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.

Schizophrenia-relevant social, attentional and cognitive traits in female RHA vs. RLA rats: Effects of neonatal handling.

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.

Contribution of the Roman rat lines/strains to personality neuroscience: neurobehavioral modeling of internalizing/externalizing psychopathologies.

The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats' phenotypic profile falls well within the "internalizing" behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats' phenotypes are consistent with a "disinhibiting externalizing" profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

Neurobehavioral Profiles of Six Genetically-based Rat Models of Schizophrenia- related Symptoms.

Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.

Atypical antipsychotics attenuate MK801-induced social withdrawal and hyperlocomotion in the RHA rat model of schizophrenia-relevant features.

RATIONALE: The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics. OBJECTIVES: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia-relevant features. We also studied whether some atypical antipsychotic drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801 and whether such effects might be dependent on the rat strain. METHODS: MK801 dose-response study was conducted in RHA and Roman Low-Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics. RESULTS: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5 mg/kg) or ziprasidone (2.5 mg/kg) partially reversed or attenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801. CONCLUSIONS: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face (MK801-induced social withdrawal and hyperactivity) and predictive (attenuation of MK801-induced effects by atypical antipsychotics) validity to the RHA rat strain as a model of schizophrenia-relevant features.

Decreased activation of parvalbumin interneurons in the medial prefrontal cortex in intact inbred Roman rats with schizophrenia-like reduced sensorimotor gating.

Prepulse inhibition (PPI) allows assessing schizophrenia-like sensorimotor gating deficits in rodents. Previous studies indicate that PPI is modulated by the medial prefrontal cortex (mPFC), which is in agreement with our findings showing that PPI differences in the Roman rats are associated with divergences in mPFC activity. Here, we explore whether differences in PPI and mPFC activity in male Roman rats can be explained by (i) differences in the activation (c-Fos) of inhibitory neurons (parvalbumin (PV) interneurons); and/or (ii) reduced excitatory drive (PSD-95) to PV interneurons. Our data show that low PPI in the Roman high-avoidance (RHA) rats is associated with reduced activation of PV interneurons. Moreover, the RHA rats exhibit decreased density of both PV interneurons and PSD-95 puncta on active PV interneurons. These findings point to reduced cortical inhibition as a candidate to explain the schizophrenia-like features observed in RHA rats and support the role of impaired cortical inhibition in schizophrenia.

A maturational shift in the frontal cortex synaptic transcriptional landscape underlies schizophrenia-relevant behavioural traits: A congenital rat model.

Disruption of brain development early in life may underlie the neurobiology behind schizophrenia. We have reported more immature synaptic spines in the frontal cortex (FC) of adult Roman High-Avoidance (RHA-I) rats, a behavioural model displaying schizophrenia-like traits. Here, we performed a whole transcriptome analysis in the FC of 4 months old male RHA-I (n=8) and its counterpart, the Roman Low-Avoidance (RLA-I) (n=8). We identified 203 significant genes with overrepresentation of genes involved in synaptic function. Next, we performed a gene set enrichment analysis (GSEA) for genes co-expressed during neurodevelopment. Gene networks were obtained by weighted gene co-expression network analysis (WGCNA) of a transcriptomic dataset containing human FC during lifespan (n=269). Out of thirty-one functional gene networks, six were significantly enriched in the RHA-I. These were differentially regulated during infancy and enriched in biological ontologies related to myelination, synaptic function, and immune response. We validated differential gene expression in a new cohort of adolescent (<=2 months old) and young-adult (>=3 months old) RHA-I and RLA-I rats. The results confirmed overexpression of Gsn, Nt5cd1, Ppp1r1b, and Slc9a3r1 in young-adult RHA-I, while Cables1, a regulator of Cdk5 phosphorylation in actin regulation and involved in synaptic plasticity and maturation, was significantly downregulated in adolescent RHA-I. This age-related expression change was also observed for presynaptic components Snap25 and Snap29. Our results show a different maturational expression profile of synaptic components in the RHA-I strain, supporting a shift in FC maturation underlying schizophrenia-like behavioural traits and adding construct validity to this strain as a neurodevelopmental model.

