Pre- and Post-Natal Stress Programming: Developmental Exposure to Glucocorticoids Causes Long-Term Brain-Region Specific Changes to Transcriptome in the Precocial Japanese Quail.

Exposure to stress during early development can permanently influence an individual's physiology and behaviour, and affect its subsequent health. The extent to which elevated glucocorticoids cause such long-term 'programming' remains largely untested. In the present study, using the Japanese quail as our study species, we independently manipulated exposure to corticosterone during pre- and/or post-natal development and investigated the subsequent effects on global gene expression profiles within the hippocampus and hypothalamus upon achieving adulthood. Our results showed that the changes in transcriptome profiles in response to corticosterone exposure clearly differed between the hippocampus and the hypothalamus. We also showed that these effects depended on the developmental timing of exposure and identified brain-region specific gene expression patterns that were either: (i) similarly altered by corticosterone regardless of the developmental stage in which hormonal exposure occurred or (ii) specifically and uniquely altered by either pre-natal or post-natal exposure to corticosterone. Corticosterone-treated birds showed alterations in networks of genes that included known markers of the programming actions of early-life adversity (e.g. brain-derived neurotrophic factor and mineralocorticoid receptor within the hippocampus; corticotrophin-releasing hormone and serotonin receptors in the hypothalamus). Altogether, for the first time, these findings provide experimental support for the hypothesis that exposure to elevated glucocorticoids during development may be a key hormonal signalling pathway through which the long-term phenotypic effects associated with early-life adversity emerge and potentially persist throughout the lifespan. These data also highlight that stressors might have different long-lasting impacts on the brain transcriptome depending on the developmental stage in which they are experienced; more work is now required to relate these mechanisms to organismal phenotypic differences.

Modifications of glucocorticoid receptors mRNA expression in the hypothalamic-pituitary-adrenal axis in response to early-life stress in female Japanese quail.

Stress exposure during early-life development can programme individual brain and physiology. The hypothalamic-pituitary-adrenal (HPA) axis is one of the primary targets of this programming, which is generally associated with a hyperactive HPA axis, indicative of a reduced negative-feedback. This reduced feedback efficiency usually results from a reduced level of the glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR) within the HPA axis. However, a few studies have shown that early-life stress exposure results in an attenuated physiological stress response, suggesting an enhance feedback efficiency. In the present study, we aimed to determine whether early-life stress had long-term consequences on GR and MR levels in quail and whether the effects on the physiological response to acute stress observed in prenatally stressed individuals were underpinned by changes in GR and/or MR levels in one or more HPA axis components. We determined GR and MR mRNA expression in the hippocampus, hypothalamus and pituitary gland in quail exposed to elevated corticosterone during prenatal development, postnatal development, or both, and in control individuals exposed to none of the stressors. We showed that prenatal stress increased the GR:MR ratio in the hippocampus, GR and MR expression in the hypothalamus and GR expression in the pituitary gland. Postnatal stress resulted in a reduced MR expression in the hippocampus. Both early-life treatments permanently affected the expression of both receptor types in HPA axis regions. The effects of prenatal stress are in accordance with a more efficient negative-feedback within the HPA axis and thus can explain the attenuated stress response observed in these birds. Therefore, these changes in receptor density or number as a consequence of early-life stress exposure might be the mechanism that allows an adaptive response to later-life stressful conditions.

Steroid hormones, stress and the adolescent brain: a comparative perspective.

Steroid hormones, including those produced by the gonads and the adrenal glands, are known to influence brain development during sensitive periods of life. Until recently, most brain organisation was assumed to take place during early stages of development, with relatively little neurogenesis or brain re-organisation during later stages. However, an increasing body of research has shown that the developing brain is also sensitive to steroid hormone exposure during adolescence (broadly defined as the period from nutritional independence to sexual maturity). In this review, we examine how steroid hormones that are produced by the gonads and adrenal glands vary across the lifespan in a range of mammalian and bird species, and we summarise the evidence that steroid hormone exposure influences behavioural and brain development during early stages of life and during adolescence in these two taxonomic groups. Taking a cross-species, comparative perspective reveals that the effects of early exposure to steroid hormones depend upon the stage of development at birth or hatching, as measured along the altricial-precocial dimension. We then review the evidence that exposure to stress during adolescence impacts upon the developing neuroendocrine systems, the brain and behaviour. Current research suggests that the effects of adolescent stress vary depending upon the sex of the individual and type of stressor, and the effects of stress could involve several neural systems, including the serotonergic and dopaminergic systems. Experience of stressors during adolescence could also influence brain development via the close interactions between the stress hormone and gonadal hormone axes. While sensitivity of the brain to steroid hormones during early life and adolescence potentially leaves the developing organism vulnerable to external adversities, developmental plasticity also provides an opportunity for the developing organism to respond to current circumstances and for behavioural responses to influence the future life history of the individual.

