Distinct phenotypes of spontaneous activity and induction of amphetamine sensitization in inbred Roman high- and low-avoidance rats: Vulnerability and protection.

The psychogenetically selected Roman high- (RHA) and low-avoidance (RLA) rats are being proposed as a valuable animal model of individual vulnerability to the two distinct neurobiological mechanisms of behavioral sensitization to psychostimulants, namely induction and expression. Most hallmarks of their divergent phenotypes are also found in the inbred RHA (RHA-I) and RLA (RLA-I) strains. For instance, they differ in the expression of sensitization to amphetamine. However, the pattern of spontaneous activity of the inbred rats seems to differ from that of outbred Roman strains. The present work shows the relevance of analyzing spontaneous activity as a covariant in order to determine the significance of day effect in the induction of behavioral sensitization to amphetamine (regime: 11 days, 1 mg/kg, i.p.) in the inbred strains and, for comparison, the standard low activity Sprague-Dawley (SD) strain. Our results also confirm that, in parallel to the outbred strains, only inbred RHA rats showed sensitization during the induction phase, here detectable from day 9 of treatment, while RLA-I and SD strains did not. Inbred RLA rats provide an interesting model to study individual resistance to sensitization, with nuances due to their underlying high spontaneous activity phenotype.

Alteraciones magnetoencefalográficas perisilvianas en pacientes con trastornos del espectro autista / Perisylvian magnetoencephalografic impairments in patients with autism spectrum disorders

Introducción. Las áreas perisilvianas se sitúan alrededor de la cisura de Silvio y están constituidas por regiones cerebrales frontales, temporales y parietales. Estas regiones están conectadas formando redes neurales especializadas y desempeñan una función elemental en el desarrollo de las habilidades lingüísticas y de la cognición social. Estas áreas son un posible sustrato neural de las alteraciones cognitivas y conductuales en los pacientes con trastornos del espectro autista (TEA). Objetivo. Localizar y cuantificar las fuentes de actividad epileptiforme mediante magnetoencefalografía en áreas frontales perisilvianas en niños con TEA primario. Pacientes y métodos. Se estudió a 68 niños con TEA idiopático mediante magnetoencefalografía. Se clasificaron en dos grupos: uno de 41 niños con trastorno autista y un grupo combinado de 27 niños con síndrome de Asperger y niños con trastorno generalizado del desarrollo no especificado. Se localizaron y se cuantificaron las fuentes de actividad epileptiforme magnetoencefalográfica detectadas en las áreas frontales perisilvianas. Resultados. La actividad epileptiforme en la región perisilviana frontal fue significativamente mayor en el grupo de niños con trastorno autista. Conclusiones. La localización y cantidad de actividad epileptiforme en áreas frontales perisilvianas difirieron significativamente entre los niños con trastorno autista y aquellos con síndrome de Asperger y trastorno generalizado del desarrollo no especificado (AU)

Introduction. The perisylvian areas, located around the Sylvian fissure, are constituted by frontal, temporal and parietal brain regions. These are connected forming specialized neural networks and play a primary role in the development of linguistic skills and social cognition. These areas are a possible neuronal substrate of cognitive and behavioral impairments in patients with autism spectrum disorders (ASD). Aim. To locate and quantify epileptiform activity sources through magnetoencephalography in frontal perisylvian areas in children with idiopathic ASD. Patients and methods. Sixty-eight children with idiopathic ASD were studied by magnetoencephalography. The children were classified into two groups: a group of 41 children with autistic disorder and a combined group of 27 children with Asperger syndrome and children with pervasive developmental disorder not otherwise specified. The sources of magnetoencephalografic epileptiform activity detected in the frontal perisylvian were localized and quantified. Results. The amount of epileptiform activity in frontal perisylvian region was significantly higher in children with autistic isorder. Conclusions. The amount of epileptiform activity in frontal perisylvian areas differed significantly between children with autistic disorder and those with Asperger syndrome and pervasive developmental disorder not otherwise specified (AU)

Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains.

The serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT2A and decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT2A, 5-HT1A, and mGlu2 mRNA and [3H]ketanserin binding levels were measured in brain homogenates. As expected, 5-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT1A receptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the HTR2A gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3ß at tyrosine 216 and increased ß-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

How we train undergraduate medical students in decoding patients' nonverbal clues.

BACKGROUND: Communication skills (CS) and the psychosocial dimensions of patient care are currently considered core competencies in medical schools. CS programs have focused on verbal communication rather than the nonverbal communication. AIM: To present a training program aimed to decode patients' nonverbal clues for second year medical students implemented at the School of Medicine of the Autonomous University of Barcelona. METHOD: A description of a theoretical framework, principles, general and specific goals, learning settings, strategies, skills, and assessment tools. RESULTS: A model of training for preclinical medical students in decoding patients' nonverbal clues is shown. The students have shown satisfaction with the program. CONCLUSIONS: The detection of patients' nonverbal clues can be regarded as a humanistic skill that can be defined, trained, and evaluated. The program can be transferable to other institutions on health sciences and adapted to other academic levels or, even, clinical specialties.

Differences in Extinction of an Appetitive InstrumentalResponse in Female Inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance Rats

An experiment was conducted with the goal of exploring strain differences between female inbred Roman High and Low Avoidance rats (RHA-I, and RLA-I, respectively) on acquisition and extinction of a food-rewarded running response in a straight alley. Acquisition proceeded faster in the less emotional RHA-I and Wistar rats (used as controls) than in the more emotional RLA-I rats. However, extinction proceeded slower in RHA-I ratsthan in RLA-I and Wistar rats. This strain-based asymmetry on instrumental performance between acquisition and extinction is discussed in terms of strain differences in locomotor activity, associative flexibility and emotional reactivity (AU)

Se realizó un experimento con el objetivo de explorar las diferencias de ejecución entre ratas Romanas consanguíneas de Alta y Baja Evitación(RHA-I y RLA-I, respectivamente) en la adquisición y la extinción de una respuesta de carrera recompensada con comida en un laberinto recto. La adquisición fue más rápida en las ratas menos emocionales RHA-I y Wistar (utilizadas como controles) que en las ratas más emocionales RLA-I. Sin embargo, la extinción fue más lenta en las ratas RHA-I que en las ratasRLA-I y Wistar. Esta asimetría en la actuación instrumental en función de la cepa entre la adquisición y la extinción se discute en términos de diferencias de cepa en la actividad locomotora, en la flexibilidad asociativa y en la reactividad emocional (AU)

Differences in Extinction of an Appetitive Instrumental Response in Female Inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance Rats

Se realizó un experimento con el objetivo de explorar las diferencias de ejecución entre ratas Romanas consanguíneas de Alta y Baja Evitación (RHA-I y RLA-I, respectivamente) en la adquisición y la extinción de una respuesta de carrera recompensada con comida en un laberinto recto. La adquisición fue más rápida en las ratas menos emocionales RHA-I y Wistar (utilizadas como controles) que en las ratas más emocionales RLA-I. Sin embargo, la extinción fue más lenta en las ratas RHA-I que en las ratas RLA-I y Wistar. Esta asimetría en la actuación instrumental en función de la cepa entre la adquisición y la extinción se discute en términos de diferencias de cepa en la actividad locomotora, en la flexibilidad asociativa y en la reactividad emocional (AU)

An experiment was conducted with the goal of exploring strain differences between female in bred Roman High and Low Avoidance rats (RHA-I, and RLA-I, respectively) on acquisition and extinction of a food-rewarded running response in a straight alley. Acquisition proceeded faster in the less emotional RHA-I and Wistar rats (used as controls) than in the more emotional RLA-I rats. However, extinction proceeded slower in RHA-I rats than in RLA-I and Wistar rats. This strain-based asymmetry on instrumental performance between acquisition and extinction is discussed in terms of strain differences in locomotor activity, associative flexibility and emotional reactivity (AU)

