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.