Epilepsy, a relatively common and chronic neurological condition, affects 1-2% of the population. The underlying pathophysiology of epileptogenesis is not completely understood. To identify potential antecedents to seizure, the effects of maternal stress and environmental enrichment (EE) were investigated. Maternal stress was modeled by exposing pregnant rats to a prenatal stress (PS; an ethologically relevant predatory threat). At birth, PS and naïve control (NC) dams and litters were either maintained in standard cages or transferred to EE until postnatal day (PD) 14. A model of febrile convulsions (FC) was used to determine seizure susceptibility of all offspring. Pup brains were processed for detection of FosB (FosB-ir) from structures in the limbic system and corticotrophin-releasing hormone (CRH-ir) from the paraventricular nucleus of the hypothalamus (PVN). Our results suggest pre- and postnatal dam-dependent effects. PS increased glucocorticoid (GC) levels in dams and decreased pup birth-weights. Seizure scores on PD14 were highly individualized and litter dependent, suggesting a dam-dependent and variable effect of controlled pre- and postnatal factors. EE increased FosBir within the hippocampus but, in other regions, EE decreased FosB-ir. EE also significantly decreased CRH-ir in the PVN. Our results support the concept that both preand postnatal environmental influences affect fetal programming and neurodevelopment.

L’évaluation psychologique à court, moyen et à long terme des survivants, de séismes démontre que certains symptômes psychiatriques sont courants dans ces populations, notamment le Trouble de Stress Post-Traumatique (TSPT) et la dépression. Les objectifs principaux de ce travail visaient à combler des lacunes de données scientifiques sur les éventuelles relations entre des facteurs pré, péri et post-traumatiques spécifiques et le développement de troubles post-traumatiques dans des groupes vulnérables suite au séisme de 2010 en Haïti. Etude no 1- Objectifs : évaluer les associations entre les croyances sur l’origine du séisme et les psychopathologies post-traumatiques, et la résilience. Les symptômes dépressifs sévères étaient courants chez les personnes d’affiliation vodouisante (x2 = 9.05, df = 1, p <0.01), ainsi que chez les personnes présentant un faible niveau de résilience (<80 au CD-RISC, x2 = 7.49, df = 1, p<0.01). Etude no 2- Objectifs : mesurer une année après le désastre, l’effet d’un support psycho-social offert à des enfants de Port-au-Prince issus des camps d’hébergement comparés à un groupe contrôle vivant sous un toit. Les deux groupes étaient homogènes sur le plan de l’intensité de la détresse péri- traumatique. Il n’y avait pas de différence significative entre eux dans les scores du TSPT, la dépression et l’index de psychopathologie. Etude no 3- Objectifs : explorer 3 années après la catastrophe les propriétés psychométriques de la version créole du PTSD Checklist, auprès de 364 mères survivantes. La prévalence du TSPT probable était de 22,3%. La version créole du PCL-S est un instrument fiable pour la mesure du TSPT chez les femmes créolophones. Etude no 4- Objectifs : Examiner la prévalence des comportements autistiques dans une cohorte de sujets de 3 ans exposés à l’âge foetale au séisme. Ainsi, 8 sur 364 (2.2%) enfants recrutés répondaient aux critères de comportements autistiques sévères. Etude no 5- Objectifs : investiguer les associations statistiques entre l’exposition maternelle prénatale au séisme de 2010 avec les comportements autistiques ou des troubles du comportement global et émotionnels chez des enfants de 3 ans. Les symptômes de TSPT chez la mère était un prédicteur indépendant des comportements autistiques (=. 370, p<. 001) et des problèmes du comportement général et émotionnels (=. 467, p<. 001) chez l’enfant. Etude no 6- Objectifs : analyser qualitativement le portrait singulier de l’évolution d’une dyade rencontrée. La sémiologie autistique s’accompagne depuis la période néo-natale de crises convulsives récurrentes. L’histoire traumatique maternelle anténatale connue et son imbrication à la comorbidité autisme/épilepsie chez la fillette devrait être au coeur de tout dispositif psychothérapeutique futur. / Short-term, mid-range and long-term psychological evaluation of earthquake survivors reveals that certain psychiatric symptoms frequently exist in these populations, specifically PTSD and Depression. The principal objectives of this work were to address current gaps in scientific knowledge related to potential relationships between specific pre, peri and post-traumatic variables and the development of posttraumatic psychopathology in vulnerable groups following the 2010 earthquake in Haiti. Study no 1- Objective : This study examines associations between religious beliefs regarding the origin of the 2010 earthquake in Haiti and posttraumatic symptomatology as well as resilience among survivors. The severity of depressive symptoms was associated with a score <80 on the CD-RISC (x2 = 7.49, df = 1,p <0.01) and were more prevalent among Voodoo Adherents than among their counterparts with different belief systems (x2 = 9.05, df = 1, p <0.01).Study no 2- Objective : This study, conducted one year after the 2010 earthquake, assessed the effect of a psycho-social intervention implemented among children residing in a displacement camp in Port-au-Prince compared with a control group. The two groups were homogeneous in terms of the intensity of the peritraumatic distress they experienced. No significant difference was noted between the experimental and control group in their endorsement of PTSD symptoms or in their scores on a depression scale. In three out of the four sub-scales of the Child Behavior Check-List, there was no significant difference noted either. Study no 3- Objective : In this study, we examined the psychometric properties of a Haitian Creole version of the PTSD checklist among 364 mothers exposed to the 2010 earthquake and the prevalence of PTSD symptoms among them, 3 years after the event. Our findings included that 22,3% of our sample would possibly meet the criteria for PTSD even three years after the earthquake. The creole version of PCL-S is a reliable measure of PTSD symptoms among female creole speakers. Study no 4- Objective : This study investigated the prevalence of autistic behaviors in a cohort of young children (n-364) who were exposed in utero to the devastating 2010 earthquake in Haiti, 3 years after theevent. A significant minority (2.2%) of our sample met criteria for severe autistics behaviors. Study no 5- Objective : This study, conducted 3 years after the 2010 Haiti earthquake targeted women who were pregnant during the earthquake and their offspring who were in utero at the time of the event. Specifically, the study assessed the association between maternal exposure to the earthquake with autistic, behavioral, and emotional symptoms of the offspring at age three. Current maternal PTSD symptoms was an independent predictor of the offspring’s autistic behaviors (=. 370, p<. 001) as well as behavioral and emotional problems (=. 467, p<. 001). Study no 6- Objective: This study comprised a qualitative analysis of a single mother and child dyadscreened in the quantitative survey. In addition to displaying symptoms of autism, the young child also suffers from recurrent seizures. Maternal history of physical and psychological trauma has implications forco-morbidity of autism and epilepsy offspring who were in utero at the time of the trauma and such dyadsshould be targeted for therapeutic intervention and follow-up in the future.

