Paternal social fear conditioning drives sex-specific behavioral alterations and septal gene regulation

Abstract The intergenerational transmission of traumatic experiences is increasingly recognized as a contributor to behavioral and neurobiological vulnerability in offspring. However, the inheritance of paternal traumatic social experiences remains poorly understood. Here, we employed the social fear conditioning (SFC) paradigm in mice to investigate the transmission of paternal socially aversive experiences to the next generation. First, we confirmed that social fear acquisition selectively impaired social approach behavior without affecting locomotion or general anxiety-related behavior in adult male mice of the F0 generation. Second, we examined the consequences of F0 paternal social fear conditioning for first-generation (F1) offspring. We found that male but not female F1 offspring of conditioned (SFC + ) fathers displayed reduced sociability. This behavioral alteration was accompanied by increased cellular activity in the lateral septum, as indicated by elevated cFos expression. Finally, exploratory transcriptomic analyses within the septum revealed that social fear acquisition was associated with an overall upregulation of synaptic plasticity-related genes in SFC + F0 males compared to SFC − F0 controls. Remarkably, this transcriptomic profile was inverted in F1 male offspring of conditioned fathers, who displayed relative downregulation of the same synaptic plasticity-associated genes. Notably, six genes ( Adcy8 , Cdh2 , Mapk1 , Nptx2 , Plcg1 , and Srf ) were significantly upregulated in F0 males but downregulated in F1 male offspring. Together, our findings establish the SFC paradigm as a selective and robust approach to study the intergenerational transmission of paternal traumatic social experiences. Moreover, they reveal specific gene expression changes associated with social behavior that may underlie behavioral deficits in the next generation, thereby highlighting molecular targets for future studies.