Epigenetic Programming of the Neuroendocrine Stress Response by Adult Life Stress

59 1

b c j dirven and others Epigenetics of stress response 59: 1 R11–R31 Review in adulthood

Epigenetic programming of the neuroendocrine stress response by adult life stress

B C J Dirven1,2, J R Homberg2, T Kozicz1 and M J A G Henckens2

1Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Correspondence Medical Centre, Nijmegen, The Netherlands should be addressed 2Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, to B C J Dirven Radboud University Medical Centre, Nijmegen, The Netherlands Email [email protected]

Abstract

The hypothalamic–pituitary–adrenal (HPA) axis is critically involved in the neuroendocrine Key Words regulation of stress adaptation, and the restoration of homeostasis following stress ff epigenetics exposure. Dysregulation of this axis is associated with stress-related pathologies like ff hypothalamic–pituitary– major depressive disorder, post-traumatic stress disorder, panic disorder and chronic adrenal axis anxiety. It has long been understood that stress during early life can have a significant ff adult lasting influence on the development of the neuroendocrine system and its neural ff stress regulators, partially by modifying epigenetic regulation of gene expression, with ff DNA methylation implications for health and well-being in later life. Evidence is accumulating that ff histone modifications epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which ff microRNA psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Journal of Molecular Endocrinology Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the Journal of Molecular identification and treatment of stress-related psychiatric disorders. Endocrinology (2017) 59, R11–R31

Glossary

Restraint stress: a stress paradigm in which the animal is with a dominant con-specific. It is most commonly restrained in a confined space for a certain period of time, established by the resident-intruder paradigm, in which during which it is unable to move. the animal (the intruder) is repeatedly placed in the cage Social defeat: a stress paradigm that entails the of a dominant animal (the resident) in a manner that (repeated) exposure of an animal to losing a confrontation allows for non-lethal contact.

10.1530/JME-17-0019 Journal of Molecular Endocrinology anxiety ( stress disorder(PTSD),panic disorderandchronic like majordepressivedisorder (MDD),post-traumatic HPA axisisassociatedwithstress-related pathologies hyperactivity afterstresscessation. Dysregulationofthe stressor andshouldbeoflimiteddurationtoprevent response shouldbeadequateforcopingwiththespecific to stress( expenditure, digestion,moodandemotionalresponsivity including theimmunesystem,energystorageand involved intheregulationofavarietybodyprocesses, (HPA)the hypothalamic–pituitary–adrenal axis,iscritically and theadrenalgland.Thiscollectionofstructures,called nucleus (PVN)ofthehypothalamus,anteriorpituitary neuroendocrine response are located in the paraventricular O’Callaghan 2002 adaptive processesfollowingstressexposure( is theneuroendocrinesystem,whichtightlyregulates response systemsinthebody. Crucialtothestressresponse homeostasis requireawidespreadactivationofdifferent Adequate respondingtostressandrestorationof Introduction habituation tothestressor. randomized manner and only repeated twice, to avoid of light-darknesscycle.Allstressorsareappliedinasemi- cage tilting,noise,overnightilluminationandalteration environment, wetbedding,foodandwaterdeprivation, consecutive days).Stressorsincludecoldswim,thermal an extendedperiodoftime(usuallyonceadayfor28 in whichtheanimalisexposedtovariousstressorsfor the stressor. manner andonlyrepeatedtwice,toavoidhabituation rotation. Allstressorsareappliedinasemi-randomized crowding, warmswim,coldisolationandcage consecutive days).Stressorsincludesocialisolation, a prolonged period of time (usually twice daily for 14 the animalisexposedtovariousmoderatestressorsfor twice toavoidhabituationthestressor. stressors areappliedinafixedorderandonlyrepeated alteration oflight-darknesscycleandrestraintstress.All food andwaterdeprivation,overnightillumination, of socialisolation,coldswim,wetbedding, consecutive days). Stressors include relatively mild sessions for aprolonged period of time (usuallytwicedaily for 14 which theanimalisexposedtovariousmildstressors DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review Chronic unpredictablestress(CUS):aparadigm Chronic variablestress(CVS):aparadigminwhich Chronic variablemildstress(CVMS):aparadigmin Tsigos &Chrousos2002 Smith &Vale 2006 ). The primary endocrine effectors of the endocrineeffectorsofthe ). Theprimary ). The neuroendocrine stress ). Theneuroendocrinestress b

). Although depression depression ). Although c

dirven andothers Printed inGreatBritain Miller & Miller & modifications tothechromatinstructurethataltergene 2013 including the neuroendocrine system ( neurobiological systems( (such asstress)caninducelong-lastingalterationsin as mechanismsbywhichenvironmentalstimuli system epigenetic modificationsinthecentralnervous disease development. of PTSD, where trauma exposure is directlylinkedto the extreme orrepeatedstressexposure,especiallyinthecase mediated by lasting neurobiological alterations caused by ( negative feedbackandoveralldecreasedcortisollevels glucocorticoid receptors(GRs),moderatingenhanced is thoughttobecharacterizedbyincreasedsensitivityof negative feedbackoftheHPA axis( axis ( pathology is linked to basal hyperactivation of the HPA ( with implicationsforhealth andwell-beinginlaterlife development ofneuralandneuroendocrinesystems, early lifecanhaveasignificantlastinginfluenceon the activator bindsatthatsite( gene transcription, depending on whether a repressor or DNA methylationcouldeitherdecreaseorincreasenearby elementby decreasing theaccessibilityofageneregulatory location andthenatureofmodification.Forexample, to becontextdependentanddeterminedbyboththe butseem transcription arenotthatstraightforward, exact consequencesofepigeneticmodificationsforgene ultimately behaviour( can inducepersistentchangesingeneexpressionand mechanisms bywhichtransientenvironmentalstimuli these epigenetic modifications constitute important of posttranscriptionalgeneexpression.Altogether, considered importantplayersintheepigeneticcontrol definition ofepigenetics,theyare,moreoftenthannot, and thereforetechnicallydonotfollowtheclassical Although miRNAsdonotalterchromatinstructure (miRNAs), which act as translational repressors ( that influenceproteinexpressionaremicroRNAs Other important epigenetic modulators phosphorylation). histone modifications(i.e.,methylation,acetylationand include DNAmethylation,hydroxymethylationand transcription withoutalteringtheDNAsequence.These increased riskonneuropsychiatric diseasebyaberrant regulation havebeensuggested tocontributethis 2010 in adulthood Epigenetics ofstressresponse Yehuda 2001 Edwards Published byBioscientifica Ltd. Recent advancesinstressresearch haveimplicated It haslongbeenunderstoodthatstressduring ). Theterm‘epigenetics’referstoreversiblechemical , Parker Tomalski &Johnson 2010 et al et al . 2003 ). This endocrine dysregulation might be ). Thisendocrinedysregulationmightbe . 2003 , Chapman Zovkic , Swaab Downloaded fromBioscientifica.com at09/28/202107:21:27PM Provencal &Binder2015 Zannas &West 2014 t al et et al ). Alterationsinepigenetic et al Burke . 2013 . 2005 . 2004 59 et al : 1 Auger & Auger ). However, the ) and impaired ) andimpaired , . 2005 Cougle ). Table 1 ), PTSD ), PTSD et al R12 b via freeaccess ). ), . Review b c j dirven and others Epigenetics of stress response 59:1 R13 in adulthood

Table 1 Overview of epigenetic modifications.

Epigenetic modification Definition DNA methylation DNA methylation (5-mC) is an epigenetic process in which a methyl group is added to nucleotides of DNA without any alterations to DNA sequence. In mammalian cells, this process predominantly occurs on the C5 position of cytosines in a cytosine-guanine dinucleotide (CpG) context. DNA methylation modulates gene expression by regulating accessibility of transcription factors to their binding sites and influencing chromatin structure. DNA methylation is mediated by a group of enzymes called DNA methyltransferases (Jones 2012) DNA hydroxymethylation The methylation state of DNA can be chemically modified by 10–11 translocation proteins, which oxidize the methyl group at the C5 position of cytosine and convert it to a hydroxymethyl group in a process called DNA hydroxymethylation (5-hmC) (Tahiliani et al. 2009). Hydroxymethylated DNA is a potential intermediary step in the demethylation pathway. Early findings suggest opposite roles of 5-mC and 5-hmC in nucleosome stability and regulation of gene expression (Mendonca et al. 2014) Histone acetylation Histone acetylation is the process whereby an acetyl functional group is transferred to the lysine residues in the N-terminal tail protruding from the histone core of the nucleosome. This modification transforms chromatin into a more relaxed structure that is associated with greater levels of gene transcription. Histone acetylation is mediated by histone acetyltransferases and histone deacetylases (Gräff & Tsai 2013) Histone phosphorylation Histone phosphorylation involves the addition of a phosphate functional group to serine, threonine, and tyrosine residues in the histone N-terminal tail. The best-known function of this process occurs during DNA breakage, when phosphorylated histone H2A(X) demarcates large chromatin domains around the damaged area. However, recent findings have also linked this epigenetic mark to transcriptional activation of a variety of genes, most often related to cell growth and proliferation (Rossetto et al. 2012) MicroRNAs MicroRNAs (miRNAs) comprise species of short non-coding RNA that can negatively control target gene expression posttranscriptionally. As such, miRNAs can not only influence the translation of a plethora of different genes directly, but they can also target the expression of genes that control epigenetic pathways, like DNMTs and HDACs (Sato et al. 2011)

DNMT, DNA methyltransferase; HDAC, histone deacetylase.

gene expression and cell differentiation during early during adulthood can induce epigenetic changes that developmental stages (Crews & Gore 2011, Maccari et al. affect brain plasticity, neuronal function and behavioural 2014). Early in development, each cell in the body starts adaptation to neuropsychological stress (Hunter et al. placing epigenetic marks during differentiation under the 2009, Roth et al. 2011). Hence, these epigenetic changes Journal of Molecular Endocrinology influence of perinatal environmental cues, with the goal of may provide a molecular mechanism for the phenotypical establishing an adaptive long-term phenotype that meets development observed e.g., after trauma exposure in PTSD, the probable demands later in life (Migicovsky & Kovalchuk explaining how phenotype and transcriptional potential 2011). This process, i.e., transdifferentiation (Waddington can change drastically and long lastingly in response to 1957) or epigenetic reprogramming (Ho & Tang 2007), environmental challenges, even when experienced in may last for weeks, months and even years, depending on adulthood. As such, more recent advancements in the the cell or tissue type. Altered environmental cues (e.g., fields of epigenetics have focused on the presence of stress- stress) may therefore greatly affect brain development, mediated epigenetic modifications in adulthood. The as well as regional gene expression throughout life, in ability of stressful events to affect epigenetic regulation an attempt to meet environmental demands. Depending in the brain has been illustrated in fear conditioning and on the environment of later life, these epigenetic extinction paradigms in rodents, where contextual fear changes can prove to be either adaptive or maladaptive, learning induced altered methylation patterns in memory- thereby protecting from or increasing the risk of mental and plasticity-related genes (Miller & Sweatt 2007, disease (McClelland et al. 2011, Provencal & Binder Lubin et al. 2008). Altered hippocampal DNA methylation 2015a). Although it is thus clear that there is a window levels have also been observed in rodent models for of sensitivity for environmentally induced epigenetic PTSD (Chertkow-Deutsher et al. 2010, Roth et al. 2011). changes during perinatal development, influencing risk These modifications of DNA transcription were shown on psychopathology, evidence is accumulating that to be persistent (Malan-Muller et al. 2014) and even epigenetic plasticity also extends into adulthood (Miller & transmissible across generations (Yehuda et al. 2014, Sweatt 2007, Lubin et al. 2008, Feng et al. 2010, Miller et al. Dias et al. 2015), underlining their importance as 2010). It has been shown that psychological trauma mediators of the imprinting of stressor experience on

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology importantly, early lifestress,suggestingthatstressduring changes wereindependent of age,ethnicityand,most to beassociatedwithPTSD ( methylation at thousands of DNA CpG sites was found plethora ofgenes. Moreover, aglobal increase inDNA (HDMTs), whichmost likelyaffectstheexpressionofa histone methyltransferases (HMTs) and demethylases cells ( H3K9 andH3K36inperipheralbloodmononuclear levels of trimethylation in histone 3 lysine 4 (H3K4), have indicatedthatPTSDpatientsdisplayincreased due to (adult) stress exposure in humans. Studies evidence forlong-lastingepigeneticmodifications Blood samplesofPTSDpatientsconstitutetheprimary Human studies Stress-related general epigeneticchanges and treatmentofstress-relatedpsychiatric disorders. challenges ofapplyingthisknowledgetotheidentification Finally, wediscusstheimplicationsofthesedataforand function andinstress-relatedneurotransmittersystems. for stress-inducedepigeneticalterationsinHPA axis for PTSD).We ofscientificevidence thenofferanoverview linked totheexperienceof(adult)lifestress(asiscase and resultingpathologycanthereforenotbecausally prior stressexposureisnoprerequisiteforMDDdiagnosis in depressedpatientswereleftoutofconsiderationhere,as increased riskonMDD( (chronic) stressexposurehasbeenclearlylinkedto exposure inadulthoodrodentsandhumans.Although changes inepigeneticmarkersasaconsequenceofstress life stress.We firstsummarizeevidencefortheglobal neuroendocrine) stressresponseasaconsequenceofadult and rodentsonepigeneticmodulationofthe(primarily ever-increasing healthcarecosts. related disability, butwouldalsosignificantlyreducethe disorders, wouldnotonlydecreaseworld-widestress- being abletoimprovetheabilitytreatneuropsychiatric cardiovascular disease( the courseofnon-psychiatricconditionslikecancerand dementia andschizophrenia)cannegativelyaffect or perpetuateotherpsychiatricdisorders(e.g.addiction, of stress-relatedmentaldisorders,itcanalsoprecipitate in adulthood not only contributes to the development exposure hasfar-reachingclinicalpotential.Stress the epigeneticmechanismsthatoccurfollowingstress brain andbehaviour. Enhancingourunderstandingof DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review Here, we provide a review of recent studies in humans Here, weprovideareviewofrecentstudiesinhumans Bam t al et . 2016 ), suggestingalteredactivityof Lueboonthavatchai 2009 Zannas &West 2014 Smith b

t al et dirven andothers Printed inGreatBritain . 2011 ). Assuch, ), studies ), studies ). These these epigeneticchangesoccurredinresponsetostress inpatients,suggestingthatthemajorityof observed for theincreased not differbetweenhealthysubjectsandpatients,except remarkably, theseepigeneticresponsestotraumadid in with increased DNA methylationat multiple CpG loci controls. Trauma exposurewasfoundtobeassociated patients andage-,gender-traumaexposure-matched DNA methylationprofileswerecomparedinPTSD indicate suchacausallink.Here,pre-andpost-trauma by Sipahiandcoworkers( epigeneticprofiles,arecentlongitudinalstudy observed a causalrelationshipbetweenstressexposureandthe retrospective dataandthuswereunabletodemonstrate transferases (DNMTs). likely throughdifferentialregulationofDNAmethyl adulthood canalterglobalDNAmethylationpatterns, DICER1 andotherDICER-like proteinsthemselvesmight global miRNAlevels( proposed asamolecularmechanism forthisdecreasein contributes to thegeneration of maturemiRNAs, has been 2014 PTSD casesvsage-matchedhealthycontrols( with severalmiRNAsbeingsignificantlydownregulated in in miRNAexpressionhave also been implicated inPTSD, chronic academicstress( transiently alteredexpressionofserummiRNAswith participants ( miRNAs directlyafteranacutesocialstresstaskinhealthy results have demonstrated the upregulation of several serum drugs and stress( environmental factors,suchaslight,sound,nutrients, have beenfoundtobealteredinresponsevarious miRNA expressionlevelsinrodentsandhumancells environmentally inducedalterationsingeneexpression. implicated miRNAsasimportantmediatorsof regulation ofthestressresponsehaveincreasingly methylation patterns,recentstudiesoftheepigenetic ( targeted inevidence-basedinterventions from pathology-relatedepigeneticchangesthatshouldbe (epigenetic) riskmarkersforPTSDandtodistinguishthese importance oflongitudinalstudiesfortheidentification PTSD inresponsetotrauma.Thisfindinghighlightsthe reflecting apre-existingriskfactorforthedevelopmentof compared tocontrolsatasingle pre-trauma DNAmethylationwashigherinthepatients regardless ofeventualbehaviouralsymptoms.Moreover, in adulthood Epigenetics ofstressresponse Published byBioscientifica Ltd. DNMT1 Besides thesewell-knownalterationsingene Although theaforementionedstudiesreliedon ). LowerexpressionofDICER1, anenzymethat , DNMT3A Vaisvaser Codocedo & Inestrosa2016 DNMT1 Wingo t al et and Honda Downloaded fromBioscientifica.com at09/28/202107:21:27PM methylation,whichwasonly Sipahi . 2016 t al et DNMT3B et al et al . 2015 ) andhaveassociated . 2013 DNMT3B . 2014 59 genes. However, : 1 ). Expressionof ). Abnormalities Box 1 ). Preliminary ). Preliminary ) actuallydid CpGsite, Zhou ). et al R14 via freeaccess . Review b c j dirven and others Epigenetics of stress response 59:1 R15 in adulthood

