Meta-analysis reveals glucocorticoid levels reflect variation in metabolic rate, not ‘stress’

Glucocorticoid (GC) variation has long been thought to reflect variation in organismal ‘stress,’ but associations between GCs and Darwinian fitness components are diverse in magnitude, direction, and highly context-dependent. This paradox reveals our poor understanding of the causes of GC variation, contrasting with the detailed knowledge of the functional consequences of GC variation. Amongst an array of effects in many physiological systems, GCs orchestrate energy availability to anticipate and recover from predictable and unpredictable environmental fluctuations and challenges. Although this is mechanistically well-known, the extent to which GC levels are quantitatively explained by energy metabolism is unresolved. We investigated this association through meta-analysis, selecting studies of endotherms in which (1) an experiment was performed that affected metabolic rate and (2) metabolic rate and GC levels were measured simultaneously. We found that an increase in metabolic rate was associated with an increase in GC levels in 20 out of 21 studies (32 out of 35 effect sizes). More importantly, there was a strong positive correlation between the increases in metabolic rate and GCs (p=0.003). This pattern was similar in birds and mammals, and independent of the nature of the experimental treatment. We conclude that metabolic rate is a major driver of GC variation within individuals. Stressors often affect metabolic rate, leading us to question whether GC levels provide information on ‘stress’ beyond the stressor’s effect on metabolic rate

Causes and consequences of glucocorticoid variation in zebra finches

Dieren leven in een wereld van constante verandering, en glucocorticoïde hormonen (zoals corticosteron & cortisol) spelen een belangrijke rol in het reageren op voorspelbare en onvoorspelbare uitdagingen vanuit hun omgeving. Gezien glucocorticoïde hormoonconcentraties aanzienlijk toenemen na een onvoorspelbare uitdaging worden deze hormonen vaak beschouwd als ‘stress hormonen’. Individuen, soorten, en populaties laten, echter, grote variatie zien in hun glucocorticoïde concentraties en het interpreteren van de oorzaken en gevolgen van deze variatie is nog steeds een omstreden kwestie. In dit onderzoek gebruiken we zebravinken die leven in buitenvolières, waarin we de mate van omgevingsuitdagingen manipuleren tijdens hun ontwikkeling en tijdens hun volwassen leven. We onderzochten omgevings- (temperatuur, tegenslag tijdens de ontwikkeling & foerageerkosten) en interne (geslacht, gewicht & glucose regulatie) factoren die de glucocorticoïde variatie aansturen en hiernaast hebben we enkele fysiologische mechanismen onderzocht die betrokken zijn bij het glucocorticoïde systeem. We concluderen dat de belangrijkste oorzaak van glucocorticoïde variatie het metabolisme is, gezien we gevonden hebben dat glucocorticoïden gemoduleerd worden in overeenstemming met veranderingen in energieverbruik (zoals psychologische stressoren, temperatuursveranderingen & foerageerkosten), in zowel gecontroleerde binnenomstandigheden als meer natuurlijke buitenvolières. Dit roept de vraag op of glucocorticoïden indicators zijn van ‘stress’, los van het effect van stressoren op het metabolisme, gezien we gevonden hebben dat de fysiologische reactie op een verlaging van de temperatuur niet te onderscheiden valt van de reactie op een psychologische stressor, welke het metabolisme op eenzelfde manier verhoogde. Ons werk biedt nieuwe inzichten op de interpretatie van glucocorticoïde variatie en ligt ten grondslag aan de noodzaak om de traditionele interpratie van glucocorticoïden als ‘stress’ indicatoren en dierwelzijn te herzien

Glucose regulation is a repeatable trait affected by successive handling in zebra finches

