Early Adverse Life Events Research Articles

Acute Postnatal Inflammation Alters Adult Microglial Responses to LPS that Are Sex-, Region- and Timing of Postnatal Inflammation-Dependent.

Adverse events in early life can have impact lasting into adulthood. We investigated the long-term effects of systemic inflammation during postnatal development on adult microglial responses to LPS in two CNS regions (cortex, cervical spinal cord) in male and female rats. Inflammation was induced in Sprague-Dawley rats by lipopolysaccharide (LPS, 1 mg/kg) administered intraperitoneally during postnatal development at P7, P12 or P18. As adults (12 weeks of age), the rats received a second LPS dose (1 mg/kg). Control rats received saline. Microglia were isolated 3 hours post-LPS from the cortex and cervical spinal cord. Gene expression was assessed via qRT-PCR for pro-inflammatory (IL-6, iNOS, Ptgs2, C/EBPb, CD14, CXCL10), anti-inflammatory (CD68, Arg-1), and homeostatic genes (P2Y12, Tmemm119). CSF-1 and CX3CL1 mRNA was analyzed in microglia-free homogenates. Basal gene expression in adult microglia was largely unaffected by early life LPS. Changes in adult microglial pro-inflammatory genes in response to LPS were either unchanged or attenuated in rats exposed to LPS during postnatal development. Ptgs2, C/EBPb, CXCL10 and Arg-1 were the genes most affected, with expression levels significantly downregulated vs control rats without postnatal LPS exposure. Cortical microglia were affected more by postnatal inflammation than spinal microglia, and males were more impacted than females. Overall, inflammatory challenge at P18 had the greatest effect on adult microglial gene expression, whereas challenge at P7 had less impact. Microglial homeostatic genes were unaffected by postnatal LPS. Long-lasting effects of postnatal inflammation on adult microglia depend on the timing of postnatal inflammation, CNS region and sex.

Association between maternal depression symptoms and child telomere length

The biological mechanisms that explain how adverse early life events influence adult disease risk are poorly understood. One proposed mechanism is via the induction of accelerated biological aging, for which telomere length is considered a biomarker. We aimed to determine if maternal depression pre- and post-partum was associated with telomere length in children at 4 years of age (n = 4299). Mothers completed structured questionnaires assessing depression during pregnancy (Edinburgh Depression Scale), at 9 months (Edinburgh Depression Scale), and at 54 months postpartum (Patient Health Questionnaire 9). Regression methods were used to investigate the relationship between telomere length (DNA from saliva) and maternal depression score recorded at each stage. Significant covariates included in the final model were: maternal age at pregnancy; child sex; child ethnicity; gestational age group, and rurality group. Child telomere length was found to be longer if their mother had a higher depression score at both postpartum time points tested (9 months of age; coefficient 0.003, SE = 0.001, P = 0.01, 54 months of age; coefficient 0.003, SE = 0.002, P = 0.02). Although these findings seem paradoxical, increased telomere length may be an adaptive response to early life stressors. We propose several testable hypotheses for these results and to determine if the positive association between depression and telomere length is a developmental adaptation or an indirect consequence of environmental factors.

Paternal use of selective serotonin reuptake inhibitors and adverse health outcomes: A nationwide cohort study on 13,547 exposed children.

The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children. This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception. All live-born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups. There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06-1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02-1.11) and 1.02 (CI: 0.97-1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram. Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period.

Two Adverse Early Life Events Induce Differential Changes in Brain CRH and Serotonin Systems in Rats along with Hyperphagia and Depression.

Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors.

The Implications of Response Patterns in Questions of Early Life Adverse Events on Health Status and Cognitive Function Later in Life in the Multi-Ethnic Study of Atherosclerosis (MESA)

The Implications of Response Patterns in Questions of Early Life Adverse Events on Health Status and Cognitive Function Later in Life in the Multi-Ethnic Study of Atherosclerosis (MESA)

Early life adversity shapes social subordination and cell type-specific transcriptomic patterning in the ventral hippocampus.

Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type-specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type-specific vulnerability to ELA.