Box 1 Epigenetic contributions to individual stress vulnerability. Stressful life events (SLEs), caused by environmental, psychological, or social situations, are important risk factors for the development of neuropsychiatric disorders, including MDD, PTSD, and anxiety disorders (Breslau 2002). While an estimated 90% of individuals in the general population are faced with one or multiple SLEs at some point in their lives, only a small percentage of these individuals ultimately develop psychiatric symptoms. This implicates interindividual differences in the underlying mechanisms constituting (natural) vulnerability or resilience to stress-induced pathology (Kessler et al. 2005). Influential studies on monozygotic twins have demonstrated that stress vulnerability can be explained partially (30–70%) by genetic variation, mainly mediated by single nucleotide polymorphisms (Afifi et al. 2010, Pitman et al. 2012). In addition, epigenetic patterns, either inherited or resulting from the cumulative environmentally-induced alterations that occurred throughout life, can shape vulnerability (i.e., the induction of pathological processes following stressor exposure) and resilience (i.e., the absence of psychiatric symptoms despite stressor exposure) to the development of psychopathology following future stressors (Zannas & West 2014). As such, neuropsychiatric disorders which develop during adulthood are most likely caused by a combination of pre-existing genetic and epigenetic vulnerability factors and alterations that are caused as a consequence of adult life stress exposure itself (Jirtle & Skinner 2007), as suggested by the diathesis-stress model for psychiatric illnesses (Monroe & Simons 1991) and the three-hit concept of vulnerability to stress-related mental disorders (Daskalakis et al. 2013). In line with this idea of differential (pre-existing) epigenetic patterns reflecting vulnerability, DNA methylation of SKA2 and BDNF prior to trauma exposure was found to predict suicidal behaviour and PTSD symptomatology (Kang et al. 2013, Kaminsky et al. 2015, Clive et al. 2016), while methylation of SLC6A4 (Swartz et al. 2016) and GRIN1 (Weder et al. 2014), which encodes subunit zeta-1 of the N-methyl-d-aspartate (NMDA) glutamate receptor, predicted depression. Furthermore, other human studies have linked the basal state of the DNA methylome to substance abuse (Andersen et al. 2015), aggression (Schechter et al. 2017), and depressive behaviour (Zhao et al. 2013).

also be epigenetically regulated, as is suggested by multiple to increase insight in the brain region-specific epigenetic studies investigating RNA-directed DNA methylation in profiles associated with stress-related psychopathology. plants (Boyko et al. 2010, Pumplin et al. 2016). Although examination of DNA extracted from Animal studies peripheral blood from patients has provided us with

Journal of Molecular Endocrinology important indications of epigenetic changes induced by A useful remedy to study the epigenetic effects of stress stressful life events, stress-related disorders are disorders exposure associated with the pathology of stress-related of the brain. Inter-individual variation in whole blood is mental disorders in brain tissue is the use of animal not a strong predictor of inter-individual variation in the models. Animal models provide us with a means to study brain (Hannon et al. 2015), and epigenetic patterns vary stress in organisms that (i) have a homogeneous genetic substantially across functionally distinct brain regions and environmental background, (ii) can be exposed to (Davies et al. 2012), making that blood- or saliva-based standardized stress paradigms in a controlled fashion, epigenetic studies provide only limited information on the (iii) can easily be longitudinally studied and (iv) allow for actual pathological neural processes. Therefore, additional more invasive (direct) measurements of brain tissue rather research in brain tissue is important for assessing the than peripheral blood. Therefore, animal studies allow for epigenetic plasticity of neural cells as a consequence of the investigation of the causal relationship between stress adult life stress. Human post-mortem studies are most exposure and changes in the epigenome and thereby to suitable in this respect, but data available is limited as dissect whether epigenetic patterns reflect psychological these studies face multiple practical issues in the collection states (as a consequence of stress) that contribute to of tissue from a sufficient amount to appropriate subjects, psychopathology (Box 2). When studying the stress response together with a detailed subject history of SLEs, stress- in rodents, multiple brain regions are of importance. First related pathology, and use of medication. Longitudinal of all, the regions involved in the HPA axis are relevant. studies (Yehuda 2004), as well as increased storage and These include the paraventricular nucleus (PVN) of the application of human post-mortem data in biobank hypothalamus, which contains neuroendocrine neurons tissue repositories, like the USA’s National Institutes of that synthesize and secrete corticotropin-releasing Health Neurobiobank (Nichols et al. 2014), are necessary hormone (CRH) and vasopressin, and the pituitary,

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology 1992 depend onthefrequencyof stressor( expression asaconsequence ofstressexposurecritically epigenetic modulationandcorresponding changesingene exposure General epigeneticeffectsofacutestress leading toadepressivephenotype( induce drasticneurochemicalalterationsintheNAc, ( and socialbondingthroughdopaminergictransmission (NAc), whereCRHfacilitatescue-elicitedmotivation substrate ofthestressresponseisnucleusaccumbens these ‘classical’regulators,anemergingneurobiological in neuropsychiatricdisorders( the emotionalandcognitiveabnormalitiesobserved asalinkbetweenthestresssystemand they mayserve formation, and emotionregulation, responding, memory form the respective anatomical substrates for emotional 2005 associated with its feed-forward excitation( associated withitsfeed-forward axis, whileamygdalarbindingof glucocorticoids has been to glucocorticoid-inducedfeedbackinhibitionoftheHPA hippocampus andprefrontalcortex(PFC)contributing are involvedintheregulationofHPA axis,withthe ( which secretesadrenocorticotropichormone(ACTH) Pecina Smith &Vale 2006 DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org (ii) (i) contributing toastress-relatedphenotype.Two importantcontrastsarestudied( in humanstudies.However, rodentstudiescanbespecificallydesignedtoyieldinformationabouttheexactfactors differences ( difficult toestablish(i)which epigeneticmarksaredirectly linkedtoacertain stressfulevent(orinsteadreflectinborn behaviouralphenotype.Yet,consider thecausalrelationshipbetweenepigeneticsignatureandobserved itis When investigatingtheepigenetic‘backbone’ofstress-relateddisorderstoimprovetreatment,itisimportant Box 2 Review ). For example, differential histone methylation ). Forexample,differential histonemethylation ). As the neuronal populations in these regions also ). Astheneuronalpopulationsintheseregionsalso two groupsareassessed.Notably, differencesreflectepigeneticchangesthatcanbedirectlylinked theobserved differencesinepigeneticregulationbetweenthe while theotheranimalsreceiveashamprocedure.Afterwards, Stressed vscontrol.Halfoftheanimalsfromageneticallyhomogeneousgroupundergocertainstressprocedure, from thebehaviourallymaladaptiveones,mayprovideusefulstartingpointsfortreatingstress-relateddisorders. epigenetic marksunderliethebehaviourallyadaptiveresponsesofresilientanimalsthatdistinguishthem have already been distinct before the procedure (and reflect innate susceptibility ( linked toanyalterationsinducedbythestressprocedureinitself,asanimals’epigeneticprofilesmight the behaviouralphenotype(i.e.,psychopathology).However, epigeneticsignatureisnotnecessarily theobserved stress exposure.Moresothaninthestressedvscontrolcontrast,thiscontrastlinksepigeneticsignaturedirectlyto vulnerable animalstodistinguishpotentialadaptivefrommaladaptiveepigeneticchangesasaconsequenceof Thebehaviourally(most)resilientanimalsarecomparedtothe symptomatology afterwards. Resilient vsvulnerable.Allanimalsfromagroupundergothesamestressprocedureandaretestedonstress-related animals, butnotnecessarilydirectlyrelatedtoanystress-induced phenotype. to stressexposure,andarelikelyreflectiveofthemeanbehaviouraldifferencesbetweenstressedcontrol t al et Epigeneticcontributionstoastress-relatedphenotype.

. 2006 Research inrodentshasindicatedthat Box 1 ). Chronic stress has been reported to ). Chronicstresshasbeenreportedto )) and(ii)whichepigeneticmarksdirectlycontributetopathology, by mere ). Limbic structures of the forebrain ). Limbicstructuresoftheforebrain McEwen 2000 b

c Di Chiara

dirven Harbuz & Lightman Harbuz &Lightman andothers Printed inGreatBritain Herman et al ). Besides ). Besides . 1999 et al ). . remained present for at least 6 weeks. While this might argue the stressepisode,eventhough thedepressivebehaviour the defeated animals returned to baseline levels 72 behaviour ( social defeat,accompanied byincreaseddepressive-like increased hippocampalH3acetylationinaratmodel of defeat stressononeday, butnotonesingle15-min session, alterations. Four consecutive 15-min sessions of social stressor seemstoincreaseitspotentialevokeepigenetic future investigation.Interestingly, repetition oftheacute (i.e., behavioural)relevanceofthesealterationsopenfor data werecollectedinthisstudy, leaving the functional the newstressfulenvironment.However, nobehavioural to chronicstressmayallowthebrainproperlyadapt to the stimulus, whereas activating specificgenesin response stress exposuremayavoidthebrainfromoverreactingto that generaltranscriptionalsilencinginresponsetoacute increased afterchronicexposure.Itcouldbehypothesized unaffected byacuteandsubchronicstress,butsignificantly activator ofgenetranscription( chronic stress.Conversely, H3K4trimethylation,aknown by bothacuteandsubchronicstress,butdecreased ( trimethylation, associatedwithtranscriptionalsilencing of restraintstress( either 1 day (acute),7 days (subchronic),or21 days (chronic) resultingfrom patterns inrathippocampuswereobserved in adulthood Epigenetics ofstressresponse Barski Published byBioscientifica Ltd. et al Hollis . 2007 et al , Hunter Karmodiya Fig. 1 . 2010 Downloaded fromBioscientifica.com at09/28/202107:21:27PM ): Box 1 t al et ). However, H3acetylationin et al . 2009 )). Still, studying which Barski . 2012 post-hoc ). H3K9 and H3K27 ). H3K9andH3K27 59 t al et : ), were increased ), were increased 1 comparisons . 2007 h after h after ), was ), was R16 via freeaccess Review b c j dirven and others Epigenetics of stress response 59:1 R17 in adulthood

Figure 1 Animal models of stress. (A) Stressed vs control contrast: half of the animals from a genetically homogeneous group undergoes a certain stress procedure, while the other half receives a sham procedure. (B) Vulnerable vs resilient contrast: all animals from a group undergo the same stress procedure and are tested on stress-related symptomatology afterwards. The behaviourally most resilient animals are compared to the behaviourally most vulnerable animals.

against the histone modification as a potential underlying suggest that the regulatory systems involved in the brain’s mechanism for the behavioural profile, transient changes innate response to stress differ between acute and chronic in histone acetylation have previously been proposed to exposure. This is especially interesting for understanding induce long-term changes in gene activity (Tsankova et al. vulnerability to PTSD, as both acute (e.g., violent personal 2006, Shahbazian & Grunstein 2007) and behaviour assault and severe car accidents) and chronic stress (e.g., Journal of Molecular Endocrinology (Weaver et al. 2004) by inducing transcription of genes war and child neglect) exposure can precipitate PTSD- that influence the transcription of other downstream associated psychopathology (Javidi & Yadollahie 2012). targets that are more long-lasting. This emphasizes that The effectiveness of acute stress to induce epigenetic their modulation, albeit transiently, can have long- changes seems to not only depend on stressor frequency, lasting consequences. In line with this modulatory role but also on stressor dimension and severity, as 15 min for stressor frequency, Renthal et al. (2007) showed that a of forced swimming and 30 min of predator exposure, single 10 min session of social defeat stress was insufficient but not 3 min of ether vapour exposure or 4 h of cold to alter levels of the histone deacetylases (HDACs) 1, 2, exposure, were found to increase H3 phosphorylation in 3, 4, 5 and 9 in the NAc of adult mice, but that a 10-day the rat dentate gyrus (DG) (Bilang-Bleuel et al. 2005). One repetition of the paradigm downregulated HDAC5 in the hour of acute restraint stress also appeared to be sufficient NAc by almost 25%. This regulation of HDAC5 expression to significantly decrease global DNA methylation levels likely contributed to the behavioural consequences of the in rat hippocampus, medial prefrontal cortex (mPFC), stressor, as in this same study it was found that HDAC5 and periaqueductal grey (Rodrigues et al. 2015). Possibly, knockout mice developed more severe social avoidance stressors with a strong psychological component (such as and anhedonia in response to the stress paradigm than restraint and predator exposure) might be more effective wild-type littermate controls. Interestingly, knockout and at inducing epigenetic changes than primarily physical wild-type mice did not differ in their behavioural responses stressors (such as cold and vapour exposure) (Bilang- to an acute defeat episode, indicating that HDAC5 is Bleuel et al. 2005). involved in the epigenetic regulation of behavioural Epigenetic involvement in the persistent behavioural adaptations to chronic, but not acute, stress. These findings consequences induced by acute stressors is also apparent

t al et . 2008 The epigeneticeffectsofchronicstresshave et al and (2009) . , ) and lateral amygdala ( Zovkic . 2010 Tsai (2014) observed increased accumbal observed ), aswellamygdalarhistone et al Gupta . (2013) , , and t al et Stankiewicz b

