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1
COTELLESSA, LUDOVICA. "THE INVOLVEMENT OF THE NOTCH PATHWAY IN THE GNRH NEURONS DEVELOPMENT." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/814079.
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The proper development of the hypothalamic-pituitary-gonadal (HPG) axis is essential for normal
reproductive competence. Misfunctions in the axis that impairs GnRH synthesis or function result in
GnRH deficiency. Idiopathic congenital hypogonadotropic hypogonadism (CHH) is a rare
reproductive disorder, with significant heterogeneity of genetic inheritance, that is primarily caused
by gonadotropin-releasing hormone (GnRH) deficiency. Clinically, the disorder is characterized by
an absence of puberty and infertility. In approximately 50% of cases, CHH patients also suffer from
a reduced or deficient sense of smell (hyposmia or anosmia, respectively). In this case, the disorder
is termed Kallmann syndrome (KS) and results from a failure or incomplete embryonic migration of
GnRH-producing neurons. The significance to elucidate the genetic causes of CHH is related to the
relatively high percentage (about 50%) of patients that are still considered idiopathic. It is known
from the literature that Notch signaling has a role in the migration of neurons in the developing cortex
and that it is expressed in the olfactory system of many species, so we would like to understand if
Notch signaling has a role in the migration of GnRH neurons in the olfactory system. Hence, the aim
of my PhD was to understand: 1) if Notch signaling molecules are expressed along the GnRH
migratory pathway in human fetal and adult post-mortem brain sections; 2) if Notch plays a role in
the establishment of the correct GnRH migratory process or GnRH axonal targeting to the
hypothalamic regions, using zebrafish as an in vivo model; 3) to address whether patients affected by
CHH present mutations in the Notch signaling pathway; 4) to functionally validate the eventual
mutations using an immortalized GnRH cell line (GN11).
We explored by multiplex fluorescent in situ hybridization and immunohistochemical assays the
expression of both JAG1, NOTCH1 and NOTCH2 in coronal human fetal sections of the nasal
compartment and nasal/forebrain junctions in early developmental stages. These experiments
revealed that JAG1, NOTCH1 and NOTCH2 are expressed along the GnRH migratory pathway during
human fetal development, suggesting a paracrine and/or autocrine mechanism. We then used
zebrafish as in vivo model to investigate the involvement of jag1 in GnRH3 neurons development
and migration. Firstly, we have demonstrated the expression of jag1a, jag1b, notch1a and GnRH3 in
the olfactory placode of zebrafish embryos, revealing a possible collaboration between these factors
in the GnRH3 neurons development. Taking advantage of the zebrafish transgenic line
tg(GnRH3:EGFP), we demonstrated that downregulation of jag1b, but not jag1a, strongly affects the
development of the GnRH3 neurons at 48 and 72hpf. Treatment of tg(GnRH3:EGFP) embryos with
the Notch inhibitor, DAPT (γ-secretase inhibitor), phenocopied the morpholino experiments, further
supporting a role for notch1/jag1 in the development of GnRH3 neurons. Additionally, we performed
migration assay on immortalized GnRH cells, and we observe that JAG1 act as a repellent factor for
the motility of these cells.
Based on the human and zebrafish data and considering the KS-like phenotype of our jag1b
morphants, we next sought in our cohort of CHH/KS patients for possible mutation in JAG1 gene and
four rare missense variants in the JAG1 gene were identified (R117G, F206Y, Y931I, 1160N).
Overexpression of all JAG1 variants in GN11 cell line coupled with an immunofluorescence assay
revealed that only the JAG1 variant D1160N was mislocalized and retained into the cytoplasm. The
functionality was evaluated through the Luciferase assay, and D1160N variant did not activate the
transcription of the Notch Responsive Element promoter. Combining morphological analysis in vivo
(in human and zebrafish), together with genetic and pharmacological manipulation in zebrafish, and
human genetic analysis, we provide compelling evidence that Notch1/Jag1 signaling has a role in the
development of GnRH neurons/olfactory system and indicate that Notch1/Jag1 signaling
insufficiency may contribute to the pathogenesis of CHH in humans.
2
Ford, Gemma. "Orexins and their involvement with the HPA axis." Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409833.
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3
Markopoulou, Kalypso. "HPA axis dysfunction in treatment resistant affective disorders." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/hpa-axis-dysfunction-in-treatment-resistant-affective-disorders(3cac2a96-2cf1-43f8-a7e6-1c2fbc0b87b7).html.
Full textAbstract:
Background: TRD (Treatment Resistant Depression) patients have been shown to have hypercortisolemia and a hyperactive HP A (hypothalamo-pituitary-adrenal) axis. The Cortisol Awakening Response (CAR) is a naturalistic measure of the HP A axis activity. Although found to be elevated in depression, it has never been explicitly studied in TRD; furthermore, results have never been compared between Treatment Resistant Unipolar Depression (TRUD) and Treatment Resistant Bipolar Depression (TRBD). In addition, dehydroepiandrosterone (DHEA), the other main adrenal steroid, and which may counteract the effects of cortisol on the brain, has never been measured in TRUD or TRBD. Aims and Methods: To assess the state and relevance of HP A axis changes in treatment-resistant depression using the following methods: (a) salivary cortisol, DHEA and the ratio of Cortisol/DHEA, measured at several points of the day over 2 days; and (b) the CAR (AUCg and AUCi), measured over 2 days. These parameters were compared: between TRUD and TRBD; between patients in episode and in remission; and with matched healthy controls. Results: TRUD patients in episode had a higher CAR (AUCg) compared to controls, remitted patients and TRBD. They also exhibited hypercortisolemia throughout the day (AUCg), and on some measures an elevated Cortisol/DHEA ratio. TRBD patients in episode exhibited a lower CAR (AUCg and AUCi) than controls, remitted patients and TRUD, particularly on Day 1. The Cortisol/DHEA ratio was also lower than controls on some measures. However, patients with remitted TRBD had higher Cortisol/DHEA ratios (but not CAR) than controls.
4
Farooq, Rai Khalid. "Implication fonctionnelle du récepteur P2X7 dans les mécanismes neuroinflammatoires associés à la dépression : étude préclinique." Thesis, Tours, 2012. http://www.theses.fr/2012TOUR4022/document.
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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 neuroendocriniensResearch 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
5
Dionne-Wilson, Laurence. "Serotonin as a Regulator of the Hypothalamic-Pituitary-Interrenal Axis in Rainbow Trout (Oncorhynchus mykiss)." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32163.
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Although empirical evidence suggests that interactions occur between serotonin (5- HT) and the hypothalamic-pituitary-interrenal (HPI) axis teleost fish, the mechanisms of serotonergic regulation of the HPI axis require elucidation. The hypothesis that 5-HT regulates the stress response in rainbow trout (Oncorhynchus mykiss) by acting at multiple levels in the HPI axis through tissue-specific 5-HT receptor subtypes was examined. Messenger RNA for 5-HT1A, 5-HT2 and 5-HT4 receptor subtypes was expressed in all HPI axis tissues. Administration of 5-HT in vivo in cannulated trout caused significant increases in plasma cortisol and glucose concentrations. In vitro head kidney preparations revealed a stimulatory effect of 5- HT, acting through the 5-HT4 receptor, on cortisol production. Collectively, these data suggest that 5-HT plays a role in HPI axis activation in rainbow trout, and that at the head kidney level, these effects likely are mediated by the 5-HT4 receptor.
6
Quillet, Raphaëlle. "Identification et caractérisation de nouveaux outils pharmacologiques sélectifs pour les différents récepteurs à peptides RF-amides." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ029.
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Les RF-amides (RFRPs, NPFF, QRFP, PrRPs, Kisspeptines) sont une famille de peptides caractérisée par une signature Arg-Phe-NH2 à l’extrémité C-terminale très conservée au cours de l’évolution. Ils exercent leurs effets via 5 récepteurs couplés aux protéines G (NPFF1R, NPFF2R, QRFPR, PrRPR, Kiss1R), et plusieurs études soutiennent leur implication dans la modulation de nombreuses fonctions physiologiques telles que la douleur et la nociception, la reproduction, ou encore le métabolisme. Néanmoins, l’étude de ces systèmes est entravée par l’absence d’outils pharmacologiques tels que des antagonistes sélectifs. C’est pourquoi mon travail de thèse a consisté au développement d’outils pharmacologiques permettant de répondre à ces attentes, particulièrement sur les récepteurs NPFF1R, NPFF2R et Kiss1R. Des études de relation structure-activité nous ont amenés à considérer l’importance de la signature Arg-Phe-NH2 dans l’activité des peptides RF-amides sur leurs récepteurs. L’introduction de modifications au niveau N-terminal ou C-terminal du dipeptide Arg-Phe-NH2 nous a conduits à l’identification d’un antagoniste hautement affin et sélectif pour le récepteur NPFF1R in vitro et in vivo. Ce dernier nous a permis d’identifier le rôle du récepteur NPFF1R dans les effets secondaires liés à l’administration d’opiacés, tels que l’hyperalgésie et la tolérance morphinique. La responsabilité du récepteur NPFF1R dans ces phénomènes a été par la suite confirmée chez des souris KO NPFF1R. De plus, des données plus récentes suggèrent l’importance de ce dernier au niveau de l’axe hypothalamo-hypophyso-gonadotropique (HHG) des animaux saisonniers, et en particulier du hamster. Notre antagoniste nous a permis de déterminer le rôle du récepteur NPFF1R dans la libération de LH induite par le RFRP-3. Pour la première fois, nous avons également mis en évidence des molécules hautement affines et sélectives pour le récepteur NPFF2R, pour lequel nous avons révélé une activité agoniste partielle in vitro. Mon travail a également mené à la caractérisation in vitro d’un antagoniste sélectif du récepteur Kiss1R, qui vient compléter l’ensemble des outils disponibles pour l’étude des fonctions physiologiques modulées par ce récepteur et son ligand, la kisspeptine. Dans l’ensemble, mon travail de thèse a permis de caractériser plusieurs ligands affins et sélectifs des récepteurs à peptides RF-amides, et de mettre en lumière le rôle du système RFRP-3/NPFF1R dans les effets à long-terme liés aux opiacésRF-amides (RFRPs, NPFF, QRFP, PrRPs, Kisspeptins) belong to a family of peptide characterized by a Arg-Phe-NH2 C-terminus highly conserved throughout the evolution. They target 5 G-protein coupled receptors (NPFF1R, NPFF2R, QRFPR, PrRPR, Kiss1R) and most studies highlight their roles in the modulation of various functions as pain and nociception, reproduction or metabolism. Nonetheless, the study of these systems is severely limited by the absence of pharmacological tools as selective antagonists. Thus, my PhD project consisted in the development of selective ligands to answer these questions, notably on NPFF1R, NPFF2R and Kiss1R receptors. Structure-Activity relationship studies highlighted the importance of Arg-Phe-NH2 signature for the activity of RF-amide peptides on their receptors. Introduction of modifications at N or C-terminus of Arg-Phe-NH2 dipeptide led us to the identification of a compound displaying high affinity, selectivity and antagonist activity for NPFF1R both in vitro and in vivo. This compound allowed us to identify the critical role played by NPFF1R in the secondary effects related to opiates administration, as hyperalgesia and analgesic tolerance. The involvement of NPFF1R was then confirmed in KO NPFF1R mice. Moreover, recent data suggest the importance of NPFF1R on hypothalamo-pituitary gonadotropic (HPG) axis of seasonal animals, and particularly of hamsters. Our antagonist allowed us to decipher the role of NPFF1R in RFRP-3-induced-LH release. For the first time, we also have characterized high affinity and selective compounds for NPFF2R that display partial agonist activity in vitro. Moreover, our work led to the in vitro characterization of a selective antagonist for Kiss1R, that complete the available tools to study the physiological functions modulated by this receptor and its ligand, the kisspeptine. Overall, my PhD thesis led to the characterization of several selective ligands for RF-amide receptors, and highlight the role of RFRP-3/NPFF1R system in the long-term effects associated to opiates
7
Kyle, Catriona Jane. "Contributions of cortisol and corticosterone to metabolic regulation in humans." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33042.