THU155 Aberrant DNA Methylation Within Genes Of The HPA-axis Two Years After Paediatric Critical Illness, Role Of Glucocorticoid Treatment And Association With Impaired Physical And Neurocognitive Development.

Abstract Disclosure: G. Coppens: None. I. Vanhorebeek: None. F. Guïza: None. I. Derese: None. P.J. Wouters: None. J.F. Koen: None. S.C. Verbruggen: None. G. Van den Berghe: None. Critically ill children requiring intensive care suffer from impaired physical, neurocognitive and behavioural development two years later. Other severe early-life adverse events, such as abuse or neglect occurring during sensitive neurodevelopmental windows, have been associated with similar developmental problems. Earlier work has demonstrated the risk of impaired development of brain regions crucial for cognition and behaviour through increased glucocorticoid-signalling that, when prolonged or excessive, can induce aberrant DNA methylation within the hypothalamus-pituitary-adrenal (HPA) axis. We hypothesised that paediatric critical illness induces long-term DNA methylation changes within the HPA-axis, possibly aggravated by treatment with glucocorticoids in the paediatric intensive care unit (PICU), which may contribute to the long-term physical, neurocognitive and behavioural impairments. We assessed buccal mucosal DNA methylation (Infinium-Human Methylation-EPIC-BeadChip) of former PICU patients two years after PICU discharge (N=608 No-glucocorticoid-treatment; N=210 glucocorticoid-treatment) and matched healthy children (N=392) among key genes of the different layers of the HPA-axis. CpG-sites differentially methylated between groups were identified with use of multivariable linear regression. Differentially methylated DNA-regions were detected via clustering of differentially methylated CpG-sites using kernel estimates. These analyses were adjusted for technical variation and baseline risk factors and corrected for multiple testing (FDR<0.05). Additionally, we investigated to what extent glucocorticoid treatment during PICU stay had played a direct role in bringing about any DNA methylation changes. Finally, we assessed whether an association with the long-term physical, neurocognitive and behavioural impairment was present, with use of multivariable linear models. Former PICU patients showed aberrant DNA methylation at 10 CpG-sites (located within NR3C1, FKBP5, TSC22D3, TNF and, HSD11B1) and one DNA-region (located within TNF). Additionally, we identified that the differential methylation of 2 CpG-sites within FKBP5 was at least partly attributable to the glucocorticoid treatment that was given during PICU stay. The aberrant DNA methylation in former PICU patients associated with impaired development. This was most pronounced for the hypomethylation within the promotor/5’UTR region of FKBP5, which associated with worse growth, intelligence, visual-motor integration, alertness and memory. Two years after critical illness in children, aberrant DNA methylation within different genes of the HPA axis was detected, some of which may partly be explained by the glucocorticoid treatment given during PICU admission. These changes associated with long-term physical and neurocognitive impairments of former PICU patients. Presentation: Thursday, June 15, 2023

Examining associations between early adverse life events and health anxiety using the DanFund study

Childhood adverse life events, in particular illness-related events, have been proposed as a risk factor for development of health anxiety. ObjectiveTo examine: 1) The association between accumulated early adverse life events and health anxiety in adulthood and 2) The influence of specific types of life events, i.e., illness, injury, loss, and the impact of their exposure time on health anxiety in adulthood. MethodA population-based, cross-sectional study including 7454 participants from the Danish study of Functional Disorders (DanFunD). Health anxiety was assessed with Whiteley-6-R and early adverse life events with the Cumulative Lifetime Adversity Measure. Caseness was defined as a Whiteley-6-R score ≥ 90%ile. Generalised linear models were used to estimate the association with relative risk (RRa, adjusted for sociodemographics). ResultsA cumulative effect was found for each additional adverse life event with 8.03% increased risk of health anxiety. Two categories were associated with a higher risk: violence (RRa = 1.65, 95% CI: 1.37–1.99, P < 0.001) and relationship stress (RRa = 1.34; 95% CI: 1.15–1.57, P < 0.001). Respondents with self-reported childhood illness were also more likely to report health anxiety (RRa = 1.52, 95% CI 1.11–2.09, P = 0.009). Timewise, health anxiety seemed associated with illness during school age and injury during adolescence. ConclusionsAccumulated adverse life events, early exposure to specific categories and specific health-related life events were associated with self-reported health anxiety in adulthood. Our findings provide new knowledge on the potential role of early life events in health anxiety which could inform early intervention.

