Enriquecimiento ambiental en ratones 3xTgAD (modelo de Alzheimer) : perfiles cognitivos y emotivos /

Descripció del recurs: el 01 setembre 2012La enfermedad de Alzheimer (AD) es un desorden neurodegenerativo relacionado con la edad que representa la causa de demencia senil más común. Este desorden se caracteriza por la pérdida de memoria acelerada e incrementada respecto al envejecimiento normal, y el deterioro de otras habilidades cognitivas que interfieren con el estado de ánimo, la razón, el juicio y el lenguaje. Existen varios modelos animales que reproducen los principales marcadores patológicos del desorden: las placas extracelulares de β-amiloide (βA) y los ovillos neurofibrilares de proteina Tau. Este es el caso del modelo de ratón triple transgénico 3xTgAD, portador de los transgenes humanos PS1M146V, APPSwe y TauP301L, que desarrolla de manera progresiva las patologías βA y Tau, con un perfil temporal y anatómico específico que reproduce el patrón que tiene lugar en el cerebro humano con Alzheimer. Diversos trabajos han demostrado que el tratamiento de enriquecimiento ambiental en ratones es capaz de inducir cambios conductuales y de reactividad emocional frente al estrés. La estimulación cognitiva aumenta la conectividad neuronal en áreas responsables del aprendizaje y la memoria, creando una reserva cognitiva, de manera que los animales enriquecidos desarrollan redes neuronales más fuertes, soportando un mayor número de daños antes de mostrar signos de declive. Basándonos en estas teorías, la presente Tesis tiene como objetivos: 1. La caracterización conductual del modelo de ratón 3xTgAD en diversas etapas del desarrollo de la neuropatología. Extendiendo el conocimiento sobre las alteraciones del perfil cognitivo (de aprendizaje y memoria), y ampliándolo con la caracterización de las alteraciones a nivel no cognitivo. La caracterización de los ratones machos 3xTgAD se llevó a cabo a los 2.5 y 6 meses de edad (Estudio I), y en etapas más avanzadas de la enfermedad, cuando las placas de βA y los ovillos de Tau ya están ampliamente extendidos por la corteza y el hipocampo, a los 12 y 15 meses de ratones 3xTgAD de ambos sexos (Estudio II). 2. El estudio de los efectos presumiblemente beneficiosos del enriquecimiento ambiental en el modelo 3xTgAD. Se realizó un tratamiento de enriquecimiento ambiental a los 6 meses de edad, hasta la posterior evaluación conductual de los animales 3xTgAD de ambos sexos a los 12 y 15 meses de edad (Estudio II). Los resultados obtenidos muestran, por primera vez a los 2.5 meses de edad (en las fases iniciales de la neuropatología), que los ratones 3xTgAD presentan leves déficits cognitivos, detectados en la memoria espacial a corto plazo. Dicho déficit cognitivo va acompañado de una ligera alteración a nivel no cognitivo/emocional, reflejada por una reducción en los niveles de actividad exploratoria, probablemente resultado de un incremento del nivel de ansiedad/temerosidad. A los 6 meses, cuando ya se detectan depósitos amiloides extracelulares difusos por la corteza, dichas alteraciones cognitivas (de aprendizaje y memoria espacial) y emocionales (de los niveles de ansiedad/temerosidad) se ven incrementadas en los ratones 3xTgAD. Los resultados obtenidos a edades más avanzadas indican que los ratones 3xTgAD de 12 y 15 meses de edad presentan déficits cognitivos de aprendizaje y memoria espacial, de memoria de trabajo y a corto plazo, de transferencia de información entre las dos edades, y los mayores niveles de ansiedad/temerosidad. Asimismo los ratones 3xTgAD presentan dimorfismo sexual, reflejado en mayores déficits cognitivos de las hembras respecto a los machos, y mayores niveles de inhibición conductual de los machos respecto a las hembras. El enriquecimiento ambiental ejerce efectos positivos, aunque moderados, principalmente de mejora de los déficits de aprendizaje/memoria de referencia, de memoria de trabajo y de transferencia de información entre ambas edades en animales 3xTgAD de 12 meses. Dichos efectos del enriquecimiento ambiental varían en función del