Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

The purpose of this thesis is to gain understanding of the load on flat target surfaces produced by projectile impact. Models are proposed from which upper and lower bounds can be derived for the transition be-tween interface defeat and normal penetration. It is shown that the dominating contribution to the normal load is generally provided by the hydrodynamic pressure due to the effect of inertia. In addition it is shown that the contributions from yield strength and compressibility are also significant. For a cylindrical tungsten alloy projectile at an impact velocity representative of to-day’s ordnance velocities, the contributions to the load intensity on the axis of symmetry from yield strength and compressibility are shown to be 15% and 3.4%, respectively, of that of inertia. Impact tests have shown that for conical projectiles transition from interface defeat to penetration occurs at a significantly lower impact velocity than for cylindrical projectiles. In order to better understand the influence of projectile shape, a conical projectile in axi-symmetric impact is studied by use of an analytical model for self-similar flow, and the results obtained are compared to results of numerical simula-tions. It is shown how the maximum load intensity, and the position of the maximum, depends on the apex angle. For an apex angle of 90º, the maximum load intensity is found to be almost three times that pro-duced by a cylindrical projectile with the same impact velocity. This maximum occurs well off the axis of symmetry and is 20% larger than the load intensity at this axis. Both the self-similar model and the nu-merical simulations show that the contribution to the load intensity from compressibility is positive below and negative above an apex angle of around 80º. The contribution of yield strength to the load in-tensity at centre of impact depends only weakly on the apex angle and is therefore similar to that of a cylindrical projectile.

No description available.

Made available in DSpace on 2015-08-20T17:10:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-03-17. Added 1 bitstream(s) on 2015-08-20T17:25:57Z : No. of bitstreams: 1 000841155.pdf: 1220968 bytes, checksum: 94a3b7cbcbdfe790ec1a15a6f90c11f5 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Nesta pesquisa abordamos aspectos do feminismo pelo viés da crítica feminista anglo-americana em duas obras ficcionais publicadas no final dos anos sessenta e início da década de setenta: La Femme Rompue (1967), de Simone de Beauvoir (1908-1986), e A Fairly Honourable Defeat (1970), da escritora irlandesa Iris Murdoch (1919-1999). Primeiramente, estabelecemos um diálogo entre o pensamento filosófico de Beauvoir e o de Murdoch. Posteriormente, estabelecemos uma relação entre a crítica literária feminista e o pensamento beauvoiriano e murdochiano no que tange a questão do papel da mulher como leitora e escritora de textos literários. Dessa forma, examinamos o papel do leitor(a) como instância fundamental no processo de desconstrução do caráter discriminatório das ideologias de gênero e demonstramos que, assim como Virginia Woolf, Beauvoir e Murdoch defendem o conceito de androginia na literatura. Finalmente, analisamos os diferentes recursos estéticos que Beauvoir e Murdoch utilizam na caracterização de suas personagens femininas, uma vez que La Femme Rompue apresenta as características de um romance moderno, enquanto A Fairly Honourable Defeat possui traços de um romance realista / The aim of this research is to address some aspects of feminism from a feminist Anglo-American critical stance in two fictional works that have been published in the late sixties and early seventies: La Femme Rompue (1967) by Simone de Beauvoir (1908-1986) and A Fairly Honourable Defeat (1970) by the Irish writer Iris Murdoch (1919-1999). First, we establish a dialogue between the philosophical thought of Beauvoir and Murdoch. Then, we firm a relationship between feminist literary criticism and Beauvoir's and Murdoch's thoughts regarding the issue of women's role as a reader and as a writer of literary texts. Thus, we explore the role of the reader as a key instance in the process of deconstruction of the discriminatory nature of gender ideologies and we demonstrate that, just as Virginia Woolf, Beauvoir and Murdoch defended the concept of androgyny in literature. Finally, we analyze the different aesthetic features that Beauvoir and Murdoch use in the characterization of female characters, since La Femme Rompue presents the characteristics of a modern novel while A Fairly Honourable Defeat has some traces of a realist novel