The capacity to adequately respond to (physiological) perturbations is a fundamental aspect of physiology, and may affect health and thereby Darwinian fitness. However, little is known of the degree of individual variation in this capacity in non-model organisms. The glucose tolerance test evaluates the individual's ability to regulate circulating glucose levels, and is a widely used tool in medicine and biomedical research, because glucose regulation is thought to play a role in the ageing process, among other reasons. Here, we developed an application of the intraperitoneal glucose tolerance test (IP-GTT) to be used in small birds, to test whether individuals can be characterized by their regulation of glucose levels and the effect of successive handling on such regulation. Since the IP-injection (intraperitoneal glucose injection), repeated handling and blood sampling may trigger a stress response, which involves a rise in glucose levels, we also evaluated the effects of handling protocols on glucose response. Blood glucose levels decreased immediately following an IP-injection, either vehicle or glucose loaded, and increased with successive blood sampling. Blood glucose levels peaked, on average, at 20 min post-injection (PI) and had not yet returned back to initial levels at 120 min PI. Glucose measurements taken during the IP-GTT were integrated to estimate magnitude of changes in glucose levels over time using the incremental area under the curve (AUC) up to 40 min PI. Glucose levels integrated in the AUC were significantly repeatable within individuals over months (r = 50%; 95% CI 30-79%), showing that the ability to regulate glucose differs consistently between individuals

Glucocorticoid receptor expression in blood, but not across brain regions, reveals long-term effects of early life adversity in zebra finches

Early-life environment can affect organisms for life on many levels. The glucocorticoid receptor (GR) gene has a pivotal role mediating organismal physiological and behavioral responses to environmental change, and is sensitive to early-life environmental conditions and epigenetic programming. Longitudinal studies require non-lethal sampling of peripheral tissues (e.g. blood), but this approach is dependent on the extent to which GR expression in peripheral tissues covaries with GR expression in central tissues. To test for the long-term effects of early life adversity on GR expression across brain and peripheral tissues, we manipulated developmental conditions of captive zebra finches (n=45), rearing them in either benign or harsh conditions through manipulation of parental foraging costs. We measured relative GR mRNA expression in blood and five brain regions in adulthood: hippocampus, hypothalamus, amygdala, ventral striatum, and the nidopallium caudolaterale (analogous to the mammalian prefrontal cortex), using qPCR. We further tested whether GR expression was modulated by natal brood size (which affected growth), age at sampling, and sex. GR expression correlations between tissues varied widely in magnitude and direction, ranging from -0.27 to +0.80, indicating that our understanding of developmental effects on GR expression and associated phenotypes needs to be region specific rather than organism wide. A more consistent pattern was that GR expression increased with age in blood, ventral striatum and hippocampus; GR expression was independent of age in other tissues. Developmental treatment did not affect GR expression in any of the tissues measured directly, but in blood and ventral striatum of adult females we found a positive correlation between nestling mass and GR expression. Thus, GR expression in blood reflected early life conditions as reflected in growth in adult females, showing patterns in one brain tissue, but not ubiquitous across brain regions. These results point at sex-dependent physiological constraints during development, shaping early life effects on GR expression in females only. Further study is required to investigate whether these tissue-dependent effects more generally reflect tissue-dependent long-term effects of early life adversity. This, together with investigating the physiological consequences of GR expression levels on individual performance and coping abilities, will be fundamental towards understanding the mechanisms mediating long-term impacts of early life, and the extent to which these can be quantified through non-lethal sampling.</p

