Ricerc@Sapienza

Exposure to aversive events during the postnatal period increases vulnerability to a variety of psychopathologies. Unpredictability of the early environment (repeated cross-fostering, RCF) has been used in mice as postnatal manipulation to model human early environmental instability. However, it is now clear that the same early life events can produce very different long-term consequences depending on both the genetic make-up and the adult experiences.
Inbred strains of mice provide valuable models for studying the interaction between genetic and environmental factors, and we have previously demonstrated that individuals belonging to DBA2/J (DBA) strain, that appear to be resilient to develop an addiction-like behavioral phenotype, showed an increased sensitivity to anhedonic-like phenotype, thus suggesting an altered response to successive stressful experiences in adulthood, while an opposite phenotype was evident in C57BL/6J (C57) strain mice.
However, the mechanism by which RCF modifies adult phenotype in a genotype-dependent manner is currently unknown.
Based on these data, here we suggest that RCF makes DBA mice more prone to develop a depression-like phenotype when exposed to chronic mild stress in adulthood affecting genes expression in the NAc. The main goal of this project will be to directly investigate the role of two candidate genes (Xlr4a and Xlr4b) in the depression-like phenotype shown by RCF DBA. These target genes were up-regulated in our RCF model of ¿instability of the early environment¿ in DBA mice, and we plan, through an innovative technique based on adeno-associated virus gene therapy, to restore control levels of these genes¿ mRNA and check subsequent effects on the depression-like phenotype. Moreover, an environmental treatment will be tested during development in order to prevent deleterious effects of RCF experience in adulthood. This project represents a first step to explore the translational nature of our results.