Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2010. / Härtill 5 uppsatser.

Prenatal stress exposure (PNS) has detrimental effects on the offspring’s brain and behaviour and has been identified as an etiological factor in inducing cognitive function deficits in rodents and humans. The neural mechanisms are unclear, however reprogramming of the neuroendocrine stress axis, the hypothalamo-pituitary- adrenal (HPA) axis is hypothesised. A psychosocial stressor (residentintruder paradigm) was used to generate PNS rat offspring, making these studies clinically compatible. The hippocampus and the medial prefrontal cortex (mPFC) are critical in regulating cognitive function and also contribute to the negative feedback control of the HPA axis via corticosteroid receptors, including the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Here the Barnes maze was used to assess spatial learning and memory in male and female PNS offspring during adulthood under different scenarios, including basal and acute and chronic stress conditions. Under basal conditions, PNS was associated with reduced GR and MR mRNA expression in the medial prefrontal cortex (mPFC) and the hippocampus, respectively; suggesting inhibitory feedback control of the HPA axis may be compromised in PNS rats. Moreover, impaired spatial learning was observed in male PNS rats following acute restraint stress. Bilateral lesions of the prelimbic cortex and central administration of an MR antagonist in control rats suggested acute stress-induced learning deficits in PNS males were a result of impaired hippocampus-mediated inhibitory feedback control of the HPA axis. Conversely, a one-week variable stress regimen facilitated spatial learning in PNS rats and this was associated with elevated MR mRNA expression in the dentate gyrus. Moreover, facilitated learning in the PNS rats exposed to chronic stress could be blocked by central administration of an MR antagonist, indicating a facilitatory role of hippocampal MR in spatial learning. In summary, opposite effects of PNS on spatial learning were observed under acute and chronic stress conditions, in which hippocampal MR played a key role in regulating behavioural performance. The effect of age was also examined in PNS rats, and the findings from middle-aged (10-11 months old) rats indicated PNS may accelerate cognitive decline. Sex differences were also studied, with control females’ out-performing males under basal conditions in terms of spatial learning and behavioural flexibility; however following prenatal or chronic stress these sex differences were no longer detected. Furthermore, acute stress impaired spatial learning to a greater extent in females, and this might be attributed to greater HPA axis responses to stress in females compared with males. In conclusion, prenatal stress alters later cognitive performance, in a sex- and stress context-dependent manner. Hippocampal MR plays a critical role in mediating spatial learning, particularly during stress conditions.

Abstract not available

Includes bibliographical references (leaves 228-257). Aims to determine the impact of maternal undernutrition during late gestation and during the periconceptional and gestational periods on fetal growth, fetal blood pressure and the fetal hypothalamo-pituitary adrenal axis in the sheep.

