Early Adverse Life Events Research Articles

Early Life Conditions, Adverse Life Events, and Chewing Ability at Middle and Later Adulthood

We sought to determine the extent to which early life conditions and adverse life events impact chewing ability in middle and later adulthood. Secondary analyses were conducted based on data from waves 2 and 3 of the Survey of Health, Ageing, and Retirement in Europe (SHARE), collected in the years 2006 to 2009 and encompassing information on current chewing ability and the life history of persons aged 50 years or older from 13 European countries. Logistic regression models were estimated with sequential inclusion of explanatory variables representing living conditions in childhood and adverse life events. After controlling for current determinants of chewing ability at age 50 years or older, certain childhood and later life course socioeconomic, behavioral, and cognitive factors became evident as correlates of chewing ability at age 50 years or older. Specifically, childhood financial hardship was identified as an early life predictor of chewing ability at age 50 years or older (odds ratio = 1.58; 95% confidence interval = 1.22, 2.06). Findings suggest a potential enduring impact of early life conditions and adverse life events on oral health in middle and later adulthood and are relevant for public health decision-makers who design strategies for optimal oral health.

The timing of maternal separation affects morris water maze performance and long‐term potentiation in male rats

The increasing evidences showed that adverse early life events have profound long lasting consequences in adult rats including neural, behavioral, and cognitive effects. Early maternal separation was one of the models of adverse early life stress, but which period acts critically was unknown until now. The purpose of this paper was to explore the effects of maternal separation in different periods, that is, postnatal Day 2-9 and postnatal Day 14-21, on spatial learning and memory and long-term potentiation (LTP) in hippocampus of adolescent rats. Rat pups were assigned to three groups: early maternal separation from postnatal Day 2-9 (EMS2-9), separation from postnatal Day 14-21 (EMS14-21), and control (Con)--rats stayed with their mother all the time before weaning. Morris water maze test (MWM) and electrophysiological test were performed at 40-50 days of age. The results indicated that EMS14-21 impaired spatial learning and memory ability. For the excitatory postsynaptic potential long-term potentiation (EPSP LTP), both the two maternal separation groups showed decreased values compared to control group. In terms of population spike long-term potentiation (PS LTP), both the two maternal separation groups also showed lower values compared with control group, but only EMS14-21 group had significant difference compared with control group. In conclusion, our results revealed that EMS14-21 showed worst in both escape latency in Morris Water Maze test and LTP compared to control group and EMS2-9 group.

Kidney stones: a fetal origins hypothesis.

Kidney stones are common, with a multifactorial etiology involving dietary, environmental, and genetic factors. In addition, patients with nephrolithiasis are at greater risk of hypertension, diabetes mellitus, metabolic syndrome, and osteoporosis, although the basis for this is not fully understood. All of these renal stone-associated conditions have also been linked with adverse early-life events, including low-birth weight, and it has been suggested that this developmental effect is due to excess exposure to maternal glucocorticoids in utero. This is proposed to result in long-term increased hypothalamic-pituitary-axis activation; there are mechanisms through which this effect could also promote urinary lithogenic potential. We therefore hypothesize that the association between renal stone disease and hypertension, diabetes mellitus, metabolic syndrome, and osteoporosis may be related by a common pathway of programming in early life, which, if validated, would implicate the developmental origins hypothesis in the etiology of nephrolithiasis.

666 Corticotropin Releasing Hormone Receptor 1 (CRH-R1) and Progestoerone Receptor (PGR) Polymorphisms Interact With Early Life Trauma in Healthy Controls (HC) and Patients With Irritable Bowel Syndrome (IBS)