State dependent effects of elevated hormone: nest site quality, corticosterone levels and reproductive performance in the common eider.

Nest shelter in incubating birds is of major importance in providing protection against unfavourable conditions such as harshness of the environment and exposure to predators. We examined the link between nest shelter, baseline corticosterone (CORT) levels and hatching success in common eiders (Somateria mollissima) incubating at nest sites with different levels of shelter. Since more sheltered nest sites could be occupied by better-quality females, we also used an experimental manipulation of nest shelter to separate the effects of the physical attributes of the nest site from those of individual quality. We compared birds with naturally sheltered nests, exposed nests and exposed nests provided with artificial nest shelters and measured clutch size, body condition, CORT levels at the end of incubation and hatching success. If nest shelter reduces CORT levels, we predicted that CORT levels would be highest at the least sheltered sites, and that the provision of artificial shelter would reduce CORT levels. We found that nest shelter was not related to CORT levels in incubating eiders. Nest shelter, however, affected body condition, with females at exposed sites losing more body mass during incubation than females at naturally and artificially sheltered nests. Interestingly however, in those birds nesting at the exposed sites, with and without artificial shelter, those with the highest CORT levels had the lowest hatching success. This relationship was not evident in females nesting at naturally sheltered sites. These results suggest that the level of nest shelter does not directly affect CORT levels in females. Instead, we suggest that the relationship between CORT levels and hatching success is state-dependent. Exposed sites are occupied by individuals that laid smaller clutches, and hence are likely to be of lower quality, and the negative effects of elevated CORT on hatching success are more pronounced in these females.

Post-natal exposure to corticosterone affects standard metabolic rate in the zebra finch (Taeniopygia guttata).

Post-natal stress has been shown to have important short and long term effects on many adult traits in birds. During stress, metabolic alterations often result in the mobilization of energy away from energy-sensitive functions such as growth, which could have significant implications for developing animals. However, little is known about the implications of stress hormones for energy consumption in growing individuals. We experimentally increased corticosterone (CORT) levels in nestling zebra finches via oral administration, between the ages of 7 and 18 days. The standard metabolic rate (SMR) of birds was measured twice overnight when birds were between 11-13 and 55-65 days of age. Developmental CORT administration significantly elevated overnight variability in SMR (sd) in nestling birds (during the treatment period), but not at 55-65 days (5-6 weeks after the treatment period). The effect on variability was seen more prominently in birds from larger brood sizes and in females. We found no effects of our treatments on mean SMR overnight. However, brood size and sex had interactive effects, with males from larger brood sizes having higher SMR at 55-65 days of age. These results suggest that stress hormones can have significant effects on energy metabolism and possibly nocturnal arousal and sleep fragmentation. However, there were no detectable long term effects of our treatments on SMR, suggesting that these effects are only short-lived, in order to maintain homeostasis in the short term.

Delayed behavioral effects of postnatal exposure to corticosterone in the zebra finch (Taeniopygia guttata).

Early developmental conditions can significantly influence the growth and survival of many animal species. We studied the consequences of exposure to corticosterone (CORT), a stress hormone, during the nestling stage on two behavioral traits (neophobia, social dominance) measured when the birds had reached independence. Nestling zebra finches (Taeniopygia guttata) were exposed twice daily to exogenous CORT via oral administration for a 12-day period up until fledging. Experimental CORT administration depressed nestling growth rates, confirming results previously obtained in this species. Our data on neophobic behavior revealed a significant interaction between sex and treatment, with CORT-dosed males showing reduced latencies to approach a novel object, while there was little effect of corticosterone treatment on female neophobia. There was no significant effect of age (30 or 50 days), however, there was a non-significant trend towards an interaction between treatment and age, with neophobia increasing with age in the CORT-dosed birds, but decreasing in controls. At 50 days of age previous exposure to corticosterone resulted in reduced success in competitions for a non-food-based resource (a perch) in both sexes. There were no effects of brood size on any behavioral traits measured here, but this may be due to the small range in brood size used. Our results show that elevated levels of stress hormones during postnatal development can have significant effects on important behavioral traits, i.e., neophobia and dominance. Moreover, they confirm the importance of rearing conditions in shaping adult phenotypes.

