Un faible apport alimentaire en acides gras polyinsaturés (AGPI) de la série n-3 a été associé à la prévalence des troubles de l'humeur chez l’Homme. Chez les rongeurs, les approches nutritionnelles visant à modéliser une alimentation pauvre en AGPI n-3 ont largement été développées au siècle dernier. En effet, un régime alimentaire carencé en AGPI n-3 sur une ou plusieurs générations induit chez le rongeur des altérations des comportements émotionnels tels que des comportements de type dépressif ou anxieux. Nous avons montré au laboratoire Nutrineuro que des souris nourries avec un régime déficient en AGPI n-3 présentent des niveaux d’AGPI n-3, en particulier l'acide docosahexaénoïque (DHA, un AGPI n-3) plus faible dans le cortex préfrontal (PFC) et dans le noyau accumbens (NAc) par rapport aux souris contrôle. De plus, nous avons pu mettre en évidence qu’une alimentation déficiente en AGPI n-3 est capable de moduler la plasticité synaptique dépendante du système endocannabinoïde (eCB). De fait, la réduction de DHA dans le CPF et le NAc est accompagnée d'une altération de la dépression à long terme (LTD-eCB) et des voies de signalisation dépendantes du système eCB au niveau du CPF (Lafourcade et al., 2011 ; Larrieu et al, 2012). Nos données indiquent que ces altérations sont dues à un découplage entre le récepteur cannabinoïde 1 (CB1R) et la protéine Gi/o. De plus, les souris déficientes en AGPI n-3 présentent des déficits comportementaux dans plusieurs tests évaluant les comportements émotionnels. Afin de mieux comprendre les mécanismes qui sous-tendent la diminution du DHA dans le CPF et les altérations des comportements émotionnels, nous avons étudié la morphologie neuronale dans le CPF et l’axe hypothalamo-hypophysaire (HPA) chez les souris déficientes en AGPI n-3. Nous avons montré que le régime alimentaire déficient en AGPI n-3 induit une atrophie de l’arborisation dendritique dans les neurones pyramidaux du CPF. L'atrophie dendritique est semblable à celle mesurée chez les souris soumises au régime équilibré en AGPI n-3 et soumises à un stress chronique de défaite sociale (CSDS). Aucun effet additionnel du CSDS sur la morphologie neuronale et le comportement émotionnel n’a été observé chez les souris déficientes en AGPI n-3. Nous avons ensuite étudié le rôle de l’axe HPA dans le développement des altérations comportementales et neurobiologiques chez les souris déficientes en AGPI n-3. Ces souris présentent une diminution de l'expression des récepteurs des glucocorticoïdes (GR) dans le CPF associée à une augmentation des taux circulants de corticostérone. Dans leur ensemble, nos résultats montrent qu’un faible apport alimentaire en AGPI n-3 peut modifier la plasticité synaptique dépendante du système eCB ainsi que l’arborisation dendritique des neurones du CPF. Nous avons également pu montrer que l’élévation des niveaux de corticostérone était impliquée dans l’altération des comportements émotionnels observée chez des souris nourries avec un régime déficient en AGPI n-3. / Low dietary intake of n-3 polyunsaturated fatty acids (PUFAs) has been associated with the prevalence of mood disorders in humans. In rodents, nutritional approaches aiming at modeling poor dietary n-3 PUFAs intake have been extensively developed in the last century. As a result, one- or multi-generation dietary n-3 deficiency induces depressive and anxiety-like behaviors. We have shown in the Nutrineuro lab that mice fed with a diet deficient in n-3 PUFAs exhibit decreased n-3 PUFAs levels, especially docosahexaenoic acid (DHA, a n-3 PUFA) levels in the prefrontal cortex (PFC) and in the nucleus accumbens (NAc). We showed that dietary n-3 PUFA is able to modulate endocannabinoid (eCB) dependent plasticity since DHA reduction in PFC and NAc is accompanied with eCB dependent long term depression (eCB-LTD) and eCB signaling impairment in the PFC (Lafourcade et al., 2011; Larrieu et al., 2012). Our data indicate that LTD alteration results from region-specific uncoupling of CB1 receptor from its effector Gi/o protein. In addition, n-3 deficient mice display behavioral deficits in several tests measuring emotional behavior. To further understand the mechanisms underlying DHA decrease in the PFC and emotional behavior alteration, we thoroughly investigated neuronal morphology and hypothalamic-pituitary-adrenal (HPA) axis in n-3 deficient mice. We showed that n-3 deficient diet induced dendritic atrophy in pyramidal neurons within the PFC. The dendritic atrophy was comparable to the one measured in control diet mice submitted to chronic social defeat stress (CSDS). No additional effect of CSDS on both neuronal morphology and emotional behavior was measured in n-3 deficient mice. We therefore investigated the role of the HPA axis deregulation in the development of behavioral and neurobiological alterations of n-3 deficient mice. We found a decreased expression of glucocorticoid receptor (GR) in the PFC of n-3 deficient mice together with increased circulating levels of corticosterone. Collectively, we unraveled one crucial mechanism underlying n-3 deficiency-induced alterations. Our results show that low dietary n-3 PUFAs can alter eCB-dependent plasticity and neuronal dendritic atrophy within the PFC leading to emotional behavior impairment. Importantly, we further demonstrated that corticosterone elevation in n-3 deficient mice was involved in the n-3 deficiency-induced emotional behavior and dendritic arborization alterations.

