Characterization of gene–environment interactions by behavioral profiling of selectively bred rats: The effect of NMDA receptor inhibition and social isolation

Abstract

Gene-environment interactions have an important role in the development of psychiatric disorders. To generate and validate a new substrain of rats with signs related to schizophrenia, we used selective breeding after postweaning social isolation and chronic ketamine treatment through several generations of animals and compared the subsequent strain to naive rats that were not genetically manipulated. We further investigated whether social isolation and ketamine treatment augmented the appearance of schizophrenic-like signs in these rats. Four experimental groups were studied (n=6-15 rats/group): naive rats without any treatment (NaNo); naive rats with postweaning social isolation and ketamine treatment (NaTr); 15th generation of selectively bred animals without any treatment (SelNo) or selectively bred rats with both isolation and ketamine treatment (SelTr). The startle reaction, tail-flick and novel object recognition tests were used to classify the animals into low- or high-risk for schizophrenia. Reduced pain sensitivity, higher degree of the startle reaction, disturbed prepulse inhibition, altered motor activity and decreased differentiation index in the memory test were observed in the 15th generation of the substrain, along with enhanced grooming behavior. Five functional indices (TF latency, startle reaction, prepulse inhibition, differentiation index, and grooming activity) were rated from 0 to 2, and the analysis of the summarized score revealed that the NaNo group had the lowest overall indication of schizophrenic-like signs, while the SelTr animals scored the highest, suggesting that both heritable and environmental factors were important in the generation of the behavioral alterations. We assume that further breeding after this complex treatment may lead to a valid and reliable animal model of schizophrenia.

Characterization of exploratory activity and learning ability of healthy and “schizophrenia-like” rats in a square corridor system (AMBITUS)

“…Healthy Wistar rats 2 to 3 months of age (mean weight of male rats: 279±9.5 g and female rats: 174±3.6 g) and the new substrain of male rats (205±6.2 g) were involved in the study (Petrovszki et al, 2013;. The healthy animals were purchased from the animal house of the Biological Research Centre, Szeged, Hungary.…”

“…Several methods are available to determine the learning ability of rodents during relatively short time period and/or repeated short trials, including novel object recognition, hole-board, and several mazes, e.g., Y maze, T maze, Morris Water maze, Barnes maze, or radial mazes with different number of arms (Casarrubea, Sorbera, Magnusson, & Crescimanno, 2010;Xu et al, 2013;Chambon, Wegener, Gravius, & Danysz, 2011;Petrovszki et al, 2013;Fitzgerald et al, 1985;Chrobal et al, 1987;Gordan et al, 2012;Locklear & Kritzer, 2014;McLean, Woolley, & Neill, 2009;van der Staay, Gieling, Pinzón, Nordquist, & Ohl, 2012;Vorhees & Williams, 2014;Roof & Stein, 2001;Vorhees & Williams, 2014). Other, more sophisticated methods, such as tasks with touch screen or lever press, require very intensive and long-lasting learning sessions (Brown et al, 2012;Chen, Wong, Chapman, & Pemberton, 2009;de Bruin et al, 2013;Dunnett, Fuller, Rosser, & Brooks, 2012;Nemeth et al, 2002;Preissmann et al, 2011;Sabbagh, Heaney, Bolton, Murtishaw, & Kinney, 2012;Bussey et al, 2008;George, RodriguezSantiago, Riley, & Abelson, 2015).…”

“…The recognition tasks with food rewards in hole-board test are based on the natural behavior of the rodents to explore novelty; thus, these tests are applied frequently for the characterization of the nose-poking activity into the holes (as exploration) and memory functions of rats (Petrovszki et al, 2013;Kekesi et al, 2015;Casarrubea et al, 2010;Hauser et al, 2012;Schroeder, Schroeder, Schwegler, & Sabel, 2000;van der Staay et al, 2012). It is well-known that in contrast to a hole-board with an open field, where the rats can show significant anxiety, rats prefer the narrow tunnels (Kimchi & Terkel, 2004).…”

“…Recently a complex animal model has been developed by selective breeding based on behavioral alterations after combined subchronic ketamine treatment (NMDA-receptor antagonist) and postweaning social isolation (Petrovszki et al, 2013). These animals showed several signs of schizophrenia, i.e., disturbed sensory gating, motor activity, pain sensitivity, cognitive function and thermoregulation; electrophysiological alterations in electroencephalographic waves; changes in the signalling properties of the cannabinoid and opioid receptors in different brain regions (Petrovszki et al, 2013;Kekesi et al, 2015;Horvath et al, 2015Horvath et al, , 2016Szűcs et al, 2016a, b).…”

“…These animals showed several signs of schizophrenia, i.e., disturbed sensory gating, motor activity, pain sensitivity, cognitive function and thermoregulation; electrophysiological alterations in electroencephalographic waves; changes in the signalling properties of the cannabinoid and opioid receptors in different brain regions (Petrovszki et al, 2013;Kekesi et al, 2015;Horvath et al, 2015Horvath et al, , 2016Szűcs et al, 2016a, b). The evaluation of these animals in this test may give further evidence about the reliability of this test tool for the investigation of animals with disturbed cognitive function.…”