abstract: Dysregulated cortisol has been linked to a variety of adverse physical and psychological consequences. Stressors in the childhood family environment can influence cortisol activity throughout development. For example, research has shown that both infants and children of depressed mothers exhibit altered levels of cortisol compared to infants and children of non-depressed mothers. It is unclear, however, whether exposure to maternal depression in childhood and adolescence is related to cortisol activity at later stages of development. The current study examined the longitudinal relation between maternal depressive symptoms during late childhood (9-12 years old) and adolescence (15-19 years old) and cortisol activity in offspring in young adulthood (24- 28 years old) in a sample of 40 young adults and their mothers. Maternal depressive symptoms were prospectively assessed at four time points across the 15 year study. Cortisol samples were collected from young adult offspring at the final time point. Findings revealed that higher levels of maternal depressive symptoms during late childhood were associated with lower total cortisol output in young adulthood. Results suggest that attenuated cortisol levels, which put these young adults at risk for a variety of stress-related physical and psychological illnesses, may be a long-term consequence of exposure to maternal depression,. Depressive symptoms in mothers during their child's adolescence, however, did not relate to cortisol output. These findings suggest a sensitive period in late childhood during which the development of HPA activity may be susceptible to the environmental stressor of maternal depression. / Dissertation/Thesis / M.A. Psychology 2011

La réduction du temps de sommeil est un phénomène de plus en plus courant. Un faisceau de données expérimentales et épidémiologiques suggère qu'un manque de sommeil pourrait être un facteur de risque d'obésité et de diabète. Dans un premier temps, puisque des modifications de l'axe Hypothalamo-Hypophyso-Surrénalien (HHS) pourraient sous- tendre la relation entre le manque de sommeil et les maladies métaboliques, j'ai évalué les effets de 2 nuits courtes sur ce système chez des jeunes hommes en bonne santé. Nous avons montré que 2 nuits de 4h au lit altéraient l'activité spontanée et la réactivité de l'axe HHS et que l'ampleur des altérations était corrélée à l'importance de la privation de sommeil. Dans un deuxième temps, j'ai tenté de déterminer si une extension de sommeil pouvait avoir des effets bénéfiques chez des jeunes obèses dormant habituellement peu. Nos résultats préliminaires montrent que par simple extension du temps passé au lit, des obèses dormant habituellement 6h, étaient capables de dormir 8h, une durée associée au plus faible risque d'obésité dans les études épidémiologiques, que leur appétit pour les aliments gras et salés et le grignotage diminuaient, que leurs taux de polypeptide pancréatique, une hormone anorexigène, étaient augmentés, et que leur prise calorique lors d'un buffet à volonté était d'autant plus diminuée que leur temps de sommeil était augmenté. Ce travail souligne l'importance d'une durée de sommeil suffisante pour une bonne santé métabolique et suggère que l'optimisation du sommeil pourrait constituer une alternative peu coûteuse pour la prévention et la prise en charge des maladies métaboliques / Voluntary sleep restriction is increasingly common in modern socities. Evidence from epidemiological and experimental studies suggest that sleep loss may be a risk factor for obesity and type 2 diabetes. First, since the modifications in Hypothalamic-Pituitary-adrenal (HPA) axis activity may underlie the relationship between sleep loss and metabolic diseases, 1 evaluated the effect of 2 short nights on this system in healthy lean young men. We showed that 2 nights of 4h in bed impaired spontaneous activity and the reactivity of the HPA axis and that the magnitude of these alterations was related of the severity of sleep loss. 1n a second step, 1 sought to determine if sleep extension could have a beneficial effect in young obese short sleepers. Our preliminary results showed that, by a simple bedtime extension, obese subjects usually sleeping 6h were able to sleep 8h, a duration associated with the lowest risk obesity risk in epidemiological studies. Moreover, their appetite for sweets and fat food, and snacking were decreased, the levels of pancreatic polypeptide, an anorexigenic hormone, were increased and the more they slept, the less they consumed calories at an ad libitum buffet. This work highlights the importance of getting enough sleep to maintain a good metabolic health and suggest that sleep optimization may have implications for novel public health interventions

