O nível de cortisol é considerado uma forma de medir o estresse de pessoas. Um estudo foi realizado a fim de verificar se crianças que trabalhavam nas ruas durante o dia tem estresse mais alto do que crianças que não trabalhavam. O nível de cortisol de uma pessoa pode ser considerado uma função crescente até atingir um máximo e depois decrescente (função quasicôncava). O cortisol das crianças foram coletados 4 vezes ao dia,sendo considerado dois grupos de crianças: aquelas que trabalham na rua e aquelas que ficavam em casa. Para a análise dos dados, foi considerada uma metanálise de um modelo de dados funcionais sob enfoque Bayesiano. Cada individuo é analisado por um modelo de dados funcionais e a metánalise foi usada para termos uma inferência para cada grupo. A geração de uma amostra da distribuição a posteriori foi obtida pelo o método de Gibbs com Metrópolis-Hasting. Na comparação das curvas calculamos a probabilidade a posteriori ponto-a-ponto da função do cortisol de um grupo ser maior do que a do outro. / The level of cortisol is considered as a measure of peoples stress. We perform an statistical analysis of the data from a study conducted to evaluate if children that work on the streets during the day have higher stress than children who does not work. The cortisol level of a person can be considered as an increasing function until reaching a maximum level and then decreasing to almost zero (quasi-concave function). Childrens cortisol were collected 4 times in one day, where two groups of children were considered: those who work in the street and those who stay at home. To analyse the data we considered a meta-analysis of a functional data model under Bayesian approach. Each individual is analysed by a functional data model, and then, a meta-analysis was used to have inference for each group. We used the Gibbs Metropolis-Hastings method to sample from the posteriori distribution. Also, we calculated the pointwise posterior probability of the cortisol function of one group being greater than the cortisol function of other group to compare the groups.

Le travail de cette thèse s’inscrit dans le cadre du projet ANR SUSoSTRESS qui a pour objectif la compréhension des mécanismes moléculaireset génétiques sous-jacents à la variabilité individuelle de réponses de stress et a collecté des données longitudinales à plusieurs niveaux biologiquessur une population d’étude porcine (race Large White). La thèse est organisé en deux partie. La première partie s’articule autour de l’analyse de données cliniques et transcriptomiques collectées à plusieurs pas de temps avant et après application de deux types de stress : injection d’ACTH et de LPS. Dans cettepartie, on cherche à développer d’un modèle fonctionnel permettant de décrire et d’intégrer au mieux l’ensemble des sources de variation génétique du fonctionnement de l’axe corticotrope et plus généralement des réponses de stress dans notre population d’étude. Plus précisément, il s’agit d’élaborer un modèle (au sens biologique du terme) décrivant les différentes réponses biologiques de stress et l’influence des variations génétiques (simples et en interaction), dans le but de prédire les leviers les plus efficaces en fonction de l’objectif de sélection. Ce travail a mis en évidence une liste de 65 gènes différentiellement exprimé au cours des réponses au stress, dont un ensemble de 8 gènes liés au au cortisol (l’hormone principale du stress) par NR3C1, le récepteur aux glucocorticoides. Ces gènes sont des biomarqueurs potentiels pouvant être fournis aux éleveurs en tant que leviers de sélection permettant un meilleur équilibre entre amélioration des caractères de production et des caractères de robustesse. La deuxième partie de ce travail s’articule autour du développement d’un outil d’analyse statistiques adapté à l’intégration de données ’omiques longitudinalesavec une variable cible d’intérêt.Nous proposons la «multiway-SIR », qui étend la méthode dual-STATIS, une méthode d’analyse de données cubiques non supervisée, au cadre de la SIR, une méthode de régression semi-paramétrique pouvant être utilisée à des fins exploratoires. Cette méthode est appliquée sur les données cliniques de l’expérience d’ACTHet permet d’y explorer l’influence de la variabilité de la réponse du cortisol à une injection d’ACTH. / This PhD thesis is part of the SUSoSTRESS project. This ANR funded project aims at improving the knowledge about molecular and genetic mechanisms underlying inter-individual variability in stress responses. Longitudinal data were collected at several biological levels on a porcine population (Large White). This work is structured in 2 parts. The first part is built around clinical and transcriptomic longitudinal data analyses collected before and after 2 types of stress factors : ACTH and LPS injection. The aim of this contribution is to develop a functional model describing all sources of genetic variation in the HPA axis activity and in stress responses in our study population.More precisely, it aims at defining a model describing the different biological stress responses and the influence of genetic variations in order to identify the most efficient selection levers according to selection goals. This work allowed for the identification of 65 differentially expressed genes during stress responses. Among them, 8 genes were highly linked to cortisol (the main stress hormone) through NR3C1 (glucocorticoid receptor (GR)). These genes are potential biomarkers and can be communicated to breeders as selection levers for a better trade-off between production and robustness traits in farmanimals. The second part is built around the development of a statistical tool suited for the data integration of repeated omicmeasurements with a real target variable.We introduce the "multiway-SIR" approach which extends the dual-STATIS (an approach to study 3-way datasets) method to the SIR framework (a semi-parametric regression model that can be used in an exploratory way). This method is illustrated on clinical data from the ACTH experiment. It allows for the exploration of the link between clinical variable response over time and inter-individual variability in the cortisol response to an ACTH injection.

