The mesocorticolimbic system is involved in fundamental processes that drive motivational behaviors essential for survival (feeding, reproduction and sexual behavior, etc.), as well as neurochemical activity involved in mood regulation. Stressful life events are an important cause of dysregulated psychological functioning, which in some leads to a pathophysiology of mood disorders. A source of such disorder could be, among other underlying factors, an impairment of synaptic plasticity induced by alterations in the levels of neurotrophins and/or aberrant glucocorticoid responses. The role of the brain derived neurotrophic factor (BDNF) and its high affinity receptor tyrosine-related kinase B (TrkB) in the mesocorticolimbic reward circuitry has been largely studied in adulthood, yet a possible role of this system in mediating memory and emotional responses induced by stress during the juvenile, adolescence period has not been elucidated. The proposed set of thesis studies are designed to investigate the roles of BDNF and TrkB signaling, via the selective and non-competitive TrkB antagonist, ANA-12 (N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl] benzo[b]thiophene-2-carboxamide), in the expression of stress-induced changes in the brain stress circuitry (including the medial prefrontal cortex (mPFC), hypothalamic-pituitary-adrenal (HPA) axis, and hippocampus) and reward signaling systems of the brain (including the nucleus accumbens (NAc) and ventral tegmental area (VTA)). In addition, experiments aim to determine behavioral changes following stress exposure in male and female Wistar rats. Finally, the possible interplay between BDNF, dopamine, glutamate and orexins in response to repeated stress is examined. Articles 1 and 2, aimed to assess the biochemical and behavioral effects of direct ANA-12 infusion (0.25 µg/ 0.5µl) into the nucleus accumbens shell during exposure to a 10-day heterotypic stress paradigm in male rats. Specifically, Article 1 demonstrated a key role for BDNF/TrkB signaling to regulate stress-induced effects. Notably, the impact of ANA-12 to attenuate anxiety-like behavior in repeatedly stressed rats while increasing anxiety behavior in non-stress rats suggest an interesting behavioral and neurochemical state-dependent process induced by TrkB receptor signaling. Article 2 supports the key role for BDNF secretion in basal and stress-induced behaviors in rats suggesting an influence of TrkB in sociability, motivation and passive avoidance. Furthermore, this role of TrkB extended to increased expression of orexin A in the Perifornical area (PfA) and a decrease in the ventral CA1 of the hippocampus, and in stress-induced elevations in orexinergic projections to the VTA, of which reductions were observed in non-stress groups treated with ANA-12. Article 3 demonstrated gender-specific behavioral and biochemical responses in different developmental periods and the impact of TrkB activation, dependent on stress exposure, to affect the regulation of TrkB receptor isoforms (full length and truncated TrkB, TrkB.FL and TrkB.T1, respectively) in adulthood. Results revealed increased CORT responses in adolescent females relative to males and attenuated CORT secretions in both genders by TrkB inhibition. Elevated activity levels in young adult females and increased passive coping behavior in the forced swim in stress-naïve females were also noted, in addition to novel observations on brain region and sex differences in TrkB receptor isoforms. Taken together, thesis findings derived from applications of ANA-12, shall foster knowledge on the contribution of BDNF in regulation of mood upon stress exposure at times when the brain is undergoing important maturation and remodelling, as well as on the relationship of stress exposure during adolescence and lasting brain and behavioral disorders in adulthood.

Background: Individuals with obesity face weight-related discrimination in many life domains, including workplace bullying, especially in female employees with obesity. However, associations between experiences of workplace bullying and psychological health impairments considering weight status and sex remain unclear. Methods: Within a representative population-based sample of N = 1290 employees, self-reported experiences of workplace bullying were examined for variations by weight status and sex. Using path analyses, sex-specific mediation effects of workplace bullying on associations between weight status and work-related psychological health impairments (burnout symptoms, quality of life) were tested. Results: Employees with obesity experienced more workplace bullying than those with normal weight. Workplace bullying was positively associated with psychological health impairments and partially mediated the associations between higher weight status and elevated burnout symptoms and lower quality of life in women, but not in men. Conclusions: The result that more experiences of workplace bullying were, compared with weight status, more strongly associated with work-related psychological health impairments in women, but not in men, uniquely extends evidence on sex-specific effects within weight-related discrimination. Continued efforts by researchers, employers, and policy makers are needed to reduce weight-related discrimination in work settings, eventually increasing employees’ health and job productivity.