The Roman High- and Low-Avoidance rat strains differ in fearpotentiated startle and classical aversive conditioning / Las cepas de ratas Roman de alta y baja evitación difieren en respuesta de sobresalto potenciada por miedo y en condicionamiento clásico aversivo

The Swiss sublines of Roman High-(RHA/Verh) and Low-(RLA/Verh) Avoidance rats have been genetically selected (and outbred) since 1972 because of their good versus extremely poor acquisition of two-way, active avoidance. Inbred strains (RHA-I and RLA-I), derived from those two lines, have been maintained at our laboratory since 1997. The RLA line/strain shows increased stress-induced endocrine responses and enhanced anxiety/fearfulness in a variety of unconditioned behavioural variables and tests. Thus far, however, the Roman rat strains have not been compared in procedures involving classical fear conditioning to cues or contexts. Therefore, the present work was aimed at comparing RHA-I and RLA-I rats in 1) two different procedures of fear-potentiated startle and 2) in a classical fear conditioning (i.e., conditioned freezing) paradigm. The results indicate that, compared to RHA-I rats, RLA-I animals display higher levels of conditioned fear (as measured either by startle responses or freezing behavior) across those different tasks (AU)

Las sublíneas suizas de ratas Romanas «High»-(RHA/Verh) y «Low»-(RLA/Verh) «Avoidance» han sido seleccionadas genéticamente, desde 1972, en función de su excelente (RHA) o extremadamente pobre adquisición de la tarea de evitación activa en dos sentidos. Cepas consanguíneas (RHA-I y RLA-I), derivadas de las dos líneas anteriores, se mantienen en nuestro laboratorio desde 1997. En comparación con la cepa RHA-I, la cepa RLA-I muestra incrementos en las respuestas hormonales al estrés, así como en conductas de ansiedad/miedo en una variedad de pruebas y variables conductuales incondicionadas. Hasta la fecha, las cepas de ratas Romanas no han sido comparadas en procedimientos de condicionamiento clásico de miedo a contextos o estímulos discretos. El presente trabajo tuvo como objetivo comparar ambas en 1) dos procedimientos de medida de la respuesta de sobresalto potenciada por miedo; y, 2) en un procedimiento de condicionamiento clásico de miedo (petrificación condicionada). Los resultados indican que las ratas RLA-I muestran niveles mayores de condicionamiento de miedo (respuesta de sobresalto y respuesta e petrificación) que las RHA-I, reforzando así los perfiles diferenciales de ansiedad/miedo de las dos cepas (AU)

The Roman High- and Low-Avoidance rat strains differ in fear-potentiated startle and classical aversive conditioning.

The Swiss sublines of Roman High-(RHA/Verh) and Low-(RLA/Verh) Avoidance rats have been genetically selected (and outbred) since 1972 because of their good versus extremely poor acquisition of two-way, active avoidance. Inbred strains (RHA-I and RLA-I), derived from those two lines, have been maintained at our laboratory since 1997. The RLA line/strain shows increased stress-induced endocrine responses and enhanced anxiety/fearfulness in a variety of unconditioned behavioural variables and tests. Thus far, however, the Roman rat strains have not been compared in procedures involving classical fear conditioning to cues or contexts. Therefore, the present work was aimed at comparing RHA-I and RLA-I rats in 1) two different procedures of fear-potentiated startle and 2) in a classical fear conditioning (i.e., conditioned freezing) paradigm. The results indicate that, compared to RHA-I rats, RLA-I animals display higher levels of conditioned fear (as measured either by startle responses or freezing behavior) across those different tasks.

Characterization of central and peripheral components of the hypothalamus-pituitary-adrenal axis in the inbred Roman rat strains.