Social preference in Roman rats: Age and sex variations relevance for modeling negative schizophrenia-like features.

Social withdrawal is one of the most relevant negative symptoms of schizophrenia. Animal models that mimic schizophrenia's symptoms, in general, and negative symptoms, in particular, are difficult to develop because of the high complexity of symptoms and neurochemical disturbances that schizophrenia patients display throughout their lives. In recent years we have shown that Roman High-Avoidance (RHA) rats exhibit some phenotypes that are thought to represent positive symptoms, cognitive/attentional symptoms, as well as some negative symptoms of the disease. In the present study, we aimed at elucidating whether the social interaction (SI) deficits exhibited by adult male RHA rats, compared to their Roman Low-Avoidance (RLA) counterparts, are also present during adolescence, as well as whether there are between-strain differences in adolescent and adult female rats. The results of the present study show that adult male RHA rats exhibited a deficit in social preference compared to their RLA counterparts. Such a deficit was not observed in adolescent RHA rats or female rats of any age. The results also show that the adult male rats of both strains had significant decreases in social preference compared to the adolescent male rats. Additionally, we also show that female adult RHA rats have greater social preference than their male counterparts. These results seem to be in line with previous rodent and human studies and add face validity to the RHA rats as a model of schizophrenia.

Different maturation patterns for sensorimotor gating and startle habituation deficits in male and female RHA vs RLA rats.

Neurodevelopmental anomalies are thought to play a crucial role in the emergence of schizophrenia. The Roman high-avoidance (RHA) rats exhibit impaired prepulse inhibition (PPI), as well as other behavioral and cognitive singularities related to schizophrenia syndromes compared to the Roman low-avoidance (RLA) rats. In the present study, we aimed at elucidating whether PPI deficits in the RHA rats take place during prepubescence, adolescence, or adulthood. Thus, we evaluated the levels of PPI of both strains and both sexes during these three developmental phases. Additionally, we also investigated the onset of startle habituation deficits in the same groups. The results showed that male RHA rats exhibit a clear-cut PPI reduction compared to their RLA counterparts in adulthood. In female RHA rats, we observed lower levels of PPI since adolescence and through adulthood. We also found no differences between PPI percentages among the three ages in RHA male rats. Contrarily, in male RLA rats, PPI levels were increased in adults compared to their adolescent and prepubescent counterparts. Finally, a deficit in startle habituation was observed in adulthood of both male and female RHA rats, although in the latter case the disturbance in startle habituation was more profound. These results further the description of the maturational trajectory of cognitive markers relevant to schizophrenia prodrome and they add face validity to the RHA rats as a model of schizophrenia-relevant phenotypes.

Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels.

The acoustic startle response and prepulse inhibition (PPI) of startle are measures related to information processing, which is impaired in schizophrenia. Some studies have provided inconclusive patterns of association between both measures in rodents. We assessed the influence of baseline startle response on PPI in large samples of Roman high-(RHA) and low-avoidance (RLA) rat strains and in genetically heterogeneous stock (HS) rats. Results show that RHAs exhibit a PPI deficit compared to RLA rats, which is present regardless of the startle response levels. HS rats were stratified in two sub-samples according to their high or low PPI (HS-highPPI or HS-lowPPI, respectively) scores, and then they were grouped by their differential baseline startle amplitude (high reactivity -HR- or low reactivity -LR-) within each sub-sample. Differences between high- and low-PPI-stratified HS rats remained regardless of their high or low startle amplitude scores. Thus, the impairments in %PPI found in both RHA and HS-LowPPI rats are present irrespective of the relatively high or low levels of startle amplitude in pulse-alone trials. Another objective of the present study was to evaluate whether habituation to the startling stimulus (i.e., pulse) depends on the initial baseline startle response. RLA rats habituated to the startling stimulus more effectively than RHAs regardless of their baseline startle responses. Conversely, there were no differences in startle habituation in the HS rats grouped by their extreme scores of baseline startle. Altogether, these findings suggest a deficit in information processing in RHA rats, which along with evidence indicating that this strain displays other attentional/cognitive impairments, strengthens the validity of the RHA strain as a putative model of schizophrenia-relevant features.

