Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress-reactive Wistar Kyoto rats

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dc.contributor.authorMcCoy, Chelsea R.en
dc.contributor.authorRana, Samiren
dc.contributor.authorStringfellow, Sara anneen
dc.contributor.authorDay, Jeremyen
dc.contributor.authorWyss, J. Michaelen
dc.contributor.authorClinton, Sarah M.en
dc.contributor.authorKerman, Ilan A.en
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentSchool of Neuroscienceen
dc.date.accessioned2017-02-22T16:28:23Zen
dc.date.available2017-02-22T16:28:23Zen
dc.date.issued2016-11-01en
dc.description.abstractEarly-life stress (ELS) can alter neurodevelopment in variable ways, ranging from producing deleterious outcomes to stress resilience. While most ELS studies focus on its harmful effects, recent work by our lab and others shows that ELS elicits positive effects in certain individuals. We exposed Wistar-Kyoto (WKY) rats, known for a stress reactive, anxiety-/depression-like phenotype, to maternal separation (MS), a model of ELS. MS exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult WKY offspring. The present study interrogates an epigenetic mechanism (DNA methylation) that may confer the adaptive effects of MS in WKY offspring. We quantified global genome methylation levels in limbic brain regions of adult WKYs exposed to daily 180-min MS or neonatal handling from postnatal day 1-14. MS exposure triggered dramatic DNA hypermethylation specifically in the hippocampus. Next-generation 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 activated protein kinase kinase kinase 5 (Map3k5). We then tested the hypothesis that enhancing DNA methylation in WKY rats would elicit adaptive changes akin to the effects of MS. Dietary methyl donor supplementation improved WKY rats’ anxiety/depression-like behaviors and also improved cardiovascular measures, similar to previous observations following MS. Overall these data suggest a potential molecular mechanism that mediates a predicted adaptive response whereby ELS induces DNA methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood.en
dc.description.versionPublished versionen
dc.format.extent2829 - 2845 (17) page(s)en
dc.identifier.doihttps://doi.org/10.1111/ejn.13404en
dc.identifier.issn0953-816Xen
dc.identifier.issue10en
dc.identifier.orcidClinton, SM [0000-0001-7158-411X]en
dc.identifier.urihttp://hdl.handle.net/10919/75131en
dc.identifier.volume44en
dc.languageEnglishen
dc.publisherWiley-Blackwellen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000388499900010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectNeurosciencesen
dc.subjectNeurosciences & Neurologyen
dc.subjectanxietyen
dc.subjectdepressionen
dc.subjectepigeneticsen
dc.subjectfolateen
dc.subjectmethyl depletionen
dc.subjectresilienceen
dc.subjectEARLY-LIFE ADVERSITYen
dc.subjectINSULIN IMPROVES MEMORYen
dc.subjectMETHIONINE-SUPPLEMENTED DIETen
dc.subjectPASSIVE-AVOIDANCE TASKen
dc.subjectIMPAIRED OLDER-ADULTSen
dc.subjectLONG-EVANS RATSen
dc.subjectGLUCOCORTICOID-RECEPTORen
dc.subjectINTRANASAL INSULINen
dc.subjectLEARNED HELPLESSNESSen
dc.subjectPREFRONTAL CORTEXen
dc.titleNeonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress-reactive Wistar Kyoto ratsen
dc.title.serialEuropean Journal of Neuroscienceen
dc.typeArticle - Refereeden
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen

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