Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats.

The "Genetically Heterogeneous National Institutes of Health (NIHHS)" stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

c-Fos expression after neonatal handling in social brain regions: Distinctive profile of RHA-rat schizophrenia model on a social preference test.

Neonatal handling (NH) is an environmental manipulation that induces long-lasting changes in behavioural, neuroendocrine, and neuroanatomical processes in rodents. We have previously reported that NH treatment increases social interaction preference in an animal model of schizophrenia-relevant features, the Roman high-avoidance (RHA) rats. The present study was aimed at evaluating whether the increase of social behaviour/preference due to NH treatment in RHA rats is associated with differences in c-Fos expression levels in some of the brain areas that integrate the "social brain". To this aim, we evaluated the performance of adult male rats from both Roman rat strains (RHA vs. RLA -Roman low-avoidance- rats), either untreated (control) or treated with NH (administered during the first 21 days of life) in a social interaction task. For the analyses of c-Fos activation untreated and NH-treated animals were divided into three different experimental conditions: undisturbed home cage controls (HC); rats exposed to the testing set-up context (CTX); and rats exposed to a social interaction (SI) test. It was found that, compared with their RLA counterparts, NH treatment increased social behaviour in RHA rats, and also specifically enhanced c-Fos expression in RHA rats tested for SI in some brain areas related to social behaviour, i.e. the infralimbic cortex (IL) and the medial posterodorsal amygdala (MePD) regions.

Increased thin-spine density in frontal cortex pyramidal neurons in a genetic rat model of schizophrenia-relevant features.

The cellular mechanisms altered during brain wiring leading to cognitive disturbances in neurodevelopmental disorders remain unknown. We have previously reported altered cortical expression of neurodevelopmentally regulated synaptic markers in a genetic animal model of schizophrenia-relevant behavioral features, the Roman-High Avoidance rat strain (RHA-I). To further explore this phenotype, we looked at dendritic spines in cortical pyramidal neurons, as changes in spine density and morphology are one of the main processes taking place during adolescence. An HSV-viral vector carrying green fluorescent protein (GFP) was injected into the frontal cortex (FC) of a group of 11 RHA-I and 12 Roman-Low Avoidance (RLA-I) male rats. GFP labeled dendrites from pyramidal cells were 3D reconstructed and number and types of spines quantified. We observed an increased spine density in the RHA-I, corresponding to a larger fraction of immature thin spines, with no differences in stubby and mushroom spines. Glia cells, parvalbumin (PV) and somatostatin (SST) interneurons and surrounding perineuronal net (PNN) density are known to participate in FC and pyramidal neuron dendritic spine maturation. We determined by stereological-based quantification a significantly higher number of GFAP-positive astrocytes in the FC of the RHA-I strain, with no difference in microglia (Iba1-positive cells). The number of inhibitory PV, SST interneurons or PNN density, on the contrary, was unchanged. Results support our belief that the RHA-I strain presents a more immature FC, with some structural features like those observed during adolescence, adding construct validity to this strain as a genetic behavioral model of neurodevelopmental disorders.

Dissociation between schizophrenia-relevant behavioral profiles and volumetric brain measures after long-lasting social isolation in Roman rats.

Social isolation rearing of rodents is an environmental manipulation known to induce or potentiate psychotic-like symptoms and attentional and cognitive impairments relevant for schizophrenia. When subjected to a 28-week isolation rearing treatment, the Roman high-avoidance (RHA-I) rats display the common behavioral social isolation syndrome, with prepulse inhibition (PPI) deficits, hyperactivity, increased anxiety responses and learning/memory impairments when compared to their low-avoidance (RLA-I) counterparts. These results add face validity to the RHA-I rats as an animal model for schizophrenia-relevant behavioral and cognitive profiles and confirm previous results. The aim here was to further investigate the neuroanatomical effects of the isolation rearing, estimated through volume differences in medial prefrontal cortex (mPFC), dorsal striatum (dSt) and hippocampus (HPC). Results showed a global increase in volume in the mPFC in the isolated rats of both strains, as well as strain effects (RLA > RHA) in the three brain regions. These unexpected but robust results, might have unveiled some kind of compensatory mechanisms due to the particularly long-lasting isolation rearing period, much longer than those commonly used in the literature (which usually range from 4 to 12 weeks).