Prenatal stress (PNS) has been shown to affect a range of different modalities, like stress responsiveness and affective traits in both animals and humans. Previously, Dr Paula Brunton’s lab has used a novel model of ethologically relevant prenatal social stress and had shown increased stress responsiveness in both first generation (F1) PNS males and females and increased anxiety-like trait in males, together with corresponding changes in mRNA expression for corticotrophin releasing hormone (Crh) and its receptors. The first aim on this project was to further explore the phenotype of PNS offspring created using this model in social context. F1 PNS females, but not males, displayed an impairment in social memory in comparison to control females, which was supported by lower vasopressin receptor type 1a (Avpr1a) mRNA expression in the anterior part of lateral septum and bed nucleus of stria terminalis. Acute stress exposure immediately prior to the social memory test, impaired social memory in control males and females, but had no effect in PNS males and markedly improved performance in PNS females. This facilitated learning in the PNS females was supported by the finding of higher Avpr1a mRNA expression in both target regions in the brain. Finally, olfactory memory for social but not non-social odours was also impaired in PNS females, compared to control females, indicating that deficits in social memory in PNS females are specific to social odours and not in the detection and/or processing of all odours. It has been shown previously that phenotypes observed in PNS animals can also be seen following disrupted maternal care in the early post-partum period and that stress can affect maternal behaviour. To investigate this possibility in the current model a maternal behaviour observation protocol was developed. Dams were observed during the first postnatal week, three times/day in 90 min blocks. Stressed dams showed an increase in pup-directed behaviours, together with an increase in arched back nursing specifically, compared to control dams. Furthermore, studies have shown that maternal behaviour patterns can be transferred from mother to daughters, therefore this possibility was also investigated here. There were no differences in maternal behaviour between F1 control and F1 PNS dams. The maternal behaviour experiment for the F1 PNS dams created a unique opportunity to study their offspring (F2). F2 PNS rats had lower body weights than their control counterparts throughout their lifetimes, while not differing significantly in their calorie intake. Increased anxiety-like behaviour was also observed in both the F2 males and females (but only during proestrous and estrous stages of their cycle). These changes were supported in males by increased Crh and Crh receptor type 1 and decreased Crh receptor type 2 mRNA expression in discrete regions of the amygdala. Furthermore, F2 PNS females exhibited exaggerated, and males attenuated ACTH and corticosterone secretion in response to acute stress, compared with controls. The reduced stress response in F2 PNS males was supported by higher glucocorticoid receptor (GR, Nr3c1) mRNA expression in field CA1 of hippocampus. In F2 PNS females, increased stress responses were associated with increased Crh and Avp mRNA expression in the medial parvocellular division of the paraventricular nucleus of the hypothalamus and lower basal Nr3c1 and mineralocorticoid receptor (MR, Nr3c2) mRNA expression in the hippocampus. As increased stress and anxiety-like responses have been linked to a depressive phenotype that possibility was also investigated. No changes were found in either sucrose preference or floating/swimming behaviour in the forced swim test between the F2 PNS and control rats, in either sex. Finally, the variation in individual stress responsiveness and anxiety-like trait and the relationship between these phenotypes was investigated in an outbred male Sprague Dawley population. It was found that three of the most commonly used anxiety tests: open field test, light dark box and elevated plus maze do not correlate as well with each other as could be expected. Secondly plasma corticosterone concentrations 30min after the onset of acute restraint stress were positively correlated with the amount of time the rats spent in the anxiogenic environments, showing perhaps counter-intuitively, that the higher the stress responses the less anxious the male rat is. The behavioural tests were also used as a selection procedure to compare gene expression by microarray in the amygdala of high and low anxious rats and hypothalamus of high and low stress-responsive rats. To summarise, stress during pregnancy has profound effects on the dams’ immediate maternal behaviour, as well as neuroendocrine and behavioural effects in both the F1 and F2 offspring. Furthermore, there is evidence of inter-individual variation in stress responsiveness and anxiety-like behaviour in an outbred rat population. This data could lead to further understanding of the origins of inter-individual variation and appreciation of the effect of stress throughout the life course.