Endocrine Disrupting Chemicals (EDC) are exogenous agents that mimic endogenous hormone activity in the body. EDC exposure during the critical period of neonatal development can potentially cause life-long neurological, behavioural and physiological disease. This thesis focuses on the EDC Bisphenol A (BPA), a synthetic xenoestrogen widely prevalent in everyday materials that has significant environmental relevance given its ubiquitous presence in humans around the world. The central research question of my thesis is: Does perinatal exposure to BPA affect rat pup development? A rodent model was selected to study the effects of BPA on the adrenal component of the hypothalamic-pituitary-adrenal axis (HPA axis) stress pathway, which has not been extensively studied. Rat dams were divided into five groups (vehicle control (VEH), positive control diethylstilbestrol (DES), BPA 5, BPA 50 and BPA 500 μg/kg bw/day) and dosed daily throughout gestation and for four days of lactation. Rat pups were sacrificed at two time-points at the beginning and the end of the stress hyporesponsive period (SHRP), at postnatal day (PND) 5 and PND 15. Changes in three morphometric parameters (bodyweight, crown-rump (CR) length and anogenital distance (AGD) were assessed based on the factors of Treatment and Sex. Adrenal gland glucocorticoid receptor (GR) and 18SrRNA expression was determined by qPCR in male pups at PND 5 and PND 15. At PND 5, compared to the VEH group, the BPA 50 pups were significantly heavier (ANOVA, Dunnett’s post-hoc) and the DES and BPA 50 pups had significantly longer CR lengths (ANOVA, Dunnetts’ post-hoc). At PND 15, xenoestrogen treatment significantly influenced CR length (ANOVA). At both time-points, males had significantly longer AGD than females, as physiologically expected (ANOVA). Adrenal gland GR expression in male pups was not significantly affected by treatment, but there was an effect of treatment in18SrRNA gene expression at PND 5 (Kruskal-Wallis). Using the Ct method to determine GR and 18SrRNA fold changes, we cautiously suggest that our experimental doses resulted in a non-monotonic dose response to BPA in the PND 5 animals and a monotonic dose response to BPA exposure in the PND 15 animals. This study highly values the importance of investigating the effects of environmentally relevant, low dose BPA exposure during the critical window of development, given the little that is known about potentially permanent alterations to the stress pathway due to exposure during this delicate period of development.

