Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2009 May 24

Bipolar disorders and recurrent depressions are two common psychiatric disorders with a life time prevalence of approximately 1% and 8%, respectively. Despite treatment these patients suffer from affective symptoms up to 50% of the time, resulting in lower well-being. The average life length is also reduced with 10-15 years, mainly attributable to suicide and cardiovascular disease. Increased stress is one of many factors that have been shown to be linked to an increased risk for developing affective disorders and some comorbid somatic conditions such as metabolic disturbances and cardiovascular disease. An increased stress level is known to cause hyperactivity of the hypothalamic-pituitary-adrenal-axis (HPA-axis) with increased cortisol secretion. Hyperactivity of the HPA-axis (or hypercortisolism) is one of the most replicated neurobiological finding in depression. In other stress related disorders it has however been shown that prolonged stress over long periods of time can lead to a state of low HPA-axis activity, hypocortisolism. Since persons with recurrent affective disorders such as bipolar disorder and recurrent depression are exposed to a high degree of recurrent and chronic stress it could be expected that in addition to hypercortisolism, a state of hypocortisolism could also develop in these disorders, potentially exerting an influence upon the psychological and somatic wellbeing among these patients. The major aim of this thesis was to evaluate whether hypocortisolism is related to relevant psychiatric and somatic phenotypes in recurrent affective disorders. In bipolar disorder, individuals with hypocortisolism exhibited a higher degree of depression and low quality of life compared to patients with normal HPA-axis activity. In recurrent depression, individuals with hypocortisolism exhibited shorter leukocyte telomere length than patients with normal or high HPA-axis activity, which is an indication of an accelerated aging process. In a sample of both bipolar and recurrent depression patients, hypocortisolism was associated with an increased proportion of obesity, dyslipidemia and metabolic syndrome compared with patients with normal or high HPA-axis activity. Patients with recurrent depression showed a higher occurrence of hypocortisolism than the control sample representative of the general population. Patients with bipolar disorder showed a similar occurrence of hypocortisolism as the control sample. Among bipolar disorder patients with a low degree of lifetime with lithium prophylaxis, there was an inverse correlation between age and HPA-axis activity. In contrast, among patients with a higher degree of lifetime with lithium prophylaxis as well as among the controls, there was no correlation between age and HPA-axis activity. Accordingly, hypocortisolism was most common among older patients with a low degree of lifetime with lithium prophylaxis. In conclusion, hypocortisolism in both recurrent depression and bipolar disorder was associated with multiple clinically-relevant phenotypes. Additionally it was shown for bipolar disorder patients that increasing age was a risk factor for hypocortisolism and that prophylactic lithium treatment was a protective factor. It is argued that the protective effect of lithium towards the HPA-axis is attributable to its mood-stabilizing effect, which in turn reduces the chronic stress level. These results provide new insight into the role of hypocortisolism and chronic stress in recurrent affective disorders warranting further studies and hopefully providing clues to improved treatment strategies.

During adolescence, animals leave the natal home and interact with potentially threatening stimuli (i.e. stressors), e.g. unfamiliar environments and conspecifics. Adolescent stressors can result in fewer interactions with unfamiliar stimuli in adulthood, plausibly due to sustained effects of glucocorticoid exposure on stress physiology (e.g. glucocorticoid secretion and receptor expression). The current thesis tested the hypothesis that adolescent glucocorticoid exposure and social experiences act as stressors by quantifying the effects of the adolescent experiences on behavioural responses to unfamiliar stimuli and the underlying neuroendocrine mechanisms when in adulthood using two captive species, zebra finches and rats. In study one, adolescent zebra finches were dosed with the glucocorticoid corticosterone. In adulthood, birds dosed with corticosterone in early adolescence took longer to enter an unfamiliar environment when tested individually and had lower expression of the glucocorticoid receptor GR in the hippocampus and hypothalamus, brain regions that regulate stress responses. Glucocorticoids therefore appear to be an endocrine mechanism behind the long-term effects of adolescent stress. Subsequent studies explored whether higher social density and more unfamiliar social interactions during adolescence act as stressors. In study two, early adolescent zebra finches were housed in groups varying in conspecific number and density. In adulthood, females raised in larger groups secreted a higher stressor-induced corticosterone concentration and, if raised at lower density, spent more time in an unfamiliar environment when group housed. In study three, adolescent female rats were housed in familiar pairs or exposed to unfamiliar conspecifics. Unfamiliar adolescent interactions had no effects on responses to unfamiliar environments or stress physiology in adulthood, but heightened ultrasonic call rates. In this thesis, adolescent social experiences do not act like stressors, but modulate (especially female) social behaviour. Adolescent stressors and social experiences therefore have distinct effects on responses to unfamiliar stimuli and stress physiology that are maintained into adulthood.

