Volumetric brain differences between the Roman rat strains: Neonatal handling effects, sensorimotor gating and working memory.

The present study was aimed at evaluating whether the differences between the Roman high- (RHA) and low-avoidance (RLA) rat strains in novelty-induced behavioural inhibition/disinhibition, sensorimotor gating (i.e., prepulse inhibition, PPI) and spatial learning/memory parallel differences in the volume of brain areas related to those behavioural phenotypes. To this aim, we conducted two experiments. In Experiment 1, we evaluated the performance of adult rats from both strains, either untreated (controls) or treated with neonatal handling (NH; administered during the first 21 days of life), in a novel object exploration test (NOE), in the elevated zero-maze test (ZM) of anxiety, and in a PPI test; moreover, magnetic resonance imaging (MRI) was used to measure the volume of limbic and cortical brain regions (amygdala -Am-, hippocampus -Hc-, striatum -St-, medial prefrontal cortex -mPFc-, anterior cingulate cortex -ACC-, nucleus accumbens -NAc-) and lateral ventricles -LV-. In Experiment 2, adult rats neonatally exposed to NH and their naïve controls were submitted to the NOE and PPI tests, and to several spatial learning/memory tasks using the Morris water maze. It was found that, compared with their RLA counterparts, RHA rats show increased exploration of the novel object in the NOE test, lowered anxiety in the ZM and impaired PPI, whereas RLAs display better spatial reference learning and memory and better cognitive flexibility in a reversal task. Furthermore, MRI measurements revealed that the volume of Hc, Am and mPFc is larger in RLA vs. RHA rats, whereas the latter have dramatically enlarged lateral ventricles. NH treatment markedly enhanced exploration in the NOE test in RLA rats, improved PPI in RHA rats but impaired it in their RLA counterparts, and produced beneficial effects on spatial working memory mainly in RHA rats. Finally, exposure to NH decreased the volume of Hc and Am in the RLA strain. The results are discussed in terms of the possible relationships between strain-related volumetric brain differences and the behavioral (anxiety-related and schizophrenia-relevant) traits that distinguish RHA from RLA rats, and highlighting the finding that, in RLA rats, NH is for the first time shown to enduringly reduce the volume of Hc and Am in parallel to the decrease of anxiety and the impairment of sensorimotor gating.

Increased exploratory activity in rats with deficient sensorimotor gating: a study of schizophrenia-relevant symptoms with genetically heterogeneous NIH-HS and Roman rat strains.

Schizophrenia involves positive, negative and cognitive symptoms, as well as comorbidity with anxiety and obsessive-compulsive disorder. Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in schizophrenia and animal models of the disease. Remarkably, impaired PPI has been related to other schizophrenia-like features in rodent models, such as cognitive deficits and hyperactivity. However, it remains to be investigated whether deficient PPI and increased exploratory activity are associated in genetically heterogeneous (outbred) naïve animals. This study was undertaken to evaluate the relationships among PPI and other schizophrenia-related symptoms, such as augmented exploratory activity, anxiety and compulsivity in the genetically heterogeneous (outbred) NIH-HS rat stock (HS) and in the genetically-selected inbred Roman High-Avoidance (RHA) and Low-avoidance (RLA) rats. Animals underwent the following tests: open-field (exploratory activity), elevated zero-maze (anxiety-like behavior), marble burying (compulsive-like behavior), and PPI. Three groups of HS rats were formed according to their PPI scores, i.e. Low-PPI, Medium-PPI and High-PPI. The HS Low-PPI group displayed higher exploratory activity in the open-field than the HS Medium-PPI and HS High-PPI groups. Likewise, compared with their RLA counterparts, RHA rats exhibited lower PPI and more intense exploratory activity in the open-field test. Correlational and factorial analyses of the whole HS sample and the RHA/RLA data globally corroborated the results of the PPI-stratified HS subgroups. These data suggest that such a consistent association between impaired PPI and increased exploratory activity in outbred HS and inbred RHA/RLA rats is a relevant parameter that must be taken into account when modeling clusters of schizophrenia-relevant symptoms.

Conservation of Phenotypes in the Roman High- and Low-Avoidance Rat Strains After Embryo Transfer.

The Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains are bi-directionally bred for their good versus non-acquisition of two-way active avoidance, respectively. They have recently been re-derived through embryo transfer (ET) to Sprague-Dawley females to generate specific pathogen free (SPF) RHA-I/RLA-I rats. Offspring were phenotyped at generations 1 (G1, born from Sprague-Dawley females), 3 and 5 (G3 and G5, born from RHA-I and RLA-I from G2-G4, respectively), and compared with generation 60 from our non-SPF colony. Phenotyping included two-way avoidance acquisition, context-conditioned fear, open-field behaviour, novelty-seeking, baseline startle, pre-pulse inhibition (PPI) and stress-induced increase in plasma corticosterone concentration. Post-ET between-strain differences in avoidance acquisition, context-conditioned freezing and novelty-induced self-grooming are conserved. Other behavioural traits (i.e. hole-board head-dipping, novel object exploration, open-field activity, startle, PPI) differentiate the strains at G3-G5 but not at G1, suggesting that the pre-/post-natal environment may have influenced these co-segregated traits at G1, though further selection pressure along the subsequent generations (G1-G5) rescues the typical strain-related differences.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats.

RATIONALE: Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. OBJECTIVES: We have carried out a pharmacological characterization of the Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RESULTS: RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-I rats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. CONCLUSIONS: These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia.

Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains.

The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes.

Divergent effects of isolation rearing on prepulse inhibition, activity, anxiety and hippocampal-dependent memory in Roman high- and low-avoidance rats: A putative model of schizophrenia-relevant features.

Social isolation of rats induces a constellation of behavioral alterations known as "isolation syndrome" that are consistent with some of the positive and cognitive symptoms observed in schizophrenic patients. In the present study we have assessed whether isolation rearing of inbred Roman high-avoidance (RHA-I) and Roman low-avoidance (RLA-I) strains can lead to the appearance of some of the key features of the "isolation syndrome", such as prepulse inhibition (PPI) deficits, increased anxious behavior, hyperactivity and memory/learning impairments. Compared to RLA-I rats, the results show that isolation rearing (IR) in RHA-I rats has a more profound impact, as they exhibit isolation-induced PPI deficits, increased anxiety, hyperactivity and long-term reference memory deficits, while isolated RLA-I rats only exhibit deficits in a spatial working memory task. These results give further support to the validity of RHA-I rats as a genetically-based model of schizophrenia relevant-symptoms.