Self-injurious behavior (SIB) is a complex phenotype that occurs with an increasing prevalence of about 7-34% in humans and 10-12% in non-human primates (NHPs). This study evaluated the efficacy of probiotic Lactobacillus reuteri as a treatment for self-injurious behavior (SIB) and sleep disruption in rhesus macaques. The treatment was proposed to alleviate mild self-biting, sleep disruption, and reduce chronically elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, all hallmark features of monkeys with this condition. The probiotic preparation included two strains of L. reuteri (L. reuteri ATCC PTA 6475 & L. reuteri DSM 17938) containing on average 200 million colony forming units per chewable tablet. The study was conducted on 14 rhesus macaque monkeys (9 males) housed at the University of Massachusetts Amherst. To our knowledge this is the first time that a Lactobacillus strain has been used as a treatment for SIB in rhesus macaques. This study utilizes motion-activated infrared camera technology, modified enzyme-immunosorbent-assays (EIAs) techniques to measure hair cortisol concentrations, and daily behavioral observations to provide an overall assessment of the behavioral, physiological, and sleep associated implications of probiotic treatment on SIB and control non-human primates (NHPs). Administration of L reuteri modestly decreased biting behavior in monkeys with SIB (F(2,12) = 5.64, p= 0.02) and showed overall decrease in nighttime activity across all subjects but did not normalize SIB to nonSIB values. Hair cortisol values are pending. These findings and the findings of previous work further strengthen the argument for probiotics as an efficacious treatment for SIB behavior.

Die depressive Störung stellt eine weltweit häufige Erkrankung dar, die trotz vieler therapeutischer Optionen zu chronischen Verläufen und Non-Response neigt. Zirka 30 bis 50% der Patienten mit einer akuten Depression respondieren nicht auf eine Behandlung mit einem Antidepressivum trotz ausreichender Dauer und Dosis, so dass nach neuen pharmakologischen Ansätzen gesucht wird. Zudem sind Prädiktionsmöglichkeiten, was wem wann hilft, kaum vorhanden, so dass die klinische Praxis ein Versuchs- und Irrtumsverfahren ist. Ätiologisch gibt es gut dokumentierte neuroendokrinologische Befunde, die für eine Dysregulation der Hypothalamus-Hypophysen-Nebennierenrinden-Achse (HPA-Achse) im Sinne einer erhöhten Aktivität und einer erhöhten Auslenkbarkeit bei Depressionen sprechen. Für verschiedene antidepressive medikamentöse Therapien ist eine Normalisierung dieser Dysregulation beschrieben worden. Der sensitivste und spezifischste Test zur Untersuchung der HPA-Achse bei psychiatrischen Patienten ist der kombinierte Dexamethason/CRH-Test. Hierbei zeigen Patienten während der depressiven Phase eine deutliche Überstimulierbarkeit, d. h. bei depressiven Patienten führte die Gabe von Dexamethason mit anschließender CRH-Injektion zu einer