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University Otago,of Dunedin, New Zealand Semmelweis University, Budapest,Hungary Academy of Sciences and Eötvös Loránd University, Budapest, Hungary This isbyarticle protected reserved. copyright. Allrights 10.1111/jne.12185 differences between this versionand theVersion Record.of Please cite this article as doi: copyediting,through the paginationtypesetting, and proofreadingprocess, which lead may to This hasarticle been accepted publicationfor andundergone peerbutfull review notbeen has hypothalamus, epigenetics,postpartum period Key words: Short title: [email protected] Email: Davis, CA 95616, USA ofYoung S. Psychology, Department of Hall, University 135 DanielleCalifornia Stolzenberg, email: [email protected] Biology, Eötvös Loránd University, Pázmány Péter sétány 1C, Budapest 1117, Hungary of Institute Prof. Neurobiology, Arpad Dobolyi, andSystems Molecular Laboratory of Corresponding Authors: 4 3 2 1 A. Dobolyi that inputsPreoptic andmechanisms :Review Article Article type Accepted Date :22-Jul-2014 Date :Revised 21-Jul-2014 Received :14-Jan-2014 Date Department of Psychology, University of California, David CA, USA CA, David California, of University Psychology, of Department Sciences, Medical Neuroendocrinology, of School Anatomy for Centre of Department and Department Neuromorphology, of Laboratory Laboratory Molecular andSystems of Neurobiol 1,2 Preoptic mechanisms of maternal responsiveness , D.R. Grattan , D.R. maternal motivation, and maternal behaviour, medial preoptic area of medial behaviour, maternal area preoptic and maternal motivation, 3 , D. Stolzenberg S. , regulate maternal responsiveness 4 of Anatomy, Histology and Embryology, Histology Anatomy, and of ogy, Institute of Biology, NAP-Hungarian Biology,NAP-Hungarian of Institute ogy,

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Allrights and hence the initiation behaviour maternal birthisof critical after constant provides requi care the mother the mammals, In most weaning. until birth from receive infants care quality of on the depends infant survival Thus, own. of surviving ontheir infants areincapable All mammalian Introduction responding. altera long-term mediates the interactions infant mother- remodelling during chromatin idea that the explore behaviour and tomaternal linked Here,likely candidate. summarize we gene expressionchanges the in MPOA been have that maintenancematernal responding the is support of Although molecular the these throughwhich mechanism alter inputs MPOA to neurones in theposterior thalamus are candidates to convey sucklingthe information to the MPOA. thatneuronessuggest containingof 39 peptide neuropeptide the residuestuberoinfundibular described. results Recent suckling pathway MPOA effects of onthe mediatingtothe the prolactinthrough levels, increased aswell as neur MPOA activate can that the litter from dams exposure. Inthepresent review, we summariz pup MPOA responseto in the of activateddifferent parts in maintenance. Neuronesare respons maternal initiation of contribute to the periodbehaviours. Whereashormonalmaternal peripartum the changesabolishes in (MPOA) area for medial preoptic required is preopticThe area awell-establishedis centretheof maternal control Anintact behaviour. for Abstract individual maternal behaviours motivation, or shiftthe in responsiveness toward infants, thanmechanismsrather that regulate caregiving behaviours. Thus, this review focu species are some there in specific differences infants, their respond to mothers how in overlap issue, this [in nest their approaching intruders towards postures andretrievewarm displacedpups lick the there, pupsandnurse them incharacteristic theyparturition: consume placenta, foetal membranes and fluids, build a nestto keep pups mouse dams display avariety of specific careg investigationsexperimental of ( 2 ) . In addition, mothers demonstrate reduced andincreasedanxiety aggression maternal behaviours have been performed in rodents. Rat and inrodents. behaviours beenperformed have maternal ( 2 red for successful infant growth, development, and survival, successful red for and infant growth, development, ) . ses on mechanismsthe that maternal underlie e the potential inputse tothe MPOA rodent of maternal responsivenessmaternal as