BACKGROUND: Although studies have suggested genetic and environmental influences interact to contribute substantially to vulnerability to illness, the search for direct genetic x environmental influences contributing to the risk for IBS have been inconclusive so far. Genes regulating the effects of stress via the HPA axis have been implicated in the physiological and pathological regulation of stress reactivity as being mediated by release of hypothalamic corticotrophin releasing hormone (CRH). HPA activity is modulated by sex hormones progesterone and estrogen. HPA axis hyperactivity may be a function of psychosocial stressors such as early adverse life events (EALs) and may show sex-specific effects on emotional arousal circuitry in the brain. The hippocampus is a major component of the emotional arousal system and expresses CRH-R1, PGR and estrogen receptors (ESR1). AIMS: To examine gene-environment interactions on hippocampal volumes in male and female IBS patients and HCs. CRH-R1, PGR, and ESR1 polymorphisms were examined for effects on hippocampal volumes and interactions with early life trauma, sex, and diagnosis. METHODS: In a racially diverse community population of IBS and HCs, three SNPs of the CRH-R1 gene (rs7209436, rs110402, and rs242924), 2 SNPs of the PGR gene (rs1042838, rs10895068) and 1 SNP of the ESR1 gene (rs9340799) were genotyped. Subjects completed structural MRI scans and the volumes of the right and left hippocampus were computed. Haplotypes were created using Mendel software for each gene of interest and were analyzed in a linear regression model controlling for age, race, and total brain volume. We tested for main effects of genotype, sex, diagnosis, early life trauma index (ETI) as well as interactions between genotype and ETI with sex and diagnosis. RESULTS: 122 IBS patients (91 female) and 205 HCs (female 164) were studied. Significant Sex x Gene x ETI interactions were seen for PGR and CRH-R1 in the right hippocampus and for PGR in the left hippocampus. For males with PGR minor alleles, higher ETI was associated with smaller right and left hippocampal volumes, while no effect was seen in females. For males with CRH-R1 major alleles, higher ETI was associated with smaller right hippocampal volume. CONCLUSION: Sex differences in interactions between EALs and polymorphisms in genes directly involved or modulating the stress reactivity CRH system were demonstrated for volume of the hippocampus, a region involved in emotional arousal. Specifically, PGR and CRH-R1 demonstrated male-specific effects of ETI on hippocampal volume. Both PGR and CRH-R1 are expressed in the hippocampus. Progesterone is involved in neurogenesis and modulates HPA activity. The results highlight the importance of considering sex in examining gene-environment effects in IBS.

667 Corticotropin Releasing Hormone Receptor 1 (CRH-R1) Polymorphisms Are Predictive of Irritable Bowel Syndrome (IBS) Status

BACKGROUND: Although studies have suggested genetic and environmental influences interact to contribute substantially to vulnerability to illness, the search for direct genetic x environmental influences contributing to the risk for IBS have been inconclusive so far. Genes regulating the effects of stress via the HPA axis have been implicated in the physiological and pathological regulation of stress reactivity as being mediated by release of hypothalamic corticotrophin releasing hormone (CRH). HPA activity is modulated by sex hormones progesterone and estrogen. HPA axis hyperactivity may be a function of psychosocial stressors such as early adverse life events (EALs) and may show sex-specific effects on emotional arousal circuitry in the brain. The hippocampus is a major component of the emotional arousal system and expresses CRH-R1, PGR and estrogen receptors (ESR1). AIMS: To examine gene-environment interactions on hippocampal volumes in male and female IBS patients and HCs. CRH-R1, PGR, and ESR1 polymorphisms were examined for effects on hippocampal volumes and interactions with early life trauma, sex, and diagnosis. METHODS: In a racially diverse community population of IBS and HCs, three SNPs of the CRH-R1 gene (rs7209436, rs110402, and rs242924), 2 SNPs of the PGR gene (rs1042838, rs10895068) and 1 SNP of the ESR1 gene (rs9340799) were genotyped. Subjects completed structural MRI scans and the volumes of the right and left hippocampus were computed. Haplotypes were created using Mendel software for each gene of interest and were analyzed in a linear regression model controlling for age, race, and total brain volume. We tested for main effects of genotype, sex, diagnosis, early life trauma index (ETI) as well as interactions between genotype and ETI with sex and diagnosis. RESULTS: 122 IBS patients (91 female) and 205 HCs (female 164) were studied. Significant Sex x Gene x ETI interactions were seen for PGR and CRH-R1 in the right hippocampus and for PGR in the left hippocampus. For males with PGR minor alleles, higher ETI was associated with smaller right and left hippocampal volumes, while no effect was seen in females. For males with CRH-R1 major alleles, higher ETI was associated with smaller right hippocampal volume. CONCLUSION: Sex differences in interactions between EALs and polymorphisms in genes directly involved or modulating the stress reactivity CRH system were demonstrated for volume of the hippocampus, a region involved in emotional arousal. Specifically, PGR and CRH-R1 demonstrated male-specific effects of ETI on hippocampal volume. Both PGR and CRH-R1 are expressed in the hippocampus. Progesterone is involved in neurogenesis and modulates HPA activity. The results highlight the importance of considering sex in examining gene-environment effects in IBS.