Le projet de cette thèse s'est attaché à caractériser le rôle de l'IL-1 beta et les récepteurs P2X7 dans la dépression. Les résultats suggèrent que chez les souris stressés et les perturbation comportementaux, l'activation microgliales et endocriniennes sont reversées par l'antagoniste des P2X7Rs. Ces résultats mettent en évidence que l'antagoniste des récepteurs P2X7 a des effets comportementaux et neuroendocriniens. / Research work of this thesis was aimed to characterize role of IL-1 beta and P2X7 receptors in depressive illness. Results suggest that i stressed mice the behavioral and neurobiochemical changes are reversed by use of P2X7R antagonist. It is an evidence of antidepressant of these compounds.

Un tiers des patients déprimés inclus dans les essais cliniques ne répondent pas à un traitement antidépresseur. La dérégulation de l’axe HPA et la réduction de la neurogènese hippocampique sont les principaux facteurs de la résistance aux antidépresseurs. L’objectif de ce travail est de développer un modèle de résistance à l’antidépresseur lié à l’axe HPA et d’utiliser ce modèle pour comprendre les mécanismes sous-jacents. Nos résultats suggèrent qu'une mauvaise régulation de rétrocontrôle négatif de l'axe HPA au début du protocole peut être un facteur prédictif de l'échec du traitement antidépresseur dans la dépression. Notre protocole montre que l’échec de la fluoxétine à induire des effets antidépresseurs a été associé à une mauvaise aptitude des composés à stimuler la prolifération des cellules dans le gyrus denté de l'hippocampe. D'autres études sont nécessaires pour étudier la relation de causalité entre ces phénomènes. / One-third of depressed patients included in clinical trials do not respond to antidepressant treatment. Dysregulation of the HPA axis and reduced hippocampal neurogenesis are the main factors of resistance to antidepressants. The objective of this work is to develop a model of resistance to antidepressant related to the HPA axis and to use this model to understand the underlying mechanisms. Our results suggest that dysregulation of negative feedback of the HPA axis at the beginning of the protocol can be a predictor of antidepressant treatment failure in depression. Our protocol shows that the failure of fluoxetine to induce antidepressant effects was associated with poor ability of compounds to stimulate cell proliferation in the dentate gyrus of the hippocampus. Further studies are needed to investigate the causal relationship between these phenomena.

Les interactions entre facteurs génétiques et environnementaux, comme le stress, jouent un rôle important dans la physiopathologie de maladies psychiatriques telles que la dépression. Les transporteurs de cation organiques (OCTs) sont des transporteurs polyspécifiques considérés comme sensibles à la corticostérone. Au cours de ma thèse, je me suis intéressé au rôle du transporteur de cation organique 2 (OCT2) dans la réponse au stress et la vulnérabilité à la dépression. OCT2 est exprimé dans de nombreuses régions impliquées dans la réponse au stress et le long de l’axe hypothalamo-hypophyso-surrénalien (HPA). L’absence d’OCT2 entraîne une augmentation de la sécrétion de corticostérone (156%) en réponse à un stress aigu, sans altération de la sensibilité des surrénales à l’hormone adrénocorticotrope (ACTH). En conséquence, les souris OCT2-/- sont plus sensibles aux effets du stress chronique imprédictible léger et développent des anomalies comportementales transitoires de la mémoire spatiale et de l’interaction sociale dans la phase précoce du stress chronique. De plus, nous avons montré que l’état fonctionnel de la GSK3β, une voie de signalisation profondément modulée par le stress et la dépression, est altéré dans l’hippocampe des souris OCT2-/-. Des expériences pharmacologiques in vivo et des Western blot suggèrent qu’une augmentation du tonus sérotoninergique chez les souris OCT2-/- pourrait expliquer la dérégulation de la GSK3β lors du stress. Ce travail a permis d’identifier OCT2 comme un déterminant important de la réponse au stress, suggérant que chez l’homme des polymorphismes ou son inhibition pharmacologique lors de traitements thérapeutiques de longue durée pourraient altérer l’activité de l’axe HPA et rendre les individus vulnérables aux effets délétères du stress. / Interactions between genetic and environmental factors like exposure to stress play an important role in the pathogenesis of mood-related psychiatric disorders such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting these transporters might play a physiological role in the response to stress. During my PhD thesis I investigated the role of organic cation transporter 2 (OCT2) during stress and vulnerability to depression. OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress (156%) without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2-/- mice were potently more sensitive to the action of unpredictable chronic mild stress and developed a transient aggravation of depression-related behaviors involving spatial memory and social interaction. We showed that the functional state of the glycogen synthase kinase-3β (GSK3β) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2-/- mice. In vivo pharmacology and Western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3β signaling in OCT2-/- mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in man OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.

