Early life stressful experiences escalate aggressive behavior in adulthood via changes in transthyretin expression and function
- Institute of Genomics and Integrative Biology, India
- All India Institute of Medical Sciences, India
Abstract
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.
Data availability
RNA sequencing data have been deposited in GEO under accession code GSE199844.All data generated or analyzed during this study are included in the manuscript and supplementary files.Source data files have been provided for Fig. 1C, Fig. 3D, Fig. 4B-4J, Fig. 4P, Fig.5B-5D, Fig.6B-6E, Fig.7 and Fig. 4-figure supplement 1
Article and author information
Author details
Funding
Department of Science and Technology, Ministry of Science and Technology, India (Inspire Faculty Award,DST/INSPIRE/04/2014/ 002261)
- Arpita Konar
Department of Biotechnology, Ministry of Science and Technology, India (Research Grant,GAP0197)
- Beena Pillai
Indian Council of Medical Research (Research Grant,IR-594/2019/RS)
- Beena Pillai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Margaret M McCarthy, University of Maryland School of Medicine, United States
Ethics
Animal experimentation: All experimental procedures involving live animals were approved by the Institutional Animal Ethics committee (IAEC) of CSIR-Institute of Genomics and Integrative Biology (IAEC Approval Number-IGIB/IAEC/3/15) that is registered under Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Department of Animal Husbandry and Dairying, Ministry of Fisheries, Animal Husbandry and Dairying, Government of India (Registration No and Date- 9/1999/CPCSEA). Male and female offspring of Balb/c mice bred in the institutional animal house were used for the study. All animals were housed under SPF conditions. They were kept in individually ventilated cages (IVC) at 24{plus minus}2ºC on a 12h light/dark cycle with ad libitum access to food and water. Animal handling and experiments were conducted in accordance with the institutional guidelines.
Version history
- Preprint posted: July 5, 2021 (view preprint)
- Received: February 17, 2022
- Accepted: October 12, 2022
- Accepted Manuscript published: October 13, 2022 (version 1)
- Version of Record published: November 3, 2022 (version 2)
Copyright
© 2022, Rawat et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Early life stressful experiences escalate aggressive behavior in adulthood via changes in transthyretin expression and function
eLife 11:e77968.
https://doi.org/10.7554/eLife.77968
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