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Schlagwörter:
anxiety; DNA methyltransferases; stress
Zusammenfassung:
Recently, it has been suggested that alterations in DNA methylation
mediate the molecular changes and psychopathologies that can occur
following trauma. Despite the abundance of DNA methyltransferases
(Dnmts) in the brain, which are responsible for catalyzing DNA
methylation, their roles in behavioral regulation and in response to
stressful challenges remain poorly understood. Here, we demonstrate that
adult mice which underwent chronic social defeat stress (CSDS) displayed
elevated anxiety-like behavior that was accompanied by a reduction in
medial prefrontal cortex (mPFC)-DNA methyltransferase 3a (Dnmt3a) mRNA
levels and a subsequent decrease in mPFC-global DNA methylation. To
explore the role of mPFC-Dnmt3a in mediating the behavioral responses to
stressful challenges we established lentiviral-based mouse models that
express lower (knockdown) or higher (overexpression) levels of Dnmt3a
specifically within the mPFC. Nonstressed mice injected with knockdown
Dnmt3a lentiviruses specifically into the mPFC displayed the same
anxiogenic phenotype as the CSDS mice, whereas overexpression of Dnmt3a
induced an opposite, anxiolytic, effect in wild-type mice. In addition,
overexpression of Dnmt3a in the mPFC of CSDS mice attenuated
stress-induced anxiety. Our results indicate a central role for
mPFC-Dnmt3a as a mediator of stress-induced anxiety.