Cognitive and emotional alterations in young Alzheimer's disease (3xTgAD) mice: effects of neonatal handling stimulation and sexual dimorphism.

Alzheimer disease is the most common neurodegenerative disorder and cause of senile dementia. It is characterized by an accelerated memory loss, and alterations of mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are ß-amyloid (ßA) plaques and neurofibrillary Tau tangles. The triple transgenic 3xTgAD mouse model develops ßA and Tau pathologies in a progressive manner which mimicks the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. The present study intended to examine whether 3xTgAD mice of both sexes present cognitive, emotional and other behavioral alterations at the early age of 4 months, an age in which only some intraneuronal amyloid accumulation is found. Neonatal handling (H) is an early-life treatment known to produce profound and long-lasting behavioral and neurobiological effects in rodents, as well as improvements in cognitive functions. Therefore, we also aimed at evaluating the effects of H on the behavioral/cognitive profile of 4-month-old male and female 3xTgAD mice. The results indicate that, (1) 3xTgAD mice present spatial learning/memory deficits and emotional alterations already at the early age of 4 months, (2) there exists sexual dimorphism effects on several behavioral variables at this age, (3) neonatal handling exerts a preventive effect on some cognitive (spatial learning) and emotional alterations appearing in 3xTgAD mice already at early ages, and 4) H treatment appears to produce stronger positive effects in females than in males in several spatial learning measures and in the open field test.

5-HT(2A) and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains.

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n=8) and RHA-I (n=8) male rats. In the more impulsive RHA-I rats, 5-HT(2A), 5-HT(1A) and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction.

Context-dependent differences in grooming behavior among the NIH heterogeneous stock and the Roman high- and low-avoidance rats.

Grooming occurs during/after stress and seems to accompany dearousal. Here, grooming was investigated under testing situations involving different levels of aversiveness, taking advantage of differences among three rat strains in fearfulness/anxiety. Inbred Roman High Avoidance (RHA-I) rats are less anxious/fearful than inbred Roman Low Avoidance (RLA-I). The outbred genetically heterogeneous stock of rats (NIH-HS), which resembles the RLA-I in many behavioral traits, was also studied. Adult male rats (RLA-I: n=9, RHA-I: n=10, NIH-HS: n=12) were observed for 30min in: a novel open-field, a novel hole-board and in the home-cage. They were also observed during two-way active avoidance training. Differences in grooming depended on test situation: (a) No differences were found in the home-cage. (b) While tested in a novel environment, RHA-I showed less grooming activity than the other rats. (c) After avoidance responses appeared, differences among the strains were opposite to the observed in novelty tests. Furthermore, results suggest that (i) grooming is mostly suppressed when assured aversive experience is under way; (ii) rostral grooming prevails when experience with aversive stimuli is unpredictable (novelty) or potential (avoidance training); (iii) body grooming increases for a period in novel environments. In general, our results support that grooming takes place during dearousal.

Differential hippocampal neuron density between inbred Roman high- (low anxious) and low-avoidance (high anxious) rats.