O Teste da Simulação de Falar em Público (SFP) é um teste sensível a drogas que interferem com a neurotransmissão mediada por serotonina (5-HT), e algumas evidências sugerem que ele possa recrutar os mesmos sistemas neuronais envolvidos na fisiopatogenia do Transtorno do Pânico (TP). Diferentes fármacos que, direta ou indiretamente, modulam receptores serotoninérgicos, já foram testados em voluntários saudáveis submetidos ao SFP, mas nenhum estudo, até o momento, utilizou drogas que permitissem avaliar o papel de receptores do tipo 5-HT1D na ansiedade. O sumatriptano, um agonista específico de receptores 5-HT1D, parece ser um bom candidato como sonda farmacológica, tendo em vista sua ampla utilização na prática clínica para o tratamento de enxaqueca, com segurança e boa tolerabilidade. A hipótese testada neste estudo foi a de que, devido à ativação de receptores pré-sinápticos 5-HT1D e conseqüente redução na liberação de 5-HT, o sumatriptano aumentaria o medo provocado pelo SFP. Para tanto, foi conduzido um estudo duplo cego, randomizado, utilizando 36 voluntários saudáveis do sexo masculino, distribuídos em três grupos de tratamento: placebo (n = 12), 50mg (n = 12) ou 100mg (n = 12) de sumatriptano, administrado duas horas antes do SFP. Antes, durante, e após o SFP, medidas subjetivas de ansiedade foram registradas através da Escala Analógica Visual do Humor (VAMS) e da Escala dos Sintomas Somáticos (ESS). Também foram tomadas medidas fisiológicas de ansiedade (pressão arterial, freqüência cardíaca, dosagem hormonal e eletrocondutância da pele). Os resultados foram submetidos à análise multivariada de variância, sendo a medida basal utilizada como covariada (MANCOVA). O grupo tratado com 100mg de sumatriptano apresentou aumento mais pronunciado da ansiedade subjetiva do que os grupos tratados com 50mg de sumatriptano e com placebo durante as fases de preparação e de desempenho. O grupo tratado com 100 mg de sumatriptano também mostrou-se mais alerta na fase de preparação e desempenho do que o grupo placebo. Não foram observados efeitos significativos do tratamento sobre as medidas de pressão arterial, freqüência cardíaca e eletrocondutância da pele. O sumatriptano provocou redução dos níveis de prolactina, independentemente da fase da sessão experimental, mas não interferiu nos níveis de cortisol plasmático. Por outro lado, observou-se um amento dos níveis de cortisol plasmático imediatamente após o SPF, em comparação com os níveis pré-teste, independente do grupo de tratamento. A redução da disponibilidade de 5-HT levou a um aumento do medo provocado pelo SFP, o que está de acordo com a proposição de que a diminuição de 5-HT na matéria cinzenta periaquedutal dorsal (MCPD) aumenta o medo incondicionado. Devido a esse efeito ansiogênico do uso agudo do sumatriptano também poder ocorrer na prática clínica, em pacientes com migrânea, deve-se atentar para a possibilidade da manifestação de sintomas semelhantes aos de ataque de pânico em pacientes ansiosos. A diminuição da função 5-HT também provocou redução dos níveis plasmáticos de prolactina, provavelmente pela facilitação da transmissão dopaminérgica. Por sua vez, embora discreto, o aumento dos níveis plasmáticos do cortisol sugerem uma atuação do eixo hipotálamo-hipófise-adrenal (HHA) pelo SFP. A interpretação da resposta do cortisol ao estresse psicológico é complexa e depende de vários fatores, como tema do discurso, tipo de avaliação social, falta de controle da situação, tamanho amostral e estratégias