of the arealesion iveness, inputs from pups are required for its for pupsiveness, arerequired inputs from iving behaviours that startiving that behaviours the time around of tions in gene expression thatmaternaltions sustain expression ingene neuronal inputs to the preoptic area are area preoptic the inputs to neuronal not yet known, altered gene known,altered yet gene is not expression a ones. The roles of potential indirect effects potential indirect of roles The ones. ( 3 ) ]. Although]. there is considerable ( 1 ) . The. most extensive Accepted Article maternal behaviour is less dependent on hormone on behaviourstimulation hormone less dependent maternal is the onset altered. of is future maternal motivation inrats, "permanently" For example, motivation extend far beyond Thus, weaning. hasa female once with pups, interacted responsiveness. Third, maternal required for of synthesizing incapable therefore oestradiol sensitization hormone stimulation continual after exposure pregnancy inthe of occur absence responsiveness this idea, of In support can maternal hormonalthis changessome individuals pupsmay issue, these [in exposure to induce in hormonal notexposed the individuals are to where paternalwhere behaviour or alloparent sustain maternal care. Second, non-hormonal fact of receipt the for circuits neural might prime 10 behaviours postpartum, days of when maternal maximal are has waned birth associated with ratioestradiol/progesterone elevated the periodlong after high postpartum duringremains the of informati care. maternal Three of pieces maintenanceinitiationis the and birth that necessary timeof for infants the at with interacting sustained for extended periods of time time of periods extended for sustained and initiated is motivation maternal context, hormonal interactionthis occursinfant in pregnancy, pl of end the occurs at This isbyarticle protected reserved. copyright. Allrights pups interact with to a lever press to orlearn novel anovel (such as environment anxiogenic, anT-maze) traverse they will that birth at infants, to increase parturition function pregnancy and infantincrease in attraction. species In all st maythis shift to infants, exclusively where unrelated mice, individuals dorespond involve an infants coupled with in an increase attraction toward infants toward aversion decrease in a this shiftinvolve may therefore, before motherhood; infants Some species, energy rearing offspring. toward responsiveness, which allows mothers to spend aconsiderable period of time devoting their Although hormonal stimulation potentiates maternal motivation, it is the experience of it isthe maternal experience motivation, potentiates stimulation Althoughhormonal The into transition The amotherhood is of shift dramatic comprised in maternal ( 28 ( ) 6 . Sensitization occur. can inmice that lack the aromatase enzyme, and are ) . At birth, mothers are so highly motivated to At so highly interact mothers birth, offspring their are motivated . with ( 23,24 ays a crucial process this aysa in role ( 7-11 ( ) 20-22 . The level of ovarian steroid hormones is very low at lowat isvery hormones steroid ovarian of level The . al al behaviour this [in occurs issue, ) . The elevated. /progesteroneestrogen ratio, which udied, including humans, the hormonal events of events hormonal the udied, including humans, on support this idea. First, maternal motivation maternal First, idea. support this on infant stimuli, but hormonal stimulation doesnot hormonal infant but stimuli, ) . maternal motivation, or responsiveness toward orresponsiveness toward motivation, maternal changes withpregnancy associated although experience-induced changes inmaternal such as rats, such asrats, are relatively to unresponsive ( 7,29 ors must also be operating in those cases to infant stimuli,inprocess a termed ) . Thus, estradiol stimulation is not . Thus, estradiol stimulation ( ( 20-22 4,5 ( ) 25 . In other species,such other as In . ) ) . In laboratory strains of In strains laboratory . . Thus, these . hormones ( 12-19 ( ) 26 . When mother- When . ) ], since these ( 27 ) ]. ]. Accepted Article maternal responsivenessthroug maternal circuit, which receives pup-related inputs fr issue, this [in circuit this responsiveness depends on howdevelopmental, hor mammals of both sexes structure