845 Early Adverse Life Events: Influence on Resting State Connectivity in Somatosensory, Cognitive and Pain Regions in Male and Female Patients With Irritable Bowel Syndrome

845 Early Adverse Life Events: Influence on Resting State Connectivity in Somatosensory, Cognitive and Pain Regions in Male and Female Patients With Irritable Bowel Syndrome

Linking Early Adversity, Emotion Dysregulation, and Psychopathology: The Case of Extremely Low Birth Weight Infants

The ability to regulate emotion is a crucial process that humans utilize in order to adapt to the demands of environmental constraints. Individuals exposed to early adverse life events such as being born at an extremely low birth weight (ELBW, 501–1000 g) are known to have problems regulating emotion which have been linked to the development of psychopathology in this population. Recent studies have used psychophysiological measures, such as electroencephalogram (EEG) and cardiac vagal tone, to index emotion regulatory processes. The purpose of this paper was three-fold: (1) to investigate the relation between ELBW and emotion regulation issues (pathway 1), (2) to review studies investigating the relation between early emotion regulation and later internalizing problems (pathway 2); and (3) to provide a model in which two psychophysiological measures (i.e., frontal EEG asymmetry and cardiac vagal tone) are suggested to understand the proposed conceptual pathways in the relation between ELBW and psychopathology.

Functional gastrointestinal diseases in children: Facing the rising tide

However, looking at the overall picture, this study suggests that use of romiplostim is safe and effective as it raised platelet count in 33/35 of the patients, with the majority peaking platelet count between two to three weeks since the first peptide injection. This may help raise platelet counts in CHC patients undergoing antiviral treatment. Currently, most of adverse effects of antiviral therapy with pegylated interferon, ribavirin, and protease inhibitors, such as anemia, leucopenia, fever, body ache, etc can be managed with supportive treatment such as erythropoietin, G-CSF injection, paracetamol, and nonsteroidal anti-inflammatory drugs. Yet no good treatment exists for thrombcyopenia. This study brings hope for CHC patients with thrombocytopenia who are in need of antiviral treatment. Understandingly, this is a phase II study, and the authors rightly caution in the concluding paragraph that further studies in larger group of patients over a longer period of time are warranted in defining the optimal treatment schedule and dosage of romiplostim. Nevertheless, studies on romiplostim will be closely watched by hepatologists like me, as this may bring hope to many patients with advanced fibrosis or cirrhosis from CHC who are excluded from current antiviral treatment due to pre-existing thrombocytopenia.