de regulação emocional do voluntário. Mais estudos são necessários para elucidar o papel dos receptores 5-HT1D na ansiedade e para compreender a resposta do cortisol ao estresse psicológico. / The Simulated Public Speaking Test (SPS) is an experimental model sensitive to drugs that interfere with the neurotransmission mediated by serotonin (5-HT). It has been proposed that the SPS recruits the same neural systems involved in the pathophysiology of panic disorder (PD). Different drugs that directly or indirectly modulate serotonin receptors, have been tested in healthy volunteers submitted to the SFP, but no study have been carried out so far for assessing the role of 5-HT1D receptors in anxiety. Sumatriptan, a specific agonist of 5-HT1D receptors, seems to be a good candidate as a probe drug, given its wide use in clinical practice for the treatment of migraine, with good safety and tolerability. The hypothesis tested in this study was that, due to the activation of presynaptic 5-HT1D receptors and consequent reduction in the release of 5-HT, sumatriptan would increase the fear caused by the SPS. To that end, we conducted a double-blind, randomized study using 36 healthy male volunteers who were divided into three treatment groups: placebo (n = 12), 50mg (n = 12) or 100mg (n = 12) of sumatriptan, administered two hours before the SFP. Before, during, and after the SPS, subjective measures of anxiety were recorded by Visual Analogue Mood Scale (VAMS) and the Bodily Symptom Scale (BSS). Physiological measures were also taken for anxiety (blood pressure, heart rate, hormone dosage and skin conductance). The results were submitted to multivariate analysis of variance (MANCOVA) with the baseline measures as covariate. The group treated with 100 mg of sumatriptan was more anxious than, respectively, 50mg and placebo groups during the test, and also proved to be more alert in preparation and performance than the placebo group. There were no significant effects of treatment on measures of blood pressure, heart rate and skin eletrocondutance. Sumatriptan caused a reduction of prolactin levels, independently of the experimental phase of the session, but did not interfere with plasma cortisol levels. On the other hand, there was an increased of plasma cortisol levels immediately after the SPF, compared with the pre-test, independently of treatment group. The reduced availability of 5-HT led to an increase of fear caused by the SFP, which is consistent with the proposition that a reduction of 5-HT in the dorsal periaqueductal gray (MCPD) increases unconditioned fear. Because of this anxiogenic effect of acute use of sumatriptan also can occur in clinical practice in patients with migraine should be alert to the possibility of manifestation of symptoms similar to panic attacks in patients anxious. The decreased function of 5-HT also caused a reduction in plasma levels of prolactin, probably by facilitating dopamine transmission. In turn, although slight, the increase in plasma cortisol levels suggest a role of the hypothalamic-pituitary-adrenal (HPA) for the SFP.The interpretation of the cortisol response to psychological stress is complex and depends on several factors, such as theme of the discourse, type of social assessment, lack of control of the situation, sample size, emotional regulation strategies of the volunteer. Further studies are needed to elucidate the role of 5-HT1D receptors in anxiety and to understand the cortisol response to psychological stress.