Developmental stress, social rank and song complexity in the European starling (Sturnus vulgaris).

Bird song is a sexually selected trait and females have been shown to prefer males that sing more complex songs. However, for repertoire size to be an honest signal of male quality it must be associated with some form of cost. This experiment investigates the effects of food restriction and social status during development on song complexity in the European starling (Sturnus vulgaris). Birds that experienced an unpredictable food supply early in life produced a significantly smaller repertoire of song phrases than those with a constant food supply. Social status during development was also significantly correlated with repertoire size, with dominant birds producing more phrase types. This study therefore provides novel evidence that social as well as nutritional history may be important in shaping the song signal in this species.

Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults.

OBJECTIVE: This study investigated (1) the effect of octreotide-LAR (Sandostatin-LAR Depot; Novartis) on the enteroinsular axis in a biracial cohort of severely obese adults, (2) whether octreotide suppression of insulin secretion occurs by both a direct beta-cell effect and through mediating a glucagon-like peptide 1 (GLP-1) response, and (3) whether differences in GLP-1 concentrations could explain racial differences in insulin concentrations. DESIGN: Prospective, open-label trial using a pre-post test design. SETTING: Single university, clinical research center. SUBJECTS: In all, 42 healthy, severely obese Caucasian and African-American (AA) adults (93% female, 64% Caucasian, age=37.8+/-1.2 y, weight=123+/-4.2 kg, BMI=44.5+/-1 kg/m(2)), recruited through physician referral and newspaper ads, participated in the study. INTERVENTIONS: Indices of beta-cell activity, insulin and GLP-1 response before and during a 75-gm oral glucose tolerance test were determined before and after 24 weeks of octreotide-LAR. RESULTS: AA exhibited higher beta-cell activity, and insulin and GLP-1 concentrations than Caucasians. Octreotide-LAR suppressed the insulin and GLP-1 levels in both groups.

Song as an honest signal of developmental stress in the zebra finch (Taeniopygia guttata).

In a wide range of bird species, females have been shown to express active preferences for males that sing more complex songs. Current sexual selection theory predicts that for this signal to remain an honest indicator of male quality, it must be associated with an underlying cost of development or maintenance. There has been considerable debate questioning the costs associated with song production and learning. Recently, the nutritional stress hypothesis proposed that song complexity could act as an indicator of early developmental history, since the song control nuclei in the brain are laid down early in life. Here we test the nutritional stress hypothesis, by investigating the effects of dietary stress on the quality of adult song produced. In addition, we tested the effects of elevated corticosterone during development on song production to test its possible involvement in mediating the effects of developmental stress. The results demonstrate that both dietary restriction and elevated corticosterone levels significantly reduced nestling growth rates. In addition, we found that experimentally stressed birds developed songs with significantly shorter song motif duration and reduced complexity. These results provide novel experimental evidence that complex song repertoires may have evolved as honest signals of male quality, by indicating early developmental rearing conditions.

Song as an honest signal of past developmental stress in the European starling (Sturnus vulgaris).

Bird song is a sexually selected male trait where females select males on the basis of song quality. It has recently been suggested that the quality of the adult male song may be determined by nutritional stress during early development. Here, we test the 'nutritional-stress hypothesis' using the complex song of the European starling. Fledgling starlings were kept under experimental treatment (unpredictable short-term food deprivations) or control conditions (ad libitum food supply), for three months immediately after independence. We measured their physiological and immune responses during the treatment and recorded song production during the following spring. Birds in the experimental group showed increased mass during the treatment and also a significantly suppressed humoral response compared with birds in the control group. There was no difference between the groups in the cell-mediated response. Next spring, males in the experimental group spent less time singing, sang fewer song bouts, took longer to start singing and also sang significantly shorter song bouts. These data support the hypothesis that both the quality and quantity of song produced by individual birds reflect past developmental stress. The results also suggest the 'nutritional-stress hypothesis' is best considered as a more general 'developmental-stress hypothesis'.

Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults.

PURPOSE: Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults. METHODS: Suppression of insulin secretion was achieved using octreotide-LAR 40 mg IM q28d for 24 weeks in 44 severely obese adults (89% female, 39% minority). Oral glucose tolerance testing was performed before and after treatment, indices of beta-cell activity (CIRgp), insulin sensitivity (CISI), and clearance (CP/I AUC) were computed, and leptin levels, 3-day food records and carbohydrate-craving measurements were obtained. DEXA evaluations were performed pre- and post-therapy in an evaluable subgroup. RESULTS: For the entire cohort, significant insulin suppression was achieved with simultaneous improvements in insulin sensitivity, weight loss, and body mass index (BMI). Leptin, fat mass, total caloric intake, and carbohydrate craving significantly decreased. When grouped by BMI response, high responders (HR; DeltaBMI<-3 kg/m(2)) and low responders (LR; DeltaBMI between -3 and -0.5) exhibited higher suppression of CIRgp and IAUC than nonresponders (NR; DeltaBMI-0.5). CISI improved and significant declines in leptin and fat mass occurred only in HR and LR. Conversely, both leptin and fat mass increased in NR. Carbohydrate intake was markedly suppressed in HR only, while carbohydrate-craving scores decreased in HR and LR. For the entire cohort, DeltaBMI correlated with DeltaCISI, Deltafat mass, and Deltaleptin. DeltaFat mass also correlated with DeltaIAUC and DeltaCISI. CONCLUSIONS: In a subcohort of obese adults, suppression of insulin secretion was associated with loss of body weight and fat mass and with concomitant modulation of caloric intake and macronutrient preference.

State-dependent behaviour in breeding barn swallows (Hirundo rustica): consequences for reproductive effort.

Life-history theory offers an explanation for the intraspecific variation in reproductive effort; increased levels of current reproductive success, for example, may trade off against residual reproductive value. Even where such trade-offs have been demonstrated, however, much variation in effort remains unexplained and the underlying causes are usually obscure. We examined body state, i.e. energy reserves, as a factor, which could moderate reproductive effort. Specifically, overnight heating and cooling treatments were used to adjust dawn energy reserves in female swallows attending their nests without impinging on the opportunities for foraging. Changes in reproductive effort were measured as 'daytime energy expenditure' (doubly labelled water technique) and the 'number of feeding visits' during brood rearing, which both relate positively to current reproductive success. Our experimental treatments and responses were then compared using the common currency of energy. In response to positive and negative state manipulations, female swallows increased and decreased, respectively, their daytime energy expenditure (and number of feeding visits). These responses to experimental manipulation of state provided evidence of a direct link between the energy expenditure, life history and behaviour, which has hitherto proved elusive. They allow that energy supply and expenditure play a regulatory role in reproductive effort, and indicate that units of energy expenditure probably carry fitness costs and benefits, which are context dependent.

A novel augmentation strategy for treating resistant major depression.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Assessment of depression in patients with brain pathology: the case of stroke.

The assessment of depression in patients with brain pathologies--a topic of considerable clinical and research interest--is complicated by a variety of factors. Among the most problematic are cognitive consequences of brain injury that can diminish the reliability and validity of information used to diagnose depression, determine its severity, ascertain its predictors, and evaluate its impact. In this article, the authors examine the challenges to depression assessment in patients who have had a stroke, the neurologically impaired population in which it has been most frequently studied. Focusing on poststroke depression research, they describe methodological limitations that may contribute to conflicting outcomes and conclusions and offer suggestions for improving the specificity, consistency, validity, and reliability of assessment methods and procedures when investigating depression in patients with brain pathologies.

HyperCard: teaching technology for successful learning.

A brief review of the effectiveness of instructional media is presented, with reference to mastery learning and the effects of illustrations. This is related to the need for instructional media to incorporate both of these essential elements if they are to succeed in enhancing the level of student performance. The role of computer technology, and in particular the authoring system HyperCard, in achieving this is discussed. An experimental program, HyperHeart, is used to illustrate the potential of such a system in biology.