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

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 trauma triggers adulthood violence and criminality, 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) as a key regulator of PPS induced escalated aggression and its intergenerational inheritance. TTR mediated long-term perturbation in hypothalamic thyroid hormone (TH) availability contributed to male aggressive 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). Escalated aggressive behavior and impaired TTR-TH signaling was also inherited in F1 male progenies. Further, we deciphered Ttr promoter hyper methylation in hypothalamus of such abnormally aggressive males across generations. Interestingly prefrontal cortex showed opposite pattern of Ttr expression as well as long term epigenetic changes. Also, T4 increase by levothyroxine in PFC did not produce any behavioral changes. Our findings reveal that trauma during puberty trigger lasting escalated aggression by epigenetic programming of TTR and consequent impaired thyroid availability in brain. TTR-TH signaling in brain can serve as potential target in reversal of escalated aggression and related psychopathologies.