maternal depressive symptoms (r=0.398, p=0.022), with lower socioeconomic status as assessed by the average number of people per room in the household (r=0.526, p=0.002) and with borderline significance with net income per person in the household (r=-0.313, p=0.087) in the bivariate analyses. In multivariable analysis, BDNF stayed positively associated with maternal depressive symptoms (β=0.404, 95% CI [7.057, 306.041], p=0.041) and lower net income per person in the household (β=-0.562, 95% CI [-914.511, -60.523], p=0.027) when controlling for maternal age, maternal pre-pregnancy BMI, fetal sex and gestational age. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed in bivariate analyses or in multivariable analyses when controlling for maternal BMI and fetal sex., Conclusion: Maternal depressive symptoms and lower socioeconomic status associated with higher fetal BDNF when controlling for confounders. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed. Further studies should investigate how early altered BDNF associate with the development and possibly psychopathology of the offspring., Competing Interests: Declaration of Competing Interest Eva Kathrin Lamadé received the Seed Money for Research grant from the Central Institute of Mental Health., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Prenatal stress (PS), in both humans and animals, presents a potential risk to the mother and her fetus throughout gestation. PS is always associated with physiological changes that alter embryonic development and predispose the individual to lifelong health problems, including susceptibility to mental illness. This study aims to identify the harmful effects of prenatal restraint stress (PRS), commonly employed to induce stress painlessly and without any lasting debilitation during gestation. This stress is applied to pregnant Swiss albino mice from E7.5 to delivery for three hours daily. Our results show that PS affects dams' weight gain during the gestational period; moreover, the PS dams prefer passive nursing, exhibit a lower percentage of licking and grooming, and impair other maternal behaviors, including nesting and pup retrieval. Concerning the offspring, this stress induces neurobehavioral impairments, including a significant increase in the time of recovery of the young stressed pups in the surface righting reflex, the latency to avoid the cliff in the cliff avoidance test, longer latencies to accomplish the task in negative geotaxis, and a lower score in swimming development. These alterations were accompanied by increased Malondialdehyde activity (MDA) at PND17 and 21 and downregulation of AchE activity in the whole brain of pups on postnatal days 7 and 9. These findings demonstrated that PS causes deleterious neurodevelopmental impairments that can alter various behaviors later in life., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes., (© 2024. The Author(s).)

Introduction: Previous studies have shown that fetal hypoxia predisposes individuals to develop addictive disorders in adulthood. However, the specific impact of maternal stress, mediated through glucocorticoids and often coexisting with fetal hypoxia, is not yet fully comprehended., Methods: To delineate the potential effects of these pathological factors, we designed models of prenatal severe hypoxia (PSH) in conjunction with maternal stress and prenatal intrauterine ischemia (PII). We assessed the suitability of these models for our research objectives by measuring HIF1α levels and evaluating the glucocorticoid neuroendocrine system. To ascertain nicotine dependence, we employed the conditioned place aversion test and the startle response test. To identify the key factor implicated in nicotine addiction associated with PSH, we employed techniques such as Western blot, immunohistochemistry, and correlational analysis between chrna7 and nr3c1 genes across different brain structures., Results: In adult rats exposed to PSH and PII, we observed increased levels of HIF1α in the hippocampus (HPC). However, the PSH group alone exhibited reduced glucocorticoid receptor levels and disturbed circadian glucocorticoid rhythms. Additionally, they displayed signs of nicotine addiction in the conditioned place aversion and startle response tests. We also observed elevated levels of phosphorylated DARPP-32 protein in the nucleus accumbens (NAc) indicated compromised glutamatergic efferent signaling. Furthermore, there was reduced expression of α7 nAChR, which modulates glutamate release, in the medial prefrontal cortex (PFC) and HPC. Correlation analysis revealed strong associations between chrna7 and nr3c1 expression in both brain structures., Conclusion: Perturbations in the glucocorticoid neuroendocrine system and glucocorticoid-dependent gene expression of chrna7 associated with maternal stress response to hypoxia in prenatal period favor the development of nicotine addiction in adulthood., (© 2024 S. Karger AG, Basel.)

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Many investigations have indicated that prenatal stress (PS) causes depressive-like disturbances in offspring rats. However, the underlying pathogenic mechanisms have not yet been fully elucidated. The prefrontal cortex (PFC) has been shown to play a role in susceptibility to stress during fetal development; thus, we focused our attention on differential protein phosphorylation in this region of PS-S (susceptibility to PS) offspring rats. The sucrose preference test was used to screen for susceptibility to PS. The validity of the prenatally stressed model was verified by other common depression-like behaviors. We used MS-based TMT quantitative proteomics in combination with the phosphopeptide enrichment method to compare phosphoproteomic profiling in the PFC of PS-S and control male offspring rats. In total, 3,418 phosphoproteins, 8,404 phosphopeptides, and 12,175 phosphosites were identified in this analysis. According to the screening criteria, 902 phosphopeptides increased and 609 decreased in the PFC of the PS-S group compared to the control rats. Gene ontology enrichment analysis indicated that the main enriched terms in the cellular component category were "synapse part," "myelin sheath," "synapse," "neuron part," and "axon." The phosphoproteins enriched in the molecular function and biological process categories were mainly related to cytoskeleton- and projection morphogenesis-associated proteins. KEGG pathway enrichment analyses identified 30 significant KEGG pathways; the top five pathways included salivary secretion, endocrine and other factor-regulated calcium reabsorption, pancreatic secretion, and insulin secretion. Motifs such as ……&#95;S&#95;P…RR, ……S&#95;PE……, ……&#95;S&#95;PV……, ……&#95;S&#95;P.H……, and …S…&#95;S&#95;PT…. were the top five motifs enriched in phosphorylated sites. PS may induce depressive-like behaviors in male offspring rats by regulating the phosphorylation of proteins mainly related to synapses, myelin sheaths, neurons, and the cytoskeleton. The phosphorylation of related proteins may act as key pathogenic hits. Data are available via ProteomeXchange with identifier PXD026563., (© 2022 S. Karger AG, Basel.)