Long-term changes in cognitive bias and coping response as a result of chronic unpredictable stress during adolescence

Animals that experience adverse events in early life often have life-long changes to their physiology and behavior. Long-term effects of stress during early life have been studied extensively, but less attention has been given to the consequences of negative experiences solely during the adolescent phase. Adolescence is a particularly sensitive period of life when regulation of the glucocorticoid “stress” hormone response matures and specific regions in the brain undergo considerable change. Aversive experiences during this time might, therefore, be expected to generate long-term consequences for the adult phenotype. Here we investigated the long-term effects of exposure to chronic unpredictable stress during adolescence on adult decision-making, coping response, cognitive bias, and exploratory behavior in rats. Rats exposed to chronic unpredictable stress (e.g., isolation, crowding, cage tilt) were compared to control animals that were maintained in standard, predictable conditions throughout development. Unpredictable stress during adolescence resulted in a suite of long-term behavioral and cognitive changes including a negative cognitive bias [F(1, 12) = 5.000, P < 0.05], altered coping response [T(1, 14) = 2.216, P = 0.04], and accelerated decision-making [T(1, 14) = 3.245, P = 0.01]. Exposure to chronic stress during adolescence also caused a short-term increase in boldness behaviors; in a novel object test 15 days after the last stressor, animals exposed to chronic unpredictable stress had decreased latencies to leave a familiar shelter and approach a novel object [T(1, 14) = 2.240, P = 0.04; T(1, 14) = 2.419, P = 0.03, respectively]. The results showed that stress during adolescence has long-term impacts on behavior and cognition that affect the interpretation of ambiguous stimuli, behavioral response to adverse events, and how animals make decisions.

Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways.

Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex

Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1–14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set-shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks.

Food allergy and abdominal nain-predominant functional gastrointestinal disorder

Abdominal pain-predominant functional gastrointestinal disorder(FGID) plays an important role in inducing functional chronic abdominal pain in children.It has been confirmed that early-life adverse events,such as neonatal maternal separation,infection,pain stimulation,acute stress,will result in the onset of the FGID in childhood and even in adult.The food allergy,particularly milk allergy,is the most common anaphylactic disease in infants,which is the main reason leading to the onset symptom of the FGID in later life.It has practical significance that the early detection and timely treatment of food allergy will prevent and treat the symptoms of FGID.This review summarizes the correlation and the progress of prevention and treatment between food allergy and FGID. Key words: Food allergy; Abdominal pain-predominant functional gastrointestinal disorder; Mast cell; Visceral hyperalgesia

Association of adverse antenatal and perinatal events with occurrence of Autism: A Case Control Study

BackgroundEarly life events, especially during perinatal and neonatal period, have been proposed as important factors in the etiologic pathways of autism.ObjectivesTo evaluate the association between selected antental and perinatal adverse events and autism spectrum disorders (ASD).MethodsA retrospective case‐control study has been nested on ongoing prospective cohort study, and it included 102 ASD cases and 102 controls.ResultsAdjusted odds ratios (OR) were generated from logistic regression models. ASD was found to be associated with social problems during pregnancy (OR = 1.39; 95% CI 1.01, 4.2), serious illness or trauma (OR = 1.5; 95% CI 1.02, 3.2), medication intake during pregnancy (OR = 1.6; 95% CI 0.96, 4.6), and premature delivery (OR = 1.7; 95% CI 1.1, 2.6). No evidence has been obtained for a significant association with gestational diabetes, anemia, and exposure to X‐ray, or caesarian section.ConclusionsThis study indicates that adverse early life events mightbe associated with increased risk of ASD. Further proof is sought through conduct of an undergoing prospective cohort study.

Gestational Restraint Stress and the Developing Dopaminergic System: An Overview

Prenatal stress exerts a strong impact on fetal brain development in rats impairing adaptation to stressful conditions, subsequent vulnerability to anxiety, altered sexual function, and enhanced propensity to self-administer drugs. Most of these alterations have been attributed to changes in the neurotransmitter dopamine (DA). In humans; dysfunction of dopaminergic system is associated with development of several neurological disorders, such as Parkinson disease, schizophrenia, attention-deficit hyperactivity disorder, and depression. Evidences provided by animal research, as well as retrospective studies in humans, pointed out that exposure to adverse events in early life can alter adult behaviors and neurochemical indicators of midbrain DA activity, suggesting that the development of the DA system is sensitive to disruption by exposure to early stressors. The purpose of this article is to provide a general overview of published studies and our own study related to the effect of prenatal insults on the development of DA metabolism and biology, focusing mainly in articles involving prenatal-restraint stress protocols in rats. We will also attempt to make a correlation between theses alterations and DA-related pathological processes in humans.