Background: The fetal origins hypothesis poses that adverse intrauterine conditions predispose to cardiovascular and metabolic diseases in adulthood. Evidence is accumulating that similar mechanisms to those identified for physical disorders may also apply to psychiatric disorders. Focusing on the activity of neurophysiological systems thought to regulate emotions from very early in life may be key to understanding how maternal stress in pregnancy impacts on the developing baby with possible long-lasting consequences for behaviour and psychopathology. Respiratory Sinus Arrhythmia (RSA), "vagal tone", is thought to reflect autonomic regulatory capabilities that may underpin emotion regulation. However, little is known about possible fetal origins of vagal tone. Animal studies increasingly point to sex differences in the effects of prenatal stress, and this is supported by human studies of the prenatal origins of cardiovascular functioning and psychopathology. The current investigation examines whether prenatal depression and anxiety predict vagal tone in infancy, and whether the associations are modified by infant sex. Method: Two hundred mothers and infants from a high-risk consecutive community sample were examined prospectively from the first trimester of pregnancy until 29 weeks postnatal. Maternal self-reports of stress (EPDS and STAI) were collected in pregnancy (20 and 32 weeks) and postnatally (5 weeks and 29 weeks). Vagal tone was ascertained across five procedures, the "Helper-Hinderer" social evaluation task, toy exploration and the "Still Face" paradigm (2 minutes of social engagement, followed by 2 minutes of maternal unresponsiveness and concluded by 2 minutes of social reunion). Results: Principal Component Analysis of the RSA scores yielded a one-factor solution explaining over 70% of the variance, and so mean of RSA scores was used as the index of overall vagal tone, and the difference between overall and RSA during the Still Face as the estimate of vagal withdrawal. There were no main effects of prenatal maternal depression or anxiety on vagal tone or vagal withdrawal. However, there were significant prenatal stress by sex of infant interactions. Follow-up analyses revealed that increasing maternal depression and anxiety at 20 weeks gestation were associated with decreasing vagal tone in males and increasing vagal tone in females. Vagal withdrawal in response to the still face showed similar patterns i.e. decreased in males and increased in girls with elevated maternal anxiety at 32 weeks gestation. These associations were not explained by possible confounding variables assessed in pregnancy, nor by postnatal maternal depression and anxiety. Conclusions: The findings support the fetal origins hypothesis for vagal tone and vagal withdrawal, but only in interaction with sex of the infant. Longitudinal study is required to determine conditions under which increasing vagal tone and withdrawal in girls associated with prenatal depression and anxiety, and decreasing vagal tone and withdrawal in boys, are associated with later resilience or vulnerability to psychopathology.