Several studies performed in outbred Roman high- and low-avoidance lines (RHA and RLA, respectively) have demonstrated that the more anxious line (RLA) is characterized by a higher hypothalamic-pituitary-adrenal (HPA) response to certain stressors than the less anxious one (RHA). However, inconsistent results have also been reported. Taking advantage of the generation of an inbred colony of RLA and RHA rats (RHA-I and RLA-I, respectively), we have characterized in the two strains not only resting and stress levels of peripheral HPA hormones but also central components of the HPA axis, including CRF gene expression in extra-hypothalamic areas. Whereas resting levels of ACTH and corticosterone did not differ between the strains, a greater response to a novel environment was found in RLA-I as compared to RHA-I rats. RLA-I rats showed enhanced CRF gene expression in the paraventricular nucleus (PVN) of the hypothalamus, with normal arginin-vasopressin gene expression in both parvocellular and magnocellular regions of the PVN. This enhanced CRF gene expression is not apparently related to altered negative corticosteroid feedback as similar levels of expression of brain glucorticoid and mineralocorticoid receptors were found in the two rat strains. CRF gene expression tended to be higher in the central amygdala and it was significantly higher in the dorsal region of the bed nucleus of stria terminalis (BNST) of RLA-I rats, while no differences appeared in the ventral region of BNST. Considering the involvement of CRF and the BNST in anxiety and stress-related behavioral alterations, the present data suggest that the CRF system may be a critical neurobiological substrate underlying differences between the two rat strains.

Divergent effect of the selective D3 receptor agonist pd-128,907 on locomotor activity in Roman high- and low-avoidance rats: relationship to NGFI-A gene expression in the Calleja islands.

RATIONALE: The inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats, differing in dopaminergic activity and novelty/substance-seeking profiles, may be a suitable model to study the implication of the dopaminergic system in vulnerability to drug abuse. Differences in D3 receptor binding recently described between the two strains (Guitart-Masip M, Johansson B, Fernández-Teruel A, Cañete T, Tobeña A, Terenius L, Giménez-Llort L, Neuroscience 142:1231-1243, 2006b) may be important in shaping the aforementioned differences in novelty seeking. OBJECTIVE: The aim of the present work was to study the effect of D3 receptor activation on novelty-induced locomotor activity in these two strains of rats. MATERIALS AND METHODS: We administered saline and PD-128,907 (0.01 and 0.1 mg/kg), a putative D3 receptor agonist, to the Roman rats and studied the locomotor activity when animals were placed in a novel environment. Thereafter, by means of in situ hybridization, nerve growth factor inducible clone A (NGFI-A) mRNA was measured in the striatum and the Calleja islands of these animals. RESULTS: We found that RLA-I rats showed stronger locomotor inhibition than RHA-I rats after PD-128,907 administration. Moreover, RLA-I rats showed stronger reduction of NGFI-A mRNA in the Calleja islands than RHA-I rats. CONCLUSIONS: These results, together with previous findings, suggest that differences in D3 receptor expression in the Calleja islands may contribute to the divergent behavioral effect of PD-128,907 administration in the two strains of Roman rats.

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain.

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.

Reduced ethanol response in the alcohol-preferring RHA rats and neuropeptide mRNAs in relevant structures.

Roman rat strains, genetically selected for high (RHA) or low (RLA) active avoidance acquisition in the two-way shuttle box, differ in dopaminergic activity. These two strains appear to be a valid laboratory model of divergent sensation/novelty and substance-seeking profiles. RHA rats show higher ethanol intake and preference than do RLA rats, and it was suggested that RHA rats are more tolerant than RLA to the effects of alcohol. In the hole-board test, we found that the non-alcohol-preferring RLA rats showed enhanced responsiveness to the stimulatory effects of intraperitoneal administration of 0.25 g/kg ethanol when compared with RHA rats. In situ hybridization analysis showed higher levels of preprodynorphin in the accumbens shell and higher levels of preproenkephalin in the cingulate cortex in RHA rats. RLA rats showed higher levels of enkephalin gene transcripts in restricted areas of the dorsal striatum. Finally, differences in cholecystokinin gene transcript, suggestive of a different arrangement of certain interneurons, were found in different cortical areas. The differences in peptide gene expression found between the two strains might reflect the differences in alcohol preference and sensitivity. RHA rats may have more predictive value than other rodent alcoholism models, as high initial tolerance to ethanol is a risk factor for alcoholism in humans.