O Teste da Simulação de Falar em Público (SFP) é um teste sensível a drogas que interferem com a neurotransmissão mediada por serotonina (5-HT), e algumas evidências sugerem que ele possa recrutar os mesmos sistemas neuronais envolvidos na fisiopatogenia do Transtorno do Pânico (TP). Diferentes fármacos que, direta ou indiretamente, modulam receptores serotoninérgicos, já foram testados em voluntários saudáveis submetidos ao SFP, mas nenhum estudo, até o momento, utilizou drogas que permitissem avaliar o papel de receptores do tipo 5-HT1D na ansiedade. O sumatriptano, um agonista específico de receptores 5-HT1D, parece ser um bom candidato como sonda farmacológica, tendo em vista sua ampla utilização na prática clínica para o tratamento de enxaqueca, com segurança e boa tolerabilidade. A hipótese testada neste estudo foi a de que, devido à ativação de receptores pré-sinápticos 5-HT1D e conseqüente redução na liberação de 5-HT, o sumatriptano aumentaria o medo provocado pelo SFP. Para tanto, foi conduzido um estudo duplo cego, randomizado, utilizando 36 voluntários saudáveis do sexo masculino, distribuídos em três grupos de tratamento: placebo (n = 12), 50mg (n = 12) ou 100mg (n = 12) de sumatriptano, administrado duas horas antes do SFP. Antes, durante, e após o SFP, medidas subjetivas de ansiedade foram registradas através da Escala Analógica Visual do Humor (VAMS) e da Escala dos Sintomas Somáticos (ESS). Também foram tomadas medidas fisiológicas de ansiedade (pressão arterial, freqüência cardíaca, dosagem hormonal e eletrocondutância da pele). Os resultados foram submetidos à análise multivariada de variância, sendo a medida basal utilizada como covariada (MANCOVA). O grupo tratado com 100mg de sumatriptano apresentou aumento mais pronunciado da ansiedade subjetiva do que os grupos tratados com 50mg de sumatriptano e com placebo durante as fases de preparação e de desempenho. O grupo tratado com 100 mg de sumatriptano também mostrou-se mais alerta na fase de preparação e desempenho do que o grupo placebo. Não foram observados efeitos significativos do tratamento sobre as medidas de pressão arterial, freqüência cardíaca e eletrocondutância da pele. O sumatriptano provocou redução dos níveis de prolactina, independentemente da fase da sessão experimental, mas não interferiu nos níveis de cortisol plasmático. Por outro lado, observou-se um amento dos níveis de cortisol plasmático imediatamente após o SPF, em comparação com os níveis pré-teste, independente do grupo de tratamento. A redução da disponibilidade de 5-HT levou a um aumento do medo provocado pelo SFP, o que está de acordo com a proposição de que a diminuição de 5-HT na matéria cinzenta periaquedutal dorsal (MCPD) aumenta o medo incondicionado. Devido a esse efeito ansiogênico do uso agudo do sumatriptano também poder ocorrer na prática clínica, em pacientes com migrânea, deve-se atentar para a possibilidade da manifestação de sintomas semelhantes aos de ataque de pânico em pacientes ansiosos. A diminuição da função 5-HT também provocou redução dos níveis plasmáticos de prolactina, provavelmente pela facilitação da transmissão dopaminérgica. Por sua vez, embora discreto, o aumento dos níveis plasmáticos do cortisol sugerem uma atuação do eixo hipotálamo-hipófise-adrenal (HHA) pelo SFP. A interpretação da resposta do cortisol ao estresse psicológico é complexa e depende de vários fatores, como tema do discurso, tipo de avaliação social, falta de controle da situação, tamanho amostral e estratégias de regulação emocional do voluntário. Mais estudos são necessários para elucidar o papel dos receptores 5-HT1D na ansiedade e para compreender a resposta do cortisol ao estresse psicológico. / The Simulated Public Speaking Test (SPS) is an experimental model sensitive to drugs that interfere with the neurotransmission mediated by serotonin (5-HT). It has been proposed that the SPS recruits the same neural systems involved in the pathophysiology of panic disorder (PD). Different drugs that directly or indirectly modulate serotonin receptors, have been tested in healthy volunteers submitted to the SFP, but no study have been carried out so far for assessing the role of 5-HT1D receptors in anxiety. Sumatriptan, a specific agonist of 5-HT1D receptors, seems to be a good candidate as a probe drug, given its wide use in clinical practice for the treatment of migraine, with good safety and tolerability. The hypothesis tested in this study was that, due to the activation of presynaptic 5-HT1D receptors and consequent reduction in the release of 5-HT, sumatriptan would increase the fear caused by the SPS. To that end, we conducted a double-blind, randomized study using 36 healthy male volunteers who were divided into three treatment groups: placebo (n = 12), 50mg (n = 12) or 100mg (n = 12) of sumatriptan, administered two hours before the SFP. Before, during, and after the SPS, subjective measures of anxiety were recorded by Visual Analogue Mood Scale (VAMS) and the Bodily Symptom Scale (BSS). Physiological measures were also taken for anxiety (blood pressure, heart rate, hormone dosage and skin conductance). The results were submitted to multivariate analysis of variance (MANCOVA) with the baseline measures as covariate. The group treated with 100 mg of sumatriptan was more anxious than, respectively, 50mg and placebo groups during the test, and also proved to be more alert in preparation and performance than the placebo group. There were no significant effects of treatment on measures of blood pressure, heart rate and skin eletrocondutance. Sumatriptan caused a reduction of prolactin levels, independently of the experimental phase of the session, but did not interfere with plasma cortisol levels. On the other hand, there was an increased of plasma cortisol levels immediately after the SPF, compared with the pre-test, independently of treatment group. The reduced availability of 5-HT led to an increase of fear caused by the SFP, which is consistent with the proposition that a reduction of 5-HT in the dorsal periaqueductal gray (MCPD) increases unconditioned fear. Because of this anxiogenic effect of acute use of sumatriptan also can occur in clinical practice in patients with migraine should be alert to the possibility of manifestation of symptoms similar to panic attacks in patients anxious. The decreased function of 5-HT also caused a reduction in plasma levels of prolactin, probably by facilitating dopamine transmission. In turn, although slight, the increase in plasma cortisol levels suggest a role of the hypothalamic-pituitary-adrenal (HPA) for the SFP.The interpretation of the cortisol response to psychological stress is complex and depends on several factors, such as theme of the discourse, type of social assessment, lack of control of the situation, sample size, emotional regulation strategies of the volunteer. Further studies are needed to elucidate the role of 5-HT1D receptors in anxiety and to understand the cortisol response to psychological stress.

A eficiência alimentar (EA) é um fenótipo complexo, controlado por diversos processos biológicos. Determinar e entender esses processos é fundamental para selecionar animais superiores ou mesmo orientar decisões de manejo com o objetivo de aumentar a produtividade e diminuir o impacto ambiental da pecuária. Neste trabalho, propusemos analisar a EA através de uma abordagem de biologia de sistemas, baseada em transcriptômica multitecidual, a fim de gerar um entendimento sistêmico dessa característica. Para isso, 18 animais extremos para consumo alimentar residual foram selecionados a partir de um grupo de 98 bovinos Nelore machos inteiros e tiveram seu transcriptoma de hipotálamo, pituitária, adrenal, músculo e fígado sequenciado (RNAseq). Os reads gerados foram alinhados com o genoma de referência bovino (UMD3.1), filtrados e a expressão de cada gene foi estimada. A partir desses dados três abordagens de análises de dados foram desenvolvidas. Na primeira, cinco critérios de inclusão foram definidos para selecionar genes e construir uma rede de co-expressão para os cinco tecidos, de forma que além de indicarmos diversos genes e processos associados à EA, também fomos capazes de determinar dois genes reguladores, o NR2F6 e o TGFB1. Na segunda abordagem focamos no eixo hipotálamo-pituitária-adrenal, também utilizando análises de co-expressão, mas dessa vez sem partir de prévia seleção de genes e concluímos que o sistema de recompensa do cérebro pode estar envolvido no estímulo para maior consumo de alimentos observado no grupo de baixa EA. Finalmente, com a terceira abordagem, identificamos RNAs longos não codificadores (lncRNAs) expressos nos cinco tecidos e encontramos 30 transcritos expressos diferencialmente entre a alta e baixa EA na pituitária, músculo e adrenal, sendo que alguns deles se mostraram relacionados a processos já previamente demostrados como sendo associados a essa característica. Concluímos que, apesar de não conseguirmos determinar nesse momento o papel da maior susceptibilidade ao estresse, reportado na literatura para animais de baixa EA, no estímulo para maior ingestão de alimentos desse grupo, o sistema de recompensa hipotalâmico parece estar envolvido nesse processo. A maior ingestão pode ser a causa da resposta inflamatória observada no fígado, sendo ela de origem bacteriana, indicada pela maior concentração de endotoxina sérica nos animais menos eficientes. O maior turnover de proteínas no músculo de animais de baixa EA já havia sido indicado como um dos fatores que levam ao maior gasto energético nesses indivíduos e foi confirmado nesse trabalho. Além de alguns fatores de transcrição serem indicados como reguladores centrais desse fenótipo, lncRNAs também parecem ter função regulatória importante na EA. / Feed efficiency (FE) is a complex phenotype, controlled by several biological processes. Determining and understanding these processes is fundamental to select