Oxytocin attenuates schizophrenia-like reduced sensorimotor gating in outbred and inbred rats in line with strain differences in CD38 gene expression.

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in many clinical conditions, including schizophrenia. The inbred Roman high-avoidance (RHA) rats, compared to their low-avoidance (RLA) counterparts, show distinct schizophrenia-like phenotypes, such as spontaneous deficits in PPI accompanied by decreased medial prefrontal cortex (mPFC) activity and volume. Schizophrenia-like deficits are usually attenuated by antipsychotic drugs, but these drugs often produce severe side effects. In order to reduce these side effects, the neuropeptide oxytocin has been proposed as an alternative natural antipsychotic for schizophrenia. Here, we examined the effects of peripheral oxytocin administration (saline, 0.04, and 0.2 mg/kg) on PPI in the RHA vs. RLA rats, as well as in the outbred heterogeneous stock (HS) rats. Our results showed that oxytocin increased PPI in the HS rats and attenuated PPI deficits in the RHA rats, but it did not significantly affect PPI in the RLAs. To explore whether these divergent effects were associated with differences in oxytocinergic mechanisms, we analyzed gene expression of the oxytocin receptor (OXTR) and the regulator of oxytocin release (CD38) in the mPFC of the Roman rats. Consistent with the differential oxytocin effects on PPI (RHA > RLA), constitutive CD38 expression was reduced in the RHA rats compared to the RLAs, while oxytocin administration increased OXTR expression in both strains. Overall, the present work reveals that oxytocin administration shows antipsychotic-like effects on PPI in outbred and inbred rats, and it suggests that these effects may be related to basal differences in oxytocin-mediated mechanisms in the mPFC.

Decreased social interaction in the RHA rat model of schizophrenia-relevant features: Modulation by neonatal handling.

The Roman-Low (RLA) and High-Avoidance (RHA) rat strains have been bidirectionally selected and bred, respectively, for extremely poor vs. rapid acquisition of the two-way active avoidance task. Over 50 years of selective breeding have led to two strains displaying many differential specific phenotypes. While RLAs display anxious-related behaviours, RHA rats show impulsivity, and schizophrenia-like positive and cognitive symptoms or phenotypes. Neonatal handling (NH) is an environmental treatment with long-lasting anxiolytic-like and anti-stress effects. NH also reduces symptoms related to schizophrenia, such as pre-pulse inhibition (PPI) impairment and latent inhibition (LI) deficits, and improves spatial working memory and cognitive flexibility. The present work was aimed at exploring whether RHAs also display negative schizophrenia-like symptoms (or phenotypes), such as lowered preference for social interaction (i.e. asociality), and whether NH would reduce these deficits. To this aim, we evaluated naïve inbred RHA and RLA rats in a social interaction (SI) test after either long- or short-term habituation to the testing set up (studies 1-2). In Study 3 we tested untreated and NH-treated RHA and RLA rats in novel object exploration (NOE) and SI tests. Compared with RHAs, RLA rats displayed increased anxiety-related behaviours in the NOE (i.e. higher behavioural inhibition, lesser exploration of the novel object) and SI (i.e. higher levels of self-grooming) tests which were dramatically reduced by NH treatment, thus supporting the long-lasting anxiolytic-like effect of NH. Remarkably, RHA rats showed decreased social preference in the SI test compared with RLAs, evidencing that RHAs would present a relative asociality, which is thought to model some negative symptomatology (i.e. social withdrawal) of schizophrenia. NH increased absolute levels of social behaviour in both strains, but with a more marked effect in RHA rats, especially in the first 5 min of the SI test. Thus, it is hypothesized that, apart from its effects on anxiety-related behaviours, NH might have long-lasting positive effects on behavioural and neurobiological processes that are impaired in schizophrenia.