Early-Life Shocks and Childhood Social Programs: Evidence of Catch-Up in Brazil

Early-life shocks often produce negative long-run consequences lasting into adulthood, but little is known about how childhood social programs interact with early-life environments. In this paper, we analyze the effect of early-life conditions on child health and evaluate whether access to a conditional cash transfer program is differentially effective among children who experienced adverse early-life events. We use variation in delays in enrollment from the rollout of Brazil’s Bolsa Família program to analyze the impact of longer treatment durations alongside a variation of in utero rainfall to determine the potential for the program to drive catch-up growth. We find that the duration of Bolsa treatment impacts stunting, obesity, and other health outcomes, with the program being most effective among children whose in utero conditions predisposed them to worse health outcomes. Finally, we find that these effects are driven by children who receive Bolsa before age five and that girls experience more health gains. Overall, the duration of treatment matters, with some effects only appearing after one to two years of transfers, as does the timing of treatment, with some effects only appearing for younger initial recipients.

Effects of Early Adverse Life Events on Depression and Cognitive Performance from the Perspective of the Heart-Brain Axis.

Early adverse life events (EALs) increase susceptibility to depression and impair cognitive performance, but the physiological mechanisms are still unclear. The target of this article is to clarify the impact of adverse childhood experiences on emotional and cognitive performance from the perspective of the heart-brain axis. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to test cognitive function and the Childhood Trauma Questionnaire (CTQ) to assess adverse childhood experiences. Heart rate variability (HRV) and electroencephalograms (EEG) were acquired at rest. We observed that subjects with depression had experienced more traumatic events during their childhood. Furthermore, they exhibited lower heart rate variability and higher power in the delta, theta, and alpha frequency bands. Moreover, heart rate variability partially mediated the association between childhood trauma exposure and depressive symptoms. Our findings suggested that adverse life events in childhood could influence the development of depression in adulthood, which might be linked to cardiac autonomic dysfunction and altered brain function.

Childhood health and educational disadvantage are associated with adult multimorbidity in the global south: findings from a cross-sectional analysis of nationally representative surveys in India and Brazil

IntroductionMultimorbidity has emerged as a major healthcare challenge in low/middle-income countries (LMICs) such as India and Brazil. Life course epidemiology suggests that adverse events in early life contribute to an...

Association between adverse childhood experiences and social integration among older people in Japan: Results from the JAGES study

Social integration, network, and support are beneficial to health. However, there is little evidence of the association between adverse childhood experiences (ACEs) and social integration in later life. This study investigates the association between ACE history and social integration in older people. We used data from the Japan Gerontological Evaluation Study (JAGES) 2013, which conducted a self-reported survey of functionally independent people aged ≥ 65 years from 30 municipalities across Japan and yielded information on ACE history. We conducted a Poisson regression analysis with robust error variances to assess the association between ACE history and social integration, adjusting for sex, age, childhood economic hardship, adult socioeconomic status, health status, living status, and trust in others. The number of respondents with at least one incident of ACE was approximately 36.8%. The prevalence ratios for those who reported a history of ACEs were as follows: housebound 1.495 (95% confidence interval [CI]: 1.19–1.88), small network size 1.146 (95% CI: 1.10–1.19), low network contact 1.059 (95% CI: 1.00–1.059), non-membership sports group 1.038 (95% CI: 1.00–1.07), and non-membership hobby group 1.06 (95% CI: 1.03–1.09). Among older people in Japan, a history of ACEs is inversely associated with social integration. These findings support the life course approach and suggest that adverse events in early life may have an impact on social life in old age. In order to promote healthy aging, it is important to recognize the significant impact of early-life adversities that can extend into later life.

The impact of environmental factors during maternal separation on the behaviors of adolescent C57BL/6 mice.