Parsons & Ressler 2013 Levenson c

dirven . 2010 , Blouin Kwapis andothers Printed inGreatBritain Monsey t al et ), havebeen et al et al and . (2016) . 2013 . 2004 t al et Wood ). ). ) . . brain, DNMT3Awasupregulatedinthecentralnucleus region-specific nature of theepigenetic changes inthe expression ofmPFCDNMT3A.Furtherconfirmingthe global methylationlevelswasassociatedwithadecreased accompanied byananxiousphenotype.Thisreductionin levels inthemPFC( were showntodisplaydecreasedglobalDNAmethylation methylation intheNAc,10-daysociallydefeatedanimals the entiregenome.Incontrasttoincreasedhistone induced epigeneticchangesintheNAcoccurthroughout lending credencetotheideathatwidespreadstress- significant evenafteraveragingacrosstheentiregenome, lasting. Moreover, theincreasesinmethylationlevelwere termination, indicatingthatthechangesareratherlong- post-stress- avoidant phenotyperemainedstable28 days Both theincreaseinhistonedimethylationand to thebehaviouralconsequencesofthischronicstressor. animals, theseepigeneticeffectsseemtobedirectlyrelated histone methylationlevelsresemblingthoseofcontrol 28 days ofchronicunpredictablestress(CUS)( 28 days in ratsfollowing and H4K12acetylationwereobserved chronic stress.SimilardecreasesinhippocampalH3K9 implying higherHDACactivityasaconsequence of acetylation intheCVSanimalscomparedtocontrols, hippocampal slicesinducedastrongerincreaseinhistone variable stress(CVS).ApplicationofHDACinhibitorsto H4K12 acetylationasaconsequenceof14-daychronic (2011) patterns whencomparedtocontrols. stressed animals also show differential histone acetylation vs resilientmiceafterchronicsocialdefeat.Chronically of thehypothalamus( found tobereducedintheparaventricularnucleus(PVN) of defeatedvscontrolmice.Additionally, DNMT3Bwas downregulated inthehippocampus( is upregulatedintheNAc( this region.OtherstudieshavereportedthatDNMT3A were notalteredinthemPFC,downregulated of the amygdala(CeA), while DNMT3B levels, which vulnerable compared to resilient mice ( ( with increasedaccumbalH3K14 acetylationintheNAc stress intheNAcofdefeated vscontrolmice,coinciding was found to be downregulated by 10-day social defeat region-specific epigeneticmodulations.Lastly, HDAC2 2007 ( HDAC5 wasfoundtobedownregulatedintheamygdala increase inHDAC5hippocampaltissue.Interestingly, 2014 in adulthood Epigenetics ofstressresponse Covington Sterrenburg Published byBioscientifica Ltd. ) inchronicallystressedrats,againpointingtowards ), whichwasaccompaniedwithasignificant reportedondecreasedrathippocampalH3K9and et al et al . 2009 . 2011 ) and in the PVN of social avoidant ), as well as the NAc ( Elliott Elliott Downloaded fromBioscientifica.com at09/28/202107:21:27PM t al et LaPlant t al et . 2010 . 2016 Ferland Hammels 59 Elliott t al et : 1 ) ofvulnerable ), whichwere Renthal . 2010 and Schrader et al et al Liu . 2010 . 2015 ) and R18 et al et al via freeaccess ) ) . . Review b c j dirven and others Epigenetics of stress response 59:1 R19 in adulthood

(Table 2 for an overview of all reported region-specific Moreover, altered miRNA expression levels have been stress-induced epigenetic changes). observed as a consequence of a model for PTSD-induction Rodent models have also demonstrated altered in rats (Balakathiresan et al. 2014) and have been proposed region-specific miRNA levels in response to both acute as mediators of resilience to chronic stress (Issler et al. (Rinaldi et al. 2010, Haramati et al. 2011, Mannironi et al. 2014, Higuchi et al. 2016). The regulation of non-coding 2013, Hosoya et al. 2016) and chronic stressors RNAs, including miRNAs, in animal models of PTSD (Meerson et al. 2010, Babenko et al. 2012, Volk et al. 2016). has been extensively reviewed by Schmidt et al. (2015).

Table 2 Overview of stress-induced general epigenetic changes in the rodent brain.

Measurement Species Paradigm post-stress Brain region Epigenetic changes References Acute stress Rat Restraint stress Immediately Hip (DG, CA1) H3K9me3 ↑ Hunter et al. (2009) (30 min) H3K27me3 ↓ Rat Restraint stress 1 day Hip, PAG 5-mC ↓ Rodrigues et al. (2015) (1 h) Rat Restraint stress Immediately Hip H3ac ↓ Fuchikami et al. (2009) (2 h) Rat Social defeat Immediately Hip H3ac ↑ Hollis et al. (2010) (4 x 15 min) Rat Forced swim 1 day Hip (DG) H3ph ↑ Bilang-Bleuel et al. (2005) (30 min) Predator stress (15 min) Chronic stress Rat Restraint stress 1 day Hip (DG) H3K9me3 ↓ Hunter et al. (2009) (21 days) H3K4me3 ↑ Mouse Social isolation 28 days NAc H3K9me2 ↑ Wilkinson et al. (2009) (10 days) Social defeat H3K27me2 ↑ (10 days) Mouse Social defeat 28 days Hip H3K27me2 ↑ Tsankova et al. (2006) Journal of Molecular Endocrinology (10 days) Mouse Social defeat 1 day mPFC 5-mC ↓ DNMT3A ↓ Elliott et al. (2016) (10 days) Amygdala (CeA) DNMT3A ↑ DNMT3B ↓ Mouse Social defeat Immediately Hypothalamus (PVN) DNMT3B ↓ Elliott et al. (2010) (10 days) Mouse Social defeat 10 days NAc DNMT3A ↑ LaPlant et al. (2010) (10 days) Mouse Social defeat 1 day Hip (DG) DNMT3A ↓ Hammels et al. (2015) (10 days) Mouse Social defeat 1 day NAc HDAC5 ↓ Renthal et al. (2007) (10 days) Mouse Social defeat 10 days NAc H3K14ac↑ HDAC2 ↓ Covington et al. (2009) (10 days) Mouse Social defeat Immediately PVN HDAC2 ↓ Elliott et al. (2010) (10 days) Rat CUS (21 days) 1 day Hypothalamus H3K9me3 ↓ Wan et al. (2014) Rat CUS (28 days) 1 day Hip H3K9ac ↓ HDAC5 ↑ Liu et al. (2014) H4K12ac ↓ Rat CVMS (14 days) 1 day Amygdala (CeA) HDAC5 ↓ Sterrenburg et al. (2011) Rat CVS (14 days) 1 day Hip (DG, CA3) H3K9ac ↓ Ferland and Schrader (2011) H4K12ac ↓

5-mC, methylated DNA; ac, acetyl; CeA, central nucleus of the amygdala; CUS, chronic unpredictable stress; CVMS, chronic variable mild stress; CVS, chronic variable stress; DG, dentate gyrus; DNMT, DNA methyltransferase; H, histone; HDAC, histone deacetylase; Hip, hippocampus; K, lysine; me, methyl; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PAG, periaqueductal grey; ph, phosphate; PVN, paraventricular nucleus.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology the brain ( 2006 of theimpairedHPA axisnegativefeedback( antidepressant treatmentisassociatedwiththeresolution episodes ( example beenshownpredictiveoftheriskfordepressive has clearclinicalrelevance;elevatedbasalcortisolfor HPA axisdysfunction( before, stress-relatedpsychopathologyisassociatedwith the HPA axisareofparticularimportance.Asmentioned those occurringingenesinvolvedtheregulationof modifications occurring after stress exposure ( While itisclearthatthereamyriadofepigenetic the HPA axis Stress-induced epigeneticmodification of often relieson Hence, identifyingimportanttargetgenesformiRNAs the levelsoftranscriptionfactors( influence the expression of even more genes by altering range ofdirectmoleculartargetsandmightindirectly remains amajorchallenge,asmiRNAsoftenhavewide processes Determining theroleofmiRNAsinregulatory 2013 ( was foundtobeaffectedinthreeindependentstudies The authorsconcludethatbesidesmiR-132,which Konopka DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org 14 acetylation at histoneH3(H3S10p-K14ac) via recruitment of histoneacetyl-transferases( kinase (MAPK)signallingpathway. andlysine Downstream kinasesofthispathwayinducedserine10phosphorylation rat hippocampalDGgranuleneuronsactivatedtheextracellular signalrelatedkinase(ERK)/mitogen-activatedprotein event through epigenetic pathways. by whichglucocorticoidsactto(amongstothers)facilitateconsolidationofmemoriesassociatedwithaspecificadverse Recent studieshavehoweverstartedtoelucidatethesemechanismsbyimplicatinganovel,non-genomicmechanism genes andbrainregions,itisstilllargelyunclearbywhichmolecularpathwaystheseeffectsareexactlyestablished. While ithasbeenknownforquitesomeyearsthatstressexposurecaninduceepigeneticmodificationsinavariety of Box 3 this glucocorticoidcontrolover epigeneticmodifications, for formationofH3S10p-K14acandIEGinduction( is necessary 2007 suggesting therequiredinvolvement ofanothermolecularpathwayinmediatingthese effects( dose ofcorticosteroneinrathippocampuswashoweverineffective toformH3S10p-K14acandinduceIEGexpression, Egr-1 the interactionofH3S10p-K14acmarkwithpromoter regionoftheimmediate-earlygenes(IEGs) possible mechanismbywhichstresscouldinducestable epigeneticand(eventually)behaviouralalterations.Indeed, induced H3S10p-K14accouldlong-lastinglyactivategenes thatweresilentbeforestressexposure,therebyofferinga remodelling, makingthemaccessiblefortranscription( 2007 Review ) by restoring corticosteroid receptor expression in ), findingsonothermiRNAswereneverreplicated. wasfoundtofacilitatetheinductionofthesegenes( ). TheNMDAreceptorwaslater identifiedasaco-activatoroftheMAPKpathway, whosesynchronisedactivation ). Thisepigeneticmarkhasbeenassociatedwiththeactivation ofsilentgenes,possiblythroughchromatin Mechanismsforstress-inducedepigeneticalterations. et al Pariante & Lightman 2008 Goodyer . 2010 in silico t al et , targetprediction. Nudelman Tsigos &Chrousos2002 . 2001 b et al

c ), whereassuccessful

), which also predicts dirven Gutierrez-Mecinas . 2010 andothers Printed inGreatBritain , et al Wang ), which Pariante Box 3 . 2013 et al Cheung et al ), ). . Gutierrez-Mecinas Reul . (2011) Schelling Corticotropin-releasing hormonesignalling the hypothalamicPVN,hippocampus,andPFC. affecting CRHandglucocorticoidsignalling,mainlyin life can mediate changes in HPA axis function through discuss howstress-inducedepigeneticalterationsinadult symptomatology ( chronic corticosteroidtreatmentofPTSDpatientsreduces shown toreducePTSDsymptoms( 2011 levels reducedPTSDincidence( 2000 ( shown predictiveofsubsequentPTSDsymptomatology In PTSD,lowcortisollevelsfollowingtraumahavebeen the patient’s long-termclinicaloutcome( have beenlinkedtobothearlyandadultlifetrauma Increased stress-induced thereafter, inratsby asobserved peaking at 30 generally increasesPVN and behavioural domain ( adaptive responses,includingtheautonomic,immune, of thestriaterminalisisrelatedtoawiderangestress- CRH expression in the PVN, amygdala and bed nucleus Weis in adulthood Epigenetics ofstressresponse McFarlane Published byBioscientifica Ltd. et al et al Reul et al ). Corticosteroidadministrationpriortotraumawas , observed that binding of glucocorticoids to GRs in observed . 2000 Witteveen . (2015) et al t al et . 2006 et al , Nowak &Corces 2000 . 2009 . . 2001 ), whereas preliminary workindicatedthat ), whereaspreliminary et al min post-stress and slowly declining . 1997 t al et Aerni ). Foranextensivereviewdescribing . 2011 , , Schelling . 2010 et al Delahanty Downloaded fromBioscientifica.com at09/28/202107:21:27PM CRH ). InjectionofaGR-occupying CRH Kovacs 2013 . 2004 mRNAandpeptidelevels, ), whereaselevatingthese transcriptional responses t al et ). Inthissection,wewill Chandramohan et al ). Thisglucocorticoid- Schelling Chandramohan Shepard Schelling . 2003 59 . 2000 ). Stress exposure : 1 Pariante 2006 t al et t al et , et al Zohar , c-Fos McFarlane . (2005) . 1999 et al . 2004 et al t al et and R20 . . via freeaccess ). . . , , Review b c j dirven and others Epigenetics of stress response 59:1 R21 in adulthood

exposure (Plotsky & Meaney 1993, Chen et al. 2012, which binds to the Crh promoter region and acts as a Mironova et al. 2013, Xu et al. 2014, Eraslan et al. 2015), transcriptional activator (Jeanneteau et al. 2012). BDNF in and epigenetic mechanisms may underlie these changes. the rat PVN has been found to be upregulated by chronic Sterrenburg et al. (2011) reported on demethylation of the restraint stress, concurrent with elevated Crh mRNA Crh promoter region and subsequent CRH upregulation levels (Naert et al. 2011). Upregulation of PVN BDNF by in the PVN of stressed rats compared to controls as a stress-induced epigenetic modifications could therefore consequence of 14-day chronic variable mild stress. contribute to the increased CRH expression and the HPA Similar alterations have been observed in the mouse axis dysfunction that is observed in rodents following PVN following chronic social defeat stress in vulnerable chronic stress in adulthood (Zhu et al. 2014) and in vs resilient animals (Elliott et al. 2010), demonstrating human stress-related pathology (Tsigos & Chrousos 2002). a direct link between the epigenetic alterations and In contrast, both acute and chronic stress have been the observed social avoidant phenotype. DNMT3B and found to reduce BDNF expression in the mouse and rat HDAC2 in the PVN were decreased and the demethylation- hippocampus, which was associated with increased local promoting factor GADD45 was substantially upregulated H3K27 methylation (Tsankova et al. 2006), decreased H3 1 h after the last social defeat session in defeated vs acetylation (Fuchikami et al. 2009), and enhanced Bdnf control animals, suggesting their involvement in Crh promoter methylation (Roth et al. 2011, Niknazar et al. demethylation. The increased CRH levels, demethylation 2016). Furthermore, hippocampal expression levels of of Crh, and the decrease in HDAC2 remained present for TrkB were reduced following forced swim stress, which at least 2 weeks after the end of social defeat. CRH is increased methylation of Trkb (Niknazar et al. 2016). thought to exert its overall anxiogenic effects by binding Decreased hippocampal BDNF has been hypothesized to CRH receptor 1 (CRHR1) (Henckens et al. 2016). to underlie hippocampal dysfunction in response to A recent study showed that 21 days of CUS decreased traumatic stress (Johnsen & Asbjornsen 2008, Moore hypothalamic H3K9 trimethylation in the rat, which 2009), as BDNF is an important neurotrophic factor that was correlated with elevated levels of local CRHR1 enhances long-term potentiation and other forms of expression and avoidance behaviour (Wan et al. 2014). synaptic plasticity in the hippocampus (Korte et al. 1996). Moreover, Sotnikov et al. (2014) showed that amygdalar Indeed, overexpression of hippocampal BDNF has been CRHR1 expression was regulated by Crhr1 methylation found to mediate behavioural resilience to chronic mild and correlated with trait anxiety, substantiating the stress in rats (Taliaz et al. 2011). Despite evidence for altered link between epigenetic regulation of the CRH-CRHR1 Bdnf methylation levels in rodent PVN and hippocampus,

