Early life trauma leads to violent behavior and its inheritance by impairing local thyroid hormone availability in brain

Violent behavior is an aberrant form of aggression that has detrimental impact on health and society. Early life trauma triggers adulthood violence and criminality, though molecular mechanisms remain elusive. Here, we provide brain region specific transcriptome profiles of peripubertal stress (PPS) exposed adult violent male and resilient female mice. We identify transthyretin (TTR) as a key regulator of PPS induced violent behavior and its intergenerational inheritance. TTR mediated long-term perturbation in hypothalamic thyroid hormone (TH) availability contributed to male violent behavior without affecting circulating hormone. Ttr gene ablation in hypothalamus impaired local TH signaling including levels of TH transporters (Mct8, Oatp1c1), deiodinase 2 (DIO2) and TH responsive genes (Nrgn, Trh and Hr). Violent behavior and impaired TTR-TH signaling was also inherited in F1 male progenies. Further, we deciphered Ttr promoter hyper methylation in hypothalamus of violent males across generations. Our findings reveal that trauma during puberty trigger lasting violent behavior by epigenetic programming of TTR and consequent impaired local thyroid availability in brain. TTR-TH signaling in hypothalamus can serve as potential target in reversal of violent behavior.