The inbred Roman low- (RLA-I) and high-avoidance (RHA-I) rats used in this study were initially selected and bred for extremely poor vs. rapid acquisition of active two-way avoidance behavior in the shuttle box. As a result of the selection for divergent avoidance acquisition, clear behavioral differences have been found between RHA and RLA rats in a variety of tasks related to anxiety and conflict. In rats of these two strains/lines previous brain studies have been performed, specifically in the striatum, the mesencephalic dopaminergic areas and the prefrontal cortex, as these brain areas are the classical ones for their critical role in sensitization and may play a role in the well-characterized anxiety response. In this study we analyzed, in RHA and RLA groups (N=5 each), the density of NeuN neurons counterstained with toluidine blue in the cingulate cortex (subdivision 1) and the hippocampus (CA1, CA2 and CA3). A statistical difference was found in the density of neurons of CA1 and CA2 (p=0.047 in both) and in the total density of the hippocampus (p=0.009). Contrary to our expectations, significant strain differences for the density of neurons in the cingulate cortex were not found. The relationship between those differences in the hippocampus and the between-strain differences in anxiety and in learning processes depending on anxiety are discussed.

The effect of partial reinforcement on instrumental successive negative contrast in inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance rats.

Frustration is an emotional response that can be induced by the sudden devaluation of a reinforcer in the presence of greater reinforcement expectancies (e.g. instrumental successive negative contrast, iSNC). This emotional response seems to be similar to anxiety and can be attenuated by previous experiences of reward loss (e.g. partial reinforcement, PR, as opposed to continuous reinforcement, CR). In this study we used iSNC and PR procedures in order to compare the performance of two strains of rats psychogenetically selected on the basis of their emotional reactivity: the inbred Roman High- (RHA-I, low anxiety) and Low- (RLA-I, high anxiety) Avoidance rats. Animals were exposed to a straight alley, where they were changed from 12 pellets in the preshift phase (presented in 100% of trials-CR vs. 50% of trials-PR) to 2 pellets in the postshift phase, or exposed to 2 pellets throughout the training. The results indicated that the iSNC only appeared in RLA-I rats exposed to CR, as opposed to RLA-I animals exposed to PR and to RHA-I rats exposed to PR or CR. These data seem to support the implication of emotional responses in both iSNC and PR situations, and indicate that the behavioral reactivity to reward loss experiences is modulated by genetic variables.

[Poor premorbid adjustment linked to deterioration in theory of mind skills: a study in stabilised schizophrenic patients]. / Ajuste premórbido pobre vinculado al deterioro en habilidades de teoría de la mente: estudio en pacientes esquizofrénicos estabilizados.

INTRODUCTION: Previous studies suggest that there is a deficit in theory of mind (ToM) in stabilised schizophrenic patients. More specifically, it has been claimed that poor premorbid adjustment covaries with the abnormalities in ToM skills detected in such patients. It has also been suggested that this deficit could be a trait marker for schizophrenic disorders. PATIENTS AND METHODS: The aim of this study was to examine the performance in mentalistic skills in 36 stabilised schizophrenic patients in comparison to a standard control group. We also sought to examine the relation between ToM skills and premorbid adjustment in our target sample. Premorbid adjustment was evaluated using the modified Cannon-Spoor premorbid adjustment scale, and ToM measurements were obtained by means of first- and second-order verbal experimental tasks. RESULTS: Schizophrenic patients presented statistically significant poorer performances in first- and second-order ToM tasks, although no differences were observed between these patients and the control sample as regards overall cognitive acuity. Poor premorbid adjustment in areas of social functioning in the patients was also associated with statistically significant poorer performance in both ToM tasks. CONCLUSIONS: Deficient premorbid adjustment in schizophrenia may be linked to a ToM deficit that can be assessed with simple tasks.

Ajuste premórbido pobre vinculado al deterioro en habilidades de teoría de la mente: estudio en pacientes esquizofrénicos estabilizados / Poor premorbid adjustment linked to deterioration in theory of mind skills: A study in stabilised schizophrenic patients