Neurobehavioral and neurodevelopmental profiles of a heuristic genetic model of differential schizophrenia- and addiction-relevant features: The RHA vs. RLA rats.

The Roman High- (RHA) and Low-(RLA) avoidance rat lines/strains were generated through bidirectional selective breeding for rapid (RHA) vs. extremely poor (RLA) two-way active avoidance acquisition. Compared with RLAs and other rat strains/stocks, RHAs are characterized by increased impulsivity, deficits in social behavior, novelty-induced hyper-locomotion, impaired attentional/cognitive abilities, vulnerability to psychostimulant sensitization and drug addiction. RHA rats also exhibit decreased function of the prefrontal cortex (PFC) and hippocampus, increased functional activity of the mesolimbic dopamine system and a dramatic deficit of central metabotropic glutamate-2 (mGlu2) receptors (due to a stop codon mutation at cysteine 407 in Grm2 -cys407*-), along with increased density of 5-HT2A receptors in the PFC, alterations of several synaptic markers and increased density of pyramidal "thin" (immature) dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats, and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. RHA rats represent a promising heuristic model of neurodevelopmental schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

A missing link between depression models: Forced swimming test, helplessness and passive coping in genetically heterogeneous NIH-HS rats.

The forced swimming test (FST) and helplessness reactions at two-way active escape/avoidance task are used in the study of depressive-like symptoms and antidepressant treatments in rodents. In both tests/tasks the animals are submitted to stressful situations, known to induce several responses that have been considered as parallels of some symptoms of the human depressive disorder. However, there is a lack of experimental evidence supporting associations between the behavioral responses displayed in both behavioral procedures by outbred rats. The objective of the present study was to evaluate the possible associations between the behavioral responses in both depression models using the National Institutes of Health genetically heterogeneous rat stock (i.e. NIH-HS rats). To this aim, 97 NIH-HS rats were submitted to both behavioral procedures (FST and two-way active escape task under a fixed ratio 2 - FR2). The statistical analyses comparing the sub-groups of rats selected by their high or low behavioral responses in either the FST or the FR2 helplessness task showed associations between the responses evaluated in both tests. Specifically, higher levels of struggling (i.e. vigorous swimming directed to escape from the FST) or less time of immobility in the first session of FST predicted lesser response failures in the FR2 two-way active escape (helplessness) task. In parallel, the stratification of rats for their high or low scores of response failures in the FR2 task was predictive of their levels of struggling in the FST. Thus, it is demonstrated for the first time that passive coping responses in one test are predictive of similar coping styles in the other task. The present findings may be relevant for the concurrent validity of both depression models.

Internet Gaming Disorder Clustering Based on Personality Traits in Adolescents, and Its Relation with Comorbid Psychological Symptoms.

In recent years, the evidence regarding Internet Gaming Disorder (IGD) suggests that some personality traits are important risk factors for developing this problem. The heterogeneity involved in problematic online gaming and differences found in the literature regarding the comorbid psychopathology associated with the problem could be explained through different types of gamers. Clustering analysis can allow organization of a collection of personality traits into clusters based on similarity. The objectives of this study were: (1) to obtain an empirical classification of IGD patients according to personality variables and (2) to describe the resultant groups in terms of clinical and sociodemographic variables. The sample included 66 IGD adolescent patients who were consecutive referrals at a mental health center in Barcelona, Spain. A Gaussian mixture model cluster analysis was used in order to classify the subjects based on their personality. Two clusters based on personality traits were detected: type I "higher comorbid symptoms" (n = 24), and type II "lower comorbid symptoms" (n = 42). The type I included higher scores in introversive, inhibited, doleful, unruly, forceful, oppositional, self-demeaning and borderline tendency traits, and lower scores in histrionic, egotistic and conforming traits. The type I obtained higher scores on all the Symptom Check List-90 items-Revised, all the State-Trait Anxiety Index scales, and on the DSM-5 IGD criteria. Differences in personality can be useful in determining clusters with different types of dysfunctionality.