Une exposition prénatale à l’alcool peut altérer le développement embryonnaire et causer le Trouble du Spectre de l’Alcoolisation Fœtale (TSAF). Les mécanismes moléculaires menant aux symptômes observés chez les enfants atteints sont toutefois méconnus. Plus encore, bien que les taux de consommation excessive d’alcool (binge-drinking) et de grossesses non-planifiées soient en hausse à travers le monde, les impacts d’une exposition prénatale à l’alcool pendant la préimplantation de l’embryon, sont inconnus et peu étudiés. Dans cette thèse, je souhaitais caractériser les impacts morphologiques d’une exposition à l’alcool pendant la préimplantation sur l’embryon en développement. De plus, je voulais définir les mécanismes moléculaires impliqués dans le cerveau antérieur ainsi que dans le placenta embryonnaire, en plus d’évaluer l’effet d’une exposition à l’alcool pendant la préimplantation sur certaines fonctions cognitives au stade post-natal. Notre hypothèse de recherche est qu’une exposition à l’alcool de type aigu pendant la préimplantation entrainera des erreurs dans l’établissement du programme épigénétique embryonnaire, causant des altérations dans les profils de méthylation d’ADN et d’expression des gènes chez l’embryon et son placenta qui persisteront tout au long de la gestation. Plus encore, nous croyons que ces dérégulations moléculaires altèreront les fonctions cognitives à long terme chez les souriceaux exposés. Pour répondre à ces questions, nous avons établi un modèle murin d’exposition à l’alcool de type aigu pendant la préimplantation en injectant des femelles gestantes au jour embryonnaire 2.5 (E2.5), correspondant au stade 8-cellules, avec deux doses de 2.5g/kg d’alcool séparées par 2 heures d’intervalle. Nous avons récolté des embryons à mi-gestation (E10.5), évaluer la morphologie puis nous avons isolé le cerveau antérieur pour étudier la méthylation d’ADN et l’expression génique. Nous avons aussi récolté des embryons en fin de gestation (E18.5) et leur placenta pour procéder à des analyses de méthylation d’ADN et de l’expression génique, en plus d’effectuer des analyses histologiques des placentas. Finalement, nous avons aussi laissé naître des souris issues de notre modèle d’exposition à l’alcool pendant la préimplantation pour évaluer certaines fonctions cognitives, notamment l’anxiété, la sociabilité et la mémoire, en procédant à des tests de comportement. Nous avons d’abord observé une augmentation des anomalies morphologiques chez l’embryon à mi-gestation à la suite de l’exposition prénatale à l’alcool. Nous avons aussi découvert que l’exposition prénatale, pendant la préimplantation, engendrait des différences de méthylation d’ADN dans le cerveau antérieur à mi-gestation et en fin de gestation, dans plusieurs voies biologiques reliées au développement embryonnaire et au fonctionnement du système nerveux. La plupart des régions différentiellement méthylées (DMRs) et des gènes différentiellement exprimés (DEGs) étaient spécifiques à chaque sexe, avec peu de régions partagées entre les mâles et les femelles. Nous avons aussi identifié des DMRs et DEGs spécifiques à chaque sexe ou partagés entre les deux sexes, dans les placentas en fin de gestation en plus de démontrer une baisse du poids fœtal chez les embryons mâles exposés à l’alcool. Enfin, nous avons démontré que l’exposition prénatale pendant la préimplantation causait une baisse de la sociabilité et de la mémoire à court-terme, sans avoir d’effet sur le niveau d’anxiété des souris En conclusion, nous avons démontré qu’une exposition prénatale à l’alcool en tout début de grossesse affecte le développement embryonnaire, via l’épigénome et le transcriptome du cerveau antérieur et du placenta, et entraine des conséquences à plus long terme sur les fonctions cognitives. En perspective, nous souhaitons établir les profils de méthylation d’ADN et d’expression génique précisément dans certains sous-types cellulaires du cerveau, dont les interneurones GABAergiques afin de mieux définir les mécanismes moléculaires derrière les altérations observées. / Prenatal alcohol exposure can alter embryonic development and lead to Fetal Alcohol Spectrum Disorder (FASD). However, the molecular mechanisms underlying the symptoms in affected children remain poorly understood. Furthermore, despite the increasing rates of binge drinking and unplanned pregnancies worldwide, the impacts of prenatal alcohol exposure during the preimplantation stage of embryonic development are largely unknown and understudied. In this thesis I aimed to characterize the morphological effects of alcohol exposure during preimplantation on developing embryos. Additionally, we sought to define the extent of DNA methylation defects and gene expression in the anterior brain and embryonic placenta. Furthermore, we aimed to evaluate the effects of our preimplantation alcohol exposure on certain cognitive functions in the postnatal stage. Our research hypothesis is that acute alcohol exposure during preimplantation will lead to errors in establishing the embryonic epigenetic program, causing alterations in DNA methylation profiles and gene expression in both the embryo and its placenta, persisting throughout gestation. We also believed that these molecular dysregulations would result in long-term cognitive impairments in exposed pups. To address these questions, we established a preclinical mouse model of acute alcohol exposure during preimplantation by injecting pregnant females on embryonic day 2.5 (E2.5), corresponding to the 8-cell stage, with two doses of 2.5g/kg of alcohol, separated by a 2-hour interval. We collected embryos at mid-gestation (E10.5), assessed for morphological defects and isolated the forebrain for DNA methylation and gene expression studies. We also collected embryos at late gestation (E18.5) along with their placenta for DNA methylation and gene expression analyses, as well as histological examinations of fixed placentas. Finally, we allowed mice from our preimplantation alcohol exposure model to be born and assessed specific cognitive functions such as anxiety, sociability, and memory through behavioral tests. First, we observed an increase in morphological anomalies in mid-gestation embryos following prenatal alcohol exposure and discovered that prenatal exposure during preimplantation led to DNA methylation differences in the forebrain at mid-gestation and late gestation, affecting various biological pathways related to embryonic development and nervous system function. Most of the differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were sex-specific, with only few regions shared between males and females. We also identified sex-specific and shared DMRs and DEGs in late gestational placentas. Additionally, we demonstrated a decrease in fetal weight in male embryos and showed that preimplantation alcohol exposure caused reduced sociability and short-term memory without affecting the anxiety levels of the mice. In conclusion, we have shown that early preimplantation alcohol exposure affects embryonic development through the epigenome and transcriptome of the anterior brain and placenta, leading to long-term cognitive consequences. Moving forward, we intend to establish DNA methylation and gene expression profiles specifically in certain brain cell subtypes, including GABAergic interneurons, to better define the molecular mechanisms underlying the observed alterations.