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Both cortisol and corticosterone circulate in human plasma however corticosterone has been relatively neglected in human research to date. There is evidence of distinct regulation within different tissues with the transmembrane transporter ABCB1, highly expressed in the brain, exporting cortisol but not corticosterone. This may account for the relative accumulation of corticosterone in the CNS. In contrast, ABCC1, highly expressed in adipose tissue and skeletal muscle, exports corticosterone but not cortisol, suggesting cortisol is the principal glucocorticoid acting in these tissues. We tested the hypotheses that: (i) corticosterone physiology in humans is different to that of cortisol; (ii) inhibition of ABCC1 increases binding of corticosterone to corticosteroid receptors in adipose tissue and skeletal muscle but has no central CNS effect; and (iii) corticosterone is superior to cortisol as a basis for glucocorticoid replacement therapy with fewer metabolic side effects. We compared paired salivary and plasma samples from 10 healthy individuals. Plasma corticosterone showed a similar diurnal variation to cortisol but salivary corticosterone was low and did not correlate with plasma concentrations. A placebo-controlled randomised crossover study was carried out in 14 healthy individuals comparing receptor occupancy of glucocorticoids centrally and peripherally with and without ABCC1 inhibition. Receptor occupancy was assessed through displacement with MR and GR antagonists potassium canrenoate and mifepristone. Centrally, ABCC1 inhibition caused increased activation of the HPA axis after MR and GR antagonism. Peripherally, we were unable to show displacement from adipose tissue or skeletal muscle. A further placebo-controlled randomised crossover study is still ongoing in 16 patients with congenital adrenal hyperplasia, comparing metabolic effects of placebo, cortisol and corticosterone infusions over 6 hours. We present interim data for n=8. ACTH and 17-OHP were suppressed with corticosterone. Metabolic parameters were similar between placebo, cortisol and corticosterone phases. These data suggest corticosterone physiology is distinct compared with cortisol in humans. We have shown ABCC1 inhibition alters the HPA axis after receptor antagonism which suggests ABCC1 may play more of a key role centrally than previously thought. Corticosterone suppresses ACTH and 17-OHP in the short term in congenital adrenal hyperplasia, highlighting the possibility of its use as an alternative glucocorticoid replacement therapy in the future.
8
VAN, HOOREN DANIELLA CHRISTINE. "GluR5 IS INVOLVED IN REGULATION OF THE HPA AXIS." University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1080156678.
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9
Peric, Tanja <1982>. "Hair: a tool to evaluate the HPA axis activity." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6253/1/WHOLE_THESIS_PERIC.pdf.
Full textAbstract:
Hair cortisol is a novel marker to measure long-term secretion cortisol free from many methodological caveats associated with other matrices such as plasma, saliva, urine, milk and faeces. For decades hair analysis has been successfully used in forensic science and toxicology to evaluate the exposure to exogenous substances and assess endogenous steroid hormones. Evaluation of cortisol in hair matrix began about a decade ago and have over the past five years had a remarkable development by advancing knowledge and affirming this method as a new and efficient way to study the hypothalamic-pituitary-adrenal (HPA) axis activity over a long time period. In farm animals, certain environmental or management conditions can potentially activate the HPA axis. Given the importance of cortisol in monitoring the HPA axis activity, a first approach has involved the study on the distribution of hair cortisol concentrations (HCC) in healthy dairy cows showing a physiological range of variation of this hormone. Moreover, HCC have been significantly influenced also by changes in environmental conditions and a significant positive correlation was detected between HCC and cows clinically or physiologically compromised suggesting that these cows were subjected to repeated HPA axis activation. Additionally, Crossbreed F1 heifers showed significantly lower HCC compared to pure animals and a breed influence has been seen also on the HPA axis activity stimulated by an environmental change showing thus a higher level of resilience and a better adaptability to the environment of certain genotypes. Hair proved to be an excellent matrix also in the study of the activation of the HPA axis during the perinatal period. The use of hair analysis in research holds great promise to significantly enhance current understanding on the role of HPA axis over a long period of time.
10
Peric, Tanja <1982>. "Hair: a tool to evaluate the HPA axis activity." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6253/.
Full textAbstract:
Hair cortisol is a novel marker to measure long-term secretion cortisol free from many methodological caveats associated with other matrices such as plasma, saliva, urine, milk and faeces. For decades hair analysis has been successfully used in forensic science and toxicology to evaluate the exposure to exogenous substances and assess endogenous steroid hormones. Evaluation of cortisol in hair matrix began about a decade ago and have over the past five years had a remarkable development by advancing knowledge and affirming this method as a new and efficient way to study the hypothalamic-pituitary-adrenal (HPA) axis activity over a long time period. In farm animals, certain environmental or management conditions can potentially activate the HPA axis. Given the importance of cortisol in monitoring the HPA axis activity, a first approach has involved the study on the distribution of hair cortisol concentrations (HCC) in healthy dairy cows showing a physiological range of variation of this hormone. Moreover, HCC have been significantly influenced also by changes in environmental conditions and a significant positive correlation was detected between HCC and cows clinically or physiologically compromised suggesting that these cows were subjected to repeated HPA axis activation. Additionally, Crossbreed F1 heifers showed significantly lower HCC compared to pure animals and a breed influence has been seen also on the HPA axis activity stimulated by an environmental change showing thus a higher level of resilience and a better adaptability to the environment of certain genotypes. Hair proved to be an excellent matrix also in the study of the activation of the HPA axis during the perinatal period. The use of hair analysis in research holds great promise to significantly enhance current understanding on the role of HPA axis over a long period of time.
11
Couroussé, Thomas. "Rôle du transporteur de cations organiques 2 dans la réponse et la vulnérabilité au stress." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P625.
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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 stressInteractions 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
12
Khemissi, Wahid. "Etude de la dérégulation de l'axe HPA dans la création d'une résistance aux antidépresseurs et son implication dans la prolifération cellulaire et la neurogénèse hippocampique." Thesis, Tours, 2014. http://www.theses.fr/2014TOUR4030.
Full textAbstract:
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 phénomènesOne-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
13
Nicola, Angela Cristina de [UNESP]. "Atuação das proteínas do relógio na senescência reprodutiva de ratas Wistar." Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/152720.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
O envelhecimento é considerado processo multidimensional no qual fatores ambientais podem proteger ou, inversamente, agravar seus sinais, de maneira não linear, nos processos fisiológicos e neurocomportamentais. Durante este processo, os ritmos circadianos são interrompidos ou fragmentados com dissociação consequente dos ritmos circadianos do indivíduo e disfunções relacionadas ao relógio circadiano contribuem para o envelhecimento e para patologias a ele relacionadas. O objetivo deste estudo foi averiguar possível alteração temporal do sistema CLOCK no eixo HPG e a relação com às alterações hormonais que caracterizam a periestropausa. Foram utilizadas fêmeas adultas com ciclo estral regular (CD) na fase do diestro e fêmeas senis com ciclo estral irregular e persistência da fase do diestro (IDP). Para análises de expressão gênica dos clock genes Per2, Rev-erbα e Bmal1 no eixo HPG, foram utilizados punchs das regiões do NSQ, onde também foi analisado RNAm de AVP, APO e HMB destes animais, além da adenohipófise e ovários dos quais se extraiu o RNA para confecção do cDNA e realização de qPCR. A determinação da atividade neuronal vasopressinérgica no NSQ foi realizada por imunoistoquíca com dupla marcação para cFos e AVP em tecido previamente fixado com paraformaldeído. A concentração plasmática de gonadotrofinas foi determinada por radioimunoensaio. De modo geral, os animais IDP revelaram alterações no perfil de expressão gênica durante o fotoperíodo, com redução de amplitude, deslocamento/desalinhamento de fase e ausência de antifase. O NSQ de animais IDP apresentou menor expressão de Rev-erbα e maior expressão de RNAm para AVP em relação ao grupo CD. A quantificação relativa de Bmal1 foi semelhante em ambos os grupos e não houve diferenças entre grupos na expressão de Per2. Na APO, animais IDP apresentaram maior expressão de Per2 e menor quantidade de RNAm para Rev-erbα. No HMB observou-se menor expressão para Per2 e Rev-erbα e maior expressão de Bmal1 nas fêmeas IDP. Per2 e Bmal1 na adenohipófise tiveram menor expressão que o gene Rev-erbα no grupo senil e o ovário destes animais revelou maior expressão para Per2 e Rev-erbα, em comparação com os animais CD. As concentrações plasmáticas de FSH foram maiores nas fêmeas com ciclo irregular (2,05 ± 0,44 ng/mL), principalmente durante a fase clara, assim como o LH (0,24 ± 0,07 ng/mL), cujos maiores valores foram encontrados durante a fase escura e com perfil semelhante ao RNAm de AVP. As imunomarcações revelaram alta atividade vasopressinérgica na porção dorsomedial do NSQ das fêmeas IDP. Juntos estes dados permitem concluir que há desarranjo na expressão temporal dos genes Per2, Rev-erbα, Bmal1 que compõem a maquinaria molecular do relógio circadiano, bem como de RNAm para AVP no NSQ, de fêmeas Wistar na periestropausa. Além disso, a maior atividade neuronal vasopressinérgica e a ausência de oscilação de Rev-erbα e Bmal1 no NSQ destes animais, comprometem a correta comunicação do relógio central do NSQ com o eixo HPG, inviabilizando a manutenção da fertilidade feminina e contribuindo para a senescência reprodutiva.
Aging is considered a multidimensional process in which environmental factors can protect or, conversely, aggravate its signals, non-linearly, in physiological and neurobehavioral processes. During this process, circadian rhythms are disrupted or fragmented with consequent dissociation of the individual's circadian rhythms and circadian clock-related dysfunctions contribute to aging and related pathologies. The objective of this study was to investigate possible temporal alteration of the CLOCK system in the HPG axis and the relation with the hormonal changes that characterize periestropause. Adult females with regular estrus cycle in the diestrous phase (RD) and old females with irregular estrous cycle and persistent diestrous phase (IPD). For analyzes of the gene expression of the genes Per2, Rev-erbα and Bmal1 in the HPG axis, punchs from the NSQ regions were used, where AVP, POA and MBH RNAm from these animals were also analyzed, as well as the adenohypophysis and ovaries from which they were extracted the RNA for cDNA production and qPCR performance. The determination of the vasopressinergic neuronal activity in the NSQ was performed by immunohistochemical with double labeling for cFos/AVP in tissue previously fixed with paraformaldehyde. The plasma concentration of gonadotrophins was determined by radioimmunoassay. In general, the IPD animals show alterations in the gene expression profile during the period analyzed, with amplitude reduction, phase shift / misalignment and absence of antiphase. The NSQ of IPD animals presented lower expression of Rev-erbα and higher RNAm expression for AVP than RD group. The relative quantification of Bmal1 was similar in both groups and there were no differences between groups in the expression of Per2. In PAO, IPD animals showed higher expression of Per2 and less amount of RNAm for Rev-erbα. MBH showed lower expression for Per2 and Rev-erbα and higher Bmal1 expression in IPD females. Per2 and Bmal1 in the adenohypophysis had lower expression than the Rev-erbα gene in the old group and the ovary of these animals showed higher expression for Per2 and Rev-erbα, in related to to the RD animals. Plasma concentrations of FSH were higher in females with irregular cycle (2.05 ± 0.44 ng / mL), mainly during the light phase, as well as LH (0.24 ± 0.07 ng / mL) whose values were found during the dark phase and with a profile similar to AVP RNAm. Immunolabeling demonstrated high vasopressinergic activity in the dorsomedial portion of the NSQ of the IPD females. Together these data allow us to conclude that there is a breakdown in the temporal expression of the Per2, Rev-erbα, Bmal1 genes that make up the molecular machinery of the circadian clock, as well as RNAm for AVP in NSQ of Wistar females in peri-masterpause. In addition, the increased vasopressinergic neuronal activity and the absence of Rev-erbα and Bmal1 oscillation in the NSQ of these animals compromise the correct communication of the central clock of the NSQ with the HPG axis, making it impossible to maintain female fertility and contributing to reproductive senescence.
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Alves, Luana Maria Silva. "Participação de receptores ER e ER na ativação do eixo hipotálamo-hipófise-adrenal por estresse hemorrágico." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-06012016-132149/.