abstract: Sleep is essential for physical and psychological health. Sleep has also been linked to the daily patterns of key stress-responsive physiological systems, specifically the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Extant research examining sleep and diurnal patterns of cortisol, the primary end product of the HPA axis, is inconsistent. Moreover, it is not clear how specific aspects of sleep behavior (e.g., sleep duration, sleep quality, sleep variability) are related to specific components of diurnal cortisol rhythms. Salivary alpha-amylase (sAA) has been recognized as a surrogate marker of ANS activity, but limited research has explored relations between sleep and sAA diurnal rhythms. The current study utilized a modified ecological momentary assessment protocol to examine within- and between-person relations between multiple facets of sleep behavior using multiple methods (e.g., subjective report, actigraphy) and salivary cortisol and sAA. First year college students (N = 76) provided saliva samples and diary entries five times per day over the course of three days. Sleep was assessed via questionnaire, through daily diaries, and monitored objectively using actigraphy over a four day period. Between-person results revealed that shorter average sleep duration and greater sleep variability was related to lower levels of waking cortisol and flatter diurnal slopes across the day. Within-person results revealed that on nights when individuals slept for shorter durations than usual they also had lower levels of waking cortisol the next day. Sleep was not related to the cortisol awakening response (CAR) or diurnal patterns of sAA, in either between-person or within-person analyses. However, typical sleep behaviors measured via questionnaire were related to waking levels of sAA. Overall, this study provides a greater understanding of how multiple components of sleep, measured in naturalistic environments, is related to cortisol and sAA diurnal rhythms, and how day-to-day, within-person changes in sleep duration contribute to daily variations in cortisol. / Dissertation/Thesis / Masters Thesis Psychology 2015

Made available in DSpace on 2014-06-11T19:22:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-03-21Bitstream added on 2014-06-13T20:07:59Z : No. of bitstreams: 1 pauli_jr_me_rcla.pdf: 1649366 bytes, checksum: 582a2977521476b101c59041c4c0ec5e (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Existem consideráveis evidências demonstrando que tanto animais quanto humanos tratados com glicocorticóides freqüentemente apresentam anormalidades no metabolismo de carboidratos, proteínas e gorduras. Os objetivos do presente estudo foram: 1) investigar as adaptações endócrino-metabólicas em ratos submetidos ao exercício físico agudo e crônico de natação associado com a administração de dexametasona durante 10 semanas. 2) analisar os efeitos do treinamento associado à utilização de baixas doses de dexametasona na funcionalidade do eixo hipotálamo-hipófise-adrenal. Com os resultados obtidos concluímos que: 1) baixa dose de dexametasona promove diversos efeitos colaterais no metabolismo intermediário. O uso crônico deste esteróide tem um importante papel no desenvolvimento da resistência à insulina periférica. A insulino resistência é um importante fator para o desenvolvimento do diabetes mellitus, hipertensão, menor tolerância aos carboidratos, e alteração lipídica; 2) o exercício regular de natação promove aumento na sensitividade à insulina e reverte estes aspectos. Alem disso, o treinamento físico promove o aumento dos estoques de energia no músculo e fígado e contribui para um menor acúmulo de tecido adiposo epididimal; 3) o exercício pode ainda preponderar sobre o feedback negativo da dexametasona na ativação do eixo hipotálamo-hipofisiário-adrenal em ratos. / There is considerable evidence that abnormalities of carbohydrate, protein and fat metabolism occur frequently to both animals and humans treated with glucocorticoid. The aims of this study were: 1) to investigate the endocrine-metabolic adaptations in rats submitted to acute and chronic swimming exercise associate to administration of dexamethasone during 10 weeks; 2) to analyze the effects of training associate to low-dose dexamethasone on the hypothalamic-pituitary-adrenal axis. The results obtained led us to conclude that: 1) Low-dose of dexamethasone promotes several side effects in intermediary metabolism. The chronic use of this steroid has an important role in the development of peripheral insulin resistance. Insulin resistance may be an important factor for the development of diabetes mellitus, hypertension, impaired carbohydrate tolerance, and lipid alteration; 2) the regular swimming exercise promoted increased insulin sensitivity and reverted this aspect. Moreover, physical training increased energy stores in muscle and liver and contributed to the lower adipose epididimal tissue accumulation; 3) Therefore, exercise can override the dexamethasone negative feedback of hypothalamy-pituitary-adrenal axis activation in rats.

