Albert Fernández-Teruel

Inbred Roman High- and Low-Avoidance Rats: Differences in Anxiety, Novelty-Seeking, and Shuttlebox Behaviors

In the present study, male inbred animals (from the 10th generation of an inbreeding program that has been carried out in parallel to that of the outbred Roman high- and low-avoidance rat lines), were compared for emotionality in different testing situations, exploratory behavior in the holeboard and two-way, active-avoidance acquisition. Compared to the inbred Roman high-avoidance (RHA-I/Verh) rats, inbred Roman low-avoidance (RLA-I-Verh) rats showed higher emotionality in the open field (reduced distance travelled and number of rearings, and increased self-grooming behavior), in the elevated plus-maze test (increased number of total and open-arm entries, reduced distance travelled in the open arms, and increased self-grooming behavior), and during the habituation period in the shuttle box (decreased number of crossings, increased self-grooming behavior and defecations). Results from the hyponeophagia test were not conclusive, probably due to the test-dependent hyperactivity shown by RHA-I/Verh rats. In the holeboard apparatus, RHA-I/Verh rats explored more than RLA-I/Verh rats, especially when novel objects were located beneath the holes. Finally, RHA-I/Verh animals rapidly acquired active, two-way (shuttlebox) avoidance, whereas RLA-I/Verh animals required four 50-trial sessions to achieve an assymptotic level of 30-40% avoidance. Thus, the behavioral patterns of the Roman inbred strains were very similar to those previously reported for the RHA/Verh outbred lines. Differences in locomotor activity, exploratory, and self-grooming behavior were actually greater between the inbred strains than between the outbred lines. Differences in defecation, however, although still significant, were not so pronounced as those noted previously at this laboratory with the outbred lines.

Neonatal Handling and Environmental Enrichment Effects on Emotionality, Novelty/Reward Seeking, and Age-Related Cognitive and Hippocampal Impairments: Focus on the Roman Rat Lines

Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats are selected and bred for extreme divergence in two-way active avoidance acquisition. In addition, compared to RLA/Verh rats, RHA/Verh rats are (behaviorally and physiologically) less anxious or reactive to stressors, show increased novelty (sensation)-seeking behavior as well as a higher preference for rewarding substances, and are usually less efficient in learning tasks not involving shock administration. The present article reviews evidence showing that neonatal handling and/or environmental enrichment leads to enduring effects (their magnitude frequently depending upon the rat line) on those behaviors. For example, it has been found that neonatal handling reduces most of the (behavioral and physiological) signs of emotionality/anxiety in RLA/Verh rats, while environmental enrichment increases their novelty seeking (also the case with RHA/Verh rats), saccharin and ethanol intake, and sensitivity to amphetamine. Finally, initial results (currently being further elaborated upon) support a preventive action of both environmental treatments on age-related impairments in learning a spatial, water maze task as well as on hippocampal neuronal atrophy.

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 Alzheimers 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.

Genetic selection and differential stress responses - The Roman lines/strains of rats

ETH, Institut fur Natztierwissenschaften, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), Spain University of Santiago de Compostela, Department of Psychobiology, E-15705 Santiago de Compostela, Spain University of Cagliari, Department of Toxicology, Viale A. Diaz 182, I-09126 Cagliari, Italy University of Magdeburg, Anatomy Institute, Leipzigerstrasse 44, D-39120 Magdeburg, Germany IUPG, Clinical Psychopharmacology Unit, 100 avenue de Bel-Air, CH-1225 Chene-Bourg (GE), Switzerland NV Organon, RE 2211, P.O. Box 20, NL-5340 BH Oss, the Netherlands University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, GB-Oxford OX3 9DU, England University of Groningen, Department of Animal Physiology, Kerklaan 30, P.O. Box 14, NL-9750 AA Haren, the Netherlands University of Delaware, Departments of Psychology and Biology, Newark, Delaware 19716 USA

The early acquisition of two-way (shuttle-box) avoidance as an anxiety-mediated behavior: Psychopharmacological validation