Association Between Early Adverse Life Events and Irritable Bowel Syndrome

Although childhood and adult abuse are more prevalent among patients with irritable bowel syndrome (IBS) than healthy individuals (controls), other types of early adverse life events (EALs) have not been well characterized. We investigated whether different types of EALs, before age 18 years, are more prevalent among patients with IBS, and the effects of sex and nongastrointestinal symptoms on the relationship between EALs and IBS. EALs were evaluated in 294 IBS patients (79% women) and 435 controls (77% women) using the Early Trauma Inventory Self-Report Form, which delineates subcategories of general trauma and physical, emotional, and sexual abuse. Validated questionnaires assessed gastrointestinal, psychological, and somatic symptoms. Compared with controls, IBS patients reported a higher prevalence of general trauma (78.5% vs 62.3%), physical punishment (60.6% vs 49.2%), emotional abuse (54.9% vs 27.0%), and sexual events (31.2% vs 17.9%) (all P < .001). These significant differences were observed mainly in women. Of the EAL domains, emotional abuse was the strongest predictor of IBS (P < .001). Eight of the 27 EAL items were significant (P < .001) and increased the odds of having IBS by 108% to 305%. Although EALs and psychological variables were related, EALs had an independent association with IBS (P = .04). Various types of EALs are associated with the development of IBS-particularly among women. Psychological distress and somatic symptoms might contribute to this relationship. When appropriate, EALs and nongastrointestinal symptoms should be assessed in IBS patients.

Long-Lasting Effects of Maternal Separation on an Animal Model of Post-Traumatic Stress Disorder: Effects on Memory and Hippocampal Oxidative Stress

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3h/day) during post-natal days 1-10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.

The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses

Several human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated. The aim of the present study was to determine the long-term effect of prenatal exposure to dexamethasone- DEX (synthetic GC widely used in clinics) in fear and anxious behavior and identify the neurochemical, morphological and molecular correlates. Prenatal exposure to DEX triggers a hyperanxious phenotype and altered fear behavior in adulthood. These behavioral traits were correlated with increased volume of the bed nucleus of the stria terminalis (BNST), particularly the anteromedial subdivision which presented increased dendritic length; in parallel, we found an increased expression of synapsin and NCAM in the BNST of these animals. Remarkably, DEX effects were opposite in the amygdala, as this region presented reduced volume due to significant dendritic atrophy. Albeit no differences were found in dopamine and its metabolite levels in the BNST, this neurotransmitter was substantially reduced in the amygdala, which also presented an up-regulation of dopamine receptor 2. Altogether, our results show that in utero DEX exposure can modulate anxiety and fear behavior in parallel with significant morphological, neurochemical and molecular changes; importantly, GCs seem to differentially affect distinct brain regions involved in this type of behaviors.

Very low birth weight survivors have reduced peak bone mass and reduced insulin sensitivity

Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long-term effects through reprogramming of metabolic systems. To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. Cross-sectional, observational, case-control study. Thirty-seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual-energy X-ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF-1, PTH and 25-OH vitamin D) and insulin sensitivity (HOMA-IR and oral glucose tolerance testing). VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS-30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls. Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.