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-01-10T15:53:45Z No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-01-12T10:50:00Z (GMT) No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) / Made available in DSpace on 2017-01-12T10:50:01Z (GMT). No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) Previous issue date: 2015-12-16 / Os objetivos desta tese foram os de investigar padr?es comportamentais e eletrofisiol?gicos associados ? resili?ncia e suscetibilidade ao estresse social induzido em camundongos. Para isso, utilizamos um protocolo de indu??o de estresse cr?nico cont?nuo a partir de derrotas sociais baseado no paradigma residente-intruso. Os resultados da tese s?o apresentados em dois estudos. No primeiro estudo, camundongos C57BL/6J submetidos a epis?dios repetidos de derrota social apresentaram motiva??o tardia para interagir com um camundongo desconhecido em sess?es prolongadas (10 min) do teste de intera??o social. Utilizando uma abordagem etol?gica associada ? an?lise computacional de v?deos foi poss?vel rastrear precisamente a posi??o dos camundongos durante a realiza??o de comportamentos de investiga??o social. Analisamos ainda a express?o detalhada de comportamentos defensivos, tais como investiga??o em postura estendida e fugas, ambos associados ao comportamento de investiga??o social. A partir dessas an?lises demonstramos que a realiza??o do comportamento de investiga??o social em postura estendida era significativamente maior para o grupo derrotado comparado ao grupo controle. Ainda, um subgrupo de camundongos derrotados apresentou investiga??o social em postura estendida de forma persistente e sem habitua??o. Utilizando uma medida da dist?ncia de investiga??o durante as investiga??es sociais calculamos um ?ndice de aproxima??o (IA) para cada animal e separamos um subgrupo apresentando fen?tipo relacionado ? ansiedade. A incid?ncia de fugas tamb?m foi maior no grupo derrotado em compara??o com os controles. A persist?ncia na ocorr?ncia desse comportamento foi observada em um subgrupo de camundongos submetidos ?s derrotas sociais. Calculamos ent?o um ?ndice de fugas (IF) que se correlacionou inversamente com a prefer?ncia por sacarose, sendo ?til para identificar animais aned?nicos. No segundo estudo, foram combinados an?lise etol?gica e registros eletrofisiol?gicos com tetrodos na ?rea tegmentar ventral de camundongos submetidos ? derrotas sociais. Utilizando crit?rios eletrofisiol?gicos e farmacol?gicos classificamos unidades na ?rea tegmentar ventral como supostos neur?nios dopamin?rgicos e n?o-dopamin?rgicos. Durante o comportamento de investiga??o social foi observado que a modula??o da taxa de disparo dessas subpopula??es neuronais distintas ocorreu de maneira oposta em animais suscet?veis e resilientes ao estresse social. Em suma, propomos que sess?es prolongadas associadas ? an?lise etol?gica detalhada durante os testes de intera??o social podem prover informa??o para classifica??o de camundongos em resilientes e suscept?veis ap?s repetidas derrotas sociais. Ainda, a express?o do fen?tipo suscet?vel parece estar associada ao comprometimento do sistema dopamin?rgico mesol?mbico na atribui??o de valor de incentivo ?s intera??es sociais normalmente associadas ao aumento da atividade neuronal mesol?mbica. / The aims of this thesis were to investigate behavioral and electrophysiological patterns associated to resilience and susceptibility to social stress in mice. For this, we used a chronic social defeat stress protocol based on the resident-intruder paradigm. The results are presented here in two studies. In the first study, C57BL/6J mice submitted to repeated social defeat episodes showed delayed motivation to interact with an unfamiliar conspecific in long duration (10 min) sessions of the social interaction test. By using an ethological approach combined with computational video analysis, it was