Maternal stress during pregnancy has been repeatedly associated with lasting changes in offspring physiology and behavior. Despite evidence linking maternal stress during pregnancy to premorbid abnormalities associated with depression, such as difficult temperament, cognitive deficits, and, in animal studies, brain abnormalities and biological profiles linked to depression, very few studies have examined maternal stress during pregnancy in relation to offspring depression itself and no study has examined sex differences in this association. The current study used data from 1,711 mother-offspring dyads enrolled in a longitudinal birth cohort study. Maternal narratives collected during pregnancy provided a direct, prospective measure of maternal stress during pregnancy and were qualitatively coded for stressful life events and stress-related themes by two independent raters. Latent class analysis (LCA) was used to identify distinct subgroups of offspring based on exposure to maternal psychosocial stress during pregnancy and other known developmental factors from the prenatal, childhood, and adolescent periods that have been previously associated with depression and/or maternal stress during pregnancy. To examine sex differences, LCA was conducted separately for males and females. Subgroups derived from the LCA were compared to determine whether and to what extent they differed on adolescent depressive symptoms. LCA revealed a subgroup of “high risk” females, characterized by higher maternal ambivalence/negativity about the pregnancy, lower levels of maternal positivity about the pregnancy, higher levels of reported routine daily hassles during pregnancy, lower levels of maternal education, higher maternal age, higher maternal pre-pregnancy body mass index (BMI), higher levels of maternal worry about finances and health concerns during childhood, higher levels of inhibition and conduct symptoms during childhood, decreased cognitive functioning during childhood and adolescence, lower levels of perceived paternal and maternal support during adolescence, and higher levels of maternal depression during adolescence. These high risk females exhibited elevated depressive symptoms during adolescence relative to both the “low risk” female group and the mean of the sample. A subgroup of males defined by similar indicators was not found to have elevated depressive symptoms during adolescence. Our findings appear to be in line with an emerging body of evidence suggesting that prenatal stress may have a lasting and sex-specific influence on offspring development. / Psychology

Epilepsy is a devastating disorder characterized by recurrent seizures. The pathophysiology of the disorder is not well understood. In this study the effects of early life, including pre- and post-natal, experiences on the seizure susceptibility of offspring was determined. Sprague-Dawley rats were air transported prior to breeding (In-House), on gestation day 9 (G9), or G16. The maternal behaviour was scored from P2-P13. On P14, seizure susceptibility of pups was assessed by randomly assigning the pups into Naïve (control), Saline, lipopolysaccharides (LPS; 200 ?g/kg), Kainic acid (KA; 1.75 mg/kg) or Febrile Convulsion (FC; LPS followed by KA) groups. No effect of prenatal transport was found on seizure susceptibility. Licking and grooming (LG) maternal behaviour was associated with higher FC seizure susceptibility of offspring. Male pups were more susceptible to FC seizure than female pups. These results emphasize the dam-dependent and sex-dependent effects of early life experiences on seizure susceptibility of offspring.

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 anti-oxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GABAergic 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 both 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, the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized levels of DHE oxidation in ganglionic eminence, and ameliorated the migration delay caused by prenatal stress. In adult male offspring, prenatally-stressed mice exhibited anxiety-like behavior on the elevated plus maze, impaired motor learning on the rotarod, cognitive flexibility on the water T-maze task, and deficits in sensorimotor gating in the pre-pulse inhibition task. Prenatally-stressed adult female offspring showed anxiety-like behavior, deficits in sociability and impaired motor learning. Maternal antioxidants prevented anxiety-like behaviors and improved sensorimotor gating in both sexes, and improved habitual learning and cognitive flexibility in adult female mice. Lastly, prenatal stress led to increases in PV+/GAD67+ cell ratios in mFC in male mice, but decreases in female mice, and antioxidant treatments eliminated those differences. Hippocampal GAD67+ cell densities were reduced by prenatal stress and restored by astaxanthin in male mice, and PV+/GAD67+ cell ratio was reduced by prenatal stress and partially restored by N-acetylcysteine in female mice. GAD67+ cell densities across regions correlated significantly with anxiety-like behavior in both male and female mice and social behavior in female mice. Through convergent redox manipulations, 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.

