Prenatal Witness Stress Induces Intergenerational Anxiety-Like Behaviors and Altered Gene Expression Profiles in Male Mice.

Prenatal cues imposed on an organism can exert long-term and even cross-generational influences on the physiology and behaviors. To date, numerous rodent models have been developed to mimic the effects of prenatal physical stress on offspring. Whether psychological stress during gestation exerts adverse influences on offspring remains investigated. Here, we report that prenatal witnessing the defeat process of the mated partner induces anxiety-like behaviors in F1 male, but not female offspring. These abnormal behaviors were not present in the F2 generation, indicating a sex-specific intergenerational effects. Genome-wide transcriptional profiling identified 71 up-regulated and 120 down-regulated genes shared in F0 maternal and F1 male hippocampus. F0 and F1 hippocampi also shared witness stress-sensitive and -resistant genes. Whole transcriptome comparison reveals that F1 dentate gyrus showed differential expression profiles from hippocampus. Few differentially expressed genes were identified in the dentate gyrus of F1 stress female mice, explaining why females were resistant to the stress. Finally, candidate drugs as the potential treatment for psychological stress were predicted according to transcriptional signatures, including the histone deacetylase inhibitor and dopamine receptor agonist. Our work provides a new model for better understanding the molecular basis of prenatal psychological stress, highlighting the complexity of stress and sex factors on emotion and behaviors.