Introducción. Estudios previos indican que existe un déficit en teoría de la mente (ToM) en pacientes esquizofrénicos estabilizados. En particular, se ha señalado que un ajuste premórbido pobre covaría con las anomalías en habilidades ToM detectadas en esos pacientes. Se sugiere que este déficit podría ser un marcador de rasgo para el trastorno esquizofrénico.Pacientes y métodos. El objetivo del presente estudio fue investigar el rendimiento en habilidades mentalísticas en 36 pacientes esquizofrénicos estabilizados comparados con un grupo normativo control, así como explorar la relación entre las aptitudesToM y el ajuste premórbido en la muestra diana. El ajuste premórbido se evaluó mediante la escala de ajuste premórbido modificada de Cannon-Spoor, y las medidas ToM se obtuvieron mediante tareas experimentales verbales de primer y segundo orden. Resultados. Los pacientes esquizofrénicos presentaron peores rendimientos, significativos estadísticamente, enlas tareas ToM de primer y de segundo orden, a pesar de la ausencia de diferencias entre ellos y la muestra control en la agudeza cognitiva global. Un ajuste premórbido desfavorable en áreas de funcionamiento social en los pacientes se asoció, además,a un peor rendimiento, estadísticamente significativo, en ambas tareas ToM. Conclusión. El ajuste premórbido deficiente en la esquizofrenia puede vincularse a un déficit ToM evaluable en tareas sencillas

Introduction. Previous studies suggest that there is a deficit in theory of mind (ToM) in stabilised schizophrenic patients. More specifically, it has been claimed that poor premorbid adjustment covaries with the abnormalities in ToM skills detected in such patients. It has also been suggested that this deficit could be a trait marker for schizophrenic disorders.Patients and methods. The aim of this study was to examine the performance in mentalistic skills in 36 stabilised schizophrenic patients in comparison to a standard control group. We also sought to examine the relation between ToM skills and premorbid adjustment in our target sample. Premorbid adjustment was evaluated using the modified Cannon-Spoor premorbid adjustmentscale, and ToM measurements were obtained by means of first- and second-order verbal experimental tasks. Results. Schizophrenic patients presented statistically significant poorer performances in first- and second-order ToM tasks, although no differences were observed between these patients and the control sample as regards overall cognitive acuity. Poor premorbid adjustmentin areas of social functioning in the patients was also associated with statistically significant poorer performance in both ToM tasks. Conclusions. Deficient premorbid adjustment in schizophrenia may be linked to a ToM deficit that can be assessed with simple tasks

Regional adaptations in PSD-95, NGFI-A and secretogranin gene transcripts related to vulnerability to behavioral sensitization to amphetamine in the Roman rat strains.

Genetically selected for high or low two-way active avoidance, Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats differ in their central dopaminergic activity, sensation/novelty- and substance-seeking profiles. These animals are, therefore, well suited to identify anatomical and neurochemical concomitants of behavioral sensitization, a phenomenon linked to addictive liability. We submitted inbred RHA (RHA-I), inbred RLA (RLA-I) and Sprague-Dawley-OFA (SD-OFA) rats to a sensitization regimen with amphetamine and studied the behavioral response to an amphetamine challenge after a 2-week withdrawal period. The expression patterns of nerve growth factor inducible clone A (NGFI-A), secretogranin, post-synaptic density protein of 95 Kd (PSD-95), prodynorphin and proenkephalin mRNA were also analyzed using in situ hybridization, after the challenge with amphetamine. RHA-I rats showed stronger sensitization than SD-OFA rats. RLA-I rats did not show sensitization but were hyper-reactive to amphetamine. Expression of behavioral sensitization in RHA-I rats activated secretogranin and PSD-95 mRNA in the nucleus accumbens core. On the other hand, high induction of NGFI-A mRNA in the central amygdala was observed in RLA-I rats when they experienced amphetamine for the first time in the challenge. Our results reveal that 1) the acute locomotor response to amphetamine does not predict vulnerability to behavioral sensitization and 2) differences in vulnerability to sensitization may involve distinctive cellular adaptations at particular brain locations which may be related to addictive vulnerability.

Successive positive contrast in one-way avoidance behavior with Roman low-avoidance rats.

