Early life stressful experiences escalate aggressive behavior in adulthood via changes in transthyretin expression and function.

Escalated and inappropriate levels of aggressive behavior referred to as pathological in psychiatry can lead to violent outcomes with detrimental impact on health and society. Early life stressful experiences might increase the risk of developing pathological aggressive behavior in adulthood, though molecular mechanisms remain elusive. Here, we provide prefrontal cortex and hypothalamus specific transcriptome profiles of peripubertal stress (PPS) exposed Balb/c adult male mice exhibiting escalated aggression and adult female mice resilient to such aberrant behavioral responses. We identify transthyretin (TTR), a well known thyroid hormone transporter, as a key regulator of PPS induced escalated aggressive behavior in males. Brain-region-specific long-term changes in Ttr gene expression and thyroid hormone (TH) availability were evident in PPS induced escalated aggressive male mice, circulating TH being unaltered. Ttr promoter methylation marks were also altered being hypermethylated in hypothalamus and hypomethylated in prefrontal cortex corroborating with its expression pattern. Further, Ttr knockdown in hypothalamus resulted in escalated aggressive behavior in males without PPS and also reduced TH levels and expression of TH-responsive genes (Nrgn, Trh, and Hr). Escalated aggressive behavior along with reduced Ttr gene expression and TH levels in hypothalamus was also evident in next generation F1 male progenies. Our findings reveal that stressful experiences during puberty might trigger lasting escalated aggression by modulating TTR expression in brain. TTR can serve as a potential target in reversal of escalated aggression and related psychopathologies.