Dans le cadre de la production d'électricité par énergie renouvelable, cette thèse a pour objectif de contribuer à l'amélioration des performances hydrodynamiques des hydroliennes à flux transverse conçues par HydroQuest. Pour y parvenir, deux axes d'étude principaux sont proposés. Le premier consiste à améliorer la compréhension de la performance de l'hydrolienne et de l'écoulement en son sein par voie numérique. L'influence du paramètre d'avance ainsi que celle de la solidité de l'hydrolienne sont étudiées. Les écoulements mis en jeux étant complexes, une méthode de type Simulation des Granges Échelles 3D est utilisée afin de les restituer au mieux. Le phénomène de décrochage dynamique, qui apparaît pour certains régimes de fonctionnement de l'hydrolienne, fait l'objet d'une étude à part entière sur un cas de profil oscillant.Le second axe se concentre sur les carénages de l’hydrolienne qui font l'objet d'une procédure d'optimisation numérique. Afin de pouvoir réaliser les nombreuses simulations requises en un temps réaliste, des méthodes de type Unsteady Reynolds-Averaged Navier-Stokes 2D moins coûteuses et fournissant une précision suffisante pour ce type d'étude sont utilisées. / Within the renewable electricity production framework, this study aims to contribute to the efficiency improvement of the Vertical Axis Hydrokinetic Turbines designed by HydroQuest. To achieve this objective, two approaches are used. The first consists in the improvement of the comprehension of the turbine efficiency such as the flow through the turbine by numerical means. The influence of the tip speed ratio such as the turbine soldity are investigated. The flow through the turbine is complex. A 3D Large Eddy Simulation type is thus used. The dynamic stall phenomenon which could occur in Vertical Axis Hydrokinetic Turbines is also studied in a oscillating blade configuration.The second approach consists in the numerical optimization of the turbine channeling device. To perform the high number of simulations required, a 2D Unsteady Reynolds-Averaged Navier-Stokes simulation type is used.

No description available.

A evolução do uso da energia eólica nas últimas décadas está diretamente relacionada ao desenvolvimento da tecnologia empregada na conversão e projeto das instalações. A viabilização de uma instalação eólica de grande porte depende da avaliação correta do potencial eólico. A fim de avaliar a capacidade de conversão de energia cinética do vento em torque, é fundamental a modelagem da esteira aerodinâmica das turbinas eólicas. Este trabalho apresenta um estudo sobre a esteira aerodinâmica formada por uma turbina eólica dimensionada conforme a teoria de otimização de Betz. Para tanto, realiza-se inicialmente uma pesquisa sobre a evolução da transformação da energia contida no vento em energia mecânica e métodos de análise adotados. Para modelagem da esteira, realiza-se a simulação numérica do escoamento sobre uma turbina de eixo horizontal empregando o Método de Volumes Finitos. Através do uso da Dinâmica dos Fluidos Computacional são resolvidas as Equações de Navier-Stokes com Médias de Reynolds (RANS) e a utilização dos modelos de turbulência k-, k- RNG, k- e k- SST. Para a solução das equações é utilizado o programa ANSYS-CFX. Define-se o perfil NACA 4412 como perfil aerodinâmico para projeto das pás da turbina, e modela-se a turbina através da teoria de dimensionamento ótimo de Betz. O domínio, discretizado em um número finito de volumes de controle, possui duas regiões distintas, uma estática e outra rotacional, representado o rotor da turbina. Inicialmente são apresentadas simulações com os diferentes modelos de turbulência e definido o modelo que apresenta os melhores resultados, o k- SST. Para o modelo escolhido são realizadas simulações incluindo estudos com a turbina inclinada em relação à direção de incidência do vento, para verificar a alteração no perfil da esteira gerada e na capacidade da turbina em transformar a energia do vento em Torque. Os resultados obtidos para os campos de velocidade e pressão são comparados com os de outros autores e mostraram-se coerentes, indicando que a simulação feita é capaz de representar o fenômeno analisado. / The evolution of the use of the wind energy in recent decades is directly related to the technology in the facilities conversion and design. The feasibility of a large wind farm depends on the correct assessment of wind potential. To evaluate the capacity of converting wind kinetic energy in torque, it is essential to model the wake aerodynamics of wind turbines. This paper presents a study on the aerodynamic wake formed by a wind turbine sized according to the Betz optimization theory. For this, initially it is performed a research on the evolution of the energy contained in wind into mechanical energy and the adopted analysis methods. For wake modeling, a horizontal axis wind turbine flow numerical simulation is done using the Finite Volume Method. Using the Computational Fluid Dynamics, the Reynolds Averaged Navier-Stokes equations are solved with the use of the k-, k- RNG, k- e k- SST turbulence models and using the software ANSYS-CFX. It is defined the NACA 4412 profile as aerodynamic profile for turbine blades and the turbine is modeled using the Betz optimization theory. The domain, discretized into a finite number of control volumes, has two distinct regions, one static and one rotational, represented the turbine rotor. Initially the simulations with different turbulence models are presented and the model k- SST is defined as the model that gives best results. For the chosen model, simulations are performed, including studies on the turbine yawed with respect to the wind incidence direction, to verify the profile change in the generated wake and turbine capacity to convert wind energy into torque. The obtained results for the velocity and pressure fields are compared to other authors are very consistent, indicating that the proposed simulation is capable of representing the analyzed phenomenon.