Journal of Molecular Endocrinology system and the anxious phenotype induced by stress. plasma BDNF levels and BDNF methylation status were A growing body of evidence demonstrates that also not found to be altered after acute psychosocial stress in miRNAs can regulate the expression of HPA axis- healthy human subjects (Unternaehrer et al. 2012). related target genes. Haramati et al. (2011) reported on decreased levels of amygdalar miR-34c following acute Corticosterone signalling social defeat, which was found to target Crhr1 via a complementary site on the 3′ untranslated region of the Glucocorticoid receptor Many of the behavioural receptor transcript. Overexpression of miR-34c appeared effects of stress-induced corticosteroid release are thought to reduce cell responsiveness to CRH by inhibiting to be mediated by activation of GRs (McKlveen et al. CRHR1 expression and induce an anxiolytic phenotype. 2013, Park et al. 2015). Moreover, corticosteroid binding Among the predicted targets of the miR-34c family were to GRs contributes to the negative feedback inhibition also other stress-related proteins, including brain-derived of the HPA axis, which is important in the termination neurotrophic factor (BDNF) and 5-HT and glutamate of the stress response. This negative feedback loop is receptors. These data suggest that miR-34c plays a role disrupted in PTSD, thought to be mediated by increased in regulating multiple amygdalar genes that collectively GR expression levels in the PFC and hippocampus modulate the behavioural response to stress. (Mizoguchi et al. 2003). This implies that altered regulation An important modulator of CRH expression is the of GR transcription by epigenetic modifications serves as BDNF. BDNF is able to induce expression of CRH in the a potential underlying mechanism. Demethylation of PVN by binding to hypothalamic tropomyosin receptor NR3C1, the gene coding for GR, was observed in blood kinase B (TrkB) receptors. TrkB activation induces and saliva from PTSD patients vs trauma-matched healthy expression of cAMP response element-binding protein, controls (Labonte et al. 2014, Vukojevic et al. 2014,

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology expression is elevated by acute stressors, but decreased by found to beupregulated in the PVN. The finding thatGR region of Indeed, miR-18a,targetingtwo sitesofthe3 mechanisms attheposttranscriptionallevel. regulatory stressed vscontrolrats,suggestingtheinvolvement of PVN GR,werefoundtobesignificantlylowerinrepeatedly 2005 used toinduceadepressive-likephenotype( following repeatedrestraintstress,aparadigmcommonly downregulation ofGRexpressionbymiRNAsintheratPVN and RNAlevel. levels, mediatedbyepigeneticmechanismsontheDNA is characterizedbyelevatedhippocampalandPFCGR inPTSD, negative glucocorticoidfeedback,asobserved 2010 decreasing DNAmethylationatthe FKBP5 expression(andthuspotentiateGRsensitivity)by anxiety-like behaviourandelevatemousehippocampal administration duringadulthoodwasshowntoincrease regulator ofGRsensitivity( regulation ofFK506bindingprotein5(FKBP5),aknown may additionallyinducealterationsintheepigenetic stress-related NR3C1upregulation.Stressexposure by adecreasein5-mC,whichcollectivelyinducedthe suggesting thattheincreasein5-hmCwasparalleled change intotalmethylationlevels(i.e.,5-mC The study by hippocampal previous findingsthatacutestressinadulthoodincreases elevated local GR expression. This would be in line with increased 5-hmC is likely associated with that the observed transcription ( ( mouse hippocampus after acute restraint stress exposure hydroxymethylation (5-hmC)ofthe differences, rodentworkhasreportedonincreasedDNA evidence foracausalroleoftraumaexposuretothese PTSD andMDD. responsible forthecontrastingHPA axisalterationsin that oppositelydirectedepigeneticalterationsmightbe 2002 peripheral ( hypermethylation of contrast, studiesinhumanpatientshaveimplicated emphasizing its relevance to psychopathology. In inversely correlatedwithPTSDsymptomseverity, Yehuda Li DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review et al In contrast, Although thesepatientstudiesdonotprovide , ). Thesefindingscollectivelysuggestthatdisrupted ) GRlevelsinthepathogenesisofMDD,suggesting Chiba . 2015 t al et Nr3c1 Yehuda et al ). Since 5-hmC is associated with active gene Li Nr3c1 . 2015 Szulwach anddownregulatinggeneexpression, was et al . 2012 Uchida et al mRNAlevelsinmice( . (2015) ). NR3C1 ). Protein,butnotmRNAlevelsof NR3C1 . 1993 t al et t al et Binder 2009 did not detect a stress-related and subsequent decreases in . 2011 ) andcortical( methylationlevelseven . (2008) b

dirven Nr3c1 ), ascorticosterone reported on the Gray locus( andothers Printed inGreatBritain ′ promoterin Webster untranslated Gregus et al + Lee 5-hmC), . 2014 et al et al et al ). . . . the affinity of the intracellular MR for cortisol and the affinityofintracellularMRforcortisoland dysregulation of the HPA axis ( altered GR/MR balance has been implicatedinpersistent receptors collectivelyorchestrate thestressresponseasan response uponbindingofglucocorticoids( involved intheappraisalprocessandonsetofstress humans isencodedbythe termination ofthestressresponse,MR,whichin associated withregulationofHPA negativefeedbackand (MR), hasreceivedlessattention.WhiletheGRis extensively studied,themineralocorticoidreceptor GR in stress response reactivity and regulation has been receptor Mineralocorticoid is oppositelyaffectedinMDDandPTSD( GR expression(andtherebynegativefeedbackregulation) that repeated stressors,mightreflectearlierobservations in trauma-exposed women. While plasma MR levels in trauma-exposedwomen. WhileplasmaMRlevels of severalCpGslocatedwithin the this. the caseof also subjecttoepigeneticregulation, but,incontrastto neuroendocrine controlofthestressresponse. exposure, whichlikelyhasimportantconsequencesfor indicate thatMRexpressionishighlyresponsivetostress by depressive-like symptomatology. These results to bedecreasedbyalmost20%dueCUS( Hippocampal plasticity inthehippocampusandamygdala( stress-induced effectsonneurotransmissionandsynaptic membrane-bound MRwasrecentlyshowntoexertrapid stress research foralong time.However, anewformof Hence, unsurprisingly, theGRhasdominatedendocrine even undernon-stressconditions( of theintracellularGR,MRsarealreadylargelyoccupied corticosterone isapproximatelytentimeshigherthanthat hippocampus ofalmostallspecies( 2005 corticosterone ( were reduced following the chronic administration of 1998 ( rat hippocampalMRdensityafteraforced swimmingtask demonstrated inapreclinicalstudyshowinganincrease regulation ofMRexpressioninresponsetostresshasbeen was previouslythought.Thepossibilityofdynamic prominent roleinthebehaviouralstressresponsethan demonstrating thattheMRmightalsohaveafarmore is 10-foldlowerthanthatofitsintracellularcounterpart, 2008 in adulthood Epigenetics ofstressresponse Gesing Published byBioscientifica Ltd. ). Co-localization of both receptors is found in the ). Co-localizationofbothreceptorsisfoundinthe ), whereas local MR (but not GR) protein levels ), whereaslocalMR(butnotGR)proteinlevels ). Theapparentaffinityofthismembrane-locatedMR Perroud et al . 2001 NR3C1 et al Nr3c2 Wu . (2014) ), which served torestraintheHPA), whichserved axis. et al , only few studies have investigated , onlyfewstudieshaveinvestigated mRNA levels were however found mRNAlevelswerehoweverfound . 2013 Downloaded fromBioscientifica.com at09/28/202107:21:27PM reported on lower methylation reportedonlowermethylation NR3C2 ), which was accompanied ), which wasaccompanied

Harris Grossmann gene, is thought to be gene,isthoughttobe Whereas the role of Whereas theroleof Patel 59 NR3C2 t al et : et al 1 Alt de Kloet et al . 2000 et al . 2013 Lopez promoter promoter Joels NR3C2 . 2010 . 2004 ). The ). The et al et al R22 et al ). As ). As is is ). via freeaccess ). ). . . . Review b c j dirven and others Epigenetics of stress response 59:1 R23 in adulthood

were significantly elevated in these same individuals, HDAC inhibitor sodium valproate not only prevented no significant correlation was found with the altered the decrease of H4 acetylation and increase of HDAC5 NR3C2 methylation status. Recent findings in rodents protein expression, but also blunted the decrease in TH (Sober et al. 2010) have also implicated miRNAs (miR-135a and TPH expression, implicating epigenetic regulation and miR-124) as potential regulators (i.e., suppressors) of neurotransmitter precursor production. Direct of NR3C2 protein expression. An independent study by evidence for altered epigenetic regulation of stress-related Mannironi et al. (2013) showed that these miRNAs were neurotransmitters as a consequence of adult life stress downregulated in the mouse amygdala following acute exposure primarily exists for the serotonergic system. restraint stress, which increased amygdalar MR expression. The serotonin transporter (5-HTT), which in humans is In conclusion, a growing body of research demonstrates encoded by SLC6A4, is an integral membrane protein in that stress-induced epigenetic alterations underlie a the central and peripheral nervous system that transports wide variety of aberrations in HPA axis function that are 5-HT back from the synaptic cleft into the pre-synaptic observed in PTSD patients and rodent models of acute and neuron, thereby waning serotonergic transmission. chronic stress. This includes increased CRH expression Reduced expression of this transporter incites high basal in the PVN, decreased hippocampal CRH and MR levels, 5-HT levels, which has been associated with enhanced and elevated hippocampal and prefrontal GR expression. vulnerability to chronic stress (Bartolomucci et al. 2010) The interesting finding that epigenetic regulation of and increased risk for life time depression (Kambeitz & paraventricular GR expression was oppositely affected by Howes 2015). Resilience to clinical depression under acute (Li et al. 2015) and repeated (Uchida et al. 2008) chronic high stress conditions was however found to restraint stress underlines that there is still a knowledge be associated with reduced methylation of the SLC6A4 gap pertaining the differential epigenetic profiles of genes promoter (Alasaari et al. 2012), which is expected involved in HPA axis regulation that underlie PTSD-like to increase 5-HTT expression (Philibert et al. 2008). and depressive-like phenotypes. This calls for a more Increased reuptake of 5-HT by 5-HTT and subsequent structured investigation of the distinct epigenetic changes basal 5-HT decrease might therefore be a mechanism of induced by severe, acute (which induces PTSD-like stress adaptation, contributing to chronic stress resilience. symptomatology) and chronic stress (known to induce a Chronic stress was also found to induce a long-lasting depressive-live behavioural phenotype). upregulation of serotonin receptor 1A (5-HT1A) RNA and protein levels in the mouse mPFC and dorsal raphe nucleus (Le Francois et al. 2015), corroborating the evidence of Stress-related epigenetic modification of Journal of Molecular Endocrinology altered epigenetic regulation of serotonergic transmission stress-related neurotransmitters as a consequence of adult life stress exposure. This Besides modulating the neuroendocrine response to stress, stress-induced increase in 5-Ht1a mRNA was paralleled epigenetic modifications may alter neurotransmitter by the increased methylation of a uniquely conserved release and signalling in brain circuits that orchestrate CpG site in 5-Ht1a that serves as a binding site for the the stress response and are known to be altered in transcriptional repressor Sp4, explaining the observed PTSD (Southwick et al. 1999). Alterations in dopamine upregulation in expression. Yet, it is unknown how (Yehuda et al. 1992), norepinephrine (NE) (Geracioti et al. these changes in 5-HT1A expression affect serotonergic 2001), and serotonin (5-HT) (Arora et al. 1993) transmission transmission, as they may upregulate 5-HT1A in different are thought to contribute to the symptoms commonly cell (interneurons vs pyramidal cells) and receptor types observed in PTSD patients, including hypervigilance, (post-synaptic receptors vs autoreceptors) which regulate impulsivity, exaggerated startle, and depressed mood, serotonergic network activity in an opposite manner. and may be subject to epigenetic regulation. For Findings from human studies have indicated example, levels of the enzymes tyrosine hydroxylase that epigenetic modifications, besides having a direct (TH) and tryptophan hydroxylase (TPH), responsible modulatory effect, can also interact with the genotype for creating precursor metabolites for the production of to shape the stress response. DNA methylation profiles dopamine (DA), epinephrine, NE, and 5-HT, were found within SCL6A4 were found to moderate the association to be significantly decreased in the hippocampus of of the 5-HTT linked polymorphic region (5-HTTLPR) and chronically stressed rats (Liu et al. 2014), concurrent with stress coping (van IJzendoorn et al. 2010, Alexander et al. decreased hippocampal acetylation of H3K9 and H4K12 2014). High serum SCL6A4 methylation was associated and increased levels of HDAC5. Administration of the with an increased risk of unresolved responses to loss or

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology in adulthood. Furthermore, to establish whether particular in adulthood.Furthermore,to establishwhetherparticular depressive andanxiousphenotypes bystressexperienced and marksthatplayarolein theinductionoflong-term yield valuableinformationabout theepigeneticprocesses several monthsafteradult lifestressinductioncould Applying similarstudydesignstofollowuprodentsfor monthsafterperinatalstress, respectively. for 6and15 Pusalkar adulthood, forexampleby the epigeneticconsequencesofearlylifestressduring Long-term research isalreadybeingperformedtostudy takes place andpose opportunity windows for treatment. which particularstress-inducedepigeneticprogramming assess whetheritispossibletodistinguishtimeframes in behavioural effectsoftransientstressexposureand(ii) to involvement ofepigeneticmechanismsinthelong-lasting It would,however, beinterestingto(i)testforthe days)post-stressexposure. and relativelyshortly(1–28 ‘snapshot’ epigeneticmarks,assessedatonetimepoint Almost allstudiesintoacuteandchronicstressinvestigated and the associated neuropsychiatric symptomatology. of stressandtraumaexposureonneuroendocrinefunction required tobettermodelthelastingandintrusivenature epigenetic changesoverprolongedperiodsof time is to adult life stress, a thorough assessment of persistent insights intotherelativelyshort-termepigeneticresponse related symptomatology. knowledge canbeofcriticalimportancetotreatstress- elevated hippocampalandprefrontalGRexpression.This the PVN,decreasedhippocampalCRHandMRlevels, chronic stress.ThisincludesincreasedCRHexpressionin in PTSD patients and rodent models of acute and observed the stress-inducedalterationsinHPA axisthatare Epigenetic mechanisms have been shown to underlie HPA axisandstress-relatedneurotransmittersystem. response, including neuroendocrine components ofthe can befoundatthelevelofmanymediatorsstress stress-related psychopathology. Thisepigeneticregulation changes ingeneexpressionandbehaviourassociatedwith stress exposureinadultlifeandtheresultingpersistent epigenetic modificationsformanimportantlinkbetween ofseverallinesevidencesuggestingthat overview In thisreview, wehaveprovidedacomprehensive Conclusion andfuture directions predicted unresolvedlossortraumainshortallelecarriers. long allelicvariant,whilelowlevelsofmethylated other traumaincarriersoftheusuallyprotective5-HTTLPR DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review While the reviewed rodent studies provide valuable While thereviewedrodentstudiesprovidevaluable t al et . (2016) , who followed up rats and mice , whofollowedupratsandmice Bockmuhl b

dirven t al et andothers Printed inGreatBritain . (2015) SCL6A4 and and

stress-induced behaviour. longevity ofthemarkeranditscorrelationtolong-lasting biomarker atmultipletimepointspost-stresstoassessthe experiment canberepeatedtolongitudinallymeasurethis markers arealsopresentinbloodorsalivasamples.Ifso,the modifications ofasinglegene)onecouldtesttoseeifthese specific tissue areidentified(especiallyinthecaseofvery brain tissue.Onceimportantepigeneticmarkersin findings inthebloodmaybehavegreatvalueasaproxyfor blood ( positions inrathippocampusandcortexaremirroredthe indicated that around 50% of differentially methylated Previous findingsfrommethylome-wideprofilinghave non-brain-based epigeneticbiomarkerssuchasblood. performed once,reiteratingtheimportanceofincluding However, invasivemeasurementsofthebraincanonlybe marks atmultipletimepointsfollowingstressinduction. would beofutmostimportancetoassessbrainepigenetic epigenetic programmingoccursinspecifictimeframes,it (i) strategies: possible intervention/treatment findingsinadultrodentshave focusedonfive Preliminary to reprogramtheepigeneticeffectsofearlylifestress. conceptually differentfromthosethatarealsobeingused reported onsuccessfultreatmentstrategiesthatarenot employing similarstrategies.Initialstudieshavealready are likelysimilarandcouldthereforeberevertedby as a consequence of stress during early life and adulthood early life,thestress-inducedepigeneticchangesoccurring increased plasticityforepigeneticprogrammingduring resilient brain?Althoughthereisclearlyawindowof and toremodelthestress-vulnerablebrainastress- to neuropathology;isitpossiblerevertthesechanges changes thatoccurafterstressexposurearelinked ofthemaladaptiveepigenetic Once wehaveanoverview prevent andtreatthesedisordersbytargetedinterventions. disorders, thenextstepshouldbetoapplythisknowledge epigenetic modifications in the pathology of stress-related in adulthood Epigenetics ofstressresponse Published byBioscientifica Ltd. While evidenceisaccumulatingforacrucialroleof stress-induced histone demethylation ( inhibitor fluoxetinehavebeenshowntorevert imipramine andtheselectiveserotoninreuptake Antidepressants. The tricyclicantidepressant stress protocols. and anxiety-likebehaviourinduced bytherespective ( Francois of demethylation of 2009 Renthal Davies Bdnf ) and methylation ( ( et al t al et et al Tsankova . 2015 . 2012 . 2007 Crh ) and decreased levels of HDAC5 , Downloaded fromBioscientifica.com at09/28/202107:21:27PM ), whichallreduceddepressive Aberg ( t al et Elliott . 2006 et al Wilkinson et al . 2013 . 2010 59 ) and : 1 ), affirming that ), methylation t al et Hunter 5-Ht1a . 2009 R24 t al et ( Le via freeaccess ), .