género.Alzheimer disease (AD) is a neurodegenerative disorder associated with age which represents the most common cause of dementia. This disorder is characterized by an increased and accelerated memory loss compared to normal aging, and deterioration of other cognitive abilities that interfere with mood, reason, judgment and language. There are several animal models that reproduce the main pathological hallmarks of the disorder: extracellular β-amyloid (βA) plaques and neurofibrillary tangles of Tau protein. This is the case of the triple tansgenic 3xTgAD mouse model, harvouring human trangenes PS1M146V, APPSwe y TauP301L, which developes in a progressive manner βA and Tau pathologies, with a specific temporal and anathomic profile that mimics the pattern that takes place in the human brain with Alzheimer's disease. 3xTgAD model shows neuropathological and cognitive profile alterations characteristic of the disease, showing βA plaques widely extended through the cortex and the hippocampus at the age of 12 month old, and neurofibrillary tangles from 15 months of age onwards. Environmental enrichment in mice induces behavioural and emotional reactivity changes. It is thought that cognitive stimulation increases neuronal connectivity in areas responsible for learning and memory, creating a cognitive reserve, so that the enriched animals develope stronger neuronal networks and therefore can handle increased amounts of neural damage before showing signs of decline. Based on these theories, the main aims of this Thesis were: 1. Behavioural caracterization of 3xTgAD mouse model at various stages of the neuropathology development. Extending the knowledge about the alterations in the cognitive profile, upgrading it with the caracterization of the non cognitive alterations of the model. To achieve it, we carried out the caracterization of 3xTgAD male mice at 2.5 and 6 months old (Study I). Moreover, a longitudinal study at advanced stages of the disease, when βA plaques and neurofibrillary tangles are already widely extended through the cortex and hippocampus, was also carried out in 12 and 15-month-old 3xTgAD mice of both sexes (Study II). 2. The study of the presumably beneficial effects of environmental enrichment in the 3xTgAD model. For this study an environmental enrichment treatment was administered, from the age of 6 month old until the behavioural evaluation (emotional reactivity/fearfulness, learning and memory) of 3xTgAD animals of both sexes at 12 and 15 months of age (Study II). Results show, for first time at the age of 2.5 months (i.e. at early stages of AD pathology), that 3xTgAD mice show minor cognitive decline, detected in the short term spatial memory. This cognitive deficit is accompained with minor non cognitive/emotional alterations, reflected by reduced levels of exploratory activity in the Open Field test, probably resulting from an increase in anxiety/fearfulness (as shows the number of defecation boluses in several tests). When 6 months old, when diffuse extracellular amyloid deposits are detected through the cortex, the cognitive deficits (spatial learning and memory) and emotional (anxiety/fearfulness levels) alterations are increased in 3xTgAD mice. Results obtained at later stages demonstrate that 3xTgAD mice show no sensory-motor deficits. Cognitive deficits of spatial learning and memory, working memory and short term memory, information "transfer" between both ages, and the increased levels of anxiety/fearfulness, are present at 12 and 15 months of age in the 3xTgAD model. 3xTgAD mice also show sexual dimorphism, reflected by higher cognitive deficits in females compared to males, and higher levels of novelty-induced behavioural inhibition in males compared to females. Environmental enrichment exerts positive effects, although moderate, by mainly improving deficits in spatial learning/memory and working memory in 12-month-old 3xTgAD mice, as well as by improving information "transfer" between both ages in 3xTgAD animals. These environmental enrichment effects vary depending on the gender