Neonatal maternal separation is a widely used method to construct an early-life stress model in rodents. In this method, pups are separated from their mothers for several hours every day during the first 2 weeks of life, which results in adverse early-life events. It is a known fact that maternal separation can exert a significant impact on the behavior and psychological health, such as anxiety and depression, in adolescent offspring. However, environmental conditions during maternal separation can differ such as the presence of other animals or by placing pups in a different dam. To investigate the differential effects of various conditions of maternal separation on the behavior of adolescent mice, we created the following groups: (1) iMS group: pups were moved to an isolated room with no other adult mice in a nearby cage, (2) eDam group: the pups randomly exchanged their dams, (3) OF group: pups were shifted to another cage with the bedding material containing maternal odor (olfactory stimulation), and (4) MS group: pups were shifted to another vivarium. From postnatal day (PND) 2-20 (i.e., 19 consecutive days), pups were separated from the dam daily for 4 h and exposed to various environments (MS, iMS, eDam, and OF) or were left undisturbed [control (CON) group]. A series of behavioral assessments were conducted to evaluate locomotion, anxiety, recognition, learning, and memory in adolescent offspring. The results showed that neonatal maternal separation led to impaired recognition memory, motor coordination, and motor skill learning across all groups. However, the iMS group exhibited anxiety-like behavior in the elevated plus maze test and enhanced the extinction of fear memory in the auditory fear conditioning test. The OF and eDam groups displayed partially recovered short-term working memory in the Y-maze test but exhibited opposite exploratory behaviors. The OF group spent more time in the center, while the eDam group spent less time. These findings demonstrated that exposure to different environmental conditions during maternal separation causes behavioral alterations in adolescent offspring, providing a potential explanation for the variation in behavioral phenotypes observed in the early-life stress models.

Behavioral effect of Cassia singueana Del. (Fabaceae) extract against isolation rearing-induced cognitive impairment in albino rats

Early life stress negatively alters brain development and couldlead to the development of psychiatricdisorder. Exposing animals to early-life adverse events, including maternal separation or social isolation, greatly affects brain development and adult behaviour and may contribute to the occurrence of psychiatric manifestations, such as positive, negative and cognitive symptoms of schizophrenia. These symptoms can be depicted in different animal models. Aim: This study is aimed at evaluating the effect of Cassia singueana on isolation rearing-induced cognitive impairment in rats. Materials and Methods: Pharmacological intervention (Risperidone 1mg/kg/day, graded doses of Cassia singueana extract or Distilled water 10ml/kg) was introduced 4 weeks(adolescence) and one group 8 weeks(young adulthood) after IR (i.e., rats were 7- or 11-week-old). The intervention lasted for 8 weeks, after which the rats in all the various groups were subjected toopen field test, forced swim test, novel object recognition test, y-maze and post isolation grooming test. Rats’ hippocampus immediately after sacrifice was removed to measure the level of MDA, SOD and GSH. Results: Cassia singueana extract significantly decrease the hyper locomotion in open field, it also significantly decrease the duration of immobility in forced swim test. CSE also increase the exploration time of novel object and improved the recognition index. The extract also significantly increases the number of actual alternation and spontaneous alternation in y-maze. However the extract did not improve the duration of grooming in isolation reared rats. CSE also significantly improved the level of antioxidant enzymes. Conclusion: The study results revalidate the utility of the isolation rearing paradigm in exploring mental disorders with neurodevelopmental origin, especially schizophrenia and Cassia singueana extract contained phytochemicals with tendency to ameliorate all the three symptoms of schizophrenia possibly through their antioxidant properties.

Implications of Response Patterns in Questions of Early Life Adverse Events as a Risk Factor for Lower Cognitive Function in the Multi‐Ethnic Study of Atherosclerosis