Review b c j dirven and others Epigenetics of stress response 59:1 R25 in adulthood

(ii) HDAC inhibitors. The HDAC inhibitors sodium References valproate and MS-275 have been shown to reduce Aberg KA, Xie LY, McClay JL, Nerella S, Vunck S, Snider S, Beardsley PM depressive and anxiety-like behaviour by reverting & van den Oord EJ 2013 Testing two models describing how stress-induced increases in HDAC2 and HDAC5 and methylome-wide studies in blood are informative for psychiatric conditions. Epigenomics 5 367–377. (doi:10.2217/epi.13.36) subsequent histone acetylation marks on H3K9, H3K14 Aerni A, Traber R, Hock C, Roozendaal B, Schelling G, Papassotiropoulos and H4K12 (Covington et al. 2009, Liu et al. 2014). A, Nitsch RM, Schnyder U & de Quervain DJ 2004 Low-dose cortisol (iii) DNMT inhibitors. The DNMT inhibitor RG108 has for symptoms of posttraumatic stress disorder. American Journal of Psychiatry 161 1488–1490. (doi:10.1176/appi.ajp.161.8.1488) been shown to reduce depressive and anxiety-like Afifi TO, Asmundson GJ, Taylor S & Jang KL 2010 The role of genes and behaviour by reverting stress-induced increases in environment on trauma exposure and posttraumatic stress disorder DNMT3A (Elliott et al. 2016). symptoms: a review of twin studies. Clinical Psychology Review 30 101–112. (doi:10.1016/j.cpr.2009.10.002) (iv) miRNAs. The amygdalar miRNA-34 has been Alasaari JS, Lagus M, Ollila HM, Toivola A, Kivimaki M, Vahtera J, identified as a repressor of stress-induced anxiety Kronholm E, Harma M, Puttonen S & Paunio T 2012 Environmental (Haramati et al. 2011). As such, miRNA-34 and other stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. PLoS ONE 7 e45813. stress-related miRNAs pose potential novel targets for (doi:10.1371/journal.pone.0045813) treatment of stress-related disorders. Alexander N, Wankerl M, Hennig J, Miller R, Zankert S, Steudte- (v) Exercise. Physical exercise has been shown to improve Schmiedgen S, Stalder T & Kirschbaum C 2014 DNA methylation profiles within the serotonin transporter gene moderate the cognitive responses to psychosocial stress and rescue association of 5-HTTLPR and cortisol stress reactivity. Translational rats from social defeat-induced anxiety-like behaviour Psychiatry 4 e443. (doi:10.1038/tp.2014.88) and memory impairment (Collins et al. 2009). This Alt SR, Turner JD, Klok MD, Meijer OC, Lakke EA, Derijk RH & Muller CP 2010 Differential expression of glucocorticoid receptor transcripts beneficial effect might potentially be mediated by in major depressive disorder is not epigenetically programmed. epigenetic mechanisms, including exercise-induced Psychoneuroendocrinology 35 544–556. (doi:10.1016/j. H3 acetylation and modulation of methylation in the psyneuen.2009.09.001) Andersen AM, Dogan MV, Beach SR & Philibert RA 2015 Current and hippocampus (Patki et al. 2014). future prospects for epigenetic biomarkers of substance use disorders. However, it is currently mechanistically unclear Genes 6 991–1022. (doi:10.3390/genes6040991) Arora RC, Fichtner CG, O’Connor F & Crayton JW 1993 Paroxetine whether the behaviourally beneficial effects of these binding in the blood platelets of post-traumatic stress disorder treatments are mediated directly through an effect on the patients. Life Science 53 919–928. (doi:10.1016/0024-3205(93)90444-8) epigenome, or through another external mediator affecting Auger CJ & Auger AP 2013 Permanent and plastic epigenesis in neuroendocrine systems. Frontiers in Neuroendocrinology 34 190–197. both behaviour and epigenetic markers independently. (doi:10.1016/j.yfrne.2013.05.003) Because these treatment strategies all have a broad scope Babenko O, Golubov A, Ilnytskyy Y, Kovalchuk I & Metz GA 2012 Journal of Molecular Endocrinology and potentially affect a wide range of processes in the body, Genomic and epigenomic responses to chronic stress involve miRNA-mediated programming. PLoS ONE 7 e29441. (doi:10.1371/ higher precision epigenetic editing might be necessary to journal.pone.0029441) specifically target epigenetic marks in the brain and enable Balakathiresan NS, Chandran R, Bhomia M, Jia M, Li H & Maheshwari personalized medicine. Still, these preliminary results show RK 2014 Serum and amygdala microRNA signatures of posttraumatic stress: fear correlation and biomarker potential. Journal of Psychiatric that it possible to attend to the behavioural consequences Research 57 65–73. (doi:10.1016/j.jpsychires.2014.05.020) of stress exposure by pharmacological and therapeutic Bam M, Yang X, Zhou J, Ginsberg JP, Leyden Q, Nagarkatti PS & Nagarkatti interventions targeting epigenetic profiles. M 2016 Evidence for epigenetic regulation of pro-inflammatory cytokines, interleukin-12 and interferon gamma, in peripheral blood mononuclear cells from PTSD patients. Journal of Neuroimmune Pharmacology 11 168–181. (doi:10.1007/s11481-015-9643-8) Declaration of interest Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, The authors declare that there is no conflict of interest that could be Chepelev I & Zhao K 2007 High-resolution profiling of histone perceived as prejudicing the impartiality of this review. methylations in the human genome. Cell 129 823–837. (doi:10.1016/j.cell.2007.05.009) Bartolomucci A, Carola V, Pascucci T, Puglisi-Allegra S, Cabib S, Lesch Funding KP, Parmigiani S, Palanza P & Gross C 2010 Increased vulnerability This work was supported by the Netherlands Organization for Scientific to psychosocial stress in heterozygous serotonin transporter Research (NWO), grant # 864.10.003 awarded to Judith R Homberg and knockout mice. Disease Models and Mechanisms 3 459–470. Veni grant # 863.15.008 awarded to Marloes J A G Henckens. (doi:10.1242/dmm.004614) Bilang-Bleuel A, Ulbricht S, Chandramohan Y, De Carli S, Droste SK & Reul JM 2005 Psychological stress increases histone H3 Acknowledgements phosphorylation in adult dentate gyrus granule neurons: This work was supported by the Netherlands Organization for Scientific involvement in a glucocorticoid receptor-dependent behavioural Research (NWO), grant # 864.10.003 awarded to Judith R Homberg and response. European Journal of Neuroscience 22 1691–1700. Veni grant # 863.15.008 awarded to Marloes J A G Henckens. (doi:10.1111/j.1460-9568.2005.04358.x)

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology Collins A,HillLE,Chandramohan Y, WhitcombD, DrosteSK&ReulJM Codocedo JF&InestrosaNC2016EnvironmentalcontrolofmicroRNAs Clive ML,BoksMP, Vinkers CH,OsborneLM,PayneJL,ResslerKJ, Chiba S,NumakawaT, NinomiyaM,RichardsMC,Wakabayashi C& Cheung P, AllisCD&Sassone-CorsiP2000Signalingtochromatin Chertkow-Deutsher Y, CohenH,KleinE&Ben-ShacharD2010DNA Chen J,EvansAN,LiuY, HondaM,SaavedraJM&AguileraG2012 Chapman DP, WhitfieldCL,FelittiVJ,DubeSR,EdwardsVJ&AndaRF Chandramohan Y, DrosteSK&ReulJM2007Noveltystressinduces Burke HM,DavisMC,OtteC&MohrDC2005Depressionandcortisol Breslau N2002Epidemiologicstudiesoftrauma,posttraumaticstress Boyko A,BlevinsT, Yao Y, GolubovA,BilichakIlnytskyyY, Hollunder Bockmuhl Y, PatchevAV, MadejskaA,HoffmannSousaJC,N, Blouin AM,SillivanSE,JosephNF&MillerCA2016Thepotentialof Binder EB2009TheroleofFKBP5,aco-chaperonetheglucocorticoid DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review through enhancementofepigenetic mechanismsandgene 2009 Exercise improvescognitiveresponsestopsychological stress neubiorev.2015.10.010) Neuroscience andBiobehavioral Reviews system: Implicationsinplasticityandbehavior.in thenervous s13148-016-0279-1) suicide predictionmodel. of aperipheraltissueDNAmethylationbiosignaturetoaugment Smith AK,Wilcox andreplication HC&KaminskyZ2016Discovery (doi:10.1016/j.pnpbp.2012.05.018) andBiologicalPsychiatry Neuro-Psychopharmacology derived neurotrophicfactorintheprefrontalcortex. expression, andattenuatesglutamatereleaseinducedbybrain- depression-like behaviors,downregulatesglucocorticoidreceptor Kunugi H2012Chronicrestraintstresscausesanxiety-and S0092-8674(00)00118-5) through histonemodifications. S146114570999071X) ofNeuropsychopharmacology Journal for theroleofpost-synapticdensityproteinDlgap2. methylation invulnerabilitytopost-traumaticstressrats:evidence Neuroendocrinology CRH transcriptionalresponsestostressinadulthood. releasing hormone(CRH)promoterhypomethylationandenhances Maternal deprivationinratsisassociatedwithcorticotrophin- (doi:10.1016/j.jad.2003.12.013) 2826.2012.02306.x) disorders inadulthood. 2004 Adversechildhoodexperiencesandtheriskofdepressive (doi:10.1111/j.1471-4159.2006.04396.x) induction. receptor andtheglucocorticoidreceptor:relevanceforc-fos neurons throughcoincidentsignallingviatheN-methyl-d-aspartate phospho-acetylation ofhistoneH3inratdentategyrusgranule psyneuen.2005.02.010) Psychoneuroendocrinology responses topsychologicalstress:ameta-analysis. Psychiatry disorder, andotherpsychiatricdisorders. pone.0009514) Dicer-like proteins. Arabidopsis tostressrequiresDNAmethylationandthefunctionof J, MeinsFJr&KovalchukI2010Transgenerational adaptationof stress. island shoreregionupregulatesNr3c1promoteractivityafterearly-life Holsboer F, AlmeidaOF&SpenglerD2015MethylationattheCpG and Memory epigenetics in stress-enhanced fear learning models of PTSD. (doi:10.1016/j.psyneuen.2009.05.021) disorders. receptor inthepathogenesisandtherapyofaffectiveanxiety Epigenetics

47 Psychoneuroendocrinology Journal ofNeurochemistry Journal

23 923–929. 576–586.

24 247–257. PLoS ONE 1055–1064. (doi:10.1016/b978-0-12-374462-3.00004-6)

Journal ofAffectiveDisorders Journal 30 (doi:10.1101/lm.040485.115) Clinical Epigenetics 846–856.

(doi:10.1080/15592294.2015.1017199) 5 e9514. Cell

(doi:10.1111/j.1365-

34 13

101 103

(Supplement1)S186–S195. (doi:10.1016/j. 347–359. 60 b

(doi:10.1371/journal. c 815–828. 263–271. 121–138.

dirven

8 113. (doi:10.1017/

andothers Printed inGreatBritain 39 (doi:10.1016/ (doi:10.1016/j.

82 (doi:10.1186/ 112–119. Progress in Journal of Journal 217–225. International International Learning Learning Davies MN,Volta M,PidsleyR,LunnonK,DixitA,LovestoneS,Coarfa Daskalakis NP, BagotRC,ParkerKJ,Vinkers CH&deKloetER2013The Crews D&GoreAC2011Lifeimprints:livinginacontaminatedworld. Covington HEIII,MazeI,LaPlantQC,Vialou VF, OhnishiYN,Berton Cougle JR,Timpano KR,Sachs-EricssonN,KeoughME&RiccardiCJ Ferland CL&SchraderLA2011Regulation ofhistoneacetylationin Feng J,ZhouY, CampbellSL,LeT, LiE, SweattJD,SilvaAJ&FanG Eraslan E,AkyaziI,ErgLEE&MaturE2015NoisestresschangesmRNA Elliott E,ManashirovS,ZwangR,GilTsoory M,ShemeshY&ChenA Elliott E,Ezra-NevoG,RegevL,Neufeld-CohenA&Chen2010 Edwards VJ,HoldenGW, FelittiVJ&AndaRF2003Relationship Dias BG,MaddoxSA,KlengelT&ResslerKJ2015Epigenetic Di ChiaraG,LoddoP&Tanda G1999Reciprocalchangesinprefrontal Delahanty DL,RaimondeAJ&SpoonsterE2000Initialposttraumatic de KloetER,JoelsM&HolsboerF2005Stressandthebrain:from in adulthood Epigenetics ofstressresponse Published byBioscientifica Ltd. (doi:10.1186/gb-2012-13-6-r43) epigenetic variationacrossbrainandblood. annotation ofthehumanbrainmethylomeidentifiestissue-specific C, HarrisRA,MilosavljevicA,Troakes C, psyneuen.2013.06.008) Psychoneuroendocrinology understanding adaptationtoearly-lifeadversityoutcome. three-hit conceptofvulnerabilityandresilience:toward ehp.1103451) Environmental HealthPerspectives JNEUROSCI.1758-09.2009) Neuroscience synaptic functioninadultforebrain neurons. 2010 Dnmt1andDnmt3amaintainDNAmethylationregulate 141–147. amygdala, andanxiety-relatedbehaviors. expressions ofcorticotropin-releasinghormone,itsreceptorsin (doi:10.1523/JNEUROSCI.0971-15.2016) behavior inadultmice. 2016 Dnmt3ainthemedialprefrontalcortexregulatesanxiety-like 1351–1353. methylation oftheCrfgeneinadultmice. Resilience tosocialstresscoincideswithfunctionalDNA 1453–1460. childhood experiencesstudy. mental healthincommunityrespondents:resultsfromtheadverse between multipleformsofchildhoodmaltreatmentandadult tins.2014.12.003) behaviors. mechanisms underlyinglearningandtheinheritanceoflearned S0006-3223(99)00236-X) of depression. stimuli afterchronicmildstress:implicationsforthepsychobiology and limbicdopamineresponsivenesstoaversiverewarding (doi:10.1016/S0006-3223(00)00896-9) vehicle accidentvictims. cortisollevelspredictsubsequentPTSDsymptomsinmotor urinary (doi:10.1038/nrn1683) adaptation todisease. Antidepressant actionsofhistonedeacetylaseinhibitors. O, FassDM,RenthalW, RushAJIII,Wu EY, (doi:10.1016/j.psychres.2009.03.008) Comorbidity Survey-Replication. and childhoodphysicalsexualabuseintheNational 2010 Examiningtheuniquerelationshipsbetweenanxietydisorders journal.pone.0004330) expression inthedentategyrus. neuroscience.2010.10.077) sirtuins. the hippocampusofchronicallystressed rats:apotentialroleof 423–430. Neuroscience (doi:10.4103/1463-1741.155838) (doi:10.1038/nn.2514) Trends inNeurosciences

(doi:10.1038/nn.2642) (doi:10.1176/appi.ajp.160.8.1453) 29 Biological Psychiatry 11451–11460.