Low birth weight is associated with an increased risk of impaired glucose tolerance and type 2 diabetes and with signs of increased hypothalamic pituitary adrenal axis activity in later life (1, 2). Low birth usually weight reflects a reduction in fetal growth, which largely depends on an adequate supply of nutrients and oxygen. Variations in supply modify the metabolic and neuroendocrine characteristics of the fetus, which in turn modulate the pattern of functional development as well as growth (3). An adverse fetal environment, evident as low birth weight, is therefore proposed to alter functional development with long term effects for the function and risk of disease in the individual later in life (4, 5). Increased HPAA impairs metabolic homeostasis and could therefore mediate effect of prenatal challenge on later metabolic control (6). It was therefore hypothesised that restriction of fetal growth, increases circulating cortisol and/or alters sensitivity to cortisol, which increases fasting blood glucose, and impairs glucose tolerance in the young adult. Large litter size in the guinea pig is characterised by reduced placental and fetal growth, reduced size at birth and insulin resistance in offspring in later life, providing a suitable model to test this hypothesis. Spontaneous restriction of fetal growth in the guinea pig, evident as small size at birth, was associated with increased salivary cortisol, in both sexes but at different stages of postnatal life. In males, salivary cortisol was increased with small size at birth in early and adult life, but reduced later with ageing. In females however, salivary cortisol was increased in juveniles and in aged adults, possibly reflecting the impact of the oestrus cycle on cortisol production in mature cycling females. Altered activity of the HPGA, which can influence that of the HPAA, has also been reported to be programmed by prenatal restriction. In the guinea pig, salivary testosterone in males increased with age and small size at birth in juveniles, young and aged adults. In females, salivary progesterone increased with age up to 300 days, and decreased with size at birth in the young guinea pig. Although testosterone inhibits HPAA activity, in males, mean salivary cortisol correlated positively with mean salivary testosterone at 100 and 300 days of age. In contrast, progesterone may enhance HPAA activity, and consistent with this, in females, mean salivary progesterone correlated with mean salivary cortisol at 400 days of age. Therefore, salivary testosterone in the male and salivary progesterone in the female guinea pig changes with maturation and has previously reported in this or other species, but small size at birth increases salivary testosterone in males with modest effects in early life in females. This together with the unexpected positive associations of salivary cortisol with testosterone in males, suggests that programming of the HPAA makes little contribution to that of the HPAA as indicated by salivary cortisol. Here we show that low birth weight is associated with increased fasting blood glucose and impaired glucose tolerance in both male and female young adult guinea pigs aged 100 days. Fasting and mean (during IVGTT) plasma cortisol was reduced in low birth weight female adult guinea pigs, and is not vary with size at birth at this age in males. This suggests that circulating cortisol does not contribute to the impaired glycaemia associated with small size at birth in the guinea pig. Glucose tolerance was increasingly impaired in males but not females, as mean plasma cortisol increased. This is consistent with cortisol impairing glycaemia in the guinea pig as in other species, in males at least. To assess the role of cortisol in prentally programmed impairment of glycaemia directly, metyrapone or vehicle containing 24% ethanol was administered to young adult guinea pigs for 3 days. Treatment with the latter impaired fasting blood glucose and glucose tolerance in females and the latter in males compared to a previous IVGTT and this was exacerbated in low birth weight females. Metyrapone prevented this impairment of fasting glycaemia and glucose tolerance in the low birth weight adult female guinea pig and in the male guinea pig regardless of birth weight class. Neither vehicle or metyrapone altered plasma cortisol, before or during a second IVGTT. Limited numbers of animals, particularly females, limited this study however and additional investigation is required. Nevertheless this shows for the first time that inhibition of glucocorticoid synthesis in the guinea pig improves glucose control. Furthermore this suggests that the low birth weight guinea pig may be more sensitive to cortisol, have increased cortisol synthesis or reduced inactivation of cortisol in peripheral tissues, leading to increased local cortisol action. In conclusion, alterations in peripheral HPAA activity in the guinea pig due to restricted fetal growth may contribute to their prenatally programmed development of impaired glucose tolerance as young adults, but the extent of that contribution may vary with age and gender. / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Following social defeat, male hamsters exhibit behavioral changes characterized by a breakdown of normal territorial aggression and an increase in submissive/defensive behaviors in the presence of a non-aggressive intruder (NAI). We have termed this phenomenon conditioned defeat (CD). By contrast, only a small subset of defeated females exhibit submissive/defensive behavior in the presence of a NAI. We hypothesized that fluctuations in gonadal hormones might contribute to differences in the display of submissive behavior in intact female hamsters. Following social defeat, proestrous females (higher endogenous estradiol) were more likely to display conditioned defeat compared with diestrous 1 (lower endogenous estradiol) females. This finding suggests that there is an estrous cycle-dependent fluctuation in the display of CD in female hamsters and suggests that increased estradiol might contribute to increased submissive behavior. We then demonstrated that ovariectomized females given estradiol prior to CD testing exhibited significantly higher submissive behavior in the presence of a NAI suggesting that estradiol increases the expression of CD in female hamsters. We have also shown that castrated males that were singly housed for four weeks displayed significantly more submissive behavior than did their intact counterparts. Interestingly, castrated and intact males that were singly housed for 10 days prior to behavioral testing displayed similar behavior during CD testing. Together these data suggest that androgens and isolation modulate the display of CD in male hamsters. Finally, we examined brain activation following CD testing in defeated males and females (in diestrus 1 and proestrus). Defeated male and proestrous females exhibited increased Fos activation in the dorsal lateral septum and hypothalamic paraventricular nucleus relative to defeated diestrous 1 females. Diestrous 1 females exhibited increased Fos expression in the lateral bed nucleus of the stria terminalis compared with both defeated groups. Collectively, these data suggest that gonadal hormones and duration of individual housing modulate the display of CD in female and male hamsters and that those animals which display CD exhibit differences in patterns of neuronal activation than do those that do not display CD.

published_or_final_version / Medicine / Master / Doctor of Medicine

The Hypothalamic Pituitary Adrenal (HPA) axis is the coordinator of adaptive responses to physical and psychological stress. The central nervous system plays a key role in modulation of both basal and adaptive HPA axis functions. In fact, since long ago, animal studies have shown that acute and chronic exposure to glucocorticoids (a stress hormone released due to HPA axis activation, cortisol in humans) affects the function and the morphology of brain areas such as the hippocampus and the cingulate cortex. This thesis is based on novel neuroimaging methodologies used to investigate the interactions of psychological stress, cortisol and the brain. It consists of three functional studies and a morphometric one. In the first functional study we show that the hippocampus (where glucocorticoid receptors are most abundant) plays a role in initiation of an HPA axis stress response. In the second study, we provide evidence that besides hippocampus, the neural activity in the so-called "default mode network" (DMN), especially the anterior cingulate cortex (ACC), relates to interindividual variations in HPA axis response to psychological stress. In the third study we have investigated the cortisol-modulation of the DMN. Again, we provide evidence for a role of the ACC and the orbitofrontal cortex in negative feedback inhibition of the HPA axis activity. Finally, we show a morphological link between the ACC and the cortisol response to awakening which is an index of basal HPA axis activity. Overall, our findings confirm the critical role of the ACC and mesolimbic system in HPA axis regulation. These findings also draw attention to the interactions between functional subregions of the medial prefrontal cortex and states of HPA axis function prior to stress onset---suggesting an interplay of the monitoring and the executive planning roles of the medial prefrontal cortex in behavioral adaptation to stress. Beyond stress research, our findings offer a framework for combining neuroimaging and neuroendocrinology to better understand the interindividual variances in behavior, and perhaps to better identify subgroups at risk of psychological disorders.

No description available.