possible to track precisely the mouse position during social investigation behavior performance. With that approach, it was analyzed the detailed expression of defensive behaviors, such as stretched attended postures and flights, both associated to social investigation behaviors. From these analyzes, it was demonstrated that social investigation behaviors based on stretched attend postures were significantly higher in defeated mice in comparison to controls. Still, a subpopulation of defeated mice showed persistently and non-habituating stretched attend postures during social investigation. By using a measure based on the investigation distance during social investigations, it was possible to compute an approach index (AI) to each animal and separate a subpopulation showing an anxiety-related phenotype. The flight incidence was also increased in defeated group as compared with controls. The persistent occurrence of this behavior was observed in a subpopulation of defeated mice. We calculated a flight index (FI) that inversely correlated with sucrose preference, showing to be useful to identify anhedonic animals. In the second study, we combined ethological approach and electrophysiological recordings in the ventral tegmental area of mice submitted to chronic social defeat stress. By using electrophysiological and pharmacological criteria, single-units recorded from the ventral tegmental area were classified as putative dopaminergic and non-dopaminergic neurons. During the social investigation behavior it was observed that firing rate modulations of distinct neuronal subpopulations occurred in opposite manner in social defeat susceptible and resilient mice. In summary, this work proposes that longer sessions of the social interaction test associated to ethological approach can provide information for the behavioral classifications of resilient and susceptible mice after social defeat stress. Furthermore, the expression of susceptible phenotype could be related to the midbrain dopaminergic system impairment in the incentive value assignment to social interactions normally associated with increased mesolimbic neuronal activity.

Transtornos depressivos afetam de 1-6% dos adolescentes a cada ano ao redor do mundo. Esse aparecimento precoce anuncia uma doença mais grave e persistente na vida adulta, sendo considerada a terceira principal causa de suicídio na faixa etária entre 14-29 anos. Os exatos mecanismos moleculares envolvidos na fisiopatologia da depressão ainda não são compreendidos, e muitos estudos destacam o processo de apoptose como um possível mecanismo de contribuição para a depressão relacionada ao estresse crônico. Desta forma, o objetivo deste trabalho foi avaliar os efeitos da submissão social em camundongos machos adolescentes, sobre comportamentos emocionais e sobre a localização celular hipocampal do fator de transcrição Max. Metodologia: Camundongos machos adolescentes, C57BL/6, foram submetidos durante 21 dias consecutivos a um modelo de submissão social e ambos os grupos, experimental (n=16) e controle (n=16) foram analisados nos aspectos comportamental, expressão gênica e localização da proteína Max. Resultados: Dados retidos devido à solicitação (publicação de dados, patentes ou diretos autorais). / Depressive disorders affect 1-6% of adolescents each year around the world. This early appearance heralds a more serious and persistent disease in adulthood, being considered the third leading cause of suicide in people aged between 14-29 years. The precise molecular mechanisms involved in the pathophysiology of depression are not yet understood, and many studies highlight the process of apoptosis as a possible mechanism contributing to depression related to chronic stress. Thus, the objective of this study was to evaluate the effects of social defeat in male adolescent mice on emotional behavior and on hippocampal cellular setting of the Max transcription factor. Methodology: C57BL/6 male mice were submitted to 21 consecutive days of a model for social defeat and, both the experimental (n=16) and control groups (n=16) were investigated for behavioral analysis and also for the Max protein expression and settings. Results: Request to retain data (publication, patent or copyright directs).

No description available.