174 Nature ReviewsNeuroscience

Journal ofNeuroscience Journal 38 Biological Psychiatry 104–114. 1858–1873. Downloaded fromBioscientifica.com at09/28/202107:21:27PM American Journal ofPsychiatry American Journal (doi:10.1523/

119 PLoS ONE

Psychiatry ResearchPsychiatry 38

46 (doi:10.1016/j. 96–107. 1208–1210. 1624–1633. (doi:10.1016/j. et al Noise andHealth

4 Nature Neuroscience e4330.

et al Genome Biology 59 48 . 2012Functional (doi:10.1016/j.

Nature Neuroscience 36 : 940–947. 1 . 2009

730–740. (doi:10.1289/ 6 (doi:10.1016/ 463–475.

177 (doi:10.1371/ 150–155. Journal of Journal

17 160

R26

R43. 13

13 via freeaccess

Review b c j dirven and others Epigenetics of stress response 59:1 R27 in adulthood

Fuchikami M, Morinobu S, Kurata A, Yamamoto S & Yamawaki S 2009 Harris AP, Holmes MC, de Kloet ER, Chapman KE & Seckl JR 2013 Single immobilization stress differentially alters the expression Mineralocorticoid and glucocorticoid receptor balance in control of profile of transcripts of the brain-derived neurotrophic factor (BDNF) HPA axis and behaviour. Psychoneuroendocrinology 38 648–658. gene and histone acetylation at its promoters in the rat (doi:10.1016/j.psyneuen.2012.08.007) hippocampus. International Journal of Neuropsychopharmacology 12 Henckens MJ, Deussing JM & Chen A 2016 Region-specific roles of the 73–82. (doi:10.1017/S1461145708008997) corticotropin-releasing factor-urocortin system in stress. Nature Geracioti TD Jr, Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, Reviews Neuroscience 17 636–651. (doi:10.1038/nrn.2016.94) Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE Jr, et al. 2001 CSF Herman JP, Ostrander MM, Mueller NK & Figueiredo H 2005 Limbic norepinephrine concentrations in posttraumatic stress disorder. system mechanisms of stress regulation: hypothalamo-pituitary- American Journal of Psychiatry 158 1227–1230. (doi:10.1176/appi. adrenocortical axis. Progress in Neuro-Psychopharmacology and ajp.158.8.1227) Biological Psychiatry 29 1201–1213. (doi:10.1016/j. Gesing A, Bilang-Bleuel A, Droste SK, Linthorst AC, Holsboer F & Reul pnpbp.2005.08.006) JM 2001 Psychological stress increases hippocampal Higuchi F, Uchida S, Yamagata H, Abe-Higuchi N, Hobara T, Hara K, mineralocorticoid receptor levels: involvement of corticotropin- Kobayashi A, Shintaku T, Itoh Y, Suzuki T, et al. 2016 Hippocampal releasing hormone. Journal of Neuroscience 21 4822–4829. microRNA-124 enhances chronic stress resilience in mice. Journal of Goodyer IM, Park RJ & Herbert J 2001 Psychosocial and endocrine Neuroscience 36 7253–7267. (doi:10.1523/JNEUROSCI.0319-16.2016) features of chronic first-episode major depression in 8–16 year olds. Ho SM & Tang WY 2007 Techniques used in studies of epigenome Biological Psychiatry 50 351–357. (doi:10.1016/S0006- dysregulation due to aberrant DNA methylation: an emphasis on 3223(01)01120-9) fetal-based adult diseases. Reproductive Toxicology 23 267–282. Gräff J & Tsai L-H 2013 Histone acetylation: molecular mnemonics on (doi:10.1016/j.reprotox.2007.01.004) the chromatin. Nature Reviews Neuroscience 14 97–111. (doi:10.1038/ Hollis F, Wang H, Dietz D, Gunjan A & Kabbaj M 2010 The effects of nrn3427) repeated social defeat on long-term depressive-like behavior and Gray JD, Rubin TG, Hunter RG & McEwen BS 2014 Hippocampal gene short-term histone modifications in the hippocampus in male expression changes underlying stress sensitization and recovery. Sprague-Dawley rats. Psychopharmacology 211 69–77. (doi:10.1007/ Molecular Psychiatry 19 1171–1178. (doi:10.1038/mp.2013.175) s00213-010-1869-9) Gregus A, Wintink AJ, Davis AC & Kalynchuk LE 2005 Effect of repeated Honda M, Kuwano Y, Katsuura-Kamano S, Kamezaki Y, Fujita K, Akaike corticosterone injections and restraint stress on anxiety and Y, Kano S, Nishida K, Masuda K & Rokutan K 2013 Chronic depression-like behavior in male rats. Behavioural Brain Research 156 academic stress increases a group of microRNAs in peripheral blood. 105–114. (doi:10.1016/j.bbr.2004.05.013) PLoS ONE 8 e75960. (doi:10.1371/journal.pone.0075960) Grossmann C, Scholz T, Rochel M, Bumke-Vogt C, Oelkers W, Pfeiffer Hosoya T, Hashiyada M & Funayama M 2016 Acute physical stress AF, Diederich S & Bahr V 2004 Transactivation via the human increases serum levels of specific microRNAs. Microrna 5 50–56. (doi: glucocorticoid and mineralocorticoid receptor by therapeutically 10.2174/2211536605666160602104659) used steroids in CV-1 cells: a comparison of their glucocorticoid and Hunter RG, McCarthy KJ, Milne TA, Pfaff DW & McEwen BS 2009 mineralocorticoid properties. European Journal of Endocrinology 151 Regulation of hippocampal H3 histone methylation by acute and 397–406. (doi:10.1530/eje.0.1510397) chronic stress. PNAS 106 20912–20917. (doi:10.1073/ Gudsnuk K & Champagne FA 2012 Epigenetic influence of stress and pnas.0911143106) the social environment. ILAR Journal 53 279–288. (doi:10.1093/ Issler O, Haramati S, Paul ED, Maeno H, Navon I, Zwang R, Gil S, ilar.53.3-4.279) Mayberg HS, Dunlop BW, Menke A, et al. 2014 MicroRNA 135 is Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor essential for chronic stress resiliency, antidepressant efficacy, and Journal of Molecular Endocrinology RE & Lubin FD 2010 Histone methylation regulates memory intact serotonergic activity. Neuron 83 344–360. (doi:10.1016/j. formation. Journal of Neuroscience 30 3589–3599. (doi:10.1523/ neuron.2014.05.042) JNEUROSCI.3732-09.2010) Javidi H & Yadollahie M 2012 Post-traumatic stress disorder. International Gutierrez-Mecinas M, Trollope AF, Collins A, Morfett H, Hesketh SA, Journal of Occupational and Environmental Medicine 3 2–9. Kersante F & Reul JM 2011 Long-lasting behavioral responses to (doi:10.4135/9781446213483.n1) stress involve a direct interaction of glucocorticoid receptors with Jeanneteau FD, Lambert WM, Ismaili N, Bath KG, Lee FS, Garabedian MJ ERK1/2-MSK1-Elk-1 signaling. PNAS 108 13806–13811. (doi:10.1073/ & Chao MV 2012 BDNF and glucocorticoids regulate corticotrophin- pnas.1104383108) releasing hormone (CRH) homeostasis in the hypothalamus. PNAS Hammels C, Prickaerts J, Kenis G, Vanmierlo T, Fischer M, Steinbusch 109 1305–1310. (doi:10.1073/pnas.1114122109) HW, van Os J, van den Hove DL & Rutten BP 2015 Differential Jirtle RL & Skinner MK 2007 Environmental epigenomics and disease susceptibility to chronic social defeat stress relates to the number of susceptibility. Nature Reviews Genetics 8 253–262. (doi:10.1038/nrg2045) Dnmt3a-immunoreactive neurons in the hippocampal dentate gyrus. Joels M, Karst H, DeRijk R & de Kloet ER 2008 The coming out of the Psychoneuroendocrinology 51 547–556. (doi:10.1016/j. brain mineralocorticoid receptor. Trends in Neurosciences 31 1–7. psyneuen.2014.09.021) (doi:10.1016/j.tins.2007.10.005) Hannon E, Lunnon K, Schalkwyk L & Mill J 2015 Interindividual Johnsen GE & Asbjornsen AE 2008 Consistent impaired verbal memory methylomic variation across blood, cortex, and cerebellum: in PTSD: a meta-analysis. Journal of Affective Disorders 111 74–82. implications for epigenetic studies of neurological and (doi:10.1016/j.jad.2008.02.007) neuropsychiatric phenotypes. Epigenetics 10 1024–1032. (doi:10.1080/ Jones PS 2012 Functions of DNA methylation: islands, start sites, gene 15592294.2015.1100786) bodies and beyond. Nature Reviews Genetics 13 484–492. Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R, Hornstein E (doi:10.1038/nrg3230) & Chen A 2011 MicroRNA as repressors of stress-induced anxiety: Kambeitz JP & Howes OD 2015 The serotonin transporter in depression: the case of amygdalar miR-34. Journal of Neuroscience 31 meta-analysis of in vivo and post mortem findings and implications 14191–14203. (doi:10.1523/JNEUROSCI.1673-11.2011) for understanding and treating depression. Journal of Affective Harbuz MS & Lightman SL 1992 Stress and the hypothalamo-pituitary- Disorders 186 358–366. (doi:10.1016/j.jad.2015.07.034) adrenal axis: acute, chronic and immunological activation. Journal of Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T, Endocrinology 134 327–339. (doi:10.1677/joe.0.1340327) Klengel T, Bradley B, Binder EB, Ressler KJ, et al. 2015 Epigenetic and

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology Lopez JF, ChalmersDT, LittleKY&Watson SJ1998 A.E.Bennett Liu D,QiuHM,FeiHZ,HuXY, XiaHJ,Wang LJ,QinJiangXH & Li S,PapaleLA,KintnerDB,SabatG,Barrett-Wilt GA,CengizP&Alisch Levenson JM,O’RiordanKJ,BrownKD,Trinh MA,Molfese DL&Sweatt Lee RS,Tamashiro KL,Yang X,Purcell A,Willour RH,Harvey VL,HuoY, Le FrancoisB,SooJ,MillarAM,DaigleM,GuisquetLemanS, LaPlant Q,Vialou V, CovingtonHEIII,DumitriuD,FengJ,Warren BL, Labonte B,AzoulayN,Yerko V, Turecki G&BrunetA2014Epigenetic Kwapis JL&Wood MA2014Epigeneticmechanisms in fear Kovacs KJ2013CRH:thelinkbetweenhormonal-,metabolic-and Korte M,StaigerV, GriesbeckO,ThoenenH&Bonhoeffer T1996The Konopka W, M,ParkitnaJR,Wawrzyniak A,NovakM,Herwerth Kiryk Kessler RC,BerglundP, DemlerO,JinR,MerikangasKR&Walters EE Karmodiya K,KrebsAR,Oulad-AbdelghaniM,KimuraH&Tora L2012 Kang HJ,KimJM,LeeJY, KimSY, BaeKY, KimSW, Shin IS,KimHR, DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review mineralocorticoid receptorinratand humanhippocampus: Research Award. Regulation of serotonin1A,glucocorticoid,and (doi:10.1177/1535370213513987) depressive rats. aminergic transmitterssynthetasesinvolvedinCUS-induced Zhou QX2014Histoneacetylationandexpressionofmono- 236–240. receptor genefollowingacutestress. RS 2015Hippocampalincreaseof5-hmCintheglucocorticoid 40545–40559. in thehippocampus. formation JD 2004Regulationofhistoneacetylationduringmemory (doi:10.1210/en.2010-0225) methylation ofFkbp5inmice. exposure increasesexpressionanddecreasesdeoxyribonucleicacid Rongione M,Wand GS&PotashJB2010Chroniccorticosterone Nature Neuroscience emotional behaviorandspineplasticityinthenucleusaccumbens. Maze I,DietzDM,Watts EL,IniguezSD, Disease Sp4site. modifying DNAmethylationofaconserved antidepressant treatmentalter5-HT1Areceptorexpressionby Minier F, BelzungC&AlbertPR2015Chronicmildstressand disorder. modulation ofglucocorticoidreceptorsinposttraumaticstress Trends inNeurosciences conditioning: implicationsfortreatingpost-traumaticstressdisorder. 25–33. behavioral responsestostress. ofPhysiology Journal long-term potentiationrevealedbygenetargetingexperiments. involvement ofbrain-derivedneurotrophicfactorinhippocampal 3030-10.2010) Neuroscience inmice. MicroRNA lossenhanceslearningandmemory M, KowarschA,MichalukP, DzwonekJ,ArnspergerT, archpsyc.62.6.593) Archives ofGeneralPsychiatry replication.DSM-IV disordersinthenationalcomorbiditysurvey 2005 Lifetimeprevalenceandage-of-onsetdistributionsof (doi:10.1186/1471-2164-13-424) stemcells. promoters inmouseembryonic elements, whileH3K14acmarksasubsetofinactiveinducible H3K9 andH3K14acetylationco-occuratmanygeneregulatory 679–685. behavior indepressivepatients. Shin MG&Yoon JS2013BDNFpromotermethylationandsuicidal (doi:10.1038/tp.2015.105) traumatic stressdisorder. genetic variationatSKA2predictsuicidalbehaviorandpost-

(doi:10.1016/j.jchemneu.2013.05.003) 82 Translational Psychiatry (doi:10.1016/j.bbr.2015.03.002) (doi:10.1016/j.jad.2013.08.001) 332–341.

30 (doi:10.1074/jbc.M402229200) 14835–14842. Experimental BiologyandMedicine

90 (doi:10.1016/j.nbd.2015.07.002) Journal ofBiologicalChemistry Journal 1137–1143.

37 157–164. 706–720. Translational Psychiatry

62 (doi:10.1523/JNEUROSCI. Journal ofChemicalNeuroanatomy Journal Endocrinology

Journal ofAffectiveDisorders Journal 4 593–602. e368. (doi:10.1038/nn.2619) (doi:10.1016/j.tins.2014.08.005) Behavioural BrainResearch b

c (doi:10.1038/tp.2014.3) et al

dirven BMC Genomics (doi:10.1001/

. 2010 Dnmt3a regulates . 2010Dnmt3aregulates 151

5 4332–4343. 239 andothers Printed inGreatBritain e627.

279 330–336. Neurobiology of et al

Journal of Journal

13 . 2010

151 424.