The inbred Roman High- (RHA-I) and Roman Low-Avoidance (RLA-I) rats, psychogenetically selected for rapid (RHA-I) vs. extremely poor (RLA-I) acquisition of two-way active avoidance, exhibit a lower or a higher level of fearfulness, respectively, that can be observed in many laboratory anxiety models. The present study analyzed the performance of female RLA-I and RHA-I rats in a successive positive contrast situation induced during one-way avoidance learning. Three groups of RLA-I and three of RHA-I rats (1-30, 30-30 and 1-1 groups, the numbers stand for the time spent in the safe compartment during the first and second phase of training) were trained to avoid an electric foot-shock administered in a "danger" compartment, by running from this compartment to a "safe" one. Only RLA-I rats showed a significant positive contrast effect, in such a way that the reinforcement increase from the lower (1 s spent in safety) to the higher reward (30 s) led to a response enhancement, surpassing the performance of rats trained with the low (1-1 s) or the high (30-30 s) reward from the beginning of training. The results are discussed in the context of an opponent process theory based upon the interaction between the motivational strength of fear and the incentive value of relief taking place during one-way avoidance learning.

Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid.

The amyloid Abeta-peptide (Abeta) is suspected to play a critical role in the cascade leading to AD as the pathogen that causes neuronal and synaptic dysfunction and, eventually, cell death. Therefore, it has been the subject of a huge number of clinical and basic research studies on this disease. Abeta is typically found aggregated in extracellular amyloid plaques that occur in specific brain regions enriched in nAChRs in Alzheimer's disease (AD) and Down syndrome (DS) brains. Advances in the genetics of its familiar and sporadic forms, together with those in gene transfer technology, have provided valuable animal models that complement the traditional cholinergic approaches, although modeling the neuronal and behavioral deficits of AD in these models has been challenging. More recently, emerging evidence indicates that intraneuronal accumulation of Abeta may also contribute to the cascade of neurodegenerative events and strongly suggest that it is an early, pathological biomarker for the onset of AD and associated cognitive and other behavioral deficits. The present review covers these studies in humans, in in vitro and in transgenic models, also providing more evidence that adult 3xTg-AD mice harboring PS1M146V, APPSwe, tauP301L transgenes, and mimicking many critical hallmarks of AD, show cognitive deficits and other behavioral alterations at ages when overt neuropathology is not yet observed, but when intraneuronal Abeta, synaptic and cholinergic deficits can already be described.

Divergent anatomical pattern of D1 and D3 binding and dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa mRNA expression in the Roman rat strains: Implications for drug addiction.

Autoradiography analysis of D1, D2 and D3 dopamine receptors and in situ hybridization analysis of mRNA for dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) were performed in brains of naïve Roman high avoidance (RHA) and Roman low avoidance (RLA) inbred rats. These strains, genetically selected for high (RHA) or extremely low (RLA) active avoidance acquisition in the two-way shuttle box, differ in indices of dopaminergic activity along with sensation/novelty and substance-seeking behavioral profiles. The present study shows no differences in D2 receptor binding between the two strains. In contrast, the D1 and D3 receptor binding in the nucleus accumbens was higher in RHA-I rats, whereas RLA-I rats show higher D3 binding in the Calleja islands. Together with previous evidence showing behavioral and presynaptic differences related to the dopamine system, the present results suggest a higher dopaminergic tone at the nucleus accumbens shell in RHA-I rats. Besides, the comparison of the expression pattern of DARPP-32 mRNA with that of dopamine receptor binding revealed a mismatch in some amygdala nuclei. In some cortical structures (prelimbic and cingulate cortices, the dentate gyrus) as well as in the central amygdala, RHA-I rats showed higher DARPP-32 mRNA expression than RLA-I rats. Hence, RHA-I and RLA-I rats may be a useful tool to identify dopamine-related mechanisms that predispose to drug and alcohol dependence.