Background: Prenatal stress is associated with increased susceptibility to psychiatric and metabolic disorders later in life. Prenatal exposure to stress mediators may have sex-dependent effects on offspring brain and metabolic function, promoting a sex-specific vulnerability to psychopathology and metabolic alterations at adulthood. In this work, the impact of prenatal stress on glucose homeostasis and peripheral metabolism of male and female offspring was investigated in a chronic anxiety animal model., Methods: Pregnant Wistar rats were injected with saline or glucocorticoid (dexamethasone: 1 mg/kg, subcutaneous) at gestational days 18 and 19. Male and female offspring weight was monitored, and anxious-like behaviour and peripheral insulin-sensitive tissues were analysed at adulthood., Results: At birth, females and males prenatally exposed to stress presented decreased body weight which remained low in females. At adulthood, a morphological disorganization of the Langerhans islets was observed in both sexes prenatally exposed to stress, yet not changes in insulin levels were detected. Also, prenatal stress increased glucose transporter 4 (GLUT-4) levels in female and male adipose tissues and decreased insulin receptor levels in the liver and skeleton muscle but only in females., Conclusions: Exposure to stress mediators in critical periods of development negatively affects behaviour and metabolism. Prenatal stress programmes offspring peripheral metabolism in a sex-specific manner, emphasizing that the response to stress in critical periods of development may be sex-specific having each sex different vulnerabilities to psychiatric and metabolic disorders. Considering sex-specificities may provide critical clues for the design of preventive strategies and for early therapeutic intervention., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Previous studies have shown that prenatal stress (PS) can potentially contribute to depression-like behavior in offspring and that this effect may be moderated by cross-fostering. However, the underlying mechanism of this effect remains to be determined. This study aimed to determine the effect of cross-fostering on the expression of EAAT2 and the SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats and to demonstrate functional effects on depression-like behavior. The impacts of cross-fostering were functionally assessed using the sucrose preference test (SPT), the forced swimming test (FST) and the elevated plus maze (EPM). Quantitative real-time PCR was used to determine changes in the expression of EAAT2 and SNAREs mRNA in the hippocampus and the prefrontal cortex of offspring rats. PS offspring rats showed significantly decreased sucrose preference and prolonged immobility time, while cross-fostering effectively increased sucrose preference and shorten the time of immobility. The expression of EAAT2 mRNA in PS offspring rats was markedly reduced, whilst the core mRNA expression of the SNARE complex increased. Our results provide strong evidence demonstrating that cross-fostering can alleviate depression-like behavior and regulate the abnormal expression levels of EAAT2 mRNA and SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats. Our findings contribute to further understanding of the pathogenesis of PS-induced depression and may help to inform the future development of novel treatment approaches., (Copyright © 2021. Published by Elsevier Inc.)

The aromatic amino acid tryptophan (Trp) is a precursor for multiple metabolites that can steer proper immune and neurodevelopment as well as social behavior in later life. Dysregulation in the Trp metabolic pathways and abundance of Trp or its derivatives, including indoles, kynurenine (Kyn), and particularly serotonin, has been associated with behavioral deficits and neuropsychiatric disorders including autism spectrum disorders (ASD) and schizophrenia. Previously, we have shown that prenatal stress (PNS) alters placental Trp and serotonin, and reduces Trp-metabolizing members of the maternal colonic microbiota. Given that PNS also results in alterations in offspring neurodevelopment, behavior and immune function, we hypothesized that PNS affects Trp metabolism and transport in both the maternal and fetal compartments, and that these alterations continue into adolescence. We surmised that this is due to reductions in Trp-metabolizing microbes that would otherwise reduce the Trp pool under normal metabolic conditions. To test this, pregnant mice were exposed to a restraint stressor and gene expression of enzymes involved in Trp and serotonin metabolism were measured. Specifically, tryptophan 2,3-dioxygenase, aryl hydrocarbon receptor, and solute carrier proteins, were altered due to PNS both prenatally and postnatally. Additionally, Parasutterella and Bifidobacterium, which metabolize Trp in the gut, were reduced in both the dam and the offspring. Together, the reductions of Trp-associated microbes and concomitant dysregulation in Trp metabolic machinery in dam and offspring suggest that PNS-induced Trp metabolic dysfunction may mediate aberrant fetal neurodevelopment., (Copyright © 2021. Published by Elsevier B.V.)

