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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 (GxE) 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" GxE 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.