Early-life adversity shapes anomalous spontaneous behavior in mice heterozygous for Cntnap2

Abstract Background: The influence of early-life experiences is widely acknowledged as a crafting tool that sculpts complex behavioral patterns and well-being of living organisms. The use of preclinical models can provide invaluable insight into how a negative environmental push interplays with genetic make-up in shaping psychiatric vulnerability. Recently, the development of automated tools to classify spontaneous behavior in mice has opened the possibility to investigate the impact of experimental manipulation onto the composition of naturalistic behavior. Methods: In this work, we applied a tool for digitalized ethological screening to identify spontaneous hallmarks of altered neurobehavioral functioning in a dual-hit mouse model. To do so, mice carrying heterozygous deletion of the gene coding for contactin-associated protein-like 2 (Cntnap2+/-)and their wild-type (WT) littermateswere raised with limited bedding and nesting (LBN) and compared to both WT and Cntnap2+/- mice raised in standard conditions, mapping their spontaneous behavior during freely-moving exploration. Results: Our data show no differences in locomotor activity or anxiety indicators across the four groups. By contrast, automated segmentation of the body-language revealed a significant impact of both genotype and early-life experience in shaping the spontaneous behavioral program. Thus, using unsupervised clustering, we unveiled two alternative behavioral profiles within our dataset. We found that one of the identified profiles largely overlapped with Cntnap2+/- mice raised with LBN, while the other was equally shared among controls. Conclusions: We conclude that the coincidence of early-life adversity and Cntnap2 haploinsufficiency drastically alters behavioral structure in rodents.