Análisis de situación y diseño del test de mercado para un nuevo producto

En este trabajo final de grado (TFG) se ha planteado un estudio para lanzar con éxito al mercado nacional el nuevo producto de la empresa “Lifeak, Job Accommodation”. “Lifeak, Job Accommodation” es una empresa altamente especializada en las necesidades de las personas con discapacidad y en la manera de cubrirlas apoyándose en la tecnología. El producto que se va a lanzar al mercado, y para el cual se ha desarrollado la presente investigación, es un secador corporal que permite a las personas con problemas de movilidad o discapacidad física secarse de forma más eficiente y cómoda. El estudio se ha enfocado principalmente hacia dos líneas de investigación. Por un lado, al estudio de los consumidores finales, su identificación y posterior análisis de preferencias. Y por otro lado, a la elaboración de la red nacional de distribuidores potenciales, el estudio de su posición estratégica y de su perfilIn this final work of degree (TFG) a study has been proposed to successfully launch on the domestic market the new product of the company "Lifeak, Job Accommodation". "Lifeak, Job Accommodation" is a highly specialized company that has committed itself to cover the needs of people with disabilities relying on technology. The product, main theme of this research, is a body dryer that will soon be launched on the market and allows people with mobility problems or physical disabilities dry more efficiently. The study was mainly focused on two lines of research: the study of end consumers, their identification and subsequent analysis of preferences; and the development of the national network of distributors and the research of their strategic position and profileGraduado o Graduada en Administración y Dirección de Empresas por la Universidad Pública de NavarraEnpresen Administrazio eta Zuzendaritzan Graduatua Nafarroako Unibertsitate Publikoa

Developmental conditions modulate DnA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.We thank A. Hidalgo, F.M. Miranda and E. Mulder for their assistance and training in the lab; S. Jörg for expertly running the hormone assays; M. Briga for training and assistance with the long-term experiment, and M. Driessen for assistance with sampling. We also thank M. Jordà for assistance with the interpretation of methylation data analysis, and the laboratory of ecophysiology and molecular ecology of the Estación Biológica de Doñana for technical support. This project was funded by an EMBO short-term fellowship grant (nº7178) and a Dr. J. L. Dobberke Foundation grant (n°0205510782), both awarded to B.J., who was further supported by the University of Groningen and the Max Planck Institute for Ornithology. E.G-D was funded by a Spanish Ministry of Economy and Competitiveness Ramon y Cajal fellowship and by Plan Nacional Grant BFU2015-65000-R.Peer reviewe

Propuesta de herramienta para la evaluación del grado de implantación de la eadministración en CCAA

El objetivo del presente proyecto es, partiendo de los criterios para la evaluación del grado de implantación de la eAdministración identificados en el Proyecto ‘Análisis de la eAdministración e identificación de criterios auditables para la evaluación del grado de implantación’, implementar una herramienta que permita evaluar el estado de implantación de la eAdministración en las Comunidades Autónomas, permitiendo además la explotación de esta información mediante la creación de informes que permitan realizar comparativas entre Comunidades así como evaluar la evolución a lo largo del tiempo del nivel de implantación de la eAdministración en ellas. Además se propondrá una clasificación de estos criterios en categorías, que aporte valor añadido a la evaluación del nivel de adaptación de la eAdministración, permitiendo ponderar según su importancia, no sólo los criterios, sino también las categorías. Además, en este trabajo, se incluye la elaboración de una serie de medidas a tomar por parte de las Comunidades Autónomas evaluadas, que permita orientarlas en los pasos a seguir para alcanzar la implantación total de la eAdministración, en caso de no obtener el nivel de implantación total en la evaluación. Las medidas se han elaborado teniendo en cuenta los distintos niveles de adaptación descritos anteriormente, partiendo de cada uno de ellos se han elaborado los pasos necesarios a dar por las Comunidades Autónomas para poder alcanzar como mínimo el siguiente nivel superior. Las medidas identificadas se incluyen como repositorio en la herramienta, indicándose las recomendadas a tomar, en los informes resultado de las evaluaciones de las Comunidades Autónomas, de modo que si, por ejemplo, una Comunidad Autónoma obtiene para un criterio (procedimiento) evaluado un nivel de adaptación parcial, nivel 3, se le propondrán las medidas oportunas para alcanzar el nivel de adaptación total, nivel 4. En resumen, los objetivos principales que alcanza el presente trabajo son: • Enmarcar la eAdministración en España y Europa. • Agrupar los criterios propuestos en el proyecto ‘Análisis de la eAdministración e identificación de criterios auditables para la evaluación del grado de implantación’ en categorías. • Elaborar un sistema que permita ponderar, de manera opcional, además de los criterios propuestos, cada una de las categorías clasificadas, obteniendo un resultado más real de la evaluación. • Implementar una herramienta de gestión de conocimiento que permita: o evaluar el nivel de implantación de la eAdministración en las CCAA. o generar un informe resultado de la evaluación con propuesta de medidas de mejora del nivel de adaptación de la eAdministración en la CA. o explotar la información recogida mediante informes configurables. • Identificar posibles medidas a tomar por las CCAA como propuesta para mejorar los niveles de adaptación obtenidos en las evaluaciones y poder utilizarlas como apoyo y guía para llegar a la adaptación total e incluirlas en la herramienta. El presente trabajo se concibe como un complemento al proyecto ‘Análisis de la eAdministración e identificación de criterios auditables para la evaluación del grado de implantación’, ampliándose el estudio de la situación de la eAdministración, así como utilizando las aportaciones realizadas en dicho proyecto como base para la implementación de la herramienta propuesta en el presente trabajo, utilizándose las evaluaciones realizadas sobre CCAA concretas del proyecto ‘Análisis de la eAdministración e identificación de criterios auditables para la evaluación del grado de implantación’ como históricos de la herramienta propuesta en este trabajo, que permitirán utilizarlas como referencia para poder realizar comparativas con las evaluaciones que se realicen posteriormente con la herramienta.Ingeniería en Informátic

