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While most <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> studies focus on its harmful effects, recent work by our laboratory and others shows that <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> elicits positive effects in certain individuals. We exposed Wistar Kyoto (<jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content>) rats, known for a stress reactive, anxiety\/depression\u2010like phenotype, to maternal separation (<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>), a model of <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult <jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content> offspring. This study interrogates an epigenetic mechanism (<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation) that may confer the adaptive effects of <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> in <jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content> offspring. We quantified global genome methylation levels in limbic brain regions of adult <jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content>s exposed to daily 180\u2010min <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> or neonatal handling from postnatal day 1\u201314. <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> exposure triggered dramatic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> hypermethylation specifically in the hippocampus. Next\u2010generation sequencing methylome profiling revealed reduced methylation at intragenic sites within two key nodes of insulin signaling pathways: the insulin receptor and one of its major downstream targets, mitogen\u2010activated protein kinase kinase kinase 5 (<jats:italic>Map3k5<\/jats:italic>). We then tested the hypothesis that enhancing <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation in <jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content> rats would elicit adaptive changes akin to the effects of <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>. Dietary methyl donor supplementation improved <jats:styled-content style=\"fixed-case\">WKY<\/jats:styled-content> rats\u2019 anxiety\/depression\u2010like behaviors and also improved cardiovascular measures, similar to previous observations following <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>. Overall, these data suggest a potential molecular mechanism that mediates a predicted adaptive response, whereby <jats:styled-content style=\"fixed-case\">ELS<\/jats:styled-content> induces <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood.<\/jats:p>","DOI":"10.1111\/ejn.13404","type":"journal-article","created":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T14:02:57Z","timestamp":1474293777000},"page":"2829-2845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Neonatal maternal separation stress elicits lasting <scp>DNA<\/scp> methylation changes in the hippocampus of stress\u2010reactive Wistar Kyoto rats"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7807-7524","authenticated-orcid":false,"given":"Chelsea R.","family":"McCoy","sequence":"first","affiliation":[{"name":"School of Neuroscience Virginia Tech University 1981 Kraft Drive, 2012 ILSB Blacksburg VA 24060 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology University of Alabama Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Anne","family":"Stringfellow","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Alabama Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy J.","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Neurobiology University of Alabama Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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