Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner. Small RNA sequencing of sperm reveals significant transcriptional differences of infected animals compared to controls. Zygote microinjection of total small RNA from sperm of infected mice partially recapitulates the behavioral phenotype of naturally born offspring, suggesting an epigenetic mechanism of behavioral inheritance in the first generation. Our results demonstrate that sperm epigenetic factors can contribute to intergenerational inheritance of behavioral changes after pathogenic infection, which could have major public health implications.
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