Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia

Abstract

Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to schizophrenia.

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

“…Remarkably, a general finding of all PPI experiments was that the total averaged %PPI was consistently lower in RHA-I than in RLA-I rats, which is in agreement with previous studies showing that the RHA-I strain displays a relative deficit in PPI (Oliveras et al 2015; Esnal et al 2016; Del Río et al 2014). …”

“…We have recently proposed that one such model, the Roman rat strains, displays genetically determined deficits/impairments in several schizophrenia-related features (Del Rio et al 2014; Oliveras et al 2015; Esnal et al 2016). The Roman high- (RHA) and low-avoidance (RLA) rat lines/strains ( lines refers to the outbred, and strains refers to the inbred animals) have been selectively and bidirectionally bred for their rapid (RHA) vs extremely poor (RLA) ability to acquire the two-way active avoidance task (Bignami 1965; Driscoll and Battig 1982; Steimer and Driscoll 2003; Escorihuela et al 1999, Rio-Alamos et al 2015).…”

“…There is extensive evidence showing that RHA/RLA rats display differential schizophrenia-relevant features. For instance, the RHA strain/line displays impaired performance in several learning/memory tasks (Aguilar et al 2002; Driscoll et al 1995; Escorihuela et al 1995b; Nil and Bättig 1981; Oliveras et al 2015) and enhanced impulsive behavior in the 5-CSRTT and DRL-20 operant tasks (Klein et al 2014; Moreno et al 2010; Zeier et al 1978). RHA rats exhibit deficits in latent inhibition (Fernandez-Teruel et al 2006; Esnal et al 2016), augmented mesocortical dopaminergic response to stress (Giorgi et al 2003), and enhanced locomotor as well as mesolimbic dopaminergic sensitization upon the repeated administration of dopaminergic psychostimulants (Corda et al 2005; Giorgi et al 2007; Guitart-Masip et al 2008a, b), a more robust functional tone of nigrostriatal and mesolimbic dopamine neurons (Tournier et al 2013) and neurochemical and neuromorphological evidence of decreased hippocampal function (Garcia-Falgueras et al 2012; Meyza et al 2009; Salles et al 2001).…”

Deficits of perceived spatial separation induced prepulse inhibition in patients with schizophrenia: relationships to symptoms and neurocognition

“…In line with that, recent studies in rat-based model of schizophrenia-relevant symptom have shown that PPI is a positive predictor of spatial working memory and latent inhibition [33, 34]. Furthermore, previous studies have also shown dysfunctions in selective spatial attention in schizophrenia [35].…”

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

“…PPI expression is regulated by a wide corticolimbic and brainstem network, upon which prefrontal cortex (PFC) exerts an important neuromodulatory role (17)(18)(19)(20)(21). Although sensorimotor gating is not a cognitive process per se, it correlates well with several cognitive domains, such as executive function (22), WM (23)(24)(25), and social cognition (26) and likely shares neural substrates with these domains. We have previously shown that Df(16)A +/− mice exhibit a robust PPI deficit (12).…”