286

Mironova V, Rybnikova E&PivinaS2013Effectofinescapablestressin Miller CA,GavinCF, WhiteJA,ParrishRR,HonasogeA,Yancey CR, Miller CA,CampbellSL&SweattJD2008DNAmethylationandhistone McClelland S,KorosiA,CopeJ,IvyA&BaramTZ2011Emergingroles Miller CA&SweattJD2007CovalentmodificationofDNAregulates Miller DB&O’CallaghanJP2002Neuroendocrineaspectsoftheresponse in mammals. Migicovsky Z&KovalchukI2011Epigeneticmemory Mendonca A,ChangEH,LiuW&Yuan C2009Hydroxymethylationof Meerson A,CacheauxL,GoosensKA,SapolskyRM,SoreqH&KauferD McKlveen JM,MyersB,FlakJN,BundzikovaJ,SolomonMB,SeroogyKB McFarlane AC,AtchisonM&Yehuda R1997Theacutestressresponse McFarlane AC2000Posttraumaticstressdisorder:amodelofthe McEwen BS2000Theneurobiologyofstress:fromserendipitytoclinical Mannironi C,CamonJ,DeVito F, BiundoA,DeStefanoME,PersiconiI, Malan-Muller S,SeedatS&HemmingsSM2014Understanding Maccari S,KrugersHJ,Morley-FletcherSzyfM&BruntonPJ2014The Lueboonthavatchai P2009Roleofstressareas,severity, and Lubin FD,RothTL&SweattJD2008EpigeneticregulationofBDNF in adulthood Epigenetics ofstressresponse Published byBioscientifica Ltd. and experienceonlearningmemory. of epigeneticmechanismsintheenduringeffectsearly-lifestress rodent modelsofdepressionandposttraumatic stressdisorderon 664–666. methylation maintainsremotememory. Rivera IM,RubioMD,RumbaughG &SweattJD2010CorticalDNA (doi:10.1016/j.nlm.2007.07.016) synaptic plasticity. formation and acetylation workinconcerttoregulatememory neuron.2007.02.022) formation. memory to stress. Frontiers inGenetics 1839 Mechanisms Biochimica etBiophysicaActa(BBA)-GeneRegulatory DNA influencesnucleosomalconformationandstabilityinvitro. s12031-009-9252-1) reactions. 2010 ChangesinbrainMicroRNAscontributetocholinergicstress (doi:10.1016/j.biopsych.2013.03.024) in stressandemotion. & HermanJP2013Roleofprefrontalcortexglucocorticoidreceptors (doi:10.1111/j.1749-6632.1997.tb48299.x) the NewYork AcademyofSciences following motorvehicleaccidentsanditsrelationtoPTSD. Psychiatry longitudinal courseandtheroleofriskfactors. 8993(00)02950-4) relevance. and Memory (doi:10.1371/journal.pone.0073385) for corticosteroiddependentstressresponse. amygdala microRNAmiR-135aandmiR-124expression:inferences Bozzoni I,FragapaneP, MeleA&PresuttiC2013Acutestressalters Brain andBehavior posttraumatic stressdisorder:insightsfromthemethylome. (doi:10.1111/jne.12175) and epigeneticadaptations. consequences ofearly-lifeadversity:neurobiological,behavioural 1240–1249. control study. stressful lifeeventsontheonsetofdepressivedisorder:acase- JNEUROSCI.1786-08.2008) Neuroscience gene transcriptionintheconsolidationoffearmemory. 43 implications fortheneurobiologyofdepression. 547–573. 1323–1329. Metabolism

(doi:10.1038/nn.2560) 61 Journal ofMolecularNeuroscience Journal Brain Research

96 28 (Supplement5)15–20;discussion21–13. (doi:10.1016/S0006-3223(97)00484-8) Journal oftheMedicalAssociation Thailand Journal 79–88. 10576–10586.

(doi:10.1016/j.bbagrm.2014.09.014) 13

Neurobiology of Learning andMemory Neurobiology ofLearning 2

Neuron 51 28. 52–68. Biological Psychiatry (doi:10.1016/j.nlm.2011.02.008) 5–10.

886 (doi:10.3389/fgene.2011.00028)

Downloaded fromBioscientifica.com at09/28/202107:21:27PM 53 Journal ofNeuroendocrinology Journal 172–189. (doi:10.1111/gbb.12102) (doi:10.1053/meta.2002.33184) (doi:10.1523/ 857–869.

821 437–441. (doi:10.1016/S0006- Nature Neuroscience (doi:10.1016/j.

Neurobiology of Learning Neurobiology ofLearning 40 74 59 PLoS ONE 47–55. 672–679. : Journal ofClinical Journal 1 Biological Psychiatry (doi:10.1007/

8 89

Journal of Journal e73385. 26

599–603. 92 707–723.

Annals of 13 Genes,

R28

via freeaccess

Review b c j dirven and others Epigenetics of stress response 59:1 R29 in adulthood

CRH and vasopressin immunoreactivity in the hypothalamic sucrose reward: paradoxical positive incentive effects in stress? BMC paraventricular nucleus. Acta Physiologica Hungarica 100 395–410. Biology 4 8. (doi:10.1186/1741-7007-4-8) (doi:10.1556/APhysiol.100.2013.4.4) Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis- Mizoguchi K, Ishige A, Aburada M & Tabira T 2003 Chronic stress Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, et al. attenuates glucocorticoid negative feedback: involvement of the 2010 Altered histone acetylation is associated with age-dependent prefrontal cortex and hippocampus. Neuroscience 119 887–897. memory impairment in mice. Science 328 753–756. (doi:10.1126/ (doi:10.1016/S0306-4522(03)00105-2) science.1186088) Monroe SM & Simons AD 1991 Diathesis-stress theories in the context Perroud N, Rutembesa E, Paoloni-Giacobino A, Mutabaruka J, Mutesa L, of life stress research: implications for the depressive disorders. Stenz L, Malafosse A & Karege F 2014 The Tutsi genocide and Psychological Bulletin 110 406–425. (doi:10.1037/0033- transgenerational transmission of maternal stress: epigenetics and 2909.110.3.406) biology of the HPA axis. World Journal of Biological Psychiatry 15 Monsey MS, Ota KT, Akingbade IF, Hong ES & Schafe GE 2011 334–345. (doi:10.3109/15622975.2013.866693) Epigenetic alterations are critical for fear memory consolidation and Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W & Madan A synaptic plasticity in the lateral amygdala. PLoS ONE 6 e19958. 2008 The relationship of 5HTT (SLC6A4) methylation and genotype (doi:10.1371/journal.pone.0019958) on mRNA expression and liability to major depression and alcohol Moore SA 2009 Cognitive abnormalities in posttraumatic stress disorder. dependence in subjects from the Iowa adoption studies. American Current Opinion in Psychiatry 22 19–24. (doi:10.1097/ Journal of Medical Genetics Part B: Neuropsychiatric Genetics 147B YCO.0b013e328314e3bb) 543–549. (doi:10.1002/ajmg.b.30657) Naert G, Ixart G, Maurice T, Tapia-Arancibia L & Givalois L 2011 Brain- Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson derived neurotrophic factor and hypothalamic-pituitary-adrenal axis MW, Milad MR & Liberzon I 2012 Biological studies of post- adaptation processes in a depressive-like state induced by chronic traumatic stress disorder. Nature Reviews Neuroscience 13 769–787. restraint stress. Molecular and Cellular Neuroscience 46 55–66. (doi:10.1038/nrn3339) (doi:10.1016/j.mcn.2010.08.006) Plotsky PM & Meaney MJ 1993 Early, postnatal experience alters Nichols L, Freund M, Ng C, Kau A, Parisi M, Taylor A, Armstrong D, hypothalamic corticotropin-releasing factor (CRF) mRNA, median Avenilla F, Joseph J, Meinecke D, et al. 2014 The National Institutes eminence CRF content and stress-induced release in adult rats. Brain of Health Neurobiobank: a federated national network of human Research: Molecular Brain Research 18 195–200. (doi:10.1016/0169- brain and tissue repositories. Biological Psychiatry 75 e21–22. 328X(93)90189-V) (doi:10.1016/j.biopsych.2013.07.039) Provencal N & Binder EB 2015a The effects of early life stress on the Niknazar S, Nahavandi A, Peyvandi AA, Peyvandi H, Akhtari AS & epigenome: from the womb to adulthood and even before. Karimi M 2016 Comparison of the adulthood chronic stress effect Experimental Neurology 268 10–20. (doi:10.1016/j. on hippocampal BDNF signaling in male and female rats. Molecular expneurol.2014.09.001) Neurobiology 53 4026–4033. (doi:10.1007/s12035-015-9345-5) Provencal N & Binder EB 2015b The neurobiological effects of stress as Nowak SJ & Corces VG 2000 Phosphorylation of histone H3 correlates contributors to psychiatric disorders: focus on epigenetics. Current with transcriptionally active loci. Genes and Development 14 Opinion in Neurobiology 30 31–37. (doi:10.1016/j.conb.2014.08.007) 3003–3013. (doi:10.1101/gad.848800) Pumplin N, Sarazin A, Jullien PE, Bologna NG, Oberlin S & Voinnet O Nudelman AS, DiRocco DP, Lambert TJ, Garelick MG, Le J, Nathanson 2016 DNA methylation influences the expression of DICER-LIKE4 NM & Storm DR 2010 Neuronal activity rapidly induces isoforms, which encode proteins of alternative localization and transcription of the CREB-regulated microRNA-132, in vivo. function. Plant Cells 28 2786–2804. (doi:10.1105/tpc.16.00554) Hippocampus 20 492–498. (doi:10.1002/hipo.20646) Pusalkar M, Suri D, Kelkar A, Bhattacharya A, Galande S & Vaidya VA Journal of Molecular Endocrinology Pariante CM 2006 The glucocorticoid receptor: part of the solution or 2016 Early stress evokes dysregulation of histone modifiers in the part of the problem? Journal of Psychopharmacology 20 79–84. medial prefrontal cortex across the life span. Developmental (doi:10.1177/1359786806066063) Psychobiology 58 198–210. (doi:10.1002/dev.21365) Pariante CM & Lightman SL 2008 The HPA axis in major depression: Renthal W, Maze I, Krishnan V, Covington HE3rd, Xiao G, Kumar A, classical theories and new developments. Trends in Neurosciences 31 Russo SJ, Graham A, Tsankova N, Kippin TE, et al. 2007 Histone 464–468. (doi:10.1016/j.tins.2008.06.006) deacetylase 5 epigenetically controls behavioral adaptations to Park HJ, Lee S, Jung JW, Kim BC, Ryu JH & Kim DH 2015 Glucocorticoid- chronic emotional stimuli. Neuron 56 517–529. (doi:10.1016/j. and long-term stress-induced aberrant synaptic plasticity are neuron.2007.09.032) mediated by activation of the glucocorticoid receptor. Archives of Reul JM, Hesketh SA, Collins A & Mecinas MG 2009 Epigenetic Pharmacal Research 38 1204–1212. (doi:10.1007/s12272-015-0548-0) mechanisms in the dentate gyrus act as a molecular switch in Parker KJ, Schatzberg AF & Lyons DM 2003 Neuroendocrine aspects of hippocampus-associated memory formation. Epigenetics 4 434–439. hypercortisolism in major depression. Hormones and Behavior 43 (doi:10.4161/epi.4.7.9806) 60–66. (doi:10.1016/S0018-506X(02)00016-8) Reul JM, Collins A, Saliba RS, Mifsud KR, Carter SD, Gutierrez-Mecinas Parsons RG & Ressler KJ 2013 Implications of memory modulation for M, Qian X & Linthorst AC 2015 Glucocorticoids, epigenetic control post-traumatic stress and fear disorders. Nature Neuroscience 16 and stress resilience. Neurobiology of Stress 1 44–59. (doi:10.1016/j. 146–153. (doi:10.1038/nn.3296) ynstr.2014.10.001) Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M & Schatzberg AF 2000 Rinaldi A, Vincenti S, De Vito F, Bozzoni I, Oliverio A, Presutti C, Glucocorticoid and mineralocorticoid receptor mRNA expression in Fragapane P & Mele A 2010 Stress induces region specific alterations squirrel monkey brain. Journal of Psychiatric Research 34 383–392. in microRNAs expression in mice. Behavioural Brain Research 208 (doi:10.1016/S0022-3956(00)00035-2) 265–269. (doi:10.1016/j.bbr.2009.11.012) Patki G, Solanki N, Atrooz F, Ansari A, Allam F, Jannise B, Maturi J & Rodrigues GM Jr, Toffoli LV, Manfredo MH, Francis-Oliveira J, Silva AS, Salim S 2014 Novel mechanistic insights into treadmill exercise Raquel HA, Martins-Pinge MC, Moreira EG, Fernandes KB, Pelosi based rescue of social defeat-induced anxiety-like behavior and GG, et al. 2015 Acute stress affects the global DNA methylation memory impairment in rats. Physiology and Behavior 130 135–144. profile in rat brain: modulation by physical exercise. Behavioural (doi:10.1016/j.physbeh.2014.04.011) Brain Research 279 123–128. (doi:10.1016/j.bbr.2014.11.023) Pecina S, Schulkin J & Berridge KC 2006 Nucleus accumbens Rossetto D, Avvakumov N & Côté J 2012 Histone phosphorylation. corticotropin-releasing factor increases cue-triggered motivation for Epigenetics 7 1098–1108. (doi:10.4161/epi.21975)

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0019 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 07:21:27PM via free access Journal of Molecular Endocrinology Sober S,LaanM&AnniloT2010MicroRNAs miR-124andmiR-135aare Smith AK,ConneelyKN,KilaruV, Mercer KB,Weiss TE, BradleyB,Tang Smith SM&Vale WW2006 Theroleofthehypothalamic-pituitary- Sipahi L,Wildman DE,AielloAE,KoenenKC,GaleaS,AbbasA&Uddin Shepard JD,LiuY, Sassone-CorsiP&AguileraG2005Roleof Shahbazian MD&GrunsteinM2007Functionsofsite-specifichistone Schouten M,AschrafiA,Bielefeld P, DoxakisE&FitzsimonsCP2013 Schmidt U,KeckME&BuellDR2015miRNAsandothernon-coding DJ2004Canposttraumatic Schelling G,RoozendaalB&DeQuervain Schelling G,RichterM,RoozendaalB,RothenhauslerHB,KrauseneckT, Schelling G,BriegelJ,RoozendaalB,StollC,RothenhauslerHB& Schelling G,StollC,KapfhammerHP, RothenhauslerHB,KrauseneckT, Schechter DS,MoserDA,PointetVC,AueT, StenzL,Paoloni-Giacobino Sato F, Tsuchiya S,MeltzerSJ&ShimizuK2011MicroRNAsand Rudenko A&Tsai and LH2014Epigeneticregulationinmemory Roth TL,ZoladzPR,SweattJD&DiamondDM2011Epigenetic Roth TL,ED&SweattJD2010Epigeneticregulationofgenesin DOI: 10.1530/JME-17-0019 http://jme.endocrinology-journals.org Review potential regulatorsofthemineralocorticoid receptorgene(NR3C2) Clinical Neuroscience adrenal axisinneuroendocrineresponsestostress. Psychological Medicine genes isassociatedwithvulnerabilitytopost-traumaticstressdisorder. M 2014LongitudinalepigeneticvariationofDNAmethyltransferase Neuropsychiatric Genetics stress disorder. system DNAmethylationandcytokine regulationinpost-traumatic Y, GillespieCF, CubellsJF&ResslerKJ2011Differential immune Neuroscience corticotropin-releasing hormonetranscriptionduringstress. glucocorticoids andcAMP-mediatedrepressioninlimiting 75–100. acetylation anddeacetylation. neuroscience.2013.02.065) conditions. microRNAs andtheregulationofneuronalplasticityunderstress (doi:10.1016/j.jpsychires.2015.03.014) and animalstudies. RNAs inposttraumaticstressdisorder:Asystematicreviewofclinical annals.1314.013) York AcademyofSciences stress disorderbepreventedwithglucocorticoids? CCM.0000069512.10544.40) Care Medicine health-related quality-of-lifeoutcomesaftercardiacsurgery. high stressintheintensivecareunitmayhavenegativeeffectson Stoll C,NollertG,SchmidtM&KapfhammerHP2003Exposureto Biological Psychiatry during septicshockonposttraumaticstressdisorderinsurvivors. Kapfhammer HP2001Theeffectofstressdoseshydrocortisone 27 and health-relatedqualityoflifeinsurvivors. hydrocortisone duringsepticshockonposttraumaticstressdisorder Durst K,HallerM&BriegelJ1999Theeffectofstressdoses Brain Research violence exposure,neuralactivity, andchildaggression. association ofserotoninreceptor3Amethylationwithmaternal A, AdouanW, ManiniA,SuardiF, Vital M, j.1742-4658.2011.08089.x) epigenetics. neuroscience.2012.12.034) cognitive disorders. 45 model ofpost-traumaticstressdisorder. modification ofhippocampalBdnfDNAinadultratsananimal (doi:10.1042/bse0480263) learning andmemory. 919–926. 2678–2683. (doi:10.1146/annurev.biochem.76.052705.162114)

Neuroscience FEBS Journal 25 (doi:10.1016/j.jpsychires.2011.01.013)

31 325 4073–4081. American Journal of Medical Genetics Part B: ofMedicalGeneticsPart American Journal (doi:10.1097/00003246-199912000-00012) 1971–1980. PartB268–277.