Epidemiological studies in humans have revealed a relationship between altered development in utero and an increased incidence of pathophysiology during postnatal life. One of the mechanisms underlying this relationship is thought to be exposure to excess glucocorticoids during critical phases of brain development. The aim of the current set of studies was to determine the effects of prenatal stress during discrete developmental windows on behaviour and endocrine function in male and female guinea pig offspring. Guinea pigs were used as the model for these studies as they are a long-gestation species that give birth to neuroanatomically mature young and fetal brain development is well characterized. Pregnant guinea pigs were exposed to a high frequency strobe light during the period of rapid fetal brain growth or the period of rapid brain myelination. Pregnant guinea pigs were allowed to deliver normally and guinea pig offspring were tested for ambulatory activity, anxiety and hypothalamic-pituitary-adrenal (HPA) axis function. Male offspring whose mothers were exposed to stress during the period of rapid brain growth exhibited increased anxiety behaviour, increased basal plasma cortisol levels and decreased plasma testosterone levels. We found that replacing testosterone in these animals reversed the behavioural and endocrine differences. Male offspring whose mothers were exposed to stress during the period of rapid myelination exhibited an increased plasma cortisol response to activation of the HPA axis. Female offspring whose mothers were exposed to stress during the period of rapid brain myelination exhibited decreased ambulatory activity and a blunted salivary cortisol response to the stress of the strobe light, but only during the estrous phase of the reproductive cycle. Therefore, the current set of studies has demonstrated the effects of prenatal stress on behaviour and HPA axis activity are dependent on; 1) the timing of the prenatal stress and 2) the hypothalamic-pituitary-gonadal axis in both male and female offspring. These studies have begun to uncover the mechanisms underlying programming and provide the basis for continuing research in humans.

Epidemiological studies in humans have revealed a relationship between altered development in utero and an increased incidence of pathophysiology during postnatal life. One of the mechanisms underlying this relationship is thought to be exposure to excess glucocorticoids during critical phases of brain development. The aim of the current set of studies was to determine the effects of prenatal stress during discrete developmental windows on behaviour and endocrine function in male and female guinea pig offspring. Guinea pigs were used as the model for these studies as they are a long-gestation species that give birth to neuroanatomically mature young and fetal brain development is well characterized. Pregnant guinea pigs were exposed to a high frequency strobe light during the period of rapid fetal brain growth or the period of rapid brain myelination. Pregnant guinea pigs were allowed to deliver normally and guinea pig offspring were tested for ambulatory activity, anxiety and hypothalamic-pituitary-adrenal (HPA) axis function. Male offspring whose mothers were exposed to stress during the period of rapid brain growth exhibited increased anxiety behaviour, increased basal plasma cortisol levels and decreased plasma testosterone levels. We found that replacing testosterone in these animals reversed the behavioural and endocrine differences. Male offspring whose mothers were exposed to stress during the period of rapid myelination exhibited an increased plasma cortisol response to activation of the HPA axis. Female offspring whose mothers were exposed to stress during the period of rapid brain myelination exhibited decreased ambulatory activity and a blunted salivary cortisol response to the stress of the strobe light, but only during the estrous phase of the reproductive cycle. Therefore, the current set of studies has demonstrated the effects of prenatal stress on behaviour and HPA axis activity are dependent on; 1) the timing of the prenatal stress and 2) the hypothalamic-pituitary-gonadal axis in both male and female offspring. These studies have begun to uncover the mechanisms underlying programming and provide the basis for continuing research in humans.

Prenatal stressors have been reported to affect postnatal cognitive, metabolic, reproductive and immune functions. This study examined immune indices and function in Brahman calves prenatally stressed by transportation of their dams on d 60, 80, 100, 120 and 140 ± 5 d of gestation. Based on assessment of cow’s temperament and their reactions to repeated transportation it was evident that temperamental cows displayed greater pre-transport cortisol (P < 0.0001) and glucose (P < 0.03) concentrations, and habituated slower to the stressor compared to cows of calm and intermediate temperament. Serum concentration of cortisol at birth was greater (P < 0.03) in prenatally stressed versus control calves. Total and differential white blood cell counts and serum cortisol concentration in calves from birth through the age of weaning were determined. We identified a sexual dimorphism in neutrophil cell counts at birth (P = 0.0506) and cortisol concentration (P < 0.02) beginning at 14 d of age, with females having greater amounts of both. Whether weaning stress differentially affected cell counts, cortisol concentrations and neutrophil function of prenatally stressed and control male calves was examined. At 2 d post weaning, all calves had increased cortisol concentration (P < 0.0001) and neutrophil cell counts (P < 0.0001). However, in vitro production of reactive oxidative species by neutrophils was decreased (P = 0.0002) 2 d post weaning. Moreover, prenatally stressed calves demonstrated a larger (P = 0.0203) decrease in their immune function relative to control calves at 2 d post-weaning. Importantly, prenatally stressed calves took longer than controls to recover from the weaning stress. Additional studies are needed to clarify if prenatally stressed calves are more susceptible than control calves to pathogens during the post weaning period. Management practices to improve animal welfare and livestock production may need modification if follow-up studies demonstrate that prenatal stress also affects reproductive development, growth, performance and meat quality.