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Em função da categoria dos estressores, vias neurais específicas são envolvidas e respostas distintas podem ser induzidas. A literatura tem reportado que o estrógeno (E 2 ) através de seus receptores de tipos (ER) e (ER) influencia a atividade do eixo hipotálamo hipófise adrenal (HPA). Além disso, há evidências de que o E2 exerça efeitos protetores em situação de choque hemorrágico. O objetivo deste trabalho foi verificar a participação dos receptores ER e ER na atividade do eixo HPA durante estresse hemorrágico. Foram utilizadas ratas Wistar ovariectomizadas que receberam injeções s.c. de DMSO (veículo), PPT (agonista ER) ou DPN (agonista ER), durante 3 dias. No segundo dia, as ratas foram canuladas para coleta seriada de sangue na manhã seguinte. Os animais receberam (controle) ou não (hemorrágicos) reposição imediata com salina. Os hormônios corticosterona (CORT), ocitocina (OT) e vasopressina (AVP) foram dosados por radioimunoensaio. Ao final do experimento, os ratos foram perfundidos e os cérebros processados para imuno-histoquímica de FOS, tirosina hidroxilase (TH) e hormônio liberador de corticotrofina (CRH). Nos animais tratados com veículo, a hemorragia gradual moderada aumentou a secreção de CORT, OT e AVP, a expressão de neurônios TH ativados na região A1C1 e de FOS no mpPVN. O PPT reduziu a secreção de CORT, na situação controle atuando no LC e mpPVN; e também após hemorragia atuando no LC, NTS, A1C1 e mpPVN. O DPN reduziu a secreção de CORT apenas após estresse hemorrágico atuando no LC, A1C1 e mpPVN. O PPT bloqueou o aumento da secreção de OT e aumentou a secreção de AVP, após hemorragia. O DPN, por sua vez, reduziu a concentração plasmática de OT e aumentou a concentração plasmática de AVP, independentemente da hemorragia. Em conclusão: o estrógeno pode exercer uma ação inibitória sobre a secreção basal de CORT somente através da ação do ER sobre o LC e mpPVN; a secreção de CORT aumenta em resposta à hemorragia gradual moderada e o estrógeno pode exercer um controle inibitório nessa resposta através de ER atuando sobre LC, NTS, A1C1 e mpPVN, bem como através de ER atuando sobre LC, A1C1 e mpPVN.Depending on the stressors category, specific neural pathways are involved and different responses can be selected. It has been reported in the literature that estrogen (E2 ) can affect hypothalamus pituitary adrenal (HPA) axis activity through its receptors type (ER) and (ER). Moreover, there is evidence that E 2 has protecting properties after hemorrhagic shock. The aim of this work was to assess the participation of ER and ER on HPA axis activity during hemorrhagic stress. It was used ovariectomized Wistar rats that received s.c. injections of: DMSO (vehicle), PPT (ER agonist) or DPN (ER agonist), during 3 days. In the second day the rats were catheterized for serial blood collect in the next morning. Animals received (control) or not (hemorrhagic) immediate reposition with same volume of isotonic saline. The hormones corticosterone (CORT), oxytocin (OT) and vasopressin (AVP) were measured by radioimmunoassay. At the end of the experiment, animals were perfused and their brains were processed for immuno-histochemistry for FOS, tyrosine hydroxylase (TH) and corticotropin releasing hormone (CRH). In vehicle treated animals, the gradual hemorrhage enhanced CORT, OT and AVP secretion, TH activated neurons expression in A1C1 and FOS expression in mpPVN. PPT decreased plasma CORT in control situation acting on LC and mpPVN, and also after hemorrhage acting on LC, NTS, A1C1 and mpPVN. DPN reduced plasma CORT only after hemorrhagic stress acting on LC, A1C1 and mpPVN. PPT blocked the increase of OT secretion and increased AVP secretion, after hemorrhage. The agonist DPN reduced OT and increased AVP levels, despite hemorrhage. In conclusion: E2 can exert an inhibitory effect on CORT basal secretion only through ER action on LC and mpPVN; CORT secretion increases after gradual moderate hemorrhage and E2 inhibit this secretion through ER action on LC, NTS, A1C1 and mpPVN, as well through ER action on LC, A1C1 and mpPVN.
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Minni, Amandine. "Rôle de la Transcortine (CBG) dans la variabilité des réponses de stress." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21875/document.
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Une grande diversité dans la réponse adaptative au stress est observée entre les individus favorisant une sensibilité variable face aux stresseurs et pouvant conduire à une vulnérabilité à développer divers troubles et pathologies. Cette diversité est sous tendue par les caractéristiques propres de chaque individu, déterminées par le patrimoine génétique en interaction avec les facteurs environnementaux. Des études génétiques menées au laboratoire ont permis de placer le gène de la Cbg comme un candidat important influençant les réponses de stress. L’équipe a alors développé un modèle de souris déficiente pour le gène Cbg (k.o. total). La CBG est une glycoprotéine plasmatique responsable de la biodisponibilité et du transport jusqu’à leur cible des glucocorticoïdes, produits finaux de l’axe corticotrope. A l’aide de ce modèle original, l’objectif de mon travail de thèse a été d’étudier les conséquences fonctionnelles de la déficience en CBG sur les réponses de stress. Nous avons ainsi analysé l’activité et la réactivité de l’axe corticotrope ainsi que les comportements émotionnels des mâles et des femelles k.o. Cbg dans des conditions de repos, de stress aigu et dans un contexte mimant l’effet d’un style de vie occidentale (modélisé par une alimentation enrichie en gras, associée à un stress chronique). Nous présentons ainsi un modèle murin unique d’hypo-réponse des glucocorticoïdes au stress associé à une réponse comportementale adaptative ralentie au niveau émotionnel et cognitif. L’ensemble de ces travaux contribue à placer la CBG et son gène comme acteur majeur de la variabilité individuelle des réponses de stressA great diversity in the adaptive response to stress is observed between individuals favoring a variable sensitivity to face stressors and leading to a vulnerability to develop various disorders and diseases. This diversity is due to the characteristics of each individual, as determined by the genetic background in interaction with environmental factors. Genetic studies conducted in the laboratory demonstrated that the Cbg gene is an important candidate influencing stress responses. The team then developed a mouse model deficient for the gene Cbg (total k.o.). CBG is a plasma glycoprotein responsible for the bioavailability and the transport of glucocorticoids, the final products of the HPA axis, to their target.Using this original model, the objective of my thesis was to study the functional consequences of CBG deficiency on responses to stress exposure. We have analyzed the activity and reactivity of the HPA axis and the emotional behaviors of males and females k.o. Cbg in resting conditions, acute stress and in a context that mimics the effect of a Western life style (modeled by a high fat diet, associated with chronic stress). We present an unique mouse model of glucocorticoid hyposignaling in response to stress associated with behavioral responses slowed down at the emotional and cognitive levels. Overall, this work contributes to place CBG and its gene as major actor of individual variability to stress
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Iliadis, Stavros I. "Personality and the HPA-axis in Association with Postpartum Depression." Doctoral thesis, Uppsala universitet, Obstetrik & gynekologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-274956.
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Postpartum depression is a psychiatric disorder affecting a substantial proportion of newly delivered women, and remains a significant cause of childbirth-related morbidity. The aim of the present thesis was to examine psychological, endocrine and genetic aspects of postpartum depression in a large, population-based sample of women in Uppsala, Sweden. All included studies were undertaken as parts of the BASIC-project, a longitudinal study on psychological wellbeing during pregnancy and the postpartum period. Study participants were screened for depressive symptoms in pregnancy week 17 and 32 as well as at six weeks and six months postpartum, mainly by use of the Swedish version of the Edinburgh Postnatal Depression Scale (EPDS). Furthermore, personality was assessed with the Swedish universities Scale of Personality (SSP) in pregnancy week 32. Evening cortisol levels in saliva were measured in pregnancy week 36 and at six weeks postpartum. Blood samples were obtained to measure corticotropin-releasing hormone levels (CRH) and to perform genetic analyses. The results of this thesis demonstrate that neuroticism is a strong and independent predictive factor of depressive symptoms at six weeks and six months postpartum, and has a significant mediatory role in the association between a single nucleotide polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene (HSD11B1) and postpartum depression. Furthermore, women with postpartum depressive symptoms present with a dysregulated hypothalamic-pituitary-adrenal axis activity in terms of elevated cortisol levels postpartum, as well as elevated CRH levels in mid-gestation. In conclusion, this thesis develops current knowledge on several attributes of postpartum depression. Further studies are required to replicate and expand on these results, which would further contribute to early identification of women at risk of postpartum depression and adoption of proper interventions that may moderate the short- and long-term consequences of the disorder.
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Kalyani, Manu. "Interaction between Prolactin and the Hypothalamic-Pituitary-Adrenal (HPA) axis." Miami University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=miami1397233916.
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Wiklund, Liselotte. "Premenstrual Dysphoric Disorder : A Review of Neural and Cognitive Changes in Women with PMDD." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-14302.
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Around 3-8% of all women in reproductive age suffer from premenstrual dysphoric disorder (PMDD) which disenables them to live an ordinary life during the luteal phase (premenstrual phase) of the menstrual cycle. Throughout the premenstrual phase these women experience emotional, cognitive and physiological changes. Hitherto, the etiology of this disorder is unknown. Some consider the source of this state as non-biological, claiming that PMDD is a social construction imbedded in gender roles, that suggests that women should not show aggressive behavior or depressive mood unless it is during the premenstrual stage. Contradictory, research made in cognitive neuroscience claim that the origin is biological. It is assumed that the increased symptoms in women with PMDD is a result from dysfunctional sensitivity for the progesterone metabolite allopregnanolone that has a receptor in the GABAA system, hence, producing an anxious effect from high levels of allopregnanolone instead of the expected sedative, soothing effects. Research suggest that structural and functional changes occur in brain areas such as the hippocampus, parahippocampus, amygdala, cerebellum as well as in brainderived neurotrophic factor which is important for brain plasticity, growth and survival of neurons. Cognitive behaviors such as anticipation for negative stimuli, working memory and lack of cognitive control also seem to be affected by PMDD. Nonetheless, the evidence is inconsistent, the area of research face multiple issues in regards to study designs, hence making generalization at this point difficult. In sum, this essay reviews recent studies conducted in neuroscience of cognitive changes in women with PMDD, with focus on functional, structural and behavioral changes between the phases of the cycle.
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Canet, Geoffrey. "Rôle central des glucocorticoïdes et de leurs récepteurs dans l’étiologie de la Maladie d’Alzheimer." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT019.