superior animals or even guide management decisions, aiming to increase productivity and reduce the environmental impact of livestock. In this work, we propose to analyze FE through a systems biology approach, based on multi-tissue transcriptomics, in order to generate a systemic understanding of this trait. For this purpose, 18 extreme animals for residual feed intake were selected from a group of 98 male Nellore cattle and had their hypothalamus, pituitary, adrenal gland, muscle and liver transcriptome sequenced (RNAseq). Reads generated were aligned with the bovine reference genome (UMD3.1), filtered and the expression of each gene was estimated. From these data three experiments were developed. In the first one, five inclusion criteria were defined to select genes and to construct a network of coexpression for the five tissues, so that besides indicating several genes and processes associated with EA, we were also able to determine two regulatory genes, NR2F6 and TGFB1. In the second experiment, we focused on the hypothalamic-pituitary-adrenal axis, also using co-expression analysis, but this time without starting from previous selected genes. We conclude that the reward system of the brain might be involved in the stimulus for higher feed intake observed in the low EA group. Finally, in the third experiment, we identified long noncoding RNAs (lncRNAs) expressed in the five tissues and found 30 transcripts differentially expressed between the high and low FE in the pituitary, muscle and adrenal, and some of them were related to previously demonstrated processes associated to this trait. We conclude that although we cannot determine at this time the role of higher susceptibility to stress, reported in the literature for animals of low FE, in the stimulus for higher feed intake of this group, the hypothalamic reward system seems to be involved in this process. The higher ingestion might be the cause of the inflammatory response observed in the liver of, being of bacterial origin, indicated by the higher concentration of serum endotoxin in less efficient animals. The higher turnover of proteins in the muscle of low FE animals had already been indicated as one of the factors that lead to higher energy expenditure in these individuals and it was confirmed in this study. In addition to some transcription factors being indicated as central regulators of this phenotype, lncRNAs also appear to play an important regulatory role in FE.

During pregnancy, the basal activity is increased in both of our major stress response systems: the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. At the same time, the reactivity towards stressors is reduced. These alterations sustain maternal and fetal homeostasis, and are involved in the regulation of gestational length. Although the feto-placental hormone synthesis produces the main endocrinological changes, also the central nervous system undergoes adaptation. Together, these profound adjustments have been suggested to make women’s mental health more vulnerable during pregnancy and postpartum period. The aim of this thesis was to examine factors connected to physiological stress responses during the late pregnancy in relation to pain, labour onset, emotional reactivity, and mental health. The first study examined the pain and sympathetic response during cold stress, in relation to time to delivery. Women with fewer days to spontaneous delivery had lower sympathetic reactivity, while no pain measure was associated with time to delivery. In the second study, acoustic startle response modulation was employed to study emotional reactivity during late gestation, and at four to six weeks postpartum. The startle response was measured by eye-blink electromyography, while the participants watched pleasant and unpleasant pictures, and positive and negative anticipation stimuli. A significant reduction in startle modulation by anticipation was found during the postpartum assessment. However, no startle modulation by pleasant, or unpleasant, pictures was detected at either time-point. The serum level of allopregnanolone, a neurosteroid implied in pregnancy-induced hyporeactivity, was analysed in relation to self-reported symptoms of anxiety and depression. Although the participants reported low levels of depression, the women with the highest depression scores had significantly lower levels of serum allopregnanolone. There was no correlation between allopregnanolone and anxiety scores. In the fourth study, the cortisol awakening response was compared between women with depression during pregnancy, women with depression prior to pregnancy, and women who had never suffered from depression. No group differences in cortisol awakening response during late pregnancy were found. The results are in line with the previously described pregnancy-induced hyporesponsiveness, and add to the knowledge on maternal stress hyporeactivity, gestational length, and maternal mental health.