Introdução: A neurobiologia dos transtornos de ansiedade (TA) é complexa e envolve interações ambientais e genéticas ainda não conhecidas. Esses transtornos, comumente, iniciam durante a infância e adolescência, persistindo ao longo da vida. O comprometimento da resposta biológica frente ao estímulo estressor, encontrado em muitos pacientes com TA, sugere a influência do eixo hipotálamo-hipófise-adrenal (HHA) nestes transtornos e, portanto, os polimorfismos associados ao eixo HHA poderiam ser estudados em genes candidatos. Os estudos que almejam entender a etiologia dos TA devem, também, explorar as alterações epigenéticas (incluindo a metilação do DNA) decorrentes das influências ambientais. Objetivos: Estudar, em adolescentes, polimorfismos genéticos funcionais do eixo HHA, interações Gene x Ambiente (G x A) e metiloma do DNA, considerando as diferentes trajetórias dos TA. Métodos: Foi realizada a extração de DNA das células do epitélio bucal de 228 adolescentes (131 casos e 97 controles para os TA) e foram genotipados, por PCR em tempo real, polimorfismos funcionais envolvidos com o eixo HHA (FKBP5: rs3800373, rs9296158, 3800373, rs9296158, 3800373, rs9296158, rs1360780, rs9470080 rs1360780, rs9470080 e rs4713916; NR3C1NR3C1 : rs6198;: rs6198;: rs6198; NR3C2NR3C2 : rs2070951;: rs2070951;: rs2070951; CRHR1CRHR1 CRHR1 : rs878886 : rs878886 e SERPINA6 SERPINA6 : rs746530) : rs746530) . Os participantes responderam à escala auto-aplicativa SCARED (Screen for Children Anxiety Related Emotional Disorder – Children rated) e realizaram entrevistas semiestruturadas para avaliação diagnóstica utilizando o K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime). O questionário CTQ (Childhood Trauma Questionnaire) foi aplicado em 90 adolescentes (54 casos e 36 controles para os TA) para avaliar a interação entre o trauma emocional e o polimorfismo do gene NR3C2 nos níveis séricos de BDNF. Uma subamostra de adolescentes (n=47) foi reavaliada, cinco anos após a primeira coleta, através das mesmas entrevistas psiquiátricas e nova extração de DNA salivar. Alguns participantes, na última avaliação, responderam ao MINI (Mini International Neuropsychiatric Interview) apropriado para a idade atual. A amostra foi organizada em 4 grupos, conforme o diagnóstico dos TA e o ano da coleta de saliva (anos de 2008 e 2013): (1) Desenvolvimento típico da adolescência (Controle; n=14); (2) Incidentes para os TA (ITA; n=11); (3) Persistentes para os TA (Caso; n=14) e (4) Remitentes para os TA (RTA; n=08). O metiloma do DNA foi analisado com o Infinium HumanMethylation 450 BeadChip da Illumina. Resultados: Não foi encontrada associação entre os polimorfismos estudados e os TA. Em relação à interação G x A, sugere-se que o polimorfismo rs2070951 do gene NR3C2 modera a associação entre negligência física e os níveis séricos de BDNF. Do ponto de vista epigenético, foi observada, nos grupos ITA e RTA, vias biológicas com padrão homogêneo e relacionadas ao sistema nervoso. Já nos grupos casos e controles para os TA, foram evidenciadas vias biológicas com padrão mais heterogêneo. Um perfil de hipometilação do DNA foi predominante nas vias encontradas. Na análise transversal, nós encontramos padrões opostos de metilação do DNA, conforme o período desenvolvimental avaliado: hipometilação no início da adolescência e hipermetilação em jovens adultos. Conclusão: Esse estudo abordou, em uma amostra de adolescentes, aspectos genéticos (genes candidatos envolvidos com o eixo HHA), ambientais (trauma emocional) e epigenéticos (metiloma do DNA) dos TA. Os achados sugerem que, embora sem associações entre os TA e genes envolvidos no eixo HHA, existe uma interação entre a presença de trauma emocional, polimorfismo genético do eixo HHA e marcadores biológicos. Os achados do metiloma do DNA sugerem, também, influências epigenéticas no curso dos TA. Novos estudos devem ser