El umbral de inhibición latente en las ratas romanas de alta evitación: ¿un modelo psicogenético de anomalías en el filtraje atencional? / Latent inhibition threshold in Roman high-avoidance rats: a psychogenetic model of abnormalities in attentional filter?

Introducción. Además de los modelos animales basados en la inducción de síntomas «psicóticos» mediante de fármacos psicoestimulantes, en la investigación sobre las alteraciones psicobiológicas de la esquizofrenia y sus tratamientos es cada vez más patente la necesidad de modelos que posean mayor validez de constructo, tales como líneas de animales que presenten espontáneamente singularidades asociadas a los trastornos psicóticos (p. ej., una mayor sensibilidad a los efectos de los psicoestimulantes o las anomalías cognitivas/atencionales típicas de los síndromes esquizofrénicos). Diversas evidencias experimentales indican que la cepa de ratas RHA (romanas de alta evitación) muestra un perfil neurobiológico y conductual consistente con tales requisitos.Métodos. Utilizando ratas RHA, en comparación con ratas Sprague-Dawley (SD) como un control estándar, se evaluó la expresión de inhibición latente (en una sesión de 100 ensayos de evitación activa en dos sentidos) en ambas cepas y en condiciones de umbral (con sólo 15 preexposiciones al estímulo condicionado).Resultados. Las ratas SD muestran en tales condiciones inhibición latente significativa en los 50 primeros ensayos y en el total de la sesión, fenómeno atencional que no aparece en la cepa RHA.Conclusiones. El déficit en inhibición latente en condiciones umbral, que mostraron los animales RHA, es compatible con la idea de que dicha cepa puede representar un modelo útil para el estudio de la vulnerabilidad a las alteraciones del espectro esquizofrénico. Una conclusión avalada por los datos que indican que los déficit en inhibición latente son una anomalía atencional característica de aquellas patologías

Introduction. Basic research devoted to the study of the psychobiological anomalies of schizophrenia, as well as of its treatments, has used animal models in which some psychotic-like symptoms are induced by administration of psychostimulant drugs. There is, however, a growing necessity of having animal models presenting better construct validity, i.e., animal lines spontaneously showing phenotypes associated to the psychotic spectrum (for instance, enhanced sensitivity to psychostimulants, or cognitive and attentional anomalies characteristic of schizophrenic disorders). Several lines of evidence suggest that the RHA (Roman high-avoidance) rat strain presents a neurobehavioral profile which is consistent with such goals. ;;Methods. RHA rats were compared to Sprague-Dawley (SD) rats (as a standard control strain) for the expression of latent inhibition (in a 100-trial session of two-way active avoidance) under threshold conditions (i.e., only 15 preexposures to the conditioned stimulus were administered). Results. Under such experimental conditions SD rats showed significant latent inhibition of the two-way active avoidance response (both during the first 50 trials and in the whole 100-trial session), while that attentional phenomenon did not appear in the RHA strain. Conclusions. The experimental results obtained here indicate that RHA rats display a deficit of latent inhibition at threshold conditions, an information processing (or attentional) anomaly which typically appears in schizophrenic patients. It is proposed that RHA rats might be an useful animal model for the study of vulnerability to some schizophrenic symptoms. This conclusion is supported by data that indicate that latent inhibition deficits are a characteristic attentional abnormality of these diseases

[Latent inhibition threshold in Roman high-avoidance rats: a psychogenetic model of abnormalities in attentional filter?]. / El umbral de inhibición latente en las ratas romanas de alta evitación: un modelo psicogenético de anomalías en el filtraje atencional?