Stressful events during the prenatal period have been related to hyperactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as metabolic changes in adult life. Moreover, regular exercise may contribute to the improvement of the symptoms associated with stress and stress-related chronic diseases. Therefore, this study aims to investigate the effects of exercise, before the gestation period, on the metabolic changes induced by prenatal stress in adult mice. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS) and exercise before the gestational period plus PNS (EX + PNS). When adults, the plasmatic biochemical analysis, oxidative stress, gene expression of metabolic-related receptors and sex differences were assessed in the offspring. Prenatal stress decreased neonatal and adult body weight when compared to the pregestational exercise group. Moreover, prenatal stress was associated with reduced body weight in adult males. PNS and EX + PNS females showed decreased hepatic catalase. Pregestational exercise prevented the stress-induced cholesterol increase in females but did not prevent the liver mRNA expression reduction on the peroxisome proliferator-activated receptors (PPARs) α and γ in PNS females. Conversely, PNS and EX + PNS males showed an increased PPARα mRNA expression. In conclusion, pregestational exercise prevented some effects of prenatal stress on metabolic markers in a sex-specific manner.

Studies have shown that an adverse environment in utero influences fetal growth and development, leading to several neuroendocrine and behavioral changes in adult life. Nevertheless, the mechanisms involved in the long-term benefits of pregestational exercise are still poorly understood. Thus, this study aimed to evaluate the effects of physical exercise before the gestational period on memory behavior and gene expression in the hippocampus of adult mice submitted to prenatal stress. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). When adults, male and female offspring were submitted to the object recognition test followed by the hippocampal evaluation of BDNF exons I and IV mRNA expression, as well as hypothalamic-pituitary-adrenal axis related genes. Pregestational exercise did not prevent the decreased recognition index, as well as GR and CRHR1 gene expression observed in PNS males. Conversely, prenatal stress did not influence female memory behavior. Moreover, exercise attenuated the effects of prenatal stress on female BDNF IV gene expression. The results indicate that pregestational exercise was able to prevent the effects of maternal stress on hippocampal BDNF IV gene expression in females, although no effects were seen on the stress-induced memory impairment in males., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A large body of literature has demonstrated that prenatal stress (PS) can induce depression-like behavior in the offspring. However, the underlying mechanism remains largely unknown. CREB-regulated transcriptional coactivator 1(CRTC1) has recently been shown to involve in mood regulation. This research aims to investigate whether CRTC1 signaling was involved in the depression-like behavior of prenatally stressed offspring rats. Sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT) were adopted to test the depression-like behavior in the male offspring rats, and CRTC1 signaling was measured. The results showed that there were significantly reduced sucrose intake in SPT and prolonged immobility time in FST in PS-exposure offspring rats. It was also found decreased levels of total CRTC1, nuclear CRTC1, calcineurin, brain-derived neurotrophic factor (BDNF) and c-fos, but increased cytoplasmic p-CRTC1 in the hippocampus (HIP) and prefrontal cortex (PFC) of the offspring rats. Furthermore, the mRNA level of CRTC1, calcineurin, BDNF, c-fos were down-regulated. Abnormal expression of CRTC1 signaling could be alleviated by fluoxetine treatment. In conclusion, our research indicated that the aberration of CRTC1 expression and/or phosphorylation activity might play a vital role in PS-induced depression-like behavior of offspring rats., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease characterized by abdominal pain. Our recent study has shown that the acid-sensitive ion channel 1 (ASIC1) in dorsal root ganglion (DRG) is involved in stomachache of adult offspring rats subjected with prenatal maternal stress (PMS). MiR-485 is predicted to target the expression of ASIC1. The aim of the present study was designed to determine whether miR-485/ASIC1 signaling participates in enterodynia in the spinal dorsal horn of adult offspring rats with PMS., Methods: Enterodynia was measured by colorectal distension (CRD). Western blotting, qPCR, and in situ hybridization were performed to detect the expression of ASICs and related miRNAs. Spinal synaptic transmission was also recorded by patch clamping., Results: PMS offspring rats showed that spinal ASIC1 protein expression and synaptic transmission were significantly enhanced. Administration of ASICs antagonist amiloride suppressed the synaptic transmission and enterodynia. Besides, PMS induced a significant reduction in the expression of miR-485. Upregulating the expression markedly attenuated enterodynia, reversed the increase in ASIC1 protein and synaptic transmission. Furthermore, ASIC1 and miR-485 were co-expressed in NeuN-positive spinal dorsal horn neurons., Conclusions: Overall, these data suggested that miR-485 participated in enterodynia in PMS offspring, which is likely mediated by the enhanced ASIC1 activities., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Introduction: Prenatal stress is known to influence fetal hypothalamic-pituitary-adrenal axis (HPA axis) development. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is a central gene in this pathway, but little is known about what influences its functioning. We assess how maternal distress influences HSD11B2 functioning, and how HSD11B2 in turn, is associated with infant HPA axis development., Methods: Data come from 24 mother-infant dyads on the Galápagos Islands. Using adjusted linear regression models, we assess the effects of maternal psychosocial (stress and depressive symptoms, measured by the Perceived Stress Scale and the Patient Health Questionnaire-8, respectively) and physiological (HPA axis dysregulation) distress during pregnancy on HSD11B2 methylation and expression and then test how these HSD11B2 measures influence infant HPA axis development., Results: Maternal HPA axis dysregulation during pregnancy is associated with lower placental HSD11B2 expression, which is associated with an exaggerated cortisol reactivity in infants. Sex-specific analyses revealed that maternal depressive symptoms may influence the functioning of placental HSD11B2 differently in girls (n = 11, 46%) than in boys (n = 13, 54%), though the sample size was small., Discussion: These results support a disrupted adaptive framework, in which the ability to upregulate HSD11B2 expression in response to acute stress diminishes as maternal stress becomes chronic. In this model, chronic stress may exhaust the protective mechanism of HSD11B2, leaving the infant vulnerable to high levels of maternal cortisol, which could injure the fetal HPA axis and disrupt long-term neurobehavioral and metabolic development. While larger studies will be needed to confirm these findings, this study offers exploratory results on the effects of maternal distress on both HSD11B2 methylation and expression and the effect of HSD11B2 on offspring HPA axis development., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Antenatal exposure to maternal stress is a factor that may impact on offspring cognitive development. While some evidence exists of an association between maternal antenatal depressive or anxiety symptoms and infants' cognitive outcomes, less is known about the role of biological indices of maternal antenatal stress in relation to infant cognitive development. The current study investigated the association between maternal depressive and anxiety symptoms, stress and inflammatory markers during pregnancy and infant's cognitive development in a sample of 104 healthy pregnant women (mean gestational age = 34.76; SD = 1.12) and their 12-week-old infants (mean postnatal weeks = 11.96; SD = 1.85). Maternal depressive and anxiety symptoms were evaluated during pregnancy, alongside measurements of serum Interleukin-6 (IL-6), C-Reactive Protein (CRP), salivary cortisol, and alpha amylase (sAA) concentrations. Infant cognitive development, maternal caregiving and concurrent anxiety or depressive symptoms were assessed 12 weeks after delivery. Hierarchical linear regressions indicated that higher maternal diurnal cortisol and CRP levels were independently associated with lower infant cognitive development scores, while adjusting for infant gender and gestational age, maternal IQ, caregiving, depressive, or anxiety symptoms. Though correlational, findings seem suggestive of a role for variation in maternal biological stress signals during pregnancy in influencing infants' early cognitive development., (© 2020 Wiley Periodicals, Inc.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Fetal/infant growth affects adult obesity and morbidities/mortality and has been associated with prenatal exposure to cortisol. Bidirectional relations between maternal stress and breastfeeding suggest that they interact to influence offspring growth. No models have tested this hypothesis, particularly regarding longer-term offspring outcomes. We used a subset of the IDAHO Mom Study ( n = 19-95) to examine associations among maternal prenatal cortisol (cortisol awakening response (CAR) and area under the curve), and standardized weight-for-length (WLZ) and length-for-age (LAZ) z-scores from birth-18 months, and main and interactive effects of prenatal cortisol and breastfeeding on infant growth from birth-6 months. CAR was negatively associated with LAZ at birth ( r = -0.247, p = 0.039) but positively associated at 13-14 months ( r = 0.378, p = 0.033), suggesting infant catch-up growth with lower birth weights, likely related to elevated cortisol exposure, continues beyond early infancy. A negative correlation between breastfeeding and 10-month WLZ ( r = -0.344, p = 0.037) and LAZ ( r = -0.468, p = 0.005) suggests that breastfeeding assists in managing infant growth. WLZ and LAZ increased from birth to 6 months ( p s < 0.01), though this was unrelated to interactions between prenatal cortisol and breastfeeding (i.e., no significant moderation), suggesting that other factors played a role, which should be further investigated. Findings add to our understanding of the predictors of infant growth.