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La maladie d’Alzheimer (MA) se caractérise au niveau cérébral par l’agrégation des peptides β-amyloïdes (Aβ) à partir du clivage de la protéine précurseur de l’amyloïde (APP), et par l’hyperphosphorylation de la protéine Tau. Dans la MA, les déficits cognitifs sont associés une dérégulation précoce de l’axe endocrinien du stress (axe hypothalamo-hypophyso-surrénalien ou HPA), à la surproduction conséquente de glucocorticoïdes (GC) et au dysfonctionnement de leurs récepteurs (GR). De nombreuses études montrent l’implication des GR dans la MA, notamment en favorisant la production d’Aβ et l’hyperphosphorylation de Tau. Dans un modèle aigu de la MA (injection icv d’une solution oligomérique de peptides oAβ25-35 chez le rat), nous avons observé un dysfonctionnement de l’axe HPA, associé à un ensemble d’altérations cellulaires rappelant la physiopathologie humaine. Il existe un cercle vicieux dans lequel la pathologie induit une surproduction de GC qui en retour potentialise la MA. L’objectif de ma thèse était donc de casser ce cercle vicieux à l’aide d’une nouvelle classe de molécules agissant comme des modulateurs sélectifs des GR (sGRm), afin de ralentir ou de renverser le décours de la pathologie. Les sGRm ont la particularité d'abroger les effets pathologiques des GR, tout en conservant leur signalisation physiologique. Dans une première étude, nous avons montré dans le modèle oAβ25-35 qu’un sGRm, le CORT113176, renversait dans l'hippocampe la totalité des modifications induites par la toxicité amyloïde (déficits de mémoire à court terme, taux de GC plasmatiques élevés, déficits synaptiques, neuroinflammation, apoptose et augmentation de la synthèse d'Aβ). Dans une deuxième étude, nous avons réalisé des analyses dans le cortex préfrontal. Cette structure d’intérêt dans la MA est également très riche en GR, suggérant que cette région est très sensible à la dérégulation de l’axe HPA. Ici, nous avons utilisé le sGRm comme outil pour caractériser l’implication des GR dans un certain nombre de voies de signalisations intracellulaires. Nous avons notamment observé l’état de phosphorylation des GR, leurs chaperonnes (HSP90/70), l’équilibre entre les voies de clivage amyloïdogénique et non-amyloïdogénique ou encore des enzymes impliquées dans la phosphorylation de GR et de Tau (GSK-3β, Cdk5, Calpain-1, Fyn). Les GR semblent être impliqués dans un grand nombre de processus associés à la toxicité induite par l’oAβ25-35, et le CORT113176 permet de renverser cette toxicité, mettant en avant le rôle central des GR dans la physiopathologie de la MA. Dans une dernière étude, suite à l'ensemble de ces premiers résultats, et afin de valider l'intérêt thérapeutique du CORT113176, nous avons tenté d’amener la preuve de concept via deux approches complémentaires. Tout d’abord, nous avons testé la robustesse du traitement avec le sGRm dans le modèle oAβ25-35 afin d’observer si le fait de casser le cercle vicieux en restaurant la physiologie de l’axe HPA, des GC et des GR permettait de lutter à long terme contre la pathologie. Les premiers résultats montrent que le CORT113176 renverse à long terme la toxicité amyloïde sur les paramètres mesurés précédemment, mais semble également renverser l’hyperphosphorylation de Tau. Enfin, nous avons voulu confirmer l’intérêt thérapeutique de casser le cercle vicieux dans un modèle de souris transgénique, la souris J20 (transgène de l’APP humain muté). Chez des animaux de 9 mois, le CORT113176 semble à nouveau renverser un grand nombre de marqueurs associés à la MA. L’ensemble de ces résultats place l’axe HPA et les GR au cœur de la physiopathologie de la MA, pouvant faire le lien entre la toxicité amyloïde et l’hyperphosphorylation de Tau. Ces travaux mettent également en évidence l’approche prometteuse représentée par les sGRm qui casse le cercle vicieux entre la dérégulation de l’axe HPA et la toxicité amyloïde, en rétablissant le rôle primaire des GC et des GR dans le maintien de l’homéostasieAlzheimer's disease (AD) is characterized in the brain by the aggregation of β-amyloid peptides (Aβ) from the cleavage of the amyloid precursor protein (APP), and by the hyperphosphorylation of the Tau protein. In AD, cognitive deficits are associated with an early dysregulation of the endocrine stress axis (hypothalamic-pituitary-adrenal axis or HPA), the consequent overproduction of glucocorticoids (GC) and the alteration of their receptors (GR). Numerous studies demonstrate the involvement of GR in AD, particularly via the increase of Aβ production and the hyperphosphorylation of Tau. In an acute model of AD (icv injection of an oligomeric solution of oAβ25-35 peptides in rat), we observed a dysregulation of the HPA axis, associated with a set of cellular alterations reminiscent of the human pathophysiology. There is a vicious cycle in which the pathology induces an overproduction of GC, which in turn potentiates AD. The objective of my thesis was therefore to break this vicious cycle using a new class of molecules acting as selective GR modulators (sGRm). The sGRm have the particularity to abrogate the pathological effects of GR, while retaining their physiological signaling. In a first study, we showed in the oAβ25-35 model that a sGRm (CORT113176) reverses in the hippocampus all the alterations induced by amyloid toxicity (short-term memory deficits, high plasma GC levels, synaptic deficits, neuroinflammation, apoptosis and increased Aβ synthesis). In a second study, we performed analyzes in the prefrontal cortex. This structure of interest in AD is also very rich in GR, suggesting that this region is very sensitive to deregulation of the HPA axis. Here, we used sGRm as a tool to characterize the involvement of GR in a number of intracellular signaling pathways. We notably observed the GR phosphorylation state, their chaperones (HSP90 / 70), the balance between the amyloidogenic and non-amyloidogenic pathways or the main enzymes involved both in GR and Tau phosphorylation (GSK-3β , Cdk5, Calpain-1, Fyn). GR appeared to be involved in numerous processes associated with oAβ25-35 toxicity, and CORT113176 reversed this toxicity, highlighting the central role played by GR in the pathophysiology of AD. In a final study, following all of these initial results, and in order to validate the therapeutic potential of CORT113176, we tried to bring the proof of concept via two complementary approaches. Firstly, we tested the robustness of the treatment with the sGRm in the oAβ25-35 model in order to observe whether breaking the vicious circle by restoring the physiology of the HPA axis, the GC and the GR could help at long-term to fight against the pathology. The first results showed that CORT113176 reversed at long-term the amyloid toxicity on the parameters measured previously, but also seems to reverse Tau hyperphosphorylation. Finally, we wanted to confirm the therapeutic interest of breaking the vicious circle in a transgenic mouse model of AD, the J20 mouse (mutated human APP transgene). In 9-month-old animals, CORT113176 again appeared to reverse a large number of markers associated with AD. All of these results place the HPA axis and GR at the heart of the pathophysiology of AD, which could make the link between amyloid toxicity and Tau hyperphosphorylation. This work also highlights the promising approach represented by sGRm which break the vicious circle between the deregulation of the HPA axis and amyloid toxicity, by restoring the primary role of GC and GR in the maintenance of homeostasis
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Heinzmann, Jan-Michael. "Central and peripheral aspects of hypothalamic-pituitary-adrenal (HPA) axis dysfunction." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-150032.
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Gallagher, Peter. "Spatial memory processes in bipolar depression : neuropsychological and HPA axis correlates." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1108.
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Background/ aims: Bipolar disorder is associated with significant impairment in a broad range of neuropsychological processes in addition to hypothalamic-pituitary-adrenal (HPA) axis dysfunction and hypercortisolaemia. As both animal and human models have highlighted the role of cortisol in the modulation of memory processes, attempting to understand this link is of critical importance. The aims of this thesis are to first profile neuropsychological and HPA axis function in individuals with a diagnosis of bipolar disorder, before examining if these functions can be altered through an intervention with an antiglucocorticoid drug. The subsequent chapters of this thesis will report analyses designed to explore specific aspects of these changes in more detail, principally alterations in spatial memory processes. Method: The thesis reports two broad phases of research. The first is a study of 20 participants diagnosed with bipolar disorder (with depressive symptoms) who first completed a broad neuropsychological assessment and profiling of afternoon cortisol and DHEA levels. These individuals then entered a randomised crossover study to examine the effects of mifepristone (RU-486), a glucocorticoid receptor antagonist, on neuropsychological functions and mood. A second cohort of 53 participants diagnosed with bipolar depression (BD) and 47 healthy controls was recruited to explore aspects of the results in more detail, particularly the fractionation of spatial memory and the integration of neuropsychological processes and their relationship with measures of HPA axis function. Results: 1) BD participants exhibited broad neuropsychological impairment across a range of cognitive domains in addition to hypercortisolaemia. 2) Administration of an antiglucocorticoid drug significantly reduced cortisol levels and improved spatial working memory performance. 3) The underlying neuropsychological component structure of BD and controls differed. 4) BD participants exhibited impairments in fine-grain metric spatial memory which, unlike other spatial processes, could not be explained by other measures. 5) A unique profile of processes underpinning aspects of visuospatial memory was observed in BD, suggesting a form of cognitive ‘scaffolding’. 6) A simple link between neuropsychological processes and peripheral HPA axis measures was not observed. Conclusion: Spatial memory processes in bipolar depression can be altered by direct HPA axis manipulation. A number of interesting avenues for future research have been identified that will further our knowledge of the integration between the biological mechanisms underlying neuropsychological impairment in mood disorders and should develop our understanding of integration between cognitive processes in general.
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Pereira, Ana Rita Salgueiro. "HPA axis function and episodic memory loss in early Alzheimer disease." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12509.
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Mestrado em Bioquímica - Bioquímica ClínicaAlzheimer’s disease (AD) is a brain neurodegenerative disease leading to progressive loss of memory and intellectual abilities. It is characterized by the appearance of amyloid-β oligomers (Aβ), which then aggregate into plaques, progressive appearance of neurofibrillary tangles composed of hyperphosphorylated tau, synaptic impairment and neuronal death. The hippocampus, a key structure responsible for memory encoding, is the first brain region affected in AD leading to early episodic memory loss. Aβ accumulation seems to have an important role in triggering chronic stress in AD, compromising the hypothalamic-pituitary-adrenal (HPA) axis function and the structures involved in its regulation, notably the hippocampus. The purpose of the present study was to evaluate the HPA axis function and episodic-like memory in a model of AD, the Tg2576 mice, in the early phase of the pathology, which was defined in these mice at about 4 months of age. To study the HPA axis function, corticosterone, the main stress hormone, was quantified by ELISA at the onset of light phase, at the onset of dark phase and after inducing the negative feedback with a dexamethasone supression test. Hippocampal glucorticoid receptors (GRs) were also quantified by Western blot. Tg2576 mice showed impairment in HPA axis, characterized by an increase in corticosterone at the onset of active phase and an absence in the negative feedback response induced by dexamethasone. Also, hippocampal GRs are increased and seems to fail in the downregulation of the stress response mediated by the HPA axis. To evaluate episodic-like memory, an object recognition task was conducted, which combines the ability to remember the ‘what, when and where’ components of an event. A deficit in the ‘where’ component of this type of memory was observed in Tg2576 mice. An in vivo treatment with the GR antagonist RU486 was then applied to evaluate if blocking GR function could reverse this deficit. Our first results suggest that blocking GR function can prevent this memory deficit in Tg2576 mice. These data demonstrate that corticostesterone levels, and thus stress signaling, are increased in the early phase of AD in these mice, due to dysfunction of the HPA axis. Furthermore, this altered signaling, via GRs, probably contributes to the early episodic memory deficits observed in these mice. These data strongly support our hypothesis that elevated stress is an environmental factor contributing to the onset of AD neuropathology.
A Doença de Alzheimer (DA) é uma doença neurodegenerativa do tecido cerebral que leva à perda da memória e das propriedades intelectuais. É caracterizada pelo aparecimento de oligómeros de amilóide-β (Aβ) que depois se agregam em placas, aparecimento progressivo de agregados neurofibrilares constituídos por proteína tau hiperfosforilada, alterações sinápticas e morte neuronal. O hipocampo, uma estrutura chave responsável pela codificação da memória, é a primeira região cerebral afectada na DA levando numa fase precoce, à perda da memória episódica. A acumulação de Aβ parece ter uma função importante no desencadeamento de stress crónico na DA levando ao comprometimento da função do eixo HPA e das várias estruturas envolvidas na sua regulação, nomeadamente o hipocampo. Neste estudo pretendeu-se estudar a função do eixo HPA e avaliar a memória episódica usando um modelo transgénico da DA, o ratinho Tg2576, numa fase precoce da doença de Alzheimer, definida neste modelo por volta dos 4 meses. Os estudos relativos à função do eixo HPA foram feitos através da quantificação de corticosterona, a hormona principal no stress, por teste ELISA na fase de repouso, na fase activa e após teste de supressão pela dexametasona. Quantificaram-se ainda os receptores aos glucocorticoides (RGs) no hipocampo por western blot. Os ratinhos Tg2576 mostraram um comprometimento do eixo HPA, caracterizada pelo aumento de corticosterona no ínicio da fase activa e ausência de regulação negativa induzida pela dexametasona. Ainda, os RGs estão aumentados e mostram comprometimento na regulação negativa induzida no eixo HPA. Para avaliar a memória episódica foi efectuado um teste de reconhecimento de objectos que combina a capacidade de recordar o ‘quê, quando e onde’ de um evento. Os ratinhos Tg2576 apresentaram um deficit na componente ‘onde’ deste tipo de memória. Foi em seguida aplicado um tratamento in vivo com um antagonista dos RGs (RU486) para avaliar se bloqueando a função dos RGs se poderia reverter o deficit observado. Os nossos primeiros resultados revelam que o bloqueia dos RGs pode prevenir o deficit na memória episódica. Assim este trabalho mostrou que os ratinhos Tg2576 apresentam uma perturbação ao nível do eixo HPA e da sua regulação pelos RG do hipocampo, traduzidos por um nível de stress aumentado, e perturbação ao nível da memória episódica. Este trabalho mostra que o nível de stress está aumentado numa fase muito precoce da DA neste ratinho devido à disfunção do eixo HPA. Para além disso, a alteração nesta sinalização mediada pelos RGs, contribui provavelmente para os deficits precoces na memória episódica observados neste ratinho. Estes resultados suportam a nossa hipótese de que o stress é um factor de risco muito importante no desenvolvimento precoce da neuropatologia na doença de Alzheimer.