delineados para corroborar as influências genéticas e ambientais neste transtorno. / Background: The neurobiology of Anxiety Disorders (AD) is complex and involves environmental and genetic interactions understood. These disorders may have their onset during childhood and adolescence, persisting throughout life. The impairment of biological response against the stressor stimulus, described in many patients with AD, suggests a possible role of genetic polymorphisms of the hypothalamic-pituitary-adrenal (HPA) axis in these individuals. Studies that aim to understand the etiology of AD should also explore the epigenetic changes (including DNA methylation) arising from environmental influences. Objective: To study, in adolescents, functional genetic polymorphisms of HPA axis, Gene x Environment (G x E) interactions and DNA methylome, considering different AD outcomes. Methods: Saliva DNA was extracted from 228 adolescents (131 cases and 97 controls to AD) and we genotyped, by real time PCR, the functional polymorphisms involved with HPA axis (FKBP5: rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; NR3C1NR3C1 : rs6198; : rs6198; : rs6198; NR3C2NR3C2 : rs2070951; : rs2070951; CRHR1CRHR1CRHR1 CRHR1: rs878886 and : rs878886 and : rs878886 and : rs878886 and SERPINA6 SERPINA6 SERPINA6SERPINA6 : rs746530) : rs746530) . Participants responded to the scale self-applied Screen for Children Anxiety Related Emotional Disorder – Children rated (SCARED) and were diagnosed according to the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime (K-SADS-PL). The Childhood Trauma Questionnaire (CTQ) was applied in 90 adolescents (54 cases e 36 controls to AD) to evaluate the interaction between emotional trauma and the NR3C2 polymorphism in the serum levels of BDNF. A sub-sample of adolescents (n = 47) was reassessed five years after the first evaluation by the same psychiatric semi-structured interviews and new extraction salivary DNA was performed. Some participants in the last evaluation responded to Mini International Neuropsychiatric Interview (MINI), which is a semi structure interview appropriate for the present age. The sample was organized in four groups according to the diagnosis of AD and the year of saliva collection (2008 and 2013): (1) Typically Developing Controls (TDC; n = 14); (2) Incident Anxiety Disorder (IAD; n = 11); (3) Persistent Anxiety Disorder (PAD; n = 14); (4) Remittent Anxiety Disorder (RAD; n = 8). DNA methylome was evaluated with Infinium HumanMethylation450 BeadChip. Results: We did not find any association between the genetic polymorphisms and AD. Considering the G x E interaction we suggest that rs2070951 polymorphism of NR3C2 gene moderates the association between physical neglect and serum BDNF levels. When we evaluated the DNA methylome, we observed more homogeneous biological pathways and mostly related with nervous system in individuals from IAD and RAD groups. On the other hand, in the TDC and PAD groups, we found biological pathways with a more heterogeneous pattern. A DNA hypomethylation profile was found predominant in the pathways. In a cross-sectional analysis, we found opposite patterns of DNA methylation, as the developmental period assessed: hypomethylation at the beginning of adolescence and hypermethylation in young adults. Conclusion: This study addressed, in an adolescent sample, genetics (candidate genes linked to HPA axis), environmental (emotional trauma) and epigenetic (DNA methylome) aspects of AD. The findings suggest that although there are no associations between AD and genes involved in HPA axis, there is an interaction between the presence of trauma, genetic polymorphism involved in this axis and biomarkers. The DNA methylome findings also suggest epigenetic influences on the course of TA. Further studies should be designed to corroborate the genetic influences in this disorder.