structure is the medial preoptic nucleus, wh Its major hypothalamus. the regionof rostral the of zone medial in the situated MPOAis The area preoptic medial The changes that may tocontribute the long-term maintenance of maternal responding. genetic interaction, as well as MPOA andepigeneticsubsequent the mother-infant during ( of behaviour,maternal onset aswell maternal asthelong-term maintenance of responding inputs. For example, somatosensor the MPOAcan for prime experiential factors maintenancethe of a maternalmemory learning maternal and of transition the the consolidation motherhood involves Therefore, into one monthup to later T-mazeresponding 4 daysa for increases maternal consecutive on parastrial nucleus between them these areas was not found cytoarchitectonically res maternal in plays role inputs and similar a ofbed nucleus the term MPOA stria (vBNST)similar inthe it terminalis receives because separation pups from periods of subsequent interaction maintains mother-infant in Forexample, profile. andhormonal species topermanently pupsrequired with experience a This isbyarticle protected reserved. copyright. Allrights ( nucleus, the whichwith dimorphic sexually is inmales than considerably larger in females subdivisions rescue pups an from environmentanxiogenic (novel T-maze) notwhich pups,mice, stimulationfor do will dependto care continue females onhormone to 24,37,38 40,41 ) . Inthisreview,. also include dorsolaterallywe the ventral subdivision adjacent the of One proposal is that there is a thatOne proposalis core neural there a is

) . In this review, weIn this review,.andneuronal inputs focusthe that onthehormonal activate ( 39 ) . The centralThe . andmedialsubdivisions of ( 33 ( 1 ) ) , butwhether infant , can stimuli onthis to act circuit elicit ]. The medial preoptic area (MPOA) a is within site critical this ( h its widespread projections projections h its widespread 20 ( y thepups from play inputs an important in derived therole 43 ) . In pup-naive, virgin female mice, 2 hours of interactionmice, 2hoursof virginfemale In pup-naive, . ) while some researchers place the anterior (or lateral) ( 22,32 ) ponsiveness. aclearseparation of Furthermore, . om allsensory and modalities coordinates ( increasedresponsiveness pup-related toward ich ich consists of central, medial and lateral lter maternal motivation motivation maternal depending onvaries lter maternal responsiveness long during maternal even 42 postpartum rats as little as 15 minutes ofminutes aslittle rats as15 postpartum circuit regulating parental behaviourcircuit all parental regulating in ) . Acceptedatlases. brain actually show the monal, and/or experiential impactfactors monal, the medial preoptic nucleus overlap overlap the medialpreopticnucleus ( 4,34-36 ( 30,31 ) . Hormonal . Hormonal and/or ) . The amount of amount The . ( 29 ) . Accepted Article prolactin as mediatora key the of ons enhanced young was again delayed from a latency of 1-2 days to4-5days to suppress endogenous prolactin secretion, the prolactin levels. steroid-treated When females towards care maternal of foster steroid this regimen young, significantly serum elevated progesterone sequentially byestradiolfollowed with latency couldbemarkedly period withdayspups, albeit several alatency of period above,described maternal induced in care canbe As in rats. particularlymodels, rodent prolactin in of role the subsequentlycharacterized behaviour insome fish induce to fresh water over eggsflow their brooding inbirds behaviour in implicated was whenprolactin early1960’s, the in identified first behaviourswere parental of the onset maternal behaviour. Central nervous system of in regulatingprolactin actions ro a support findings that strongbody of isa There Prolactina asof regulator preopticneurones in mothers prolactin, bind which toreceptors in the MPOA to regulate maternalresponding. of peripheraloxytocin release and and suckling the central example, affects stimulation For withthelitteron alsocanby MPOA Interaction have hormones. activityeffects mediated responsiveness feeding e.g. affecting behavioursother, behaviours withoutmaternal Large electrical wellas axon-sparing excitotoxic lesions of the MPOA all eliminate preopticthe plays areaa roleinmaintenance the initiationof crucial behaviours. and maternal