AbstractBackgroundEarly‐life disadvantage may increase the risk for later cognitive decline. Recently, other aspects of early‐life adversity (ELA) have received attention but their associations with cognitive decline in later life has not been widely studied. Due to the sensitivity of such questions and the potential for systematic bias, we examined (1) predictors of response patterns to ELA questions, and (2) among those who completed ELA questions, we examined whether responses were associated with cognitive decline in the Multi‐Ethnic Study of Atherosclerosis (MESA).MethodELA was self‐reported via a 7‐item telephone assessment of socioemotional and physical threat or deprivation at MESA annual follow‐up call in 2019. Descriptive statistics were grouped by completion status: not completed, partially completed, and fully completed. Continuous variables were compared across groups with t‐tests; categorical variables were compared with chi‐square tests. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI) at MESA Exams 5 (2010‐2012) and 6 (2016‐2018). Multinomial logistic regression was used to determine predictors of completion group membership. Cognitive decline from Exam 5 to 6 by completion group was assessed using multivariable linear regression.ResultOf the 3,990 participants interviewed, the mean age was 59.2y (SD = 8.8), 55% were female, and 40% were White (n = 1,604), 13% Chinese (n = 508), 26% Black (n = 1,036), and 21% Hispanic/Latino (n = 842). The odds of partial response was higher for those born outside of the U.S. (2.17, CI 95%: 1.53‐3.09), and among participants who spoke Spanish (2.82, CI 95%: 1.74‐4.58) or Chinese (2.04, CI 95%: 1.08‐3.88) at baseline. Among participants with completed ELA (n = 3,173), one component of childhood adversity: how often was your household well‐organized/managed, was associated with better Exam 6 CASI score (β = 0.80, SE = 0.33; p = 0.015) adjusting for age, race, education, gender, language, years in the U.S., socio‐economic status (SES), and parental birthplace. There was no significant association between cognitive change from Exam 5 to Exam 6 and ELA completion.ConclusionFactors associated with acculturation including country of participant’s birth and language preference predicted completion status on questions of ELA. Future studies should be mindful of the potentially differential response patterns and the implications for interpretation when analyzing ELA data.

Understanding Attachment, Emotional Regulation, and Childhood Adversity and Their Link to Chemsex

Background: Although evidence shows that engaging in chemsex can be associated with poor mental health, little is known about the relationship between psychological factors and this type of drug use. We aim to explore associations between engagement in chemsex and several psychological variables (adverse life events, attachment styles, emotional regulation skills, self-care patterns) in a sample of gay, bisexual, and other men who have sex with men (GBMSM) with drug-related problems. Methods: A group of GBMSM engaged in chemsex (n = 41) and a control group of GBMSM (n = 39) completed an online survey to assess drug-related problems and the abovementioned psychological variables, in which both groups were compared. All analyses were adjusted for covariates showing significant differences between groups. Results: Compared to the control group, participants engaged in chemsex showed significantly higher frequencies of an avoidant-insecure attachment style and early adverse life events, regardless of all covariates (HIV status, job situation, and place of birth). Poorer emotional regulation and self-care patterns and a higher frequency of sexual abuse were also found in participants engaged in chemsex, though we cannot rule out the influence of HIV status on this second group of variables. Conclusions: Some people with drug-related problems engaged in chemsex might have suffered early adverse events and might have an avoidant-insecure attachment style. Moreover, those who have been diagnosed with HIV might show higher emotional dysregulation and poorer self-care patterns. These variables should be routinely evaluated in this population.

The Potential Role of PPARs in the Fetal Origins of Adult Disease.

The fetal origins of adult disease (FOAD) hypothesis holds that events during early development have a profound impact on one's risk for the development of future adult disease. Studies from humans and animals have demonstrated that many diseases can begin in childhood and are caused by a variety of early life traumas, including maternal malnutrition, maternal disease conditions, lifestyle changes, exposure to toxins/chemicals, improper medication during pregnancy, and so on. Recently, the roles of Peroxisome proliferator-activated receptors (PPARs) in FOAD have been increasingly appreciated due to their wide variety of biological actions. PPARs are members of the nuclear hormone receptor subfamily, consisting of three distinct subtypes: PPARα, β/δ, and γ, highly expressed in the reproductive tissues. By controlling the maturation of the oocyte, ovulation, implantation of the embryo, development of the placenta, and male fertility, the PPARs play a crucial role in the transition from embryo to fetus in developing mammals. Exposure to adverse events in early life exerts a profound influence on the methylation pattern of PPARs in offspring organs, which can affect development and health throughout the life course, and even across generations. In this review, we summarize the latest research on PPARs in the area of FOAD, highlight the important role of PPARs in FOAD, and provide a potential strategy for early prevention of FOAD.