Metabotropic Glutamate Receptor 2 and Dopamine Receptor 2 Gene Expression Predict Sensorimotor Gating Response in the Genetically Heterogeneous NIH-HS Rat Strain.

Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.

Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume.

Prepulse inhibition (PPI) of startle response is a measure of sensorimotor gating that is impaired in schizophrenia and in many other clinical conditions. Rat models using pharmacological or surgical strategies reveal that PPI is modulated by the cortico-striatal-pallido-thalamic (CSPT) circuit. Here, we explore whether spontaneous variation in PPI in intact inbred and outbred rats is associated with functional and structural differences in the CSPT circuit. Inbred Roman High-(RHA) and Low-avoidance (RLA) and outbred heterogeneous stock (HS) rats were assessed for PPI, brain activity, and brain volume. Brain activity was assessed by c-Fos expression and brain volume by magnetic resonance imaging. Relevant structures of the CSPT circuit were evaluated, such as the medial prefrontal cortex (mPFC), cingulate cortex, hippocampus (HPC), amygdala, nucleus accumbens (NAc), and dorsal striatum. RHA showed lower PPI than RLA rats, while HS rats were stratified by their PPI levels in three groups. Reduced PPI was accompanied by decreased mPFC activity in Roman and HS rats and increased NAc shell activity in HS rats. Low PPI was also associated with decreased mPFC and HPC volumes in Roman and HS rats. This study reports a consistent relationship between decreased function and volume of the mPFC and spontaneous low-PPI levels in inbred and outbred intact rats. Moreover, our findings suggest that, apart from a hypoactive and smaller mPFC, a hyperactive NAc and smaller HPC may underlie reduced PPI levels. Our results support the notion that sensorimotor gating is modulated by forebrain structures and highlight the importance of the mPFC in its regulation.

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.

Differential expression of synaptic markers regulated during neurodevelopment in a rat model of schizophrenia-like behavior.

Schizophrenia is considered a neurodevelopmental disorder. Recent reports relate synaptic alterations with disease etiology. The inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance rat strains are a congenital neurobehavioral model, with the RHA-I displaying schizophrenia-related behaviors and serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptor alterations in the prefrontal cortex (PFC). We performed a comprehensive characterization of the RHA-I/RLA-I rats by real-time qPCR and Western blotting for 5-HT1A, 5-HT2A, mGlu2, dopamine 1 and dopamine 2 receptors (DRD1 and DRD2), AMPA receptor subunits Gria1, Gria2 and NMDA receptor subunits Grin1, Grin2a and Grin2b, as well as pre- and post-synaptic components in PFC and hippocampus (HIP). Besides corroborating decreased mGlu2 (Grm2) expression, we found increased mRNA levels for Snap25, Synaptophysin (Syp), Homer1 and Neuregulin-1 (Nrg1) in the PFC of the RHA-I and decreased expression of Vamp1, and Snapin in the HIP. We also showed alterations in Vamp1, Grin2b, Syp, Snap25 and Nrg1 at protein levels. mRNA levels of Brain Derived Neurotrophic Factor (BDNF) were increased in the PFC of the RHA-I rats, with no differences in the HIP, while BDNF protein levels were decreased in PFC and increased in HIP. To investigate the temporal dynamics of these synaptic markers during neurodevelopment, we made use of the open source BrainCloud™ dataset, and found that SYP, GRIN2B, NRG1, HOMER1, DRD1 and BDNF expression is upregulated in PFC during childhood and adolescence, suggesting a more immature neurobiological endophenotype in the RHA-I strain.

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.