Glucose tolerance predicts survival in old zebra finches

The capacity to deal with external and internal challenges is thought to affect fitness, and the age-linked impairment of this capacity defines the ageing process. Using a recently developed intra-peritoneal glucose tolerance test (GTT), we tested for a link between the capacity to regulate glucose levels and survival in zebra finches. We also investigated for the effects of ambient factors, age, sex, and manipulated developmental and adult conditions (i.e. natal brood size and foraging cost, in a full factorial design) on glucose tolerance. Glucose tolerance was quantified using the incremental 'area under the curve' (AUC), with lower values indicating higher tolerance. Glucose tolerance predicted survival probability in old birds, above the median age, with individuals with higher glucose tolerance showing better survival than individuals with low or intermediate glucose tolerance. In young birds there was no association between glucose tolerance and survival. Experimentally induced adverse developmental conditions did not affect glucose tolerance, but low ambient temperature at sampling and hard foraging conditions during adulthood induced a fast return to baseline levels (i.e. high glucose tolerance). These findings can be interpreted as an efficient return to baseline glucose levels when energy requirements are high, with glucose presumably being used for energy metabolism or storage. Glucose tolerance was independent of sex. Our main finding that old birds with higher glucose tolerance had better survival supports the hypothesis that the capacity to efficiently cope with a physiological challenge predicts lifespan, at least in old birds

Corticosterone levels reflect variation in metabolic rate, independent of 'stress'

Variation in glucocorticoid hormones (GCs) is often interpreted as reflecting 'stress', but this interpretation is subject of intense debate. GCs induce gluconeogenesis, and we hypothesized therefore that GC variation can be explained by changes in current and anticipated metabolic rate (MR). Alternatively, GC levels may respond to psychological 'stress' over and above its effect on metabolic rate. We tested these hypotheses in captive zebra finches, by inducing an increase in MR using a psychological stressor (noise), and compared its effect on corticosterone (CORT, the primary avian GC) with the effect induced by a decrease in ambient temperature increasing MR to a similar extent. We found the increase in CORT induced by the psychological stressor to be indistinguishable from the level expected based on the noise effect on MR. We further found that a handling and restraint stressor that increased CORT levels also resulted in increased blood glucose levels, corroborating a key assumption underlying our hypothesis. Thus, GC variation primarily reflected variation in energy expenditure, independently of psychological stress. GC levels have many downstream effects besides glucose mobilization, and we propose that these effects can be interpreted as adjustments of physiological functions to the metabolic level at which an organism operates.publishe