ELABORACION DE UN PLAN DE IGUALDAD EN UNA PYME ARAGONESA

El presente trabajo de Fin de Grado tiene como tema central el “Plan de Igualdad”. A modo de resumen los puntos que tratamos son los siguientes: 1.- Explicamos que es un Plan de Igualdad y cuáles son las fases que hay que seguir para que una empresa lo implante. 2.- Definimos el marco legal existente sobre el tema tanto a nivel europeo, nacional y de nuestra comunidad autónoma. 3.- Elaboramos y desarrollamos cada una de las fases llevadas a cabo en la implantación del Plan de Igualdad en una Pyme aragonesa del sector químico, Certest Biotec S.L Por último, presentamos una serie de conclusiones para cerrar el proyecto.<br /

Neonatal handling decreases unconditioned anxiety, conditioned fear, and improves two-way avoidance acquisition: a study with the inbred Roman high (RHA-I)- and low-avoidance (RLA-I) rats of both sexes

The present study evaluated the long-lasting effects of neonatal handling (H; administered during the first 21 days of life) on unlearned and learned anxiety-related responses in inbred Roman High- (RHA-I) and Low-avoidance (RLA-I) rats. To this aim, untreated and neonatally-handled RHA-I and RLA-I rats of both sexes were tested in the following tests/tasks in baseline acoustic startle (BAS) test, a context-conditioned fear (CCF) test and the acquisition of two-way active –shuttle box- avoidance (SHAV). RLA-I rats showed higher unconditioned (NOE, ZM, BAS) and conditioned (CCF, SHAV) anxiety. H treatment increased exploration of the novel object in the NOE test as well as exploration of the open sections of the ZM test in both rat strains and sexes, although the effects were relatively more marked in the (high anxious) RLA-I strain and in females. Neonatal handling did not affect BAS, but reduced context-conditioned fear in both strains and sexes, and improved shuttle box avoidance acquisition especially in RLA-I (and particularly in females) and in female RHA-I rats. These are completely novel findings, and may suggest that H-induced changes in hippocampal function, which is enhanced in RLA-Is vs RHA-I rats, could be a candidate mechanism underlying the observed long-lasting benefits of neonatal handling on known hippocampal-dependent responses/tasks

Social Memory and Social Patterns Alterations in the Absence of STriatal-Enriched Protein Tyrosine Phosphatase

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. Our data robustly demonstrated that STEP KO mice presented specific social memory impairment as indicated by the three-chamber sociability test, the social discrimination test, the 11-trial habituation/dishabituation social recognition test, and the novel object recognition test (NORT). This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. However, STEP KO mice showed lower exploratory activity, reduced interaction time with an intruder, less dominant behavior and higher immobility time in the tail suspension test than controls, suggesting alterations in motivation. Moreover, the extracellular levels of dopamine (DA), but not serotonin (5-HT), were increased in the dorsal striatum of STEP KO mice. Overall, our results indicate that STEP deficiency disrupts social memory and other social behaviors as well as DA homeostasis in the dorsal striatum

Propuestas didácticas de carácter interdisciplinar para la enseñanza/Aprendizaje del espacio y el tiempo en la educación infantil

En este artículo se desarrollan propuestas didácticas de carácter interdisciplinar que el maestro de educación infantil puede aplicar en su práctica educativa para conseguir que niños y niñas interioricen las nociones de espacio y tiempo. Estas propuestas se enmarcan en el ámbito del conocimiento del entorno natural y social, que en esta etapa educativa no se configura como un área independiente. Se parte de la idea de que el propio cuerpo es el primer punto de referencia de la percepción y que desde la percepción del propio esquema corporal se llegará a dominar la percepción del espacio representativo. En la segunda parte, ampliamos el horizonte espacial e introducimos las nociones temporales, en base a la percepción que el niño tiene de los cambios que se producen en su entorno cercano, especialmente de los cambios rítmicos (rutinas en el día, cambios estacionales, cambios en la familia…). Por último, en la tercera parte, se plantea el descubrimiento, correcta percepción y comprensión por parte del niño, de un espacio más amplio: en la calle, el barrio, el pueblo o la ciudad. Cada uno de los tres apartados se acompaña de propuestas didácticas que permiten implementar y llevar a la práctica con facilidad, las argumentaciones teóricasIn this article we present interdisciplinary educational proposals that young children teachers could apply in their educational practice to ensure that children internalize the notions of space and time. These proposals concern the natural and the social environments, which in this level of education are not considered independent areas but one complex field. Each proposal contains specific activities with a theoretical basis which justifies them. We start in the first part from the concept that for human beings the body is the first benchmark of perception. From the perception of the body scheme itself, we finally acknowledge representative space. Then, in the second part, we expand the field and introduce temporal notions, taking into account the perception that children have of changes that occur in their immediate environment, especially recurrent changes (routines during the day, seasonal changes, within the family...). Finally, in the third part, we elaborate on the discovery, correct perception and understanding by the child, of a wider space: the street, the neighborhood, the town or cit

Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/Nih-HS) rats

Physiological and environmental variables, or covariates, can account for an important portion of the variability observed in behavioural/physiological results from different laboratories even when using the same type of animals and phenotyping procedures. We present the results of a behavioural study with a sample of 1456 genetically heterogeneous N/Nih-HS rats, including males and females, which are part of a larger genome-wide fine-mapping QTL (Quantitative Trait Loci) study. N/Nih-HS rats have been derived from 8 inbred strains and provide very small distance between genetic recombinations, which makes them a unique tool for fine-mapping QTL studies. The behavioural test battery comprised the elevated zero-maze test for anxiety, novel-cage (open-field like) activity, two-way active avoidance acquisition (related to conditioned anxiety) and context-conditioned freezing (i.e. classically conditioned fear). Using factorial analyses of variance (ANOVAs) we aimed to analyse sex differences in anxiety and fear in this N/Nih-HS rat sample, as well as to assess the effects of (and interactions with) other independent factors, such as batch, season, coat colour and experimenter. Body weight was taken as a quantitative covariate and analysed by covariance analysis (ANCOVA). Obliquely-rotated factor analyses were also performed separately for each sex, in order to evaluate associations among the most relevant variables from each behavioural test and the common dimensions (i.e. factors) underlying the different behavioural responses. ANOVA analyses showed a consistent pattern of sex effects, with females showing less signs of anxiety and fear than males across all tests. There were also significant main effects of batch, season, colour and experimenter on almost all behavioural variables, as well as "sex × batch", "sex × season" and "sex × experimenter" interactions. Body weight showed significant effects in the ANCOVAs of most behavioural measures, but sex effects were still present in spite of (and after controlling for) these "body weight" effects. Factor analyses of relevant variables from each test showed a two-fold factor structure in both sexes, with the first factor mainly representing anxiety and conditioned fear in males, while in females the first factor was dominated by loadings of activity measures. Thus, besides showing consistent sex differences in anxiety-, fear- and activity-related responses in N/Nih-HS rats, the present study shows that females' behaviour is predominantly influenced by activity while males are more influenced by anxiety. Moreover, the results point out that, besides "sex" effects, physiological variables such as colour and body weight, and environmental factors as batch/season or "experimenter", have to be taken into account in both behavioural and quantitative genetic studies because of their demonstrated influences on phenotypic outcomes

Social memory and social patterns alterations in the absence of striatal-enriched protein tyrosine phosphatase

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. Our data robustly demonstrated that STEP KO mice presented specific social memory impairment as indicated by the three-chamber sociability test, the social discrimination test, the 11-trial habituation/dishabituation social recognition test, and the novel object recognition test (NORT). This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. However, STEP KO mice showed lower exploratory activity, reduced interaction time with an intruder, less dominant behavior and higher immobility time in the tail suspension test than controls, suggesting alterations in motivation. Moreover, the extracellular levels of dopamine (DA), but not serotonin (5-HT), were increased in the dorsal striatum of STEP KO mice. Overall, our results indicate that STEP deficiency disrupts social memory and other social behaviors as well as DA homeostasis in the dorsal striatum

High-resolution genome screen for bone mineral density in heterogeneous stock rat

We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10(-6)). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3×10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis

Equipo de ensayo para la determinación in situ de la tenacidad ala fractura de uniones encoladas

Equipo de ensayo para la determinación in situ de la tenacidad a la fractura de uniones encoladas. Se trata de un equipo de ensayos que puede ser trasladado y aplicado in situ sobre la estructura a ensayar para determinar su resistencia al pelado, y consta fundamentalmente de un tambor (2) con elementos de fijación (1) para fijarse a una probeta (100) que va a ser pelada de la unión adhesiva híbrida de la estructura, un carro (4) desplazable sobre el que se monta el tambor (2), un bastidor (6) a lo largo del que se desplaza el tambor (2), y un mecanismo de actuación que determina el movimiento lineal del carro (4) o de giro del tambor (2) y, que por reacción de la probeta (100), determina respectivamente el giro del tambor (2) o el desplazamiento lineal del carro (4).Españ