The present study covers the causes of victory and defeat in the light of chapter eight of the Holy Qur'an. It has been prompted by the current situation facing Muslims in many parts of the world, which is characterized by despair, reversals and loss, This study is thus reflexive in nature. In order to obtain a satisfactory response to this predicament, the relevant text in addition to several of its commentaries were scrutinized. The latter search remained unsatisfactory since their focus of inquiry was merely exegetical and failed to reveal any didactic element, which is crucial for obtaining guidance. This work has successfully managed to deduce this aspect from the text which amplifies the importance of extensive sacrifice for gaining glory. / Religious Studies and Arabic / M.A. (Islamic studies)

Les antidépresseurs ISRS (inhibiteurs sélectifs de la recapture de sérotonine) sont parmi les plus prescrits pour traiter les épisodes dépressifs majeurs. Cependant, leur efficacité n’est pas optimale. En effet, ils montrent un long délai d’action, de nombreux effets indésirables et sont inefficaces pour une proportion non négligeable de patients. La dépression étant actuellement un enjeu de santé publique majeur, il est donc nécessaire de développer de nouvelles molécules possédant un meilleur profil thérapeutique. Récemment, un intérêt croissant a été porté sur le récepteur 5-HT3, notamment depuis le développement de la vortioxétine, ISRS de nouvelle génération ayant des propriétés antagonistes pour ce récepteur localisé dans les zones cérébrales contrôlant l’humeur. Le but de ce travail de thèse a été d’étudier le rôle du récepteur 5-HT3 dans la réponse aux antidépresseurs, ainsi que dans la physiopathologie de la dépression. Dans ce cadre, nous avons utilisé une approche génétique, en caractérisant un modèle de souris knockout (KO) dont le gène de la sous-unité 3A du récepteur 5-HT3 a été invalidé. Le phénotype de ces animaux et leurs contrôles de type sauvage (Wild-Type, WT) a tout d’abord été évalué dans des tests comportementaux de screening de molécules anxiolytiques et antidépressives, puis leur réponse à des traitements aigus d’ISRS a été mesurée par ces mêmes approches. L’effet de traitements antidépresseurs chroniques a quant à lui été évalué par une technique d’électrophysiologie in vitro. Enfin, les souris ont été soumises au modèle du stress de défaite sociale chronique (CSDS), afin de déterminer le rôle du récepteur 5-HT3 dans la réponse au stress. En conditions basales, le turn-over de la sérotonine est diminué chez les souris 5-HT3 KO par rapport aux souris WT. Cet effet est accompagné par une augmentation de l’expression génique des récepteurs 5-HT1A et de leur couplage aux protéines G au niveau du noyau raphé dorsal (NRD) des souris KO par rapport aux WT. Au niveau comportemental, les souris KO 5-HT3 montrent un phénotype apparenté à celui induit par un anxiolytique et par un antidépresseur. Lorsqu’elles reçoivent une injection de citalopram, un ISRS sélectif, les souris 5-HT3 KO ne se comportent pas différemment de leurs contrôles WT dans les tests de screening des antidépresseurs. Cependant, dans ces mêmes tests, l’effet de la fluoxétine, ISRS possédant des propriétés antagonistes pour le récepteur 5-HT3, est perdu chez les souris 5-HT3 KO. Le traitement chronique par le citalopram (20 mg/kg/j) induit une désensibilisation similaire des autorécepteurs 5-HT1A localisés sur les neurones sérotoninergiques du NRD chez les animaux WT et KO. Dans les mêmes conditions, mais en utilisant une dose de citalopram plus faible (5 mg/kg/j), la désensibilisation des autorécepteurs 5-HT1A est plus forte chez les animaux KO que chez les WT, confortant ainsi l’effet potentialisateur de l’invalidation des récepteurs 5-HT3 dans l’efficacité thérapeutique des ISRS. Afin de disséquer le rôle des récepteurs 5-HT3 dans la réponse au stress chronique, le CSDS a fait l’objet d’une validation avec l’agomélatine, antidépresseur de nouvelle génération. Ce stress a engendré des altérations de la mémoire à long terme, en lien avec des modifications de l’expression génique de l’exon IV du BDNF et d’enzymes de régulation épigénétique. Ces effets délétères du stress ont été traités efficacement par l’agomélatine (50 mg/kg/j) en injection chronique, mais cette molécule n’a cependant pas modifié les effets du CSDS sur les phénotypes de type anxieux et dépressifs observés après le stress. Nous avons montré que le CSDS augmentait l’expression génique de la sous-unité 3A du récepteur 5-HT3 dans différentes structures cérébrales des souris WT. De plus, les altérations de l’expression génique de CamkIIa et SOD1 induites par le stress dans le cortex préfrontal des souris WT n’ont pas été retrouvées chez les souris 5-HT3 KO (...) / SSRI (selective serotonin reuptake inhibitor) antidepressants are among the most prescribed drugs to treat major depression. However, their efficacy is not optimal yet. Indeed, they possess a long delay of action, various side effects and show not efficacy in some patients. As depression is currently a global burden, there is a great need for new molecules with a better therapeutic efficacy. Recently, an increased attention has been taking to 5-HT3 receptors, notably since the development of vortioxetine, a new generation SSRI that antagonizes this receptor. The aim of the study was to assess the role of 5-HT3 receptor in the antidepressant response and the physiopathology of depression. In this context, we used a genetic approach, by characterizing a knockout (KO) mice model lacking the 3A subunit of the 5-HT3 receptor. Their phenotype and the one of wild-type (WT) control mice was first evaluated in behavioral tests widely used for antidepressant and anxiolytic drugs screening, then following acute SSRI treatments. Effect of chronic SSRI administration was assessed by in vitro electrophysiology. Finally, mice were submitted to the chronic social defeat stress (CSDS) model, to determine the role of 5-HT3 receptor in stress response. In basal conditions, 5-HT turnover was decreased in 5-HT3 KO mice compared with WT mice. This effect was accompanied by an increase in the 5-HT1A receptor gene expression and their coupling to G proteins at the dorsal raphe nucleus (DRN) level. 5-HT3 KO mice displayed anxiolytic-like and antidepressive-like phenotype. When injected with citalopram, a very selective SSRI, 5-HT3 KO mice behaved similarly as WT mice in antidepressant screening tests. However, in the same tests, the effect of fluoxetine, a SSRI that possesses 5-HT3 receptor antagonist properties, was blunted in 5-HT3 KO mice. Chronic treatment with citalopram (20 mg/kg/d) induced in WT and KO mice a similar desensitization of 5-HT1A autoreceptors located on DRN 5-HT neurons. In the same conditions, but using a lower citalopram dose (5 mg/kg/d), 5-HT1A autoreceptor desensitization was higher in 5-HT3 KO mice than in WT mice, thus reinforcing the potentiating effect of the 5-HT3 receptor in the SSRI efficacy. In order to assess the role of 5-HT3 receptor in chronic stress response, CSDS paradigm was validated using agomelatine, a new generation antidepressant drug. This stress model provoked long term memory alterations, linked with modifications in hippocampal mRNA levels of BDNF exon IV and epigenetic modifying enzymes. These deleterious stress effects were prevented by chronic agomelatine treatment (50 mg/kg/d), but this molecule did not modify the stress-induced anxious- and depressive-like phenotypes. We showed that subunit 3A gene expression was increased in various WT mice brain structures subjected to CSDS. Moreover, stress-induced modifications of CamkIIa and SOD1 gene expression in the prefrontal cortex of WT mice were not present in KO mice. Genetic invalidation of 5-HT3 receptor blocked the effects of social stress in some behavioral tests (splash test, saccharine preference test) and on body weight gain. Taken altogether, these data show that 5-HT3 receptor plays an important role in anxiety- and depression-related behaviors. Moreover, invalidation of this receptor increased the effect of a low dose chronic SSRI treatment, and blunted the effect of a SSRI targeting 5-HT3 receptor. These results highlight the interest of this receptor in the development of innovating therapies to treat anxio-depressive disorders. Finally, the reduced sensitivity of 5-HT3 KO mice to chronic stress suggests an involvement of this receptor in stress-related behaviors and depression physiopathology.