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Radtke, Karl [Verfasser]. "Early adversities and epigenetic modifications of HPA-AXIS genes / Karl Radtke." Konstanz : Bibliothek der Universität Konstanz, 2017. http://d-nb.info/1124780823/34.
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Finn, David Patrick. "Monoamines and the neuroendocrine response to stress : the role of imidazoline I₂ binding sites and α₂-adrenoceptors." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340303.
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Henderson, Dallas Wade. "Stress Response and Acclimation in the Adult Turquoise Killifish Nothobranchius furzeri." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/theses/1941.
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The turquoise killifish Nothobranchius furzeri is an increasingly popular model species for comparative vertebrate research. As such, the basic physiology, including responses to one or multiple stress events are of primary interest to the present study. After successful rearing, adult male and female killifish were exposed to one or more acute confinement events. Whole-blood was taken from adult males, in addition to male and female whole-body samples for cortisol analysis. Separate adults were also sampled for tissue specific expression of corticotropin releasing hormone (CRH), mineralocorticoid receptor (MR), and glucocorticoid receptor (GR) mRNA within the cranium, gills, and liver. Following a 30 minute confinement stress, male plasma cortisol significantly differed from baseline at 30 minutes (P=0.04). Similarly, both male and female whole-body cortisol were significantly increased (P=0.004 and P=0.04, respectively) at 15 and 30 minutes post-stress. Whole-body cortisol did not differ between the sexes at any sampling point, however; expression of gill MR at 15 minutes was significantly higher in males (P=0.05). Exposure to daily repeated confinement affected the cortisol response in both males and females, resulting in lower baseline and 60 minutes post-stress values in repeatedly-stressed males (P=0.04 and P=0.006, respectively) and lower cortisol at 30 and 120 minutes post-stress in repeatedly-stressed females (P=0.04 and P=0.04). Repeated exposure also resulted in increased cranial CRH and MR at 15 minutes post-stress (P=0.02 and P=0.05, respectively) compared to singly-stressed males. In females, repeated exposure increased gill MR at 120 minutes (P=0.05), but a single stressor resulted in relatively greater expression of cranial CRH at 120 minutes (P=0.02) and MR at 15 minutes (P=0.05). Collectively, the reduced cortisol production observed in repeatedly-stressed adults coupled with only transient changes in receptor expression suggest acclimation to daily stressors can be detected in as little as one week in adult turquoise killifish. This is also the first description of the stress response on this important model species.
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Zhang, Xiaowei. "Application of toxicogenomic approaches to study chemical-induced effects on the hypothalamic-pituitary-gonadal (HPG) axis of the Japanese medaka (Oryzias latipes)." Diss., Connect to online resource - MSU authorized users, 2008.
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Thesis (Ph. D.)--Michigan State University. Dept. of Zoology & Environmental Toxicology, 2008.Title from PDF t.p. (viewed on Mar. 30, 2009) Includes bibliographical references. Also issued in print.
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Evanson, Nathan K. "Rapid regulation of the hypothalamus-pituitary-adrenal axis by glutamate and glucocorticoids." Cincinnati, Ohio : University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view.cgi?acc_num=ucin1227289026.
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Thesis (Ph.D.)--University of Cincinnati, 2008.Advisor: James Herman PhD (Committee Chair), Randall Sakai PhD (Committee Member), Stephen Woods PhD (Committee Member), David D'Alessio MD (Committee Member), Yvonne Ulrich-Lai PhD (Committee Member). Title from electronic thesis title page (viewed Feb. 9, 2009). Keywords: HPA axis; glutamate; cannabinoids; nongenomic; glucocorticoids. Includes abstract. Includes bibliographical references.
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Riel, Els van. "Dysregulation of the HPA-axis implications for serotonin responses in the hippocampus /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/73464.
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Schreckenbach, Monika [Verfasser]. "Dissociative stress response corresponds with downregulation of the HPA-axis / Monika Schreckenbach." Konstanz : KOPS Universität Konstanz, 2019. http://d-nb.info/1198113375/34.
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Seale, Josephine Victoria. "Gonadal steroids : modulators of hypothalamo-pituitary-adrenal (HPA) axis activity throughout life." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414189.
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Shin, Andrew Changhun. "Unveiling diet-induced obesity leptin insensitivity and dysregulation of the HPA axis /." Diss., Connect to online resource - MSU authorized users, 2008.
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Bakirtzi, Georgia. "Epigenetic regulation of POMC : implications for the hypothalamic-pituitary-adrenal (HPA) axis." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9455/.
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Alves, Luana Maria Silva. "Efeitos de estrógeno e de progesterona na atividade basal do eixo hipotálamo hipófise adrenal." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-03082015-135704/.
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Há evidencias de interação bidirecional dos eixos HPA e HPG envolvendo diferentes estruturas, entretanto, os mecanismos envolvidos são pouco compreendidos. Situações de estresse podem alterar a função reprodutiva, e hormônios gonadais podem modificar a resposta de estresse. O objetivo deste trabalho foi verificar se estrógeno (E 2) e progesterona (P4) modificam a atividade basal do eixo hipotálamo-hipófise-adrenal (HPA), analisada pelas secreções de corticosterona (CORT) e de P4 e pelas expressões de receptores para corticosteróides (mineralocorticóides, MR e glicocorticóides, GR) em sítios cerebrais de retroalimentação do eixo HPA. Ratas Wistar adultas foram mantidas em ciclo claro-escuro de 12h e acesso livre à ração e água. O ciclo estral foi monitorado por esfregaço vaginal e a determinação da secreção de hormônio luteinizante (LH) foi realizada para confirmação do proestro. Seis amostras de sangue foram coletadas através de cateter na jugular, durante a tarde (13-18h), dos seguintes grupos de ratas: ovariectomizadas (OVX); controles em proestro; tratadas com antagonista de E 2 (tamoxifen) ou de P4 (RU486), ou ambos; tratadas com os respectivos veículos dos antagonistas. O plasma foi separado e estocado para dosagens hormonais por radioimunoensaio. Após a última coleta de sangue, os animais foram anestesiados e perfundidos para remoção dos cérebros, que foram manipulados para verificação por imunofluorescência, da expressão de MR e de GR na região CA1 e no subículo do hipocampo ventral, e de GR no núcleo paraventricular (PVN). Os resultados mostram que: a secreção de LH confirmou a fase de proestro; a secreção basal de CORT não foi alterada pelas manipulações de injeções nem pela remoção dos ovários; ocorreu pico de secreção de CORT e de P 4 às 14h em todos os grupos experimentais; os antagonistas de E 2 e de P 4 não alteraram a secreção total de CORT, porém o RU486 aumentou (às 13 e 15h) e o tamoxifen reduziu (às 15h) a concentração de CORT; um segundo pico de secreção de P 4 no final da tarde (17-18h) foi bloqueado pela ovariectomia e por Tamoxifen , e amplificado por RU486; o segundo pico de P 4 também não ocorreu em ratas tratadas com Tamoxifen e RU486 ; não houve alteração do número de neurônios com expressão de GR e MR na região CA 1 e no subículo do hipocampo ventral nem de GR no PVN. Em conclusão, nossos resultados indicam que: E2 e P 4 podem exercer efeitos antagônicos sobre a secreção basal de CORT, respectivamente estimulatório e inibitório; os picos de secreção de P 4 têm origens diferentes, o primeiro (14h) da adrenal e o segundo (17-18h) do ovário; E 2 estimula a secreção ovariana de P 4 na tarde de proestro; E2 e P 4 não alteram o número de neurônios que expressam GR e MR em sítios de retroalimentação do eixo HPA, mas não se pode descartar que alterem a atividade desses neurônios.There is evidence for a bidirectional communication between HPA and HPG axis involving different structures, however the involved mechanisms are poorly known. Stress situations may alter the reproductive function, and gonadal steroids may modify the stress response. The aim of this study was verify if estrogen (E 2) and progesterone (P 4 ) can alter the basal activity of hypothalamic-pituitary-adrenal axis, analyzed by corticosterone (CORT) and P 4 secretions and by mineralocorticoid and glicocorticoid receptors (MR and GR, respectively) expression at HPA axis central feedback sites. Adult female Wistar rats were kept in 12h light-dark cycle and had free access to food and water. The estrous cycle was monitored by vaginal smears and the luteinizing hormone dosage was done to confirm proestrus. Six samples of blood were collected by jugular cannula, during the afternoon (13-18h), of the following groups: ovariectomized (OVX), proestrus controls, treated with E 2 or P 4 antagonists (tamoxifen or RU486, respectively), or with both, and treated with antagonists vehicle. The plasm was stored for hormonal dosages by radioimmunoassay. After the last blood sample, animals were anesthetized, perfused, and the brains were removed and processed for immunofluorescence to analyze MR and GR expression at ventral hippocampus CA 1 and subiculum, and GR expression at paraventricular nucleus (PVN). The results showed that: LH secretion confirmed the proestrus; CORT basal secretion was not altered by injections neither by ovariectomy; there was a CORT and a P4 secretion peak at 14h in all experimental groups, E 2 and P 4 antagonists did not modify the CORT total secretion, however RU486 increased (at 13 and 15h) and tamoxifen reduced (at 15h) CORT levels, another P4 secretion peak in the late afternoon (17-18h) was blocked by ovariectomy and tamoxifen, but enhanced by RU486, the P 4 second peak did not occur in rats treated with both tamoxifen and RU486, there were no changes in the number of neurons expressing GR and MR at ventral hippocampus CA 1 and subiculum neither of GR expressing neurons at PVN. In conclusion, our results indicate that: E2 and P 4 can have antagonistic effects over basal CORT secretion; stimulatory and inhibitory, respectively; the P 4 secretion peaks have different origins, the first (14h) is adrenals and the second (17-18h) is ovarian: E2 stimulates ovarian P 4 secretion in the proestrus afternoon; E 2 and P 4 do not alter the number of neurons that express MR and GR at HPA axis feedback sites, but one can not exclude the possibility that they alter the activity of these neurons.
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Nayar, Shweta. "NOCICEPTIN/ORPHANIN FQ (N/OFQ) REGULATION OF THE STRESS RESPONSE: INTERACTION BETWEEN PROLACTIN AND THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS." Miami University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1382509698.
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Engman, Robin. "HPA* Used With a Triangulation-Based Graph." Thesis, Blekinge Tekniska Högskola, Institutionen för kreativa teknologier, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-5630.
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Context: Pathfinding is an important phase when it comes to AI. The AI needs to know how to get from one point to another when there are obstacles ahead. For that reason, different pathfinding algorithms have been created. Objective: In this paper a new pathfinding algorithm, THPA*, is described, and it will also be compared to the more common algorithms, A*, and HPA* which THPA* is based on. Methods: These algorithms are then tested on an extensive array of maps with different paths and the results consisting of the execution times will be compared against each other. Results: The result of those tests conclude that THPA* performs better in terms of execution time in the average case; however it does suffer from low quality paths. Conclusions: This paper concludes that THPA* is a promising algorithm albeit in need of more refinement to make up for the negative points.
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Katopodis, Angela. "Gender differences in the response of the HPA-axis to alcohol and stress." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82262.
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Stress plays a significant role in the initiation and continuation of drinking. Furthermore, epidemiological studies have shown a higher incidence of alcoholism in males than females. Objective. The current studies aimed to investigate the presence of gender differences in the interactions of ethanol and stress with the Hypothalamic-Pituitary-Adrenal (HPA) axis. Methods. Participants included 12 males and 10 females with no previous personal or familial history of alcoholism. Plasma levels of ACTH and cortisol were estimated following a placebo drink, a low and a high dose of alcohol and a psychological stress task performed 30 minutes after the ingestion of the placebo, the low and the high alcohol drinks. Results. Male participants presented a more pronounced response of the HPA-axis to both alcohol and psychological stress. Prior ingestion of the low and to a lesser extent of the high dose of alcohol induced a more pronounced and longer lasting attenuation of the HPA-axis response to stress in males than females. Conclusions. There are gender differences in the interactions of ethanol and stress with the HPA-axis, which may contribute to the gender differences in alcohol consumption.