Several lines of evidence have established that performance during the initial steps of acquisition on a shuttle-box avoidance task is an anxiety-mediated behavior (i.e., the differences between strains selectivity bred for emotionality; the effects of postnatal handling; the course of the corticosterone response and behavioral measures of fear during acquisition). The present study was carried out to add pharmacological evidence to that view by testing the action of anxiogenic and anxiolytic drugs. Single 40-trial sessions with mild shocks (0.4 mA-0.6 mA) were used. In the first experiments the action of sodium pentobarbital (1.25, 2.5 and 5 mg/kg) and three benzodiazepines (diazepam, 2 and 4 mg/kg; alprazolam, 1, 1.25 and 1.5 mg/kg and adinazolam, 1, 2, 4 and 6 mg/kg) were tested. The last two experiments tested a possible proanxiety action of Ro 15-4513 (2, 5 and 10 mg/kg) and FG 7142 (5, 10 and 15 mg/kg), two partial inverse agonists of benzodiazepine receptors, which previous data had suggested to be anxiogenic. The results showed that the measure of acquisition of a two-way active avoidance is a sensitive mean for detecting either anxiolytic or anxiogenic effects of drugs, independently of their effects on locomotor activity, thus suggesting that such test could be a valid model of anxiety in animals.

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.

Behavior of the Roman/Verh high- and low-avoidance rat lines in anxiety tests: relationship with defecation and self-grooming

The Swiss sublines of Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats have been selected and bred for rapid (RHA/Verh) vs. extremely poor (RLA/Verh) acquisition of two-way active avoidance. Behavioral and physiological measures of emotionality, or reactivity to stress, appear to be among the most prominent characteristics differentiating both rat lines. The present study shows that RLA/Verh rats are more sensitive, as compared to their RHA/Verh counterparts, to the conflict involved in the shock-induced suppression of drinking paradigm, as well as in a hyponeophagia test. RLA/Verh rats also showed higher defecation values which were significantly correlated with the main hyponeophagia test variables. Likewise, self-grooming was more frequent in RLA/Verh rats than in their RHA/Verh counterparts and showed significant correlations with conflict-related behaviors (i.e., latency to start eating and time spent eating) from the hyponeophagia test. These results give additional support to the contention that RLA/Verh rats present higher anxiety (emotionality) than their RHA/Verh counterparts.

Environmental enrichment reverses the detrimental action of early inconsistent stimulation and increases the beneficial effects of postnatal handling on shuttlebox learning in adult rats.

Certain types of environmental stimulation administered during critical periods of neural development can enduringly modify adult behavior. The present experiments show that postnatal handling of Sprague-Dawley rats (administered from postnatal days 1 to 22) and/or living in an enriched environment (EE; from weaning until the age of 100 days) clearly improved the ability to learn a two-way active avoidance task in adulthood. In addition the results demonstrated that postnatal inconsistent stimulation (from postnatal days 1 to 22) impaired avoidance acquisition in the same task. This detrimental effect of inconsistent stimulation was reversed by EE. Our findings provide evidence that different types of early experience can influence learning abilities in distinct directions and with different strengths.

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 Parkinsons disease patients.

Infantile (handling) stimulation and behavior in young Roman high- and low-avoidance rats

The effect of infantile handling stimulation on exploratory and emotional behavior of Roman high- and low-avoidance (RHA/Verh and RLA/Verh) weanling rats was investigated. Postnatally handled and nonhandled, 4-week-old males and females from both psychogenetically selected lines were exposed to a hexagonal tunnel maze, including an illuminated central arena. Postnatal handling increased exploratory behavior and decreased emotional reactivity as expressed by increased entries into the central arena and a reduction in defecations in both lines of rats. These effects were more pronounced in the RLA/Verh rats. In agreement with earlier studies using nonselected adult rats, the females of both lines (especially those from the RHA/Verh line) were more sensitive than males to the positive influences of early stimulation.