L’axe hypothalamo-hypophyso-surrénalien joue un rôle essentiel dans l’adaptation et la réponse au stress. Toutefois, l’hyperactivation de cet axe ou des niveaux chroniquement élevés de glucocorticoïdes (GC) entraînent des conséquences pathologiques. Le système dopaminergique mésocortical, qui se projette dans le cortex préfrontal médian (CPFm), joue un rôle adaptatif en protégeant contre le stress. Jusqu’à présent, les interactions fonctionnelles entre les GC (ex : corticostérone) et le système dopaminergique mésocortical ne sont pas élucidées. Dans ce mémoire, nous avons évalué les effets des GC sur les fonctions dopaminergiques préfrontales en élevant chroniquement, à l’aide de minipompes osmotiques, les niveaux de corticostérone aux concentrations physiologiques maximales (1 mg/kg/h pendant 7 jours). Ce traitement n’a pas modifié significativement, chez les rats stressés ou non, les niveaux post mortem de dopamine et de son métabolite dans le tissu du CPFm. Toutefois, l’évaluation par voltamétrie in vivo des changements de dopamine extracellulaire dans le CPFmv a permis d’observer que la corticostérone augmente significativement la libération de dopamine en réponse à l’exposition à l’odeur de renard et au pincement de la queue. Nos études nous permettent de conclure que la corticostérone potentialise la fonction dopaminergique mésocorticale qui, à son tour, facilite la régulation négative en période de stress. / The hypothalamic-pituitary-adrenal axis plays an essential role in responding and adapting to stress, however overactivation of this axis or chronically high levels of glucocorticoids lead to pathological outcomes. The mesocortical dopamine (DA) system, terminating in the medial prefrontal cortex (mPFC), plays an adaptive role in protecting against stress, yet the functional interactions between glucocorticoids (eg. corticosterone) and the mesocortical DA system are not clear. In the present studies, we investigated the effects of glucocorticoids on prefrontal DA function using osmotic minipumps to chronically elevate corticosterone levels in the high physiological range (1 mg/kg/hr for 7 days). Chronic corticosterone treatment did not significantly affect post mortem levels of DA and its metabolites in PFC tissue in either unstressed or stressed rats. However, using in vivo voltammetry to monitor changes in extracellular DA release in PFC, corticosterone significantly increased DA release in response to both types of stress examined, exposure to predator odor and tail pinch stress. We conclude that corticosterone indeed potentiates mesocortical DA function, which in turn facilitates negative feedback regulation in times of stress.

Chez la souris, la puberté de la femelle est accélérée par des phéromones urinaires émises par le mâle (effet Vandenbergh). Les mécanismes neuroendocriniens sous-Jacents et les conséquences comportementales restent peu connus. Par une approche multidisciplinaire alliant immunohistochimie, chromatographie gazeuse couplée à la spectrométrie de masse et chirurgie expérimentale, mon travail de thèse montre que les neurones synthétisant la kisspeptine, un neuropeptide hypothalamique jouant un rôle essentiel dans le contrôle de la puberté, sont régulés positivement par les phéromones accélératrices de la puberté. Les neurones à kisspeptine reçoivent le signal phéromonal via le système olfactif accessoire et le transmettent aux neurones à GnRH. De plus, des analyses comportementales montrent qu’outre leur effet physiologique connu, les phéromones accélératrices de la puberté modifient à long terme le comportement sexuel de la souris femelle. En effet, la préférence de la femelle pour l’odeur du mâle s’exprime plus tôt à l’âge adulte après l’exposition péripubère aux phéromones émises par la souris mâle. / In the mouse, female puberty onset is accelerated by male urinary pheromones (Vandenbergh effect). The neuroendocrine mechanisms underlining this effect and the behavioral consequences are poorly understood. Through a multidisciplinary approach using immunohistochemistry, gas chromatography coupled to mass spectrometry and experimental surgery, my thesis research show that neurons that synthesize kisspeptin, a hypothalamic neuropeptide which plays a master role in the control of puberty onset, are positively regulated by puberty-Accelerating pheromones. Kisspeptin neurons receive pheromone signal via the accessory olfactory system and transmit it to GnRH neurons. Moreover, behavioral analyses show that besides their known physiological effect, puberty-Accelerating pheromones also have long-Term effects on sexual behavior of the female mouse. Indeed, puberty-Accelerating pheromones induce a precocious expression of male-Directed odor preference in adult female mice.

