Altered DNA methylation in the developing brains of rats genetically prone to high versus low anxiety

Chelsea R. McCoy, Matthew E. Glover, Leigh T. Flynn, Rebecca K. Simmons, Joshua L. Cohen, Travis Ptacek, Elliot J. Lefkowitz, Nateka L. Jackson, Huda Akil, Xiaowei Wu, Sarah M. Clinton

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report alteredDNAmethylation markers (alteredDNAmethyltransferase protein levels and increased globalDNAmethylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylation profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior.

Original languageEnglish
Pages (from-to)3144-3158
Number of pages15
JournalJournal of Neuroscience
Issue number16
Publication statusPublished - 17 Apr 2019


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