PsyCoP – A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat

Abstract

Recently, hundreds of risk genes associated with psychiatric disorders have been identified. These are thought to interact with environmental stress factors in precipitating pathological behaviors. However, the individual phenotypes resulting from specific genotype by environment (G×E) interactions remain to be determined. Toward a more systematic approach, we developed a novel standardized and partially automatized platform for systematic behavioral and cognitive profiling (PsyCoP). Here, we assessed the behavioral and cognitive disturbances in Tcf4 transgenic mice (Tcf4tg) exposed to psychosocial stress by social defeat during adolescence using a “two-hit” G×E mouse model. Notably, TCF4 has been repeatedly identified as a candidate risk gene for different psychiatric diseases and Tcf4tg mice display behavioral endophenotypes such as fear memory impairment and hyperactivity. We use the Research Domain Criteria (RDoC) concept as framework to categorize phenotyping results in a translational approach. We propose two methods of dimension reduction, clustering, and visualization of behavioral phenotypes to retain statistical power and clarity of the overview. Taken together, our results reveal that sensorimotor gating is disturbed by Tcf4 overexpression whereas both negative and positive valence systems are primarily influenced by psychosocial stress. Moreover, we confirm previous reports showing that deficits in the cognitive domain are largely dependent on the interaction between Tcf4 and psychosocial stress. We recommend that the standardized analysis and visualization strategies described here should be applied to other two-hit mouse models of psychiatric diseases and anticipate that this will help directing future preclinical treatment trials.

Spironolactone alleviates schizophrenia-related reversal learning in Tcf4 transgenic mice subjected to social defeat

“…The PsyCoP test battery consists of a diverse panel of well-established behavioral tests and most of the procedures are at least partially automated to minimize the influence of the experimenter. In this and previous studies 17 , 18 , we found impairments in cognitive flexibility and fear memory in the Tcf4 tg x SD ( Tcf4 SD) GxE mouse model, making it particularly suited to study aspects of cognitive symptoms of schizophrenia spectrum disorders in pharmacological validation experiments. Although the genetics of psychiatric disorder endophenotypes were found to be complex, modeling selected endophenotypes based on conserved neurobiological systems is thought to yield higher construct validity than trying to model complex neuropsychiatric disorders in mice 19 , 20 .…”

“…In this study, we used the previously established profiling platform PsyCoP to assess the effect of spironolactone, particularly on the cognitive performance in the Tcf4 SD ‘2-hit’ mouse model 17 . We treated the mice either with aripiprazole alone or in combination with spironolactone as an add-on treatment (Fig.…”

“…Tcf4 tg-mice were all subjected to social stress during early adolescence ( Tcf4 tgSD). The behavioral tests were performed according to the previously published PsyCoP protocol with tail suspension test and pre-pulse inhibition test reversed and in order of increasing aversiveness 17 . B Overview of the data analysis pipeline.…”

“…In a previous study, we established a standardized platform for systematic cognitive and behavioral profiling (PsyCoP) to characterize Tcf4 transgenic mice ( Tcf4 tg) subjected to social defeat (SD) during adolescence as a ‘2-hit’ gene by environment interaction (GxE), schizophrenia-related mouse model 17 . The PsyCoP test battery consists of a diverse panel of well-established behavioral tests and most of the procedures are at least partially automated to minimize the influence of the experimenter.…”

DiffBrainNet: differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions

“…Animal models of gain and loss of function of Tcf4 have shown its relevance for cognition, sensorimotor gating and neuroplasticity [68]. In addition, gene x psychosocial stress interactions have been reported for Tcf4 [69], but little is known about relevant molecular pathways and brain regions for this interaction. With DiffBrainNet we showed that Tcf4 mediates GCs effects in two sub-regions of the hippocampal formation, ventral and dorsal DG, at the gene- and at the network-levels since it is DE in those but only at the network-level for the PFC where is not a DE gene.…”