Transgenerational Epigenetic Inheritance of Early-Life Stress from Grand-Dams Through Paternal Gametes: Impaired Social Cognition and Reduced Reactivity to Aversive Predictors in DAT-HET Rats

Transgenerational epigenetic inheritance has emerged as a compelling mechanism by which early-life stress can shape behavior in descendants with no direct exposure to trauma. However, whether such heritable modifications affect subtle behavioral phenotypes, like processing of social and emotional stimuli, remains poorly understood. In this study, we investigated the behavioral profile of fourth-generation heterozygous dopamine-transporter (DAT-HET) rats. Compared to control (SX) rats, our experimental group (labelled SIKK) consisted of animals (at G4, F3) born from MIK sires (at G3, F2), who descended from grand-dams (at G2, F1) who were in turn exposed to early-life maltreatment by their own DAT-KO mothers (the great-grand-dams, at G1, F0). To probe inhibitory control and social cognition, we employed the signaled licking / avoidance of punishment (SLAP) task, the elicited preference test (EPT), and the social recognition test (SRT). In the SLAP task, SIKK rats exhibited slower acquisition of passive avoidance, suggesting dampened sensitivity to predictive aversive cues. In the EPT, wild-type focal rats displayed a clear preference for SX over SIKK conspecifics, indicating reduced social appeal of epigenetically altered animals. In the SRT, SX rats successfully discriminated between a novel and a familiar DAT-KO conspecific, while SIKK rats failed to do so, revealing impaired social cognition. Together, these findings indicate that, despite the absence of direct trauma in their infancy, SIKK rats exhibit a distinct behavioral phenotype characterized by increased reactivity to threat and deficits in social preferences and cognition. These alterations reflect inherited dysfunctions in limbic dopaminergic circuits, particularly within PFC. Our study highlights how an ancestor's adversity can shape adaptive behavior in future generations, providing a powerful model for understanding the biological basis of vulnerability to psychiatric disorders.