Adolescence is a remarkable period of brain development. Prenatal stress can increase the risk of various neuropsychiatric disorders. This research investigated neurochemical and behavioural changes in the offspring rats (especially adolescences) who were treated with repeated variable prenatal stress (PNS) during the third week of gestation. The study tested the concentration of brain-derived neurotrophic factor (BDNF), cluster of differentiation 68 (CD68), synaptotagmin-1(Syt-1), 5-hydroxytryptamine (5-HT), dopamine (DA), glucocorticoid receptors (GRs) and oestrogen receptors (ERs) in the PFC (prefrontal cortex). We also tested prepulse inhibition (PPI) of the acoustic startle reflex (ASR) (a measure of sensorimotor gating). The main results were as follows: PNS increased the BDNF and CD68 concentrations in adolescent females, and increased the Syt-1 concentration in adolescent males. The increases in BDNF/CD68 concentration (in females) and Syt-1/DA concentration (in males) with age were disturbed by PNS, and PNS changed the sex differences in CD68 concentration in adolescence and disturbed the sex differences in the Syt-1 concentration (in adolescence) and DA concentration (in adults). In conclusion, we found that PNS lead to Sex-dependent aberrant PFC development, and might accelerate the development of the adolescent PFC, and so that lessened the age difference (between adolescence and adulthood) and the sex difference., (© 2020 International Society for Developmental Neuroscience.)

