Sperm Transcriptional State Associated with Paternal Transmission of Stress Phenotypes

Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hy-pothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend on paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination (AI) reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing (RNA-seq), we report substantial and distinct changes in the transcriptomic pro -files of sperm following CSDS in susceptible versus resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominat-ing especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in dif-ferentially expressed genes (DEGs) in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience.

Automated summary

Studies have shown that paternal stress can lead to long-lasting changes in germ cells, with differences in transmission patterns between stress-resilient and stress-susceptible mice. Research on chronic social defeat stress (CSDS) has revealed significant alterations in sperm transcriptomes of susceptible versus resilient fathers, particularly in the regulation by long noncoding RNAs (lncRNAs). These findings advance our understanding of intergenerational epigenetic transmission of behavioral experience.