title: Dnmt3a in the Medial Prefrontal Cortex Regulates Anxiety-Like Behavior in Adult Mice.
abstract: 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. Significance statement: DNA methylation is suggested to mediate the molecular mechanisms linking environmental challenges, such as chronic stress or trauma, to increased susceptibility to psychopathologies. Here, we show that chronic stress-induced increase in anxiety-like behavior is accompanied by a reduction in DNA methyltransferase 3a (Dnmt3a) mRNA levels and global DNA methylation in the medial prefrontal cortex (mPFC). Overexpression or knockdown of mPFC-Dnmt3a levels induces decrease or increase in anxiety-like behavior, respectively. In addition, overexpression of Dnmt3a in the mPFC of chronic stressed mice attenuated stress-induced anxiety. We suggest that mPFC-Dnmt3a levels mediates anxiety-like behavior, which may be a primary molecular link between chronic stress and the development of anxiety disorders, including post-traumatic stress disorder.
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel, Faculty of Medicine, Bar Ilan University, Safed, 13215, Israel.
authors.forename: Evan
authors.initials: E
authors.lastname: Elliott
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel, Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany, and.
authors.forename: Sharon
authors.initials: S
authors.lastname: Manashirov
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Raaya
authors.initials: R
authors.lastname: Zwang
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Shosh
authors.initials: S
authors.lastname: Gil
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-0441-8757
authors.initials: M
authors.lastname: Tsoory
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel, Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany, and.
authors.forename: Yair
authors.initials: Y
authors.lastname: Shemesh
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel, Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany, and alon.chen@weizmann.ac.il alon_chen@psych.mpg.de.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism* / Q000523:psychology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis*; D000090205:DNA Methyltransferase 3A; D055785:Gene Knockdown Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism / Q000523:psychology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methyltransferases; anxiety; stress