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Berg, Ingrid Helene. "The Relationship Between Insomnia and CFS/ME : The HPA Axis as a Mediator." Thesis, Norges teknisk-naturvitenskapelige universitet, Psykologisk institutt, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-25191.
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Fatigue is common in the general population, and is the hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Although the occurrence of sleep difficulties is known to be common in subjects with fatigue, research on insomnia in such subjects is absent. The current study sought to examine the impact comorbid insomnia has on level of fatigue in subjects with chronic fatigue. The aim of this study is to assess the relationship between insomnia and chronic fatigue, and examine if the relationship is affected by the endocrine activity in the HPA axis. The following hypotheses were tested: 1) Do patients with chronic fatigue and comorbid insomnia experience more fatigue than patients with chronic fatigue without comorbid insomnia? 2) Do patients with chronic fatigue and with initially comorbid insomnia experience more fatigue after treatment than chronic fatigue patients without comorbid insomnia? 3) Do patients with chronic fatigue who experience improvement in insomnia after treatment also experience less fatigue by the end of treatment compared with patients who do not experience improvement in insomnia? 4) Is the potential relationship between insomnia and chronic fatigue influenced by the activity of the HPA axis as expressed by variation in cortisol output measured by Trier Social Stress Test for Groups (TSST-G)? The study sample consisted of 75 patients with chronic fatigue. Thirty-three met criteria for insomnia, while 42 did not. While staying at Hysnes Rehabilitation Center in Trondheim, Norway, they received a work-related Acceptance and Commitment Therapy (ACT) treatment intervention lasting 3.5 weeks. In addition, they participated in a standardized stress test (Trier Social Stress Test) pre- and post-treatment. Saliva cortisol samples were collected during the test in order to measure variation in cortisol output. The current finding is the first description of how insomnia in patients with chronic fatigue is associated with higher levels of fatigue (p < .05). Further, this study gives preliminary support indicating that remission of insomnia in patients with chronic fatigue can significantly reduce levels of fatigue (p < .05), and furthermore improve the physiological stress-response (p < .05). These results might encourage clinicians to assess and provide specific treatment for insomnia in patients with chronic fatigue as this might improve their treatment results. An aim for further research should be to investigate the effect of specified treatment for insomnia in patients with chronic fatigue.
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Faturi, Claudia de Brito [UNIFESP]. "Consequências da privação materna para o comportamento tipo-ansioso: participação do eixo hipotálamo-pituitária-adrenal e do sistema de neurotransmissão GABAaérgico." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9250.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Alguns estudos pré-clínicos têm demostrado que eventos adversos na infância e adolescência representam um fator de vulnerabilidade para o surgimento de transtornos psiquiátricos na idade adulta, e que a redução da resiliência à eventos estressantes deve desempenhar um papel importante neste fenômeno. As manipulações em animais de laboratório, como a privação materna (PM) por 24 h durante o período de hiporresposividade ao estresse (PHRE), podem ser um instrumento útil para a compreensão de como os eventos no período precoce do desenvolvimento resultam em alterações comportamentais e da atividade do eixo Hipotálamo-Pituitária-Adrenal (HPA) na idade adulta. Alguns autores têm observado que a PM, quando imposta no 3° dia de vida (antes do início) ou no 11° dia (no vale) do PHRE, resulta em padrões de atividade do eixo HPA distintos. A PM no 3° dia induz à hiperatividade do eixo, enquanto que no 11° dia, resulta na hipoatividade, alterações estas observadas em animais jovens. Assim, os principais objetivos do presente trabalho foram os de estudar como a PM afetaria a atividade do eixo HPA durante o PHRE, e verificar se essas alterações teriam conseqüências duradouras. Os resultados mostraram que os efeitos da PM na liberação de ACTH mantiveram o mesmo padrão de atividade relatado na adolescência, ou seja, hiperresponsividade no grupo submetido à PM no 3o dia de vida e hiporresponsividade no grupo submetido à mesma manipulação no 11o dia de vida. No entanto, essa alteração não se refletiu na liberação da corticosterona (CORT), pois não se observou diferença na secreção deste hormônio entre os grupos. Além disso, a PM não alterou a liberação de CORT em resposta ao Teste de supressão à Dexametasona, indicando que não houve alterações no sistema de retroalimentação negativa no nível hipofisário do eixo HPA. A PM afetou o comportamento do tipo ansioso nos animais de ambos os grupos PM, sendo que tal alteração parece não ter sido mediada por mudanças na densidade do sítio benzodiazepínico do receptor GABAA. Os resultados indicaram que, embora a PM não leve a alterações permanentes na secreção da corticosterona, este pode ser um modelo animal interessante para se estudar o substrato neurobiológico que faz com que um evento adverso durante o desenvolvimento aumente a vulnerabilidade aos transtornos relacionados à ansiedade.
Adverse events in childhood have been associated to the development of psychopathologies, such as depression and anxiety disorders. In rats, stressful events during neonatal period, like 24h Maternal Deprivation (MD), may be an interesting tool to understand how stress during early life leads to changes in behavior and stress response in adulthood. According to some studies, MD on the 3rd day (MD 3-4) or 11th day (MD 11- 12) of life results in opposite changes in the activity of the Hypothalamus-Pituitary- Adrenal (HPA) axis, i.e., hyper and hyporresponsiveness, respectively. Since in human beings psychopathologies has been related to impairment in resilience to stress the aim of this work was to investigate whether MD leads to long lasting changes in HPA axis functioning and differential behavioral features in animal models of anxiety. The results obtained indicate that only the ACTH release presented the pattern we hypothesized. Conversely the corticosterone (CORT) plasmatic levels do not reflect this pattern. Moreover, MD did not affect the CORT release in response to the Dexamethasone Suppression Test, indicating that there are MD did not alter the negative feedback system. Although MD did not lead to convincing alteration to CORT levels it did change anxiety-like behavior in the group MD 11-12. However this behavioral change did not seem to be mediated by expression of benzodiazepine site in GABAA receptors. The results indicate that even though the MD procedure does not lead to consistent changes in the peripheral component of the HPA axis it could still be an interesting animal model to study the neurobiological underpinnings of how adverse events in early life increase the vulnerability to psychopathologies.
FAPESP: 2006/06415-4
TEDE
BV UNIFESP: Teses e dissertações
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Duncan, Peter James. "Regulation of murine corticotroph cell excitability." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17965.
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Corticotroph cells from the anterior pituitary are an integral component of the hypothalamic-pituitary-adrenal (HPA) axis, which controls the neuroendocrine response to stress. Following stressful stimuli, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus act synergistically to stimulate adrenocortiotrophin hormone (ACTH) secretion from corticotroph cells. ACTH is released into the circulation where it stimulates the secretion of glucocorticoids from the adrenal cortex. The HPA axis is kept in fine balance through an elegant negative feedback system where elevation of plasma glucocorticoids results in inhibition at the level of both the pituitary and the hypothalamus. During acute stress, glucocorticoids can be beneficial however chronic elevation of glucocorticoids can have many adverse effects on health. Corticotroph cells are electrically excitable and have been shown to fire single-spike action potentials as well as complex bursting patterns. Stimulation of corticotrophs with physiological concentrations of CRH/AVP results in a robust increase in firing frequency and a transition from spiking to bursting. Intracellular Ca2+ increases to a greater extent during bursting which has been proposed to drive hormone secretion. There is evidence to suggest that large conductance calcium- and voltage-gated potassium (BK) channels promote bursting behaviour in anterior pituitary cells. Glucocorticoids have been shown to regulate ACTH secretion and also modulate BK channel activity. However, the effects of glucocorticoids on native corticotroph excitability are currently unknown. The aim of this study was to first characterise the electrical properties of corticotrophs under basal conditions and following exposure to CRH/AVP. Secondly, to investigate the regulation of corticotroph excitability by glucocorticoids. Finally, establish the role of the BK channel in regulating bursting behaviour and CORT regulation in corticotroph cells. Corticotroph cells were acutely isolated by trypsin digestion from mice aged 2-5 months constitutively expressing GFP under control of the POMC promoter (POMC-GFP). Mice used for pituitary cell culture were male unless otherwise stated. Cells were maintained in a serum free media and electrophysiological recordings obtained 24-96 hours post-isolation. Current clamp recordings were obtained from corticotrophs using the perforated patch technique. Although spontaneous activity of corticotroph cells was variable, they displayed predominantly single-spike action potentials under basal conditions. Stimulation with physiological concentrations of CRH and AVP (0.2 nM and 2 nM respectively) resulted in a membrane depolarisation accompanied by an increase in firing frequency and a transition to bursting. Individually, CRH and AVP were able to increase corticotroph excitability. However, only CRH was able to drive an increase in bursting suggesting that bursting is primarily regulated through the cAMP/PKA pathway. Experiments were performed to investigate the modulation of corticotroph activity by glucocorticoid negative feedback. Acute exposure (< 10 min) to corticosterone resulted in a decrease in spontaneous activity as well as shortening the response to CRH/AVP. Pretreatment of corticotrophs with 100 nM corticosterone (90 min) resulted in a membrane hyperpolarisation and a decrease in spontaneous firing frequency. Following corticosterone pretreatment, CRH/AVP failed to induce a significant transition from spiking to bursting. Increasing the pretreatment time to 150 minutes resulted in a further suppression of both spontaneous and CRH/AVPevoked activity. Fast activation of BK channels during the upstroke of an action potential has been proposed to promote bursting behaviour in other pituitary cells. Corticotrophs treated with a BK channel blocker (1 μM paxilline) or isolated from BK-/- mice showed no significant difference in basal activity but displayed a reduction in CRH/AVPevoked bursting activity. In both cases, bursting was significantly reduced but not completely abolished. Corticosterone treatment of BK-/- cells resulted in a further decrease in both firing frequency and bursting behaviour. Taken together, these results suggest that although BK channels play an important role in bursting, they are not the only component. Comparisons of male and female corticotrophs revealed subtle differences in their properties. Following CRH/AVP stimulation, male cells displayed a high degree of bursting activity whereas female cells exhibited predominantly an increase in singlespike action potential frequency. Treatment of female corticotrophs with corticosterone (150 min) resulted in a significant reduction in firing frequency but no measurable change in bursting behaviour. BK-/- cells from female mice showed no difference in bursting activity following CRH/AVP compared to wild types. This data suggests that modulation of firing frequency is the more important component in female corticotroph cells. In conclusion, CRH/AVP is proposed to drive ACTH secretion in male corticotroph cells through an increase in bursting activity. Corticosterone pretreatment suppresses both spontaneous and CRH/AVP-evoked activity. It is possible that corticosterone regulates corticotroph excitability through two mechanisms. Corticosterone suppresses bursting activity following CRH/AVP stimulation through multiple targets which might include the BK channel. Additionally, corticosterone reduces firing frequency through a mechanism independent of BK channels. It is important to further characterise the physiology of corticotroph cells and how ACTH secretion is regulated through their electrical excitability. This would lead to a greater understanding of the role of corticotrophs in the HPA axis. Further study of corticotrophs could potentially lead to pharmacological manipulation of the stress response and novel treatments for stress-related disorders.
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Figueiredo, Danielle. "Influence of Life Events on the Stress Response in Healthy Children and Adolescents." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41220.
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A life event is as an occurrence that involves a subsequent change in the life pattern of an individual (Holmes & Rahe, 1967). The current study investigated whether exposure to life events over the past year influenced hypothalamic-pituitary-adrenocortical (HPA) axis function in healthy children and adolescents, and explored whether sex, age, behavioural inhibition, trait anxiety, anxiety sensitivity, perceived parental bonding, and parental history of anxiety moderated this relationship. The sample included 147 healthy children and adolescents. Participants were administered Coddington’s Life Events Scale (CLES) and salivary cortisol was collected for the determination of the cortisol awakening response (CAR), diurnal cortisol, and cortisol reactivity to a laboratory stressor. Separate linear regression models were conducted for each cortisol profile. Results revealed that life events significantly predicted total CAR output, diurnal cortisol response, and cortisol reactivity to a laboratory stressor. Further, behavioural inhibition, trait anxiety, not having a parental history of anxiety, and paternal caring positively moderated some of the relationships between life events and cortisol profiles. Considering the physiological and psychological effects of early exposure to stress, this study is significant in understanding the impact of life events to improve the health of children and adolescents.