A single episode of maternal deprivation impairs the motivation for cocaine in adolescent mice

Early-life adverse events, like maternal deprivation (MD), have been associated with the later development of mood and anxiety disorders. Scarce data are available describing behavioural and endocrine alterations in maternally deprived (DEP) animals during the periadolescent period. We hypothesize that a single episode of MD early in life would alter reward function and lead to a long-lasting behavioural and neuroendocrine changes during adolescence. Our aim was to evaluate the effects of a single episode of MD in CD1 adolescent mice (postnatal day 35) on a range of tests for anxiety- and depression-related behaviours (open field, elevated plus maze and tail suspension test). We further assess whether these effects could affect cocaine self-administration behaviour. In order to correlate behavioural and neuroendocrine responses to stress, brain-derived neurotrophic factor (BDNF) levels were assessed in brain structures related to emotional and cognitive processes. During the cocaine self-administration, the time required for achieving the acquisition criteria was significantly increased and the breaking point values in progressive schedule were significantly reduced in DEP adolescent mice, suggesting impairment in rewarding functions. The behavioural tests also confirm an increase in anxiety- and depression-related behaviours in DEP adolescent mice. The results on BDNF level indicated a decrease in response to MD in amygdala and hippocampus, confirming the behavioural data. Our findings demonstrated for the first time that a single episode of early MD can impair the motivation for cocaine consumption in adolescent mice and can be associated with anxiety- and depressive-like behaviour.

2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer (CC) Cells to TRAIL-Mediated Apoptosis Through Modulation of Death Receptor (DR)5 and Survivin

Background and Aims: IBS is a complex disease with recurring clusters of symptoms. Genetic mutations and single nucleotide polymorphisms do not fit these traits.We reported previously that neonatal inflammatory insult enhances smooth muscle reactivity to ACh in adulthood, which enhances colonic motor function to induce diarrhea-like conditions. In this study, we tested the hypothesis that adverse early life events reprogram the expression of genes encoding vasoactive intestinal polypeptide (VIP) and pore-forming α1C-subunit of the Cav1.2b channels (Canca1c) by epigenetic mechanisms in colonic muscularis externa to induce colonic motility dysfunction in adulthood.Methods: Ten-day old rat neonates received intraluminal 130 mg/kg TNBS in the colon; control pups received saline. Colonic muscularis externae (ME) were obtained 6 to 8-week later. Results: qRT-PCR and western blotting showed significant increases in the mRNA and protein expressions of VIP and α1C-subunit in the ME of about 50% of adult rats that received neonatal inflammatory insult (IBS-rats). Chromatin immunoprecipitation assays showed marked increase in acetylation of histone H3 lysine 9 (H3K9Ac, a marker of transcriptional activation) (0.8±0.1 vs. 0.45±0.06 Ctr., p<0.05) and attenuation in trimethylation of histone H3 lysine 9 (H3K9me3, a marker of transcriptional repression) (0.8±0.07 vs.1.2±0.03 Ctr., p<0.05) in the core promoter region of Cacna1c in IBS-rats. As a result, the RNA polymerase II (RNAP II) association with the Cacna1c promoter significantly increased, indicating enhanced Cacna1c gene transcription. We investigated the role of VIP in the epigenetic modification of Cacna1c by incubating ME from naive rats with 100 ng/ml VIP for 24 hours. VIP-treatment markedly increased H3K9Ac and decreased H3K9me3 at the upstream CREB-binding site (-2062/-2055) and around the transcription start site (+21 ~ +168), and hence enhanced RNAP II interaction with this promoter region suggesting that VIP modulates epigenetic components at the Cacna1c promoter to stimulate Cacna1c gene transcription. VIP antagonist, (p-Chloro-D-Phe6,Leu17)VIP, abrogated VIP-mediated RNAP II binding, H3K9 acetylation and trimethylation at the Cacna1c promoter. Intraperitoneal administration of 100 mM sodium butyrate, a histone deacetylase inhibitor, significantly elevated Cacna1cmRNA inME of naive adult rats (1.5±0.06 vs. 1±.01 Ctr., p<0.05), indicating that histone hyperacetylation is necessary for α1C gene transcription. Conclusions: Our findings reveal the epigenetic mechanisms by which adverse early life events alter the gene expression of specific cell signaling proteins to cause colonic motor dysfunction in adulthood. The intensities of epigenetic modifications are modifiable by environmental influences, such as stress, which explains relapses and remissions of symptoms in IBS patients.