Le diabète de type 2 et la dépression sont des problèmes majeurs de santé publique associés par un lien bidirectionnel. La dérégulation de l'axe hypothalamo-hypophyso-surrénalien (HPA), accompagnée par un taux élevé de glucocorticoïdes circulants, pourrait constituer un mécanisme commun à ces pathologies. L'axe HPA est régulé principalement au niveau de l'hypothalamus, siège de régulations nutritionnelles et émotionnelles. En ciblant les noyaux hypothalamiques, la néoglucogenèse intestinale (NGI) a des effets bénéfiques contre le développement du diabète de type 2 via la stimulation des nerfs vagal et spinal. Nous avons donc testé si la NGI, par sa communication avec l'hypothalamus, pourrait également réguler les comportements émotionnels et ainsi exercer des effets bénéfiques sur les maladies métaboliques et émotionnelles.L'absence de NGI provoque un dysfonctionnement de l'axe HPA et de son rétrocontrôle négatif (via des modifications moléculaires), caractérisés par une hypersécrétion de glucocorticoïdes et le développement d'une résistance aux glucocorticoïdes. Grâce à des études comportementales et moléculaires, nous montrons que les souris dépourvues de NGI développent des altérations phénotypiques et neurobiologiques caractéristiques d'un état anxio-dépressif. La restauration de la NGI par une perfusion de glucose portale rétablit les altérations neurobiologiques de l'axe HPA. L'induction de la NGI par un régime riche en protéines exerce des effets anxiolytiques et antidépresseurs. Ces données suggèrent que la NGI en ciblant l'hypothalamus, contrôle le métabolisme et, via l'axe HPA, les comportements émotionnels / Type 2 diabetes and major depressive disorder are major health concerns, which are highly comorbid. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, associated with elevated circulating levels of glucocorticoids, was suggested to be a common mechanism for those pathologies. The hypothalamus, which mainly regulates the HPA axis, is a key integrative center, playing a role in both metabolic and emotional processes. By targeting hypothalamic nuclei, intestinal gluconeogenesis (IGN) exerts beneficial effects against the development of type 2 diabetes through the stimulation of the vagal and spinal nerves. We therefore evaluated whether IGN, via the hypothalamus, may represent a putative common regulator of metabolic and emotional disorders.In the absence of IGN, mice exhibited HPA axis dysregulation along with decreased glucocorticoid-mediated negative feedback (due to molecular modifications), highlighted by hypercortisolism and glucocorticoid resistance. Using behavioral and molecular studies, we demonstrated that mice lacking IGN displayed phenotypic and neurobiological hallmarks of anxiety/depression-like state. Rescuing IGN by portal glucose infusion reversed neurobiological alterations of the HPA axis. Induction of IGN by a protein-enriched diet had anxiolytic and antidepressant effects. Together, these data raise the possibility that IGN by targeting hypothalamus, controls metabolism and, via the HPA axis, emotional behavior

Indiana University-Purdue University Indianapolis (IUPUI) / Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is found in heavy alcohol users. Negative urgency is a personality trait reflecting the tendency to act rashly in response to negative emotional states, and is associated with problematic alcohol consumption. The current study examined the relationship between negative urgency and HPA axis functioning following (1) negative mood induction and (2) intravenous alcohol administration among heavy social drinkers (proposed n = 40). I hypothesized the following: (1) Negative mood induction would result in an increase of cortisol release as compared to neutral mood induction; (1a) Negative urgency would be related to increased cortisol release in response to negative mood induction; (1b) Negative urgency would partially mediate the relationship between mood induction and cortisol release; (2) Acute IV alcohol administration would result in increased cortisol levels in the neutral mood condition, but decreased cortisol levels in the negative mood condition; and (2a) Negative urgency would be related to the suppression of cortisol release in the negative mood condition in response to acute IV alcohol administration. Repeated measures analyses of variance, the PROCESS macro, and paired samples t-tests were used to examine study hypotheses. Hypotheses were largely unsupported. Writing mood induction procedures reduced salivary cortisol levels in negative mood (t(35)= 2.49, p= 0.02) and there was a trend decrease in neutral mood (t(35)= 1.87, p= 0.07). Alcohol administration also reduced salivary cortisol levels in both negative mood (t(35)= 3.99, p< 0.01) and neutral mood (t(35)= 2.60, p= 0.01). However, salivary cortisol changes were no different than typical circadian patterns in response to mood induction (t(231)= 0.37, p=0.71) or in response to acute alcohol administration (t(231)= 0.44, p= 0.64). Negative urgency had a trend main effect on salivary cortisol level in response to acute IV alcohol administration, such that those higher in negative urgency were more similar to typical circadian patterns (F(19,28)= 1.59, p=0.13). This could serve as preliminary support for a psychological mechanism for the alcohol sensitivity hypothesis. Overall these findings suggest the current study failed to sufficiently manipulate salivary cortisol levels. Future studies should consider methodological techniques when exploring these relationships, including IV compared to oral alcohol administration, mood compared to stress manipulations, and cortisol compared to other HPA axis biomarkers.

Indiana University-Purdue University Indianapolis (IUPUI) / Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.