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Tahera, Yeasmin. "Modulation of the HPA axis alters the sensitivity of the cochlea to acoustic trauma /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-932-7/.
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Baiamonte, Matteo. "Developmental ethanol exposure and its impact on behaviour and HPI axis activity of zebrafish." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/7873.
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Ethanol exposure during pregnancy is one of the leading causes of preventable birth defects, leading to a range of symptoms collectively known as fetal alcohol spectrum disorder (FASD). More moderate levels of prenatal ethanol exposure (PNE) lead to a range of behavioural deficits including aggression, poor social interaction, poor cognitive performance and increased likelihood of addiction in later life. Current theories suggest that adaptation in the hypothalamic-pituitaryadrenal (HPA) axis and neuroendocrine systems contributes to mood alterations underlying behavioural deficits and vulnerability to addiction. This has led to the suggestion that corticotrophin-releasing factor (CRF) antagonists and glucocorticoid (steroid) inhibitors may be potential therapeutics to address the deficits of PNE and for the treatment of addiction. The zebrafish (Danio rerio) has several advantages over mammalian models, such as low cost of maintenance, short life cycle, easy embryological manipulation and the possibility of large-scale genetic screening. By using this model, our aim is to determine whether developmental ethanol exposure provokes changes in the HPA axis (HPI axis in fish), as it does in mammalian models, therefore opening the possibilities of using zebrafish to elucidate the mechanisms involved, and to test novel therapeutics to alleviate deleterious symptoms. Thus this thesis focuses solely on the effect of developmental ethanol exposure on the functioning of the HPI axis in zebrafish. Stress-reactivity in zebrafish larvae ethanol-treated 1-9 days post 4 fertilisation (dpf) was assessed using thigmotaxis and thigmotaxis following airstress. In both tests, lower stress-related responses were obtained with ethanol treated animals, in that they spent less time at the edges of the apparatus (P<0.01, n=3). They also showed lower total body cortisol (P=0.04, n=14). Larvae also showed the same behaviour pattern two weeks after ethanol exposure, (23dpf) (P=0.04, n=3), again with reduced total cortisol (P=0.03, n=4). HPI-related gene transcription was also assessed in 9dpf ethanol treated zebrafish larvae, by qRT-PCR. Revealing up-regulation of CRH, CRHBP and CRHR2, normalized against β-Actin, Elav1 and Gap43 housekeeping genes. In situ hybridization revealed no spatial changes in CRH, CRH-BP and POMC with animals at the same stage. Behavioural stress-reactivity differences in 6-months old adults that had been exposed developmentally to ethanol were assessed using novel tank diving and thigmotaxis. Both assays indicated a decrease in stress-like behaviour due to early ethanol exposure compared to controls (P<0.05, n=5 both). Finally, cortisol levels were assayed from 9dpf larvae and 6-month-old adults that had been treated with ethanol during early development showed a significant reduction in cortisol output when air-exposed stressed compared to controls (P=0.04, n=5). Conclusion: Early ethanol exposure produced significant changes in cortisol, HPI gene mRNA expression and stress-reactive behaviour in 9dpf animals. Changes in cortisol and behaviour were still detected in 6-months old adults, developmentally treated with ethanol, indicating that early ethanol exposure has permanent effects on the HPI axis. 5 As our data contradicts the findings in mammalian literature where early ethanol exposure increases stress-like behaviour in later life, it is also possible that more permanent effects of PNE in mammals may arise through maternal-offspring interactions, during and post gestation, such as breastfeeding and maternal grooming of the offspring, which are absent in the zebrafish model.
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Michailidou, Zoi. "Modelling altered glucocorticoid sensitivity : from HPA axis to metabolic abnormalities in mice and humans." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/2689.
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The primary determinants of tissue glucocorticoid action are glucocorticoid receptor (GR) density and intracellular levels of ligand, the latter determined both by activity of the hypothalamic-pituitary-adrenal (HPA) axis and cellular activity of 11beta- hydroxysteroid dehydrogenase (11beta-HSD) enzymes that interconvert active 11- hydroxy (corticosterone, cortisol) and inactive 11-keto (11-dehydrocorticosterone, cortisone) glucocorticoids. Here, the contribution of GR density and ligand levels in determining body composition and metabolic phenotype have been investigated in mice and in humans. Genetic evidence in humans implicates variations in the GR gene in the regulation of the HPA axis as well as the control of body fat distribution, metabolic parameters and blood pressure. Although GR deficient mouse models have been previously generated (with homozygous nulls dying at birth), the effects of altered GR density upon fat distribution and blood pressure have not been described. This study addresses the relationship between GR density and metabolic parameters, including body fat distribution, insulin resistance and hypertension. A novel line of mice harbouring a null mutation in the GR gene (GR+/-) was generated from an ES cell line in which a beta-galactosidase-neomycin phosphotransferase (beta geo) reporter cassette was fused with GR. The resulting fusion protein lacks part of the DNA binding domain and the entire ligand binding domain and is transcriptionally inactive. In addition, the beta-galactosidase enzyme activity “reports” activity of the GR gene promoter. GR-/- mice are present in a normal Mendelian ratio before birth. Intriguingly, 1 (of 36/146 expected if null allele not lethal) survived to adulthood suggesting this might be a hypomorphic rather than a null allele. Heterozygous 15 (GR+/-) mice showed 40-45% reductions in GR mRNA levels in the hippocampus, paraventricular nucleus of the hypothalamus, pituitary gland and adipose tissue, 30% in liver, 56% in muscle and 67% in adrenals. X-gal staining of GR+/- brain sections showed that GR-beta gal is present throughout, mirroring GR mRNA expression. Adult GR+/- mice had larger adrenals, higher evening plasma corticosterone levels and greater corticosterone responses following 10 minute restraint suggesting a hyperactive HPA axis. Compared to GR+/+ littermates, GR+/- mice had similar body weight gain on normal chow or high fat diet, with unaltered fat depot (inguinal, epididymal, mesenteric) weights and similar glucose and insulin tolerance. However, GR+/ - mice had higher (10%) systolic blood pressure, associated with activation of the renin-angiotensin system. Thus GR haploinsufficiency in mice causes increased blood pressure and accords with data associating GR polymorphisms with hypertension in humans. The role of altered GC sensitivity was also investigated in a mouse model of HPA axis hypoactivity pro-opiomelanocortin null (POMC) mice. POMC-null mice are obese due to central melanocortin deficiency. In contrast to most rodent models of obesity, POMC-null mice are also glucocorticoid deficient due to ACTH deficiency. Previous data have shown that glucocorticoid replacement in POMC-null mice exaggerated hyperphagia, obesity and insulin resistance and caused hypertension. Here, the contribution of peripheral glucocorticoid sensitivity was investigated. POMC-null mice have increased liver and retroperitoneal fat GR mRNA levels but, specifically in adipose tissue, decreased levels of mRNA encoding 11beta-HSD1, a reductase which regenerates active glucocorticoids, thus amplifying their action.
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Di, Rollo Emma Margaret. "Role of 5α-reductase type 1 in modifying anxiety, appetite and the HPA axis." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/10026.
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Glucocorticoid excess is associated with adverse effects on a number of physiological parameters, leading to obesity, dysfunction of the hypothalamic-pituitary- adrenal (HPA) axis and behavioural changes such as anxiety and impaired learning and memory. Circulating and local tissue glucocorticoid levels are tightly controlled by the HPA axis but an additional level of control exists in tissues such as brain, liver and adipose tissue. In these structures, enzymes including 5α-reductase 1 (5αR1), catalyse the conversion of corticosterone to A-ring reduced metabolites, which have a different spectrum of activities. This thesis investigates the role of 5αR1 in regulating central glucocorticoid actions which control HPA axis function and behaviour in a mouse model with genetic disruption of 5αR1 (5αR1-KO). Preliminary data showed 5αR1-KO mice were susceptible to developing insulin resistance and obesity and had reduced HPA axis responses to acute stress. Additionally, male 5αR1-KO mice were more prone to obesity than wild-type (WT) when fed a high-fat diet whilst female 5αR1-KO mice gained more weight than WT even on a normal chow diet. Intriguingly, female 5αR1-KO mice subjected to social isolation stress lost this extra weight and became comparable to WT controls. This study tested the hypothesis that 5αR1-KO mice are less able to inactivate glucocorticoids in the periphery and within tissues, resulting in a predisposition to metabolic disturbances and behavioural alterations. These were hypothesised to include hyperphagia, weight gain, impaired stress responses, anxiety (exacerbated by environmental stress) and cognitive deficits. It was also thought that many of these features would be more pronounced in female vs. male mice. The main aims of this study were to determine if 5αR1-KO induced weight gain and if this was correlated to altered gene expression of key hypothalamic neuropeptides which regulate appetite, to determine the central mechanisms which underpin attenuated HPA axis responses to acute stress and to determine whether behaviours such as anxiety and learning and memory ability are affected by global 5αR1 loss. It was hypothesised that female 5αR1-KO mice have increased appetite and reduced locomotor activity compared with WT and male 5αR1-KOs. However, male 5αR1- KO mice (on a mixed genetic background, C57Bl/6j/SvEv/129) were hyperphagic on a normal chow diet but did not gain extra weight, while female 5αR1-KO mice gained more weight vs. WT despite hypophagia. Free ambulatory activity was unaffected by genotype in either sex. Male 5αR1-KO mice appeared less anxious but responses of female 5αR1-KO mice in tests of anxiety did not differ from WT controls. Mice lacking 5αR1 generally had a poorer metabolic profile with impaired glucose tolerance and hyperinsulinaemia; with hepatic steatosis evident in female mice. There was evidence of compensatory changes in hypothalamic orexigenic and anorexigenic peptides. Phenotypes were sexually dimorphic such that male mice had a poorer metabolic profile vs. females, which was particularly marked in male 5αR1- KO animals. 5αR1-KO mice were previously shown to have attenuated HPA axis responses to acute stress and it was hypothesised that disruption of 5αR1 would result in altered expression of genes related HPA axis regulation with a view to increased negative feedback. Here, male and female 5αR1-KO mice demonstrated altered corticosteroid receptor expression within the hippocampus and the pituitary, two key structures in the HPA cascade. In situ hybridisation showed reduced mRNA for MR in the hippocampus and for Crh in the hypothalamus of 5αR1-KO mice. These modifications along with decreased Crhr-1 mRNA (CRH‘s main receptor) may be due to a lack of corticosterone metabolism within the brain resulting in enhanced negative feedback and reduced HPA axial drive. In order to study behaviour in detail and also to test whether potential central glucocorticoid excess may predispose to cognitive decline with ageing, a separate cohort of female 5αR1-KO backcrossed onto a uniform C57Bl/6j background was studied both when young (6 months) and when aged (14-15 months). Additionally, mice were housed in either groups or singly (social isolation) to investigate the potentially additive effects of environmental stress. It was hypothesised that local glucocorticoid increases in the brains of 5αR1-KO mice would be associated with anxiety and cognitive deficiencies and that these phenotypes would be exaggerated by the stress of social isolation as well as ageing. Behavioural differences were not observed at 6 months of age. However aged, 5αR1-KO mice housed singly showed increased anxiety and had higher plasma corticosterone levels than group-housed mice. Moreover, aged mice lacking 5αR1 performed less well than WT in tests of memory and had a marginally greater cognitive decline when learning ability at 14- 15 months old was compared to that of the same animals tested at 6 months old. Overall, mice with global 5αR1 loss appeared susceptible to anxiety as well as some degree of age-associated cognitive impairment, but only when subjected to social isolation stress which is a known chronic stressor. The final set of experiments aimed to determine the effect of mouse strain on 5αR1- KO phenotypes. It was hypothesised that glucocorticoid clearance would be attenuated to a lesser degree in 5αR1-KO mice bred onto a congenic C57Bl/6j strain compared to those of the mixed strain and that this would manifest as less disruption of metabolism and less suppression of HPA axis stress responses. Although social isolation again induced weight-loss in female mice and more so in 5αR1-KO animals, mice on the C57Bl/6j background strain did not show dampened HPA axis responses to acute stress as seen previously. It was subsequently shown in adrenalectomised mice that animals bred on the C57Bl/6j strain cleared active corticosterone from plasma and liver faster than mixed strain mice. This may have rendered mixed strain 5αR1-KO mice more susceptible to excessive corticosterone levels producing a more exaggerated phenotype in this group. In conclusion, these data suggest a role for the enzyme 5αR1 in modifying glucocorticoid concentrations in the brain and liver, influencing not only metabolic and peripheral effects such as weight gain and insulin resistance, but also in modifying cognition, appetite stimulation and affective behaviours. It has been highlighted that outside factors such as housing and age can modify these phenotypes and are important considerations for future studies. This study has also highlighted the importance of choosing an appropriate genetic background for genetically modified animals since phenotypes can be enhanced or attenuated depending on strain. Finally, 5αR inhibitors are used to treat disorders such as benign prostatic hyperplasia in men, and it is important to consider that these drugs may have a wide array of associated side effects both systemically and in the central nervous system.