Orientador: Eliete Luciano / Banca: Gustavo Puggina Roggato / Banca: Maria Alice Rostom de Mello / Resumo: Existem consideráveis evidências demonstrando que tanto animais quanto humanos tratados com glicocorticóides freqüentemente apresentam anormalidades no metabolismo de carboidratos, proteínas e gorduras. Os objetivos do presente estudo foram: 1) investigar as adaptações endócrino-metabólicas em ratos submetidos ao exercício físico agudo e crônico de natação associado com a administração de dexametasona durante 10 semanas. 2) analisar os efeitos do treinamento associado à utilização de baixas doses de dexametasona na funcionalidade do eixo hipotálamo-hipófise-adrenal. Com os resultados obtidos concluímos que: 1) baixa dose de dexametasona promove diversos efeitos colaterais no metabolismo intermediário. O uso crônico deste esteróide tem um importante papel no desenvolvimento da resistência à insulina periférica. A insulino resistência é um importante fator para o desenvolvimento do diabetes mellitus, hipertensão, menor tolerância aos carboidratos, e alteração lipídica; 2) o exercício regular de natação promove aumento na sensitividade à insulina e reverte estes aspectos. Alem disso, o treinamento físico promove o aumento dos estoques de energia no músculo e fígado e contribui para um menor acúmulo de tecido adiposo epididimal; 3) o exercício pode ainda preponderar sobre o feedback negativo da dexametasona na ativação do eixo hipotálamo-hipofisiário-adrenal em ratos / Abstract: There is considerable evidence that abnormalities of carbohydrate, protein and fat metabolism occur frequently to both animals and humans treated with glucocorticoid. The aims of this study were: 1) to investigate the endocrine-metabolic adaptations in rats submitted to acute and chronic swimming exercise associate to administration of dexamethasone during 10 weeks; 2) to analyze the effects of training associate to low-dose dexamethasone on the hypothalamic-pituitary-adrenal axis. The results obtained led us to conclude that: 1) Low-dose of dexamethasone promotes several side effects in intermediary metabolism. The chronic use of this steroid has an important role in the development of peripheral insulin resistance. Insulin resistance may be an important factor for the development of diabetes mellitus, hypertension, impaired carbohydrate tolerance, and lipid alteration; 2) the regular swimming exercise promoted increased insulin sensitivity and reverted this aspect. Moreover, physical training increased energy stores in muscle and liver and contributed to the lower adipose epididimal tissue accumulation; 3) Therefore, exercise can override the dexamethasone negative feedback of hypothalamy-pituitary-adrenal axis activation in rats / Mestre

No description available.

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.

No description available.

Glucocorticoids are effective immunosuppressive and anti-inflammatory agents, but some aspects of stress appear to be proinflammatory. This study investigates this apparent paradox as it applies to stress exposure and the development of arthritis in a rat strain that has subnormal hypothalamic-pituitary-adrenal (HPA) responsiveness. Female Lewis rats were subjected to 1 week of rotating, psychological stressors for 5 h daily, beginning 7 days following inoculation with type [I collagen. The collagen-induced arthritis (CIA) group exposed lo stress showed reduced ankle width increase (p < 0.001) and decreased hindlimb severity scores (p < 0.001). At sacrifice, 2 days following stress termination, no differences in either measure remained and there was no difference in hind paw volume. However, the area of the tibia invaded by stroma, as quantitated by image analysis, was reduced in the stressed rats (p < 0.05). In animals exposed to stress, adrenal weights were increased (p < 0.005) and plasma corticosterone levels were elevated at sacrifice (p < 0.02). Both injected groups had significantly larger adrenal (p < 0.005) and lower thymus weights (p < 0.05) than did uninjected controls. Likewise, both CIA groups had reduced glucocorticoid receptor immunoreactivity in synovial membranes compared to controls (p < 0.001), suggesting that the Lewis rat's HPA deficiency may be intensified by glucocorticoid receptor downregulation during the induction of CIA. These data indicate that the responsiveness of the HPA axis to psychological stress in this strain is sufficient to alter disease progression.