Background: Maternal prenatal stress associates with infant developmental outcomes, but the mechanisms underlying this association are not fully understood. Alterations in the composition and function of infant intestinal microbiota may mediate some of the observed health effects, a viewpoint that is supported by animal studies along with a small human study showing that exposure to prenatal stress modifies the offspring's intestinal microbiota. In the current study, we aim to investigate the associations between maternal prenatal psychological distress (PPD) and hair cortisol concentration (HCC) with infant fecal microbiota composition in a large prospective human cohort., Methods: The study population was drawn from FinnBrain Birth Cohort Study. Maternal PPD was measured with standardized questionnaires (EPDS, SCL, PRAQ-R2, Daily Hassles) three times during pregnancy (n = 398). A measure addressing the chronicity of PPD was composed separately for each questionnaire. HCC was measured from a five cm segment at gestational week 24 (n = 115), thus covering the early and mid-pregnancy. Infant fecal samples were collected at the age of 2.5 months and analyzed with 16S rRNA amplicon sequencing., Results: Maternal chronic PPD (all symptom measures) showed positive associations (FDR < 0.01) with bacterial genera from phylum Proteobacteria, with potential pathogens, in infants. Further, chronic PPD (SCL, PRAQ-R2, and Daily Hassles negative scale) associated negatively with Akkermansia. HCC associated negatively with Lactobacillus. Neither maternal chronic PPD nor HCC associated with infant fecal microbiota diversity., Conclusion: Chronic maternal PPD symptoms and elevated HCC associate with alterations in infant intestinal microbiota composition. In keeping with the earlier literature, maternal PPD symptoms were associated with increases in genera fromProteobacteria phylum. Further research is needed to understand how these microbiota changes are linked with later child health outcomes., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus-pituitary-adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models., (© 2019 Wiley Periodicals, Inc.)

Background: The fetal programming hypothesis suggests that prenatal maternal stress (PNMS) influences aspects of fetal development, such as the Hypothalamic Pituitary Adrenal (HPA) axis, enhancing susceptibility to emotional problems. No study (to our knowledge) has investigated this pathway considering development of preschool anxiety symptoms. Using data from the Queensland Flood study (QF2011), our objective was to determine whether toddler HPA-axis functioning mediated the association between aspects of flood-related PNMS and child anxiety symptoms at 4-years, and whether relationships were moderated by the timing of the stressor in utero or by the child's sex., Methods: Women, pregnant during the 2011 Queensland floods (N = 230), were recruited soon afterwards and completed questionnaires regarding their objective hardship (e.g., loss of personal property), subjective distress (post-traumatic-like symptoms) and cognitive appraisal of the disaster. At 16 months, indexes of the child's diurnal cortisol rhythm (awakening response, total daily output, diurnal slope [N = 80]), and stress reactivity (N = 111), were obtained. At 4-years, N = 117 mothers reported on their own mood and their children's anxiety symptoms; of these, N = 80 also had valid child cortisol reactivity data, and N = 64 had diurnal cortisol rhythm data., Results: A greater cortisol awakening response at 16 months mediated the relationship between subjective PNMS and anxiety symptoms at 4-years. Greater toddler daily cortisol secretion predicted more anxiety symptoms, independent of PNMS. The laboratory stressor did not elicit a cortisol response. PNMS effects were not dependent upon child sex nor on gestational timing of flood exposure., Conclusions: Indexes of diurnal cortisol in toddlerhood may represent vulnerability for anxiety symptoms in preschoolers, both independent of, and following, exposure to disaster-related prenatal maternal subjective distress., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Maternal stress during pregnancy can influence the trajectory of fetal development, shaping offspring physiology and health in enduring ways. Some research implicates fetal programming of the hypothalamic-pituitary-adrenocortical (HPA) axis as a mediator of these effects. The present study is the first to examine child hair cortisol concentration (HCC) and maternal stress during pregnancy in a diverse, low-income sample., Methods: The sample consisted of 77 healthy, low-income (M annual income: $13,321), mother-children pairs (M child age = 3.81 years, SD = 0.43). The children were 57 % girls, 43 % boys. Mothers were 65 % Latina/Hispanic, 28 % Non-Hispanic White, 7% Black/African American. Maternal prenatal stress was measured with the Perceived Stress Scale administered by interview in the second and third trimesters, and again approximately four years later when child hair samples for assaying HCC were collected., Results: On average maternal perceived stress increased significantly across pregnancy, then returned to lower levels 4 years after birth. Regression analysis revealed that child HCC was not significantly predicted by maternal perceived stress at either single prenatal time point. Exploratory analysis revealed evidence of a relation between increases in maternal prenatal stress from second to third trimester and child HCC four years later (r = .37, p =  .04)., Conclusions: These results suggest that measures of prenatal maternal stress at any one time point may not be predictive of offspring long-term HPA output in low-income child samples, but that increases in stress levels across pregnancy may provide important information undetected by individual time point measures., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Context: Imbalances in maternal 1-carbon nutrients (vitamin B12, folate) have been shown to be associated with higher offspring cardiometabolic risk markers in India., Objective: We examined the hypothesis that low plasma vitamin B12 (B12) and high folate and homocysteine concentrations in the mother are associated with higher hypothalamic-pituitary-adrenal axis (cortisol) and cardiovascular responses during the Trier Social Stress Test for Children (TSST-C) in an Indian birth cohort., Methods: Adolescents (n = 264; mean age: 13.6 years), whose mothers' plasma B12, folate and total homocysteine concentrations had been measured during pregnancy, completed 5-minutes each of public speaking and mental arithmetic tasks in front of 2 unfamiliar "judges" (TSST-C). Baseline and poststress salivary cortisol concentrations were measured. Heart rate, blood pressure, stroke volume, cardiac output, and total peripheral resistance were measured continuously at baseline, during the TSST-C, and for 10 minutes after the TSST-C using a finger cuff; beat-to-beat values were averaged for these periods, respectively., Results: Maternal low B12 status (plasma B12 < 150 pmol/L) was associated with greater cortisol responses to stress in the offspring (P < .001). Higher homocysteine concentrations were associated with greater offspring heart rate response (P < .001). After adjustment for multiple comparisons, there were nonsignificant associations between higher maternal folate concentrations and offspring total peripheral resistance response (P = .01)., Conclusion: Our findings suggest that maternal 1-carbon nutritional status may have long-term programming implications for offspring neuroendocrine stress responses., (© Endocrine Society 2020.)