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Seltzer, Molly K. "DISCRIMINATION, HPA-AXIS ACTIVITY, AND RACIAL IDENTITY IN AFRICAN-AMERICAN ADOLESCENT RISK FOR DEPRESSION." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/536392.
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PsychologyPh.D.
Culturally relevant models of social, psychological, and biological risk for depression in African American youth have long been called for, to account for unique risk factors they experience (e.g., discrimination) and that incorporate culturally specific protective assets (e.g., racial identity). Yet few studies have directly examined physiological mechanisms that might mediate the connection between discrimination and depression, nor the way in which cultural assets may attenuate such pathways. The present study is an explicit test of a model of risk for depression that integrates discrimination during adolescence, the hypothalamic-pituitary-adrenal (HPA)-axis as a biological regulator of social stress, and dimensions of racial identity as potential moderators of HPA-axis dysregulation. A subsample of 109 African-American adolescents (age 11-17; M = 12.88, SD = 1.11) who completed a social stress paradigm was drawn from a larger longitudinal study on risk for depression. Utilizing a longitudinal design, variables were collected on prior discrimination experience, cortisol reactivity and recovery during the stress paradigm, racial identity at the time of the stress paradigm, and concurrent and prospective depressive symptoms. A series of regression analyses and t-tests were conducted to test the impact of discrimination on cortisol regulation and depressive symptoms, and the moderating role of racial identity in the relation between cortisol regulation and depressive symptoms. Youth who reported discrimination experienced higher mean levels of depression. Discrimination was not related to cortisol regulation, nor were racial identity dimensions significant moderators in risk for depressive symptoms. This study, the first to explicitly test a culturally relevant model of risk for depression, points to the importance of capturing nuances in stress reactivity to discrimination in explicit tests of culturally-relevant models of depression in minority youth.
Temple University--Theses
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Sautron, Valerie. "Biologie intégrative des réponses de stress et robustesse chez le porc." Thesis, Toulouse, INPT, 2016. http://www.theses.fr/2016INPT0086/document.
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Le travail de cette thèse s’inscrit dans le cadre du projet ANR SUSoSTRESS qui a pour objectif la compréhension des mécanismes moléculaireset génétiques sous-jacents à la variabilité individuelle de réponses de stress et a collecté des données longitudinales à plusieurs niveaux biologiquessur une population d’étude porcine (race Large White). La thèse est organisé en deux partie. La première partie s’articule autour de l’analyse de données cliniques et transcriptomiques collectées à plusieurs pas de temps avant et après application de deux types de stress : injection d’ACTH et de LPS. Dans cettepartie, on cherche à développer d’un modèle fonctionnel permettant de décrire et d’intégrer au mieux l’ensemble des sources de variation génétique du fonctionnement de l’axe corticotrope et plus généralement des réponses de stress dans notre population d’étude. Plus précisément, il s’agit d’élaborer un modèle (au sens biologique du terme) décrivant les différentes réponses biologiques de stress et l’influence des variations génétiques (simples et en interaction), dans le but de prédire les leviers les plus efficaces en fonction de l’objectif de sélection. Ce travail a mis en évidence une liste de 65 gènes différentiellement exprimé au cours des réponses au stress, dont un ensemble de 8 gènes liés au au cortisol (l’hormone principale du stress) par NR3C1, le récepteur aux glucocorticoides. Ces gènes sont des biomarqueurs potentiels pouvant être fournis aux éleveurs en tant que leviers de sélection permettant un meilleur équilibre entre amélioration des caractères de production et des caractères de robustesse. La deuxième partie de ce travail s’articule autour du développement d’un outil d’analyse statistiques adapté à l’intégration de données ’omiques longitudinalesavec une variable cible d’intérêt.Nous proposons la «multiway-SIR », qui étend la méthode dual-STATIS, une méthode d’analyse de données cubiques non supervisée, au cadre de la SIR, une méthode de régression semi-paramétrique pouvant être utilisée à des fins exploratoires. Cette méthode est appliquée sur les données cliniques de l’expérience d’ACTHet permet d’y explorer l’influence de la variabilité de la réponse du cortisol à une injection d’ACTHThis PhD thesis is part of the SUSoSTRESS project. This ANR funded project aims at improving the knowledge about molecular and genetic mechanisms underlying inter-individual variability in stress responses. Longitudinal data were collected at several biological levels on a porcine population (Large White). This work is structured in 2 parts. The first part is built around clinical and transcriptomic longitudinal data analyses collected before and after 2 types of stress factors : ACTH and LPS injection. The aim of this contribution is to develop a functional model describing all sources of genetic variation in the HPA axis activity and in stress responses in our study population.More precisely, it aims at defining a model describing the different biological stress responses and the influence of genetic variations in order to identify the most efficient selection levers according to selection goals. This work allowed for the identification of 65 differentially expressed genes during stress responses. Among them, 8 genes were highly linked to cortisol (the main stress hormone) through NR3C1 (glucocorticoid receptor (GR)). These genes are potential biomarkers and can be communicated to breeders as selection levers for a better trade-off between production and robustness traits in farmanimals. The second part is built around the development of a statistical tool suited for the data integration of repeated omicmeasurements with a real target variable.We introduce the "multiway-SIR" approach which extends the dual-STATIS (an approach to study 3-way datasets) method to the SIR framework (a semi-parametric regression model that can be used in an exploratory way). This method is illustrated on clinical data from the ACTH experiment. It allows for the exploration of the link between clinical variable response over time and inter-individual variability in the cortisol response to an ACTH injection
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Čulig, Luka. "Effets de l'augmentation de la neurogénèse adulte dans un modèle murin écologique de dépression." Thesis, Tours, 2017. http://www.theses.fr/2017TOUR4021.
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La dépression majeure (DM) est une pathologie complexe et hétérogène associée avec des altérations du réseau cérébral, une dérégulation de l’axe hypothalamus-pituitaire-surrénales et avec des déficits de la neurogenèse adulte hippocampique (NHA). De nombreuses évidences pointent sur l’implication de la NHA dans les troubles de l’humeur et les troubles anxieux, ce qui a conduit à la formulation de l’ « hypothèse neurogénique », laquelle postule que des neurones néo-formés dans l’hippocampe du sujet adulte sont impliqués dans l’étiologie et dans l’efficacité du traitement de la DM. L’objectif de cette étude a été de déterminer le rôle des neurones formés à l’âge adulte après que les animaux aient été exposés à un stress ainsi que les mécanismes sous-jacents. Nos résultats suggèrent que l’augmentation de la neurogenèse est suffisante pour estomper les effets d’un stress chronique au niveau comportemental et hormonal, et donc pour induire un effet de type antidépresseur, comportementalement et physiologiquement. Les effets surviennent sans doute via le noyau du lit de la strie terminale antéro-dorsaleMajor depressive disorder (MDD) is a complex and heterogeneous disorder hypothesized to be associated with alterations in brain circuitry, dysregulations of the hypothalamic–pituitary–adrenal axis and impairments in adult hippocampal neurogenesis (AHN). Multiple lines of evidence point to the involvement of AHN in mood and anxiety disorders, leading to the formation of the “neurogenesis hypothesis”, which postulates that adult-born hippocampal neurons are involved in the etiology and treatment efficacy of MDD. The purpose of this study was to determine the role of adult-born neurons after the onset of stress exposure and the mechanism that underlies the observed results. Our results suggest that increasing neurogenesis is sufficient to buffer against the effects of chronic stress on certain behavioral and endocrine levels and thus to display antidepressant-like effects, both behaviorally and physiologically. Adult-born neurons might have exerted some of their effects via the anteromedial division of the bed nucleus of the stria terminalis (BSTMA)
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Brureau, Anthony. "Effet de l’injection intracérébroventriculaire du peptide Aβ 25-35 chez le rat mâle adulte au cours du temps : toxicité amyloïde et implication dans la dérégulation de l’axe Hypothalamo-hypophyso-surrénalien." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20079.
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La maladie d'Alzheimer (MA) est une maladie neurodégénérative caractérisée par la présence d'enchevêtrements neurofibrillaires et de plaques séniles. Le composant majoritaire des plaques séniles est le peptide amyloïde Aβ.Dans une première partie de cette thèse, l'objectif a été de caractériser la toxicité du peptide Aβ25-35 après son injection au niveau des ventricules latéraux chez le rat au cours du temps. Nous avons ainsi pu démontrer, entre autre, qu'une seule injection, engendre des déficits mnésiques à court et à long terme qui persistent six semaines après l'injection. Nous avons également montré, entre autre, une astrogliose, une microgliose, une élévation du stress oxydant, ainsi que des phénomènes apoptotiques dans les différentes structures cérébrales étudiées. Le deuxième objectif de cette thèse a été de caractériser le rôle du peptide Aβ25-35 dans la régulation de l'axe hypothalamo-hypophyso-surrénalien (HPA) au cours du temps. Dans un premier temps nous avons démontré une hyperactivité de l'axe, qui se caractérise par une modification de l'expression des hormones et une modification d'expression et de localisation des récepteurs aux glucocorticoïdes (GC). Nous avons montré que l'injection d'Aβ25-35 induisait un comportement anxieux. Néanmoins la fonctionnalité du rétrocontrôle négatif des GC reste intacte. Alors que l'injection de l'Aβ25-35 modifie la réponse de l'axe HPA à un stress. Nos résultats, dans un modèle pathomimétique, de la MA, montrent que la toxicité amyloïde modifie la fonctionnalité et la réactivité de l'axe HPA, ce qui pourrait participer à la pathophysiologie de la MAAlzheimer's disease (AD) is characterized by neurofibrillary tangles and seniles plaques. The major component of senile plaques is the amyloid-β peptide (Aβ). In a first part of this thesis, we characterized the time course toxicity effect of the Aβ25-35 intracerebroventricular (icv) injection in the rat brain. We particulary demonstrated, that only one injection induced memories impairments at short and long term which persisted six weeks after the icv injection. We also shown, a sustain astrogliosis and microgliosis, oxidative stress, apoptotics processes in the differents brain structure of interest.In a second part of this thesis, we characterized the time course impact of Aβ25-35 on hypothalamo-pituitary-adrenal axis during the time. First, we demonstrated an the hyperactivity of the axis, which is characterized by modifications of hormonal concentration associated with modification of the expression and localization of glucocorticoids (GC) receptors. We also demonstrated Aβ25-35 an anxious behavioural in animals. Nevertheless, the functionality of negative feedback is not modified. However, Aβ25-35 injection modify the HPA axis reactivity after acute stress. In conclusions, we shown, in a pathomimetic model of AD that the Aβ25-35 toxicity modifes the reactivity and the functionality of HPA axis, that could be partly involved in the pathophysiology of AD
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Neigh, Gretchen N. "Neural and immune changes that occur following psychological and physical stressors." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1092752738.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains 258 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 17.
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Salander, Katarina. "Early life stress and psychopathology : The effects of early life stress on brain development: Implications for psychopathology." Thesis, University of Skövde, School of Humanities and Informatics, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-3475.
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Several studies have shown that children who grow up under adverse care giving conditions are prone to develop a broad spectrum of different problems, ranging from mild depression to severe psychosomatic pathology later in life. A carefully treated child develops a different attachment strategy and biochemical response than a maltreated child. Early adverse events seem to program the stress response to become either over or under reactive which in turn have the potential to alter brain development. Major consequences include reduced plasticity and abnormal frontal lobe activity. This review further investigates the emotional and cognitive development in children exposed to early life abuse or neglect, trying to get a comprehensive picture of different symptoms that might contribute to later psychopathology.