Stressfaktoren begegnen uns sehr häufig in unserem tagtäglichen Leben und können sowohl positive als auch negative Effekte auf unser Wohlbefinden haben. Während akuter Stress motivierend oder auch leistungssteigernd wirken kann, wird chronischer Stress meist zur Belastung. Langanhaltender Stress wurde bereits mehrfach mit psychischen Erkrankungen wie Depressionen, aber auch systemischen Erkrankungen wie Diabetes in Verbindung gebracht. Der Körper reagiert auf Stress über eine Aktivierung des endokrinen Stresssystems, welches über das Gehirn gesteuert wird und gezielt die Ausschüttung von Stresshormonen kontrolliert. Diese Hormone ermöglichen beispielsweise den erhöhten Energiebedarf bei Stress und regulieren andererseits ihre eigene Aktivität über ein negatives Feedback. Die Stressantwort ist demnach ein essenzielles Netzwerk verschiedener Organe und bedarf einer genauen Regulierung. Es konnte gezeigt werden, dass chronischer Stress oder frühkindlicher Stress dieses System dauerhaft verändern kann, was eine erhöhte Wahrscheinlichkeit einer späteren Erkrankung zur Folge haben kann. Die zugrundeliegenden Ursachen hierfür sind bis heute nicht vollständig geklärt. Eine Theorie besagt, dass Stammzellen in endokrinen Drüsen einen Anteil an chronischen Veränderungen haben könnten. Es wurde bereits gezeigt, dass der Hypothalamus, die Hypophyse und die Nebennierenrinde Stammzellen aufweisen. Die Funktion dieser Stammzellen ist noch nicht vollständig aufgeklärt und insbesondere der Einfluss von Stress auf diese Zellen oder der Zellen auf die Stressantwort ist weitestgehend unbekannt. Die Stammzellen der Organe weisen unterschiedliche Merkmale auf und sind nicht direkt miteinander vergleichbar. Es gibt jedoch Hinweise darauf, dass sie durch einen Signalweg reguliert werden, den YAP/TAZ Signalweg, welcher zuvor bereits mit Stress und Belastungsstörungen in Verbindung gebracht wurde. Das Ziel dieser Studie war demnach, aufzuklären, ob dieser Signalweg in Hypophyse und Nebennierenrinde durch Stress beeinflusst wird und ob dies eine Regulation der Stammzellen in den jeweiligen Organen zur Folge hat. Die Regulierung der Stammzellpopulationen wurde zunächst in einem Stressmodell charakterisiert. Anschließend wurden molekulare Methoden, wie RT-qPCR, RNAscope mRNA in situ Hybridisierung, Western Blot und Immunofluoreszenz, für weitere Analysen herangezogen. Stammzellen des Nebennierencortex und der Hypophyse wurden zusätzlich in vitro kultiviert, um ihre Regulierung weiter zu analysieren. Es wurde zuerst der YAP/TAZ Signalweg im Detail in der Nebennierenrinde analysiert. Es konnte aufgezeigt werden, dass die Komponenten des Signalwegs zwar in der ganzen Nebennierenrinde exprimiert wurden, der Transkriptionsfaktor YAP hingegen hauptsächlich in den äußersten Zellschichten aktiv war, wo auch die Stammzellen lokalisiert sind. YAP und auch klassische Zielgene wie Ctgf wurden außerdem in den Zellen gefunden, welche in vorherigen Studien durch spezifische Marker als Vorläuferzellen oder Stammzellen definiert wurden. Ein anschließend durchgeführtes Stressexperiment zeigte auf, dass insbesondere Ctgf vermehrt in der Stammzellnische exprimiert wurde. Die Vorläuferzellen in der Nebennierenrinde werden normalerweise hauptsächlich durch den WNT Signalweg reguliert, welcher durch Stress inhibiert wurde. Da dies in vorherigen Studien als wichtiger Schritt zur Neubildung von Zellen aus den Vorläuferzellen aufgezeigt wurde, wurden zusätzlich Nebennieren von Glucocorticoid-behandelten Mäusen analysiert, welche eine Nebennierenrindenatrophie und verringerte Zelldifferenzierung aufzeigten. Diese zeigten eine dem Stress gegensätzliche Aktivität der beiden Signalwege auf. In einem Zellkulturmodell konnte aufgezeigt werden, dass die Regulation der beiden Signalwege während des Differenzierungsprozesses in vitro die Regulation der Signalwege während der Stressantwort in vivo widerspiegelten. Dasselbe Stressprotokoll wurde dann herangezogen, um die Regulation des YAP/TAZ Signalweges in der Adenohypophyse zu analysieren. Die Stammzellpopulation in der Hypophyse wird generell durch den Marker SOX2(+) definiert und wird unter anderen durch den YAP/TAZ Signalweg reguliert. Wiederholter Stress führte zu einer stark erhöhten Genexpression klassischer YAP/TAZ Zielgene, Ctgf und Cyr61. Beide wurden in den SOX2(+) Zellen der Adenohypophyse exprimiert, was einen potenziellen Einfluss von Stress auf SOX2(+) Zellen suggerierte. Die Daten ließen aber vermuten, dass diese Zellen keine erhöhte Proliferations- oder Differenzierungsrate aufwiesen. Vielmehr zeigten in vitro Studien auf, dass SOX2(+) Zellen CTGF ausschütteten, um potenziell über parakrine Signalwege benachbarte Zellen zu beeinflussen. Weitere Untersuchungen legten dar, dass Glucocorticoide die Ctgf Expression und Ausschüttung des Signalpeptids in den SOX2(+) Zellen vermehrt anregten. Diese Ergebnisse deuten also darauf hin, dass das negative Feedback von der Nebenniere in Stress auch Stammzellen in der Hypophyse beeinflussen könnte, welche wiederum eine Rolle in der Regulation der hormonproduzierenden Zellen über parakrine Signalwege haben könnten. Zusammenfassend demonstriert die vorliegende Arbeit, dass Stress einen Einfluss auf Signalwege in der endokrinen Stressachse haben kann, welche Vorläuferzellpopulationen in verschiedenen Organen beeinflussen können. Dies kann verschiedene Konsequenzen für das jeweilige Organ haben und Vorläuferzellen könnten so die Stressantwort im Allgemeinen beeinflussen. Diese Ergebnisse verdeutlichen, dass ein weitreichenderes Verständnis der Regulation von Stammzellen in Stress helfen könnte, die zugrundeliegenden Ursachen der Krankheitsentstehung in Folge von chronischem oder frühkindlichem Stress zu verstehen.