INTRODUCTION: Basic research devoted to the study of the psychobiological anomalies of schizophrenia, as well as of its treatments, has used animal models in which some psychotic-like symptoms are induced by administration of psychostimulant drugs. There is, however, a growing necessity of having animal models presenting better construct validity, i.e., animal lines spontaneously showing phenotypes associated to the psychotic spectrum (for instance, enhanced sensitivity to psychostimulants, or cognitive and attentional anomalies characteristic of schizophrenic disorders). Several lines of evidence suggest that the RHA (Roman high-avoidance) rat strain presents a neurobehavioral profile which is consistent with such goals. METHODS: RHA rats were compared to Sprague-Dawley (SD) rats (as a standard control strain) for the expression of latent inhibition (in a 100-trial session of two-way active avoidance) under threshold conditions (i.e., only 15 preexposures to the conditioned stimulus were administered). RESULTS: Under such experimental conditions SD rats showed significant latent inhibition of the two-way active avoidance response (both during the first 50 trials and in the whole 100-trial session), while that attentional phenomenon did not appear in the RHA strain. CONCLUSIONS: The experimental results obtained here indicate that RHA rats display a deficit of latent inhibition at threshold conditions, an information processing (or attentional) anomaly which typically appears in schizophrenic patients. It is proposed that RHA rats might be an useful animal model for the study of vulnerability to some schizophrenic symptoms. This conclusion is supported by data that indicate that latent inhibition deficits are a characteristic attentional abnormality of these diseases.

Successive negative contrast in one-way avoidance learning in female Roman rats.

The inbred RLA (Roman Low-Avoidance) and RHA (Roman High-avoidance) rat strains have been psychogenetically selected for rapid (RHA) vs. extremely poor acquisition (RLA) of two-way active avoidance. As a consequence of this selective breeding, RLA animals exhibit a higher level of emotionality that can be observed in many anxiety models. The present study was conducted in order to analyze the performance of female RLA, RHA and Wistar rats in a behavioral test of anxiety that involves the reduction of the magnitude of an expected reward: the negative contrast effect that is obtained in one-way avoidance learning by reducing the time spent in the safe compartment. To this aim, three groups of animals (30-1/RLA, 30-1/RHA and 30-1/W) were trained to avoid an electric foot-shock administered in a "danger" compartment, by running from this compartment to a "safe" compartment. We observed an impairment of the avoidance response when time spent in the safe compartment was reduced from 30 to 1 s, when 30-1/RLA and 30-1/W groups were compared with control groups that were trained with a constant safe time (1-1/RLA and 1-1/W, respectively). We also obtained significant differences between 30-1/RLA and 30-1/RHA groups in the postshift phase. These results indicate that RLA rats respond more negatively to the frustration triggered by the reduction in time spent in the safe compartment, suggesting that animal models based on negative contrast effects can be useful tools for studying the genetic basis of anxiety.

Enduring effects of environmental enrichment on novelty seeking, saccharin and ethanol intake in two rat lines (RHA/Verh and RLA/Verh) differing in incentive-seeking behavior.

The Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rat lines represent, respectively, low emotional/anxious and high novelty seeker vs. high emotional/anxious and low novelty seeker profiles. In the present study, RLA/Verh and RHA/Verh rats, either reared in pairs from weaning (untreated) or reared in groups of 8-10 in an enriched environment until the age of 7 months, were tested for exploratory and novelty-seeking behavior in the hole board (including novel objects under the holes), as well as for their preference for saccharin-water and ethanol-water in a two-bottle free-choice paradigm. Testing started when rats were 20 months old in order to study the long-lasting effects of differential rearing. RHA/Verh rats explored more and showed greater preference for (and intake of) saccharin as well as for ethanol than RLA/Verh rats, thus confirming their validity as a rat model for sensation/reward seeking. Environmental enrichment (EE) increased head-dipping behavior (i.e., novelty seeking) in both rat lines, without affecting locomotor activity. EE treatment increased the preference for, and volume intake of, saccharin (especially at the higher concentrations tested) in the relatively low saccharin-preferring RLA/Verh rats, and also enhanced ethanol consumption in both rat lines. Thus, the results demonstrate consistent and enduring effects of EE on incentive-seeking behavior and further the analysis of how individual differential predispositions for the need of novelty and contact with (or consumption of) rewarding substances arise through either biological (genetic) or early environmental factors, or both.