überschießenden ACTH- und auch Cortisol-Antwort. Der Einfluss einer Behandlung mit Antidepressiva auf die HPA-Achse und der Zusammenhang möglicher Veränderungen der HPA-Achsen-Regulation mit dem Ansprechen oder Nicht-Ansprechen auf die Pharmakotherapie ist noch unzureichend beforscht. Teilweise gibt es sogar divergierende Befunde. In der vorliegenden Arbeit wurde mit Hilfe des Dexamethason/CRH-Tests der Einfluss einer antidepressiven Pharmakotherapie mit Citalopram auf die Regulation der HPA-Achse bei 30 vorwiegend unbehandelten Patienten mit einer Majoren Depression untersucht. Die SSRI sind die am häufigsten angewendeten Antidepressiva. Citalopram ist neben seinem S-Enantiomer Escitalopram der selektivste SSRI, der gewählt wurde, um gezielt die Auswirkungen einer rein serotonergen antidepressiven Behandlung zu untersuchen. Vor Beginn der Therapie und nach vierwöchiger Behandlung wurden mittels kombinierten Dexamethason/CRH-Tests bei den Patienten Cortisol- und ACTH-Konzentrationen im Serum gemessen. Die Diagnosen wurden mit SKID I und II bestätigt. Im wöchentlichen Rhythmus wurde während des vierwöchigen Studienverlaufs die aktuelle depressive Symptomatik sowie der Gesamtkrankheitszustand der Patienten mittels Selbst- (BDI) und Fremdratingbögen(HAM-D, CGI) erhoben. Ebenfalls im wöchentlichen Rhythmus wurden medikamentenassoziierte Nebenwirkungen systematisch erfasst. Unter der Behandlung zeigten sich erfreulich viele Responder auf die antidepressive Pharmakotherapie mit Citalopram (23 von 30 Patienten). Eine Herabregulierung der HPA-Achse zeigte sich unter der Behandlung nur auf der Hypophysenebene für die ACTH-Antwort, allerdings nicht auf der Nebennierenrindenebene für die Cortisol-Antwort. Trotz geringerer ACTH-Konzentrationen wurde nach vier Wochen noch die gleiche Menge an Cortisol in der Nebennierenrinde produziert. Die AUC total für ACTH betrug vor der antidepressiven Behandlung mit Citalopram 2077 ± 1260. Nach vier Wochen antidepressiver Pharmakotherapie zeigte sich ein Wert von 1393 ± 485 und damit ein signifikanter Unterschied (p=0,010). Für die AUC total für Cortisol zeigte sich wie bereits erwähnt kein signifikanter Unterschied (AUC total vor Behandlung: 4755 ± 3411 und nach vier Wochen Behandlung: 4901 ± 3688; p=0,813). Möglicherweise ist dies auf einen direkten Effekt von Citalopram auf die Nebennieren im Sinne einer Sensibilisierung zu verstehen. Wirkungen in dieser Richtung wurden bislang nicht beschrieben. Ein prädiktiver Wert für das Ansprechen auf die Behandlung konnte für den Dex/CRH-Test nicht gefunden werden. Responder und Non-Responder unterschieden sich nicht. Auch das aufwendige Procedere des Testes limitiert ihn für eine regelhafte Anwendung in der Klinik. Allerdings besteht weiterhin in diesem Bereich Forschungsbedarf, um die unterschiedlichen Befunde einordnen zu können. Dabei wären z. B. Studien mit einer größeren Fallzahl sowie ein Vergleich mit einer Placebobehandlung wünschenswert.