Background: Prenatal stress has been associated with adverse outcomes in offspring, including elevated risk of psychopathology. Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been posited as a biological mechanism underlying such consequences. The present study aimed to examine whether dysregulation of the offspring HPA axis mediates the relationship between prenatal stress exposure and adolescent psychopathology., Methods: Five months after the Quebec ice storm of 1998, women who had been pregnant at the time of the storm completed questionnaires about their objective hardship and subjective distress from the disaster. A total of 45 of their children, exposed to the ice storm in utero, participated at 13 years of age. Adolescents completed the Trier Social Stress Test while providing salivary samples to measure circulating cortisol levels. Maternal report of adolescent behaviors was assessed with the Child Behavior Checklist., Results: Results from the study found that greater objective hardship was associated with elevated offspring cortisol reactivity at 13 years of age. Furthermore, greater subjective distress was associated with greater externalizing behaviors. While lower cortisol reactivity predicted greater externalizing behaviors, it did not mediate the association between maternal objective hardship or subjective distress and offspring externalizing or internalizing behaviors., Conclusions: Findings suggest that objective hardship in pregnancy has long-term implications for offspring HPA axis functioning, which is also associated with externalizing behaviors. While dysregulation of the offspring HPA axis did not mediate the association between prenatal stress and offspring psychopathological symptoms, further research is warranted to investigate programming of alternative biological systems., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Prenatal stress (PRS) is considered a risk factor for depressive disorder. Adult hippocampal neurogenesis is believed to play a role in the regulation of affective behaviors. GABAergic interneuron is a key modulator in adult hippocampal neurogenesis. Growing evidence indicates that PRS has adverse effects on adult hippocampal neurogenesis and DNA epigenetic modifications of the GABAergic system. The aim of this study was to investigate whether epigenetic GABAergic dysfunction participates in the negative impact of PRS on adult hippocampal neurogenesis and related emotional behaviors., Methods: Behavioral tests were used to explore PRS-induced depression-like behaviors of adult female mice. Immunohistochemistry staining, real-time reverse transcription-polymerase chain reaction, western blot, and chromatin immunoprecipitation were employed to detect adult neurogenesis and epigenetic changes of the GABAergic system in the hippocampus of PRS mice., Results: PRS mice developed a depression phenotype accompanied by the inhibited maturation of hippocampal newborn neurons. Compared with control mice, PRS mice showed decreased expression of glutamic acid decarboxylase 67 at the mRNA and protein levels. GABAA receptor agonist phenobarbital could rectify the decrease of 5-bromo-2-deoxyuridine/neuronal nuclei double-positive (BrdU+/NeuN+) cells in PRS mice. PRS mice also showed increased expression of DNA methyltransferase 1 and increased binding of DNA methyltransferase 1 to glutamic acid decarboxylase 67 promoter region. The treatment with DNA methyltransferase 1 inhibitor 5-aza-deoxycytidine restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in PRS mice via improving GABAergic system., Conclusions: The present results indicate that epigenetic changes of the GABAergic system are responsible for adult hippocampus neurogenesis and depression-like behaviors in PRS mice., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

We studied the possibility of developing an autism model based on chronic prenatal psychological stress caused by variable frequency ultrasound 20-45 kHz. The offspring of female rats stressed during pregnancy demonstrated reduced time of social contacts in the social interaction test, increased anxiety in the open-field test, and memory impairment in the Morris water maze test in comparison with the control (intact) rat offspring. We also found a reducing trend in the BDNF gene expression in the amygdala in males of the experimental group. The results showed the possibility of developing the animal autism model based on prenatal stress.