Early life events in functional abdominal pain disorders in children.

Functional abdominal pain disorders (FAPDs) are common gastrointestinal problems in children, and the pathophysiology is thought to be multifactorial. Adverse early life events (ELE) induce alterations in the central nervous system, perhaps predisposing individuals to develop FAPDs. We aimed to study the potential adverse ELE that are associated with FAPDs. We steered a school-based survey involving 1000 children from 4 randomly selected schools. FAPDs were assessed using the translated Rome III questionnaire, and ELE were identified using a pre-tested, parental questionnaire. FAPDs were diagnosed using the Rome III criteria. Hundred and eighty-two (182) children had FAPDs (62.1% girls, mean age 8.5, SD 2.1). ELE of them were compared with 571 children without FAPDs (51.1% girls, mean age 8.8, SD 1.9). According to the binary logistic regression analysis, family members with abdominal pain, family member with chronic pain other than abdominal pain, prenatal maternal complications and interventional deliveries, were recognized as potential risk factors for the development of FAPDs. Breast feeding over two years has shown to reduce the prevalence of FAPDs.a. Prenatal maternal medical problems are associated a with higher prevalence of FAPDs later in life. Prolonged breastfeeding and normal vaginal delivery could be considered as factors that reduce the vulnerability of developing FAPDs in children. Therefore, minimizing pregnancy-related complications, encouraging vaginal deliveries, and encouraging breastfeeding are potentially valuable measures to prevent FAPDs during childhood.

Identification of bacterial lipopeptides as key players in IBS

ObjectivesClinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut...

Upregulation of Netrin-1 in the hippocampus mediates the formation of visceral hypersensitivity induced by maternal separation

Early adverse life events (EALs), such as maternal separation (MS), can cause visceral hypersensitivity, which is thought to be a key pathophysiological mechanism of irritable bowel syndrome (IBS). Previous studies mainly focused on EALs-induced visceral hypersensitivity in adulthood but did not consider that it may have occurred in the preadult period. We previously found that rats who experienced MS suffered from visceral hypersensitivity starting from the post-weaning period. Moreover, the hippocampus is considered to be critical in regulating the formation of visceral hypersensitivity induced by MS. But the underlying mechanisms throughout different life periods are unclear. In this study, behavioral tests, RNA-seq, lentiviral interference, and molecular biology techniques were applied to investigate the molecular mechanism in the hippocampus underlying MS-induced long-lasting visceral hypersensitivity. It was found that both visceral sensitivity and anxiety-like behaviors were significantly increased in MS rats in post-weaning, prepubertal, and adult periods, especially in the prepubertal period. Subsequently, RNA-seq targeting the hippocampus identified that the expression level of Netrin-1 was significantly increased in all periods, which was further confirmed by quantitative real-time PCR and Western blot. Knocking-down hippocampal Netrin-1 in the post-weaning period by lentivirus interference alleviated visceral hypersensitivity and anxiety-like behaviors of MS rats in the later phase of life. In addition, deleted in colorectal cancer (DCC), instead of neogenin-1(Neo-1) or uncoordinated (UNC5), was proved to be the specific functional receptor of Netrin-1 in regulating visceral hypersensitivity, whose upregulation may result in the most severe symptoms in the prepubertal period. Furthermore, the activation of the Netrin-1/DCC pathway could enhance long-term potentiation (LTP) in the hippocampus, probably via recruitment of the AMPA receptor subunit GluA1, which finally resulted in the formation of visceral hypersensitivity. These novel findings suggest that long-lasting over-expression of Netrin-1 can mediate visceral hypersensitivity and anxiety disorder from the post-weaning period to adulthood by activating DCC/GluA1 pathway in the hippocampus. Moreover, early intervention of Netrin-1 in the post-weaning period could lead to significant symptom relief afterward, which provides evidence that the Netrin-1/DCC/GluA1 signaling pathway may be a potential therapeutic target for the treatment of visceral hypersensitivity in clinics.