Neuroscience Journal ofPsychiatricResearchJournal

8 44 383–395. 978–985. Essays inBiochemistry 3165–3179.

1032

241 156B 278 (doi:10.1523/JNEUROSCI.0122-05.2005) 188–205. 1598–1609. (doi:10.1097/01. 158–166. 700–708. Annual ReviewofBiochemistry

(doi:10.1016/S0006-3223(01)01270-7) 264 (doi:10.1016/j.bbr.2016.10.009) (doi:10.1017/S0033291714000968) 51–63. b (doi:10.1016/j.

c Journal ofPsychiatricResearchJournal (doi:10.1196/ (doi:10.1002/ajmg.b.31212)

dirven et al

(doi:10.1016/j. 48 Critical Care Medicine 263–274. . 2017The

andothers 65 Printed inGreatBritain Annals oftheNew Dialogues in 1–8.

Behavioural

Journal of of Journal Critical 76

Swartz JR,HaririAR&Williamson DE2016 Anepigeneticmechanism Swaab DF, BaoAM&LucassenPJ2005Thestresssysteminthehuman Sterrenburg L,GasznerB,BoerrigterJ,SantbergenBraminiM,Elliott Stankiewicz AM,SwiergielAH&LisowskiP2013Epigeneticsofstress JH&Charney Southwick SM,PaigeS,MorganCAIII,BremnerJD,Krystal Sotnikov SV, MarktPO,MalikV, ChekmarevaNY, NaikRR,SahA, van IJzendoornMH,CaspersK,Bakermans-Kranenburg MJ,BeachSR& Tomalski P&JohnsonMH2010Theeffectsofearlyadversityonthe Taliaz D,LoyaA,GersnerR,HaramatiS,ChenA&Zangen2011 Tahiliani M,KohKP, ShenY, PastorWA, BandukwalaH,BrudnoY, Szulwach KE,LiX,Y, SongCX,Wu H,DaiQ,IrierUpadhyayAK, Vaisvaser S,ModaiFarberov L,LinT, SharonH,Gilam A,Volk N, Unternaehrer E,LuersP, Mill J,DempsterE,MeyerAH,StaehliS,LiebR, Uchida S,NishidaA,HaraK,KamemotoT, SuetsugiM,Fujimoto Tsigos axis, C&ChrousosGP2002Hypothalamic-pituitary-adrenal Tsankova NM,BertonO,RenthalW, KumarA,NeveRL&Nestler EJ in adulthood Epigenetics ofstressresponse Published byBioscientifica Ltd. (doi:10.1038/mp.2016.82) brain indepressionandneurodegeneration. (doi:10.1371/journal.pone.0028128) corticotropin-releasing factorgeneintherat. induces sex-specificalterationsinmethylationandexpressionof E, ChenA,PeetersBW, RoubosEW&KoziczT2011Chronicstress (doi:10.1016/j.brainresbull.2013.07.003) adaptations inthebrain. serotonin. DS 1999NeurotransmitteralterationsinPTSD:catecholaminesand Psychiatry receptor 1asepigeneticplasticitygeneintheamygdala. rescue ofextremegeneticpredispositionstoanxiety:impactCRH Singewald N,HolsboerF, CzibereL&LandgrafR2014Bidirectional 727–732. expression. dynamics duringpostnatalneurodevelopmentandaging. Gearing M,LeveyAI, function inhigh-riskadolescents. links socioeconomicstatustochangesindepression-relatedbrain 141–194. methylation densityandserotonin transporter genotypepredicts Philibert R2010Methylationmatters: interactionbetween ONE model ofdepressionandantidepressantaction. 2006 Sustainedhippocampalchromatinregulationinamouse 233–238. adult anddevelopingbrain. (doi:10.1523/JNEUROSCI.5725-10.2011) derived neurotrophicfactor. Resilience tochronicstressismediatedbyhippocampalbrain- science.1170116) by MLLpartnerTET1. 5-methylcytosine to5-hydroxymethylcytosineinmammalianDNA S,IyerLM,LiuDR,AravindL, Agarwal Neuroscience of acutestressresponseinhumans: the caseofmicroRNA-29c. L,Fruchter E, Admon R,Edry tp.2012.77) psychosocial stress. methylation ofstress-associatedgenes(OXTR,BDNF)afteracute Hellhammer DH&MeinlschmidtG2012DynamicchangesinDNA 2250–2261. of theglucocorticoidreceptor. rats: possibleinvolvementofmicroRNA-mediateddown-regulation Characterization ofthevulnerabilitytorepeatedstressinFischer344 Watanuki T, Wakabayashi Y, OtsukiK,McEwenBS, 53 neuroendocrine factorsandstress. 519–525. 865–871.

11 e0146236.

(doi:10.1016/j.bbrc.2009.11.128) (doi:10.1016/j.arr.2005.03.003) (doi:10.1038/nn1659) (doi:10.1097/YCO.0b013e3283387a8c) 4 Seminars inClinicalNeuropsychiatry e359.

Biochemical andBiophysicalResearch Communications (doi:10.1111/j.1460-9568.2008.06218.x) 14 (doi:10.1016/S0022-3999(02)00429-4) 1607–1616. (doi:10.1038/tp.2013.127) (doi:10.1371/journal.pone.0146236) Translational Psychiatry et al Science Brain Research Bulletin . 20115-hmC-mediatedepigenetic Downloaded fromBioscientifica.com at09/28/202107:21:27PM (doi:10.1038/nn.2959) Current OpinioninPsychiatry Journal ofNeuroscience Journal

et al 324 European Journal ofNeuroscienceEuropean Journal . 2016 Neuro-epigenetic indications . 2016Neuro-epigeneticindications 930–935. Molecular Psychiatry Journal ofPsychosomaticResearchJournal et al

2 . 2009Conversionof

(doi:10.1126/ e150. Ageing Research Reviews 59 4 PLoS ONE 242–248.

: 98 Nature Neuroscience 1

76–92. 31 (doi:10.1038/ et al

4475–4483. 22

. 2008 6

209–214. Translational 23 e28128. Nature

R30 PLoS PLoS 27

391

via freeaccess

9 4

Review b c j dirven and others Epigenetics of stress response 59:1 R31 in adulthood

unresolved loss or trauma. Biological Psychiatry 68 405–407. Wu TC, Chen HT, Chang HY, Yang CY, Hsiao MC, Cheng ML & Chen (doi:10.1016/j.biopsych.2010.05.008) JC 2013 Mineralocorticoid receptor antagonist spironolactone Volk N, Pape JC, Engel M, Zannas AS, Cattane N, Cattaneo A, Binder EB prevents chronic corticosterone induced depression-like behavior. & Chen A 2016 Amygdalar microRNA-15a is essential for coping Psychoneuroendocrinology 38 871–883. (doi:10.1016/j. with chronic stress. Cell Reports 17 1882–1891. (doi:10.1016/j. psyneuen.2012.09.011) celrep.2016.10.038) Xu L, Sun Y, Gao L, Cai YY & Shi SX 2014 Prenatal restraint stress is Vukojevic V, Kolassa IT, Fastenrath M, Gschwind L, Spalek K, Milnik A, Heck associated with demethylation of corticotrophin releasing hormone A, Vogler C, Wilker S, Demougin P, et al. 2014 Epigenetic modification (CRH) promoter and enhances CRH transcriptional responses to of the glucocorticoid receptor gene is linked to traumatic memory and stress in adolescent rats. Neurochemical Research 39 1193–1198. post-traumatic stress disorder risk in genocide survivors. Journal of (doi:10.1007/s11064-014-1296-0) Neuroscience 34 10274–10284. (doi:10.1523/JNEUROSCI.1526-14.2014) Yehuda R 2001 Biology of posttraumatic stress disorder. Journal of Clinical Waddington CH 1957 The Strategy of the Genes. London, UK: George Psychiatry 62 (Supplement 17) 41–46. (doi:10.4088/JCP.v62n0109) Allen & Unwin Ltd. Yehuda R 2004 Understanding heterogeneous effects of trauma Wan Q, Gao K, Rong H, Wu M, Wang H, Wang X, Wang G & Liu Z exposure: relevance to postmortem studies of PTSD. Psychiatry 67 2014 Histone modifications of the Crhr1 gene in a rat model of 391–397. (doi:10.1521/psyc.67.4.391.56572) depression following chronic stress. Behavioural Brain Research 271 Yehuda R, Southwick S, Giller EL, Ma X & Mason JW 1992 Urinary 1–6. (doi:10.1016/j.bbr.2014.05.031) catecholamine excretion and severity of PTSD symptoms in Vietnam Wang RY, Phang RZ, Hsu PH, Wang WH, Huang HT & Liu IY 2013 In combat veterans. Journal of Nervous and Mental Disease 180 321–325. vivo knockdown of hippocampal miR-132 expression impairs (doi:10.1097/00005053-199205000-00006) memory acquisition of trace fear conditioning. Hippocampus 23 Yehuda R, Boisoneau D, Mason JW & Giller EL 1993 Glucocorticoid 625–633. (doi:10.1002/hipo.22123) receptor number and cortisol excretion in mood, anxiety, and Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, psychotic disorders. Biological Psychiatry 34 18–25. Dymov S, Szyf M & Meaney MJ 2004 Epigenetic programming by (doi:10.1016/0006-3223(93)90252-9) maternal behavior. Nature Neuroscience 7 847–854. (doi:10.1038/ Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine nn1276) I, Flory JD, Bierer LM & Meaney MJ 2014 Influences of maternal and Webster MJ, Knable MB, O’Grady J, Orthmann J & Weickert CS 2002 paternal PTSD on epigenetic regulation of the glucocorticoid Regional specificity of brain glucocorticoid receptor mRNA receptor gene in Holocaust survivor offspring. American Journal of alterations in subjects with schizophrenia and mood disorders. Psychiatry 171 872–880. (doi:10.1176/appi.ajp.2014.13121571) Molecular Psychiatry 7 985–994, 924. (doi:10.1038/sj.mp.4001139) Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F, Weder N, Zhang H, Jensen K, Yang BZ, Simen A, Jackowski A, Lipschitz Makotkine I, Daskalakis NP, Marmar CR & Meaney MJ 2015 Lower D, Douglas-Palumberi H, Ge M, Perepletchikova F, et al. 2014 Child methylation of glucocorticoid receptor gene promoter 1F in abuse, depression, and methylation in genes involved with stress, peripheral blood of veterans with posttraumatic stress disorder. neural plasticity, and brain circuitry. Journal of the American Academy Biological Psychiatry 77 356–364. (doi:10.1016/j.biopsych.2014.02.006) of Child and Adolescent Psychiatry 53 417–424.e415. (doi:10.1016/j. Zannas AS & West AE 2014 Epigenetics and the regulation of stress jaac.2013.12.025) vulnerability and resilience. Neuroscience 264 157–170. Weis F, Kilger E, Roozendaal B, de Quervain DJ, Lamm P, Schmidt M, (doi:10.1016/j.neuroscience.2013.12.003) Schmolz M, Briegel J & Schelling G 2006 Stress doses of Zhao J, Goldberg J, Bremner JD & Vaccarino V 2013 Association hydrocortisone reduce chronic stress symptoms and improve health- between promoter methylation of serotonin transporter gene and related quality of life in high-risk patients after cardiac surgery: a depressive symptoms: a monozygotic twin study. Psychosomatic Journal of Molecular Endocrinology randomized study. Journal of Thoracic and Cardiovascular Surgery 131 Medicine 75 523–529. (doi:10.1097/PSY.0b013e3182924cf4) 277–282. (doi:10.1016/j.jtcvs.2005.07.063) Zhou J, Nagarkatti P, Zhong Y, Ginsberg JP, Singh NP, Zhang J & Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D, Nagarkatti M 2014 Dysregulation in microRNA expression is Kodadek TJ & Nestler EJ 2009 Imipramine treatment and resiliency associated with alterations in immune functions in combat veterans exhibit similar chromatin regulation in the mouse nucleus with post-traumatic stress disorder. PLoS ONE 9 e94075. accumbens in depression models. Journal of Neuroscience 29 (doi:10.1371/journal.pone.0094075) 7820–7832. (doi:10.1523/JNEUROSCI.0932-09.2009) Zhu LJ, Liu MY, Li H, Liu X, Chen C, Han Z, Wu HY, Jing X, Zhou HH, Wingo AP, Almli LM, Stevens JS, Klengel T, Uddin M, Li Y, Bustamante Suh H, et al. 2014 The different roles of glucocorticoids in the AC, Lori A, Koen N, Stein DJ, et al. 2015 DICER1 and microRNA hippocampus and hypothalamus in chronic stress-induced HPA axis regulation in post-traumatic stress disorder with comorbid depression. hyperactivity. PLoS ONE 9 e97689. (doi:10.1371/journal.pone.0097689) Nature Communications 6 10106. (doi:10.1038/ncomms10106) Zohar J, Juven-Wetzler A, Sonnino R, Cwikel-Hamzany S, Balaban E & Witteveen AB, Huizink AC, Slottje P, Bramsen I, Smid T & van der Ploeg Cohen H 2011 New insights into secondary prevention in post- HM 2010 Associations of cortisol with posttraumatic stress traumatic stress disorder. Dialogues in Clinical Neuroscience 13 301–309. symptoms and negative life events: a study of police officers and Zovkic IB, Guzman-Karlsson MC & Sweatt JD 2013 Epigenetic regulation firefighters. Psychoneuroendocrinology 35 1113–1118. (doi:10.1016/j. of memory formation and maintenance. Learning and Memory 20 psyneuen.2009.12.013) 61–74. (doi:10.1101/lm.026575.112)

Received in final form 19 January 2017 Accepted 17 March 2017 Accepted Preprint published online 17 March 2017