Introduction: Findings concerning the relationship between maternal prenatal and child cortisol concentrations are inconsistent. This study examined whether the influence of an objective traumatic stressor during pregnancy, distance from a natural flood disaster, moderated the association between prenatal maternal diurnal cortisol and 9-year old offspring hair cortisol concentrations., Methods: Data were collected from 56 of the mothers who took part in a study of flood-related pregnancy outcomes in 2009 and their children. Data included distance of the maternal home from evacuation areas, four maternal saliva cortisol assessments (waking, 30 min after waking, afternoon, and before bed) provided within 3-months of the flood crest and child hair samples to assess cortisol secretion over the past month., Results: There was a significant interaction between proximity to flooding during pregnancy and maternal cortisol AUC predicting child hair cortisol, after controlling for maternal age, gestational age at cortisol sampling, sex of the child, current socioeconomic status and current maternal stress. At greater distance from flooding (lower stress conditions) there was a non-statistically significant positive association between maternal cortisol and child cortisol. In contrast, living closer to flooding (higher stress conditions) produced a significant negative association between maternal and child cortisol., Conclusion: Experiencing a traumatic stressor during pregnancy may alter maternal-fetal programming of the hypothalamic-pituitary-adrenal axis. The direct threat of flooding led to offspring cortisol concentrations that resembled cortisol production seen in mothers with symptoms of PTSD and their offspring. This alteration is evident in nine-year-old offspring and may help explain inconsistencies in the previous literature., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Numerous rodent studies have evaluated the effects of maternal stress (MS) on later in life susceptibility to Metabolic Syndrome (MetS) intermediate phenotypes with varying results. The aim of this study was to quantitatively synthesize the available data on the effects of MS on offspring obesity, estimated indirectly by body mass (BM), body fat (BF) and plasma leptin; systolic blood pressure (SBP); plasma glucose (and insulin) and blood lipid concentrations., Methods: Literature was screened and summary estimates of the effect of MS outcomes were calculated by using random-effects models. Data on the effects of exogenous corticosteroid administration (or inhibition of 11β-HSD2) during pregnancy in rodents was analysed separately to characterize the direct phenotypic effects of prenatal corticosteroid excess (PCE)., Results: We conducted 14 separate meta-analyses and synthesized relevant data on outcomes scarcely reported in literature. Both MS and PCE were associated with low birth weight without rapid catch-up growth resulting in decreased body mass later in life. Our analysis also revealed significant and contradictory effects on offspring adiposity. Little evidence was found for effects on glucose metabolism and blood lipids. We identified increased SBP in offspring exposed to PCE; however, there is not enough data to draw any conclusion about effects of MS on SBP., Conclusions: Neonatal weight proved to be decreased in offspring prenatally exposed to stress or corticosteroids, but laboratory rodents in the absence of a challenging environment did not show catch-up growth. The available evidence is inconclusive regarding the effect on adiposity revealing clear methodological and knowledge gaps. This meta-analysis also confirmed a significant positive association between PCE and SBP. Nevertheless, additional studies should address the association with MS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Gonadal steroid hormones affect the organization of the brain during sensitive periods of development, resulting in sex differences in the neuroendocrine function and behaviour of the offspring. Although alterations in developmental testosterone exposure have been hypothesized to play a role in male-biased neurodevelopmental disorders, the underlying mechanisms remain unknown. The present study investigated the hypothesis that early prenatal exposure to low concentrations of testosterone might affect the control of stress responses in later life. Pregnant CD1 mice were treated with 10 μg of testosterone propionate or sesame oil control on embryonic days 12, 14, and 16. Effects on development were assessed by measuring litter size, composition and weight, first appearance of hair, eye and ear opening, and adult body weight. Reproductive development was assessed by measuring testosterone levels in neonatal and adult males, gonad weights in both sexes and reproductive cyclicity in females. The function of the hypothalamic-pituitary-adrenal axis was determined by measuring corticosterone in hair samples from juvenile animals, as well as in plasma following restraint stress in adulthood. Prenatal testosterone treatment had no significant effects on any of the overall developmental or reproductive endpoints assessed. However, in adulthood, corticosterone responses to restraint stress were reduced in the male but not the female offspring, with no significant effect on basal corticosterone levels in either sex. Thus, a small prenatal increase in maternal testosterone may be sufficient to produce a lasting sex-specific alteration in the sensitivity of the male HPA axis to stress., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research ( n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

The placenta plays a central role in the epigenetic programming of neurodevelopment by prenatal stress (PS), but this pathway is not fully understood. It difficult to study in humans because the conditions for intense, traumatic PS are almost impossible to create ethically. This study was able to capitalize on a 2012 disaster that hit New York, Superstorm Sandy, to examine the impact of traumatic stress on placental gene expression while also examining normative PS, and compare the two. Of the 303 expectant mothers participating in the Stress in Pregnancy Study, 95 women were pregnant when Superstorm Sandy struck. During their pregnancy, participants completed self-report measures of PS and distress that were combined, using latent profile analysis, into one global indicator of normative PS. Placental tissue was collected at delivery and frozen for storage. RNA expression was assessed for 40 placental genes known to associate with the stress response system and neurodevelopment in offspring. Results showed that normative PS increased expression of just MECP2, HSD11B2, and ZNF507, whereas Superstorm Sandy PS decreased expression of CDKL5, CFL1, DYRK1A, HSD11B2, MAOA, MAOB, NCOR1, and ZNF507. Interaction analyses indicated that Superstorm Sandy PS was associated with decreased gene expression for the low and high PS group for CFL1, DYRK1A, HSD11B2, MAOA, and NCOR1 and increased expression for the moderate PS group for FOXP1, NR3C1, and NR3C2. This study supports the idea that a moderate amount of normative PS may buffer the impact of traumatic PS, in this case caused by Superstorm Sandy, on placental gene expression, which suggests that the placenta itself mirrors the organism's ability to develop an epigenetic resilience to, and inoculation from, stress., Competing Interests: The authors have declared that no competing interests exist.