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that may develop in response to traumatic or stressful events. Dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been implicated in the disorder. Studies support such dysfunction as being a consequence of PTSD, rather than a precursor. However, most studies of the HPA are either cross-sectional or have been carried out in adults. The aim of the present study was to identify whether HPA dysregulation interacts with stressful experiences to increase the likelihood of developing PTSD symptoms in a community-recruited sample of healthy adolescent girls. Adolescent girls (N = 550) and one of their parents participated. Adolescents’ clinical symptoms were assessed at baseline and at a nine month follow-up. Saliva samples were collected from all adolescent participants at waking, 30 minutes after waking, and 8 pm on 3 consecutive days. Flattened diurnal slope of cortisol at baseline was associated with increased PTSD symptoms nine months later. Baseline cortisol awakening response (CAR) per se was not prospectively related to developing PTSD symptoms, but its interactions with stressful experience was associated with elevated PTSD symptoms at follow-up. Effects were small and need to be replicated in samples with more severe stressors, as well as more clinical levels of PTSD. Nevertheless, findings suggest that dysregulated basal HPA functioning may be involved in the development of PTSD symptoms.

There is increasing recognition of the relationship between depression and obesity in the pediatric population and recently, there has been a focus on inflammation as a potential link. Both conditions are considered to be pro-inflammatory states, and certain inflammatory markers are linked to depression in obese adults and vice versa. Leptin has also been implicated in depression as a potential mediator between inflammation and depression. Brain derived neurotrophic factor (BDNF), which is associated with depression and obesity, is influenced by inflammation and leptin in animal models as well. Few studies have examined the interactions between depression, adiposity, and biological markers in obese youth and therefore, our objective was to explore the determinants of depression in obese youth in a clinical setting. We studied 244 youth aged 8-17 years (125 girls, 119 boys) at the time of entry to a weight management program, as part of a prospective, longitudinal study. The CES-DC depression-screening tool was used to assess depressive symptoms, and a participant was classified as having high depressive symptoms if the CES-DC score ≥15 or taking antidepressants. Questionnaires assessed socio-demographic factors and puberty while adiposity was measured using dual-energy X-ray absorptiometry (DXA). Inflammatory markers (IL-6, TNFα, CRP, IL-10), leptin, and BDNF were quantified by immunoassays. Of the 244 participants, 8 were on antidepressants and 88 (36.4%) met the criteria for high depressive symptoms. We confirmed previous findings that household income and body fat were important determinants of depressive symptoms. However for the first time, it was identified that leptin levels predicted CES-DC score independent of body fat. Neither inflammatory markers nor BDNF were significantly related to depression scores. Our findings suggest that leptin may mediate the relationship of adiposity and depression but it is uncertain if this is related to direct action or to the phenomenon of leptin resistance. / Thesis / Master of Science (MSc) / Obesity has a significant impact on depression in children and adolescents. Inflammation – the body’s response to injury – is measured through markers in the blood and leptin – the marker of body fat – have shown to be related to depression. Research indicates that depression influences these factors to act on obesity. However, research on the interactions of biological and socio-demographic factors with depression in youth with obesity is lacking. Therefore, our objective was to explore the impact of these factors on depression in obese youth entering into a weight management program. Using a depression-screening tool, we studied 244 youth under 18 years and confirmed that household income and body fat were important factors of depression. However for the first time, we found leptin influenced depression regardless of the amount of fat present suggesting that depression acts on obesity through leptin but it is uncertain how this occurs and further research is warranted.

Soziale Ausgrenzung ist ein wesentlicher emotionaler Stressor. Ziel der Arbeit war die Erfassung hormoneller Prozesse nach cyberball-induzierter sozialer Ausgrenzung sowie nachfolgendem TSST, Frauen zeigen nach sozialer Ausgrenzung eine Aktivierung der HPA-Achse im Sinne eines verstärkten ACTH-Anstieges im Gegensatz zu den integrierten Frauen oder männlichen Testpersonen.

No description available.

<p>Salivary cortisol and electrocardiogram data was collected at baseline and after a stress-anticipation task in extremely low birth weight (ELBW; < 1000 grams) survivors and normal birth weight (NBW) controls, in order to examine the moderating influence of emotion regulation on the relationship between being born at ELBW and internalizing problems in adulthood. The stress manipulation was an adapted Trier Social Stress Task. The participants were told they would have three minutes to create a speech on one of three predetermined topics (i.e., gun control, same sex marriage, or abortion). After three minutes passed, the particpants were told that there would be no speech. All participants showed a decrease in salivary cortisol levels throughout the day, and an increase in heart rate during the stress anticipation task. When a median split was used to create high and low stress reactive cortisol and heart rate groups, an interaction was found between birth status (ELBW vs. NBW) and group (High vs. Low Stress Reactive Cortisol) on self-reported internalizing problems (anxiety, depression, withdrawal). Those born at ELBW who had high stress reactive cortisol self-reported significantly higher levels of internalizing problems compared to ELBWs with low stress reactive cortisol. Those born at NBW did not differ on self-reported internalizing problems based on their stress reactive cortisol levels. When the moderating effect was probed with a linear regression analysis, the ELBW group was driving the relation between stress reactive cortisol levels and internalizing problems. Taken together, the results suggest that emotion regulation, as indexed by the neuroendocrine system, is moderating the relation between being born at ELBW and internalizing problems in adulthood. This is indicative of a differential susceptibility of risk and resilency in ELBW survivors depending on their ability to regulate their emotions, specifically during periods of stress.</p> / Master of Science (MSc)