Adverse experiences during childhood can have long-lasting impacts on physical and mental health. At the heart of most theories of how these effects are transduced into health impacts is the activity of stress-mediating systems, most notably the hypothalamic-pituitary-adrenocortical (HPA) axis. Here we review the anatomy and physiology of the axis, models of stress and development, the development of the axis prenatally through adolescence, the role of experience and sensitive periods in shaping its regulation, the social regulation of the axis at different points in development, and finally conclude with suggestions for future research. We conclude that it is clear that early adversity sculpts the stress system, but we do not understand which dimensions have the most impact and at what points in early development. It is equally clear that secure attachment relationships buffer the developing stress system; however, the mechanisms of social buffering and how these may change with development are not yet clear. Another critical issue that is not understood is when and for whom adversity will result in hypo- vs hyperactivity of stress-mediating systems. These and other issues are important for advancing our understanding of how early adversity "gets under the skin" and shapes human physical and mental health., (© 2020 Elsevier Inc. All rights reserved.)

The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress., (© 2020 Elsevier Inc. All rights reserved.)

Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and antioxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GAD67GFP+ interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence (GE), the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized DHE oxidation levels in GE and ameliorated the migration delay caused by prenatal stress. Through convergent redox manipula-tions, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Susceptibility and resilience to stress depend on 1) the timing of the exposure with respect to development, 2) the time across the life span at which effects are measured, and 3) the behavioral or biological phenotype under consideration. This translational review examines preclinical stress models that provide clues to causal mechanisms and their relationship to the more complex phenomenon of stress-related psychiatric and cognitive disorders in humans. We examine how genetic sex and epigenetic regulation of hormones contribute to the proximal and distal effects of stress at different epochs of life. Stress during the prenatal period and early postnatal life puts male offspring at risk of developing diseases involving socialization, such as autism spectrum disorder, and attention and cognition, such as attention-deficit/hyperactivity disorder. While female offspring show resilience to some of the proximal effects of prenatal and early postnatal stress, there is evidence that risk associated with developmental insults is unmasked in female offspring following periods of hormonal activation and flux, including puberty, pregnancy, and perimenopause. Likewise, stress exposures during puberty have stronger proximal effects on girls, including an increased risk of developing mood-related and stress-related illnesses, such as depression, anxiety, and posttraumatic stress disorder. Hormonal changes during menopause and andropause impact the processes of memory and emotion in women and men, though women are preferentially at risk for dementia, and childhood adversity further impacts estradiol effects on neural function. We propose that studies to determine mechanisms for stress risk and resilience across the life span must consider the nature and timing of stress exposures as well as the sex of the organism under investigation., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Development of the brain prenatally is affected by maternal experience and exposure. Prenatal maternal psychological stress changes brain development and results in increased risk for neuropsychiatric disorders. In this review, multiple levels of prenatal stress mechanisms (offspring brain, placenta, and maternal physiology) are discussed and their intersection with cellular stress mechanisms explicated. Heat shock factors and oxidative stress are closely related to each other and converge with the inflammation, hormones, and cellular development that have been more deeply explored as the basis of prenatal stress risk. Increasing evidence implicates cellular stress mechanisms in neuropsychiatric disorders associated with prenatal stress including affective disorders, schizophrenia, and child-onset psychiatric disorders. Heat shock factors and oxidative stress also have links with the mechanisms involved in other kinds of prenatal stress including external exposures such as environmental toxicants and internal disruptions such as preeclampsia. Integrative understanding of developmental neurobiology with these cellular and physiological mechanisms is necessary to reduce risks and promote healthy brain development., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Prenatal stress (PS) leads to a wide variety of behavioral and emotional aberration observed in later life, particularly in the impairment of spatial learning and memory in offspring. Icariin (ICA) is a naturally occurring furanocoumarin and exhibits many pharmacological properties, including potent improvement on learning and memory., Purpose: We pretend to investigate the improvement of ICA on learning and memory impairment in PS., Methods: Female PS offspring rats were used to explore the effects of ICA on learning and memory impairment. After 28 days of ICA (20, 40 and 80 mg/kg/day) treatment, we measured Morris water maze and 8-Arm Maze, the HPA axis and the related pathway in the hippocampus., Results: We reported that ICA ameliorated the spatial learning and memory and working memory impairment in the female offspring rats. Correspondingly, ICA prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus. ICA significantly decreased the serum adrenocorticotropin, corticotropin-releasing hormone and corticosterone levels in offspring rats exposed to PS, associated with increased GR expression. Additionally, ICA treatment significantly increased the neurogranin (Ng) and c-fos protein expression of hippocampus in the offspring rats. Furthermore, the protein of relative content of p-EKR/ERK, p-CaMKIIα/CaMKIIα, p-CREB/CREB were remarkably increased after ICA treatment in the offspring rats., Conclusion: Taken together, ICA may be an effective therapeutic for learning and memory dysfunction in female offspring exposed to PS, its neuroprotective effect was mediated in part by normalizing the HPA axis and up-regulating of ERK/CaMKIIα/CREB signaling, Ng and c-fos protein., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)