thatbehaviour. thisof Extensive indicates work from evidence theregulation maternal in area This isbyarticle protected reserved. copyright. Allrights contrast, electrical stimulationof the MPOA increased responsivenessmaternal potentially similar area) were the most effective in eliminating maternal behaviours nestabolish building and retrieving in rat lesions of dorsal the MPOA, sexual notthe but pharmacological of MPOAinactivation similareffects produces the location of oxytocinergic neurones in the area area describe medial preoptic the and the to vBNST of border nucleus tothe subcommissural maternal litter toregulate the from information receive sensory must MPOA The A numberof different approaches have used been to of role the examine the preoptic ( 5 ) . Sensory information reaches the MPOA through neuronal inputs. reaches. Sensoryneuronal the MPOA through information ( 53 ) , nest building rabbits , nest in behaviour shortened when shortened virgin weretreatedgonadectomised, rats ( 50 were concurrently treated with bromocriptine with treated concurrently were ) et of maternal care. These These behavioural effects maternal care. et of . In mice, the lesions the central MPOA (a the central lesions the mice, In . virgin female rats with repeated exposureto with rats virgin female onset of onset behaviourmaternal towards foster ( ( 44,45 28 le for prolactin in the central stimulation of stimulation the central in prolactin for le ly nucleus, dimorphic were sufficient to ( ) 57 . Bridges colleagues and . thatthisfound ) ) . . As well. as stimulating a rapid onset ( 58 ( ( 48,49 54,55 ) ( , strongly implicating 56 ) ( . Much. work has 46,47 ) ) . Small Small bilateral . andfin-fanning ( 52 ) . Temporal ) . ( 51 ) . In Accepted Article pup-induced maternal pup-induced care inboth virgin Prlr andprimiparous prolactin the in was confirmed care maternal indefinite period reproductiveafter experience contribute tothe“maternalmemory” thatenab result of experience.reproductive It seem responsiveness of during this lactation region prolactin to levels of prolactin receptor expression inthe MPOA inmice behaviour to hypothalamus stimulate andnest buildingin mice maternal in the acting prolactin a rolefor workimplicated earlier in rats, As parturition. after females receptor i.e. arcuate, paraventriculari.e. arcuate, nucleus as MPOA, responsivenessprolactin the within to the onset of maternal care in the rat. the an oftheregulationof for in MPOAprovidesupport involvement receptor in theprolactin behaviour invirgin byabout2days rats onset the of maternal delayed MPOAbilateral infusions of the putative prolactin receptor antagonist S179D-prolactin lactation of MPOApopulation neurones, withneurones a inalarge 5 phosphorylation of signal transducer(Stat5) transcription andactivator of ( behaviour maternal stimulate action to prolactin for site critical a regionas this identified colleagues have Bridges and Prolactin Prolactin actions onmaternal behaviour notlimited tothe inmice are medial preoptic area. prolactin/placental lactogenorother actions of receptorligands onthe prolactin behaviourmaternal maternal behaviour parous in animals). Interes severe deficit in virgin Prlr virgin in deficit severe This isbyarticle protected reserved. copyright. Allrights effect if administeredwithout peripherally lactogen wi orplacental prolactin of icvinfusion behaviour aremediated in nervous demonstrated central the by observation system, that the of prolactin be can mimicked by placental lactogen 61-64 ) , and levels are increased during are levels lactationincreased , and While mice show behavi spontaneousmaternal While mice Interestingly, reproductive experience experience Interestingly, reproductive appears to provide along-term change in the ( ( 70 67,68 ) as well theresponse as of this system to aprolactin challenge ) (Fig. 1).Using (Fig. establishedthe hormone steroid regimen, it was found that ( 75 ) , possibly as a result of embryonic or neonatal exposureto embryonic or neonatal a resultof , possibly as -/- animals ( 60 ) . Prolactin receptors . Prolactin are expressed throughout region this ( 70 ( ) 74 . Basal expression of the long form of the prolactin prolactin the long of of the form Basal expression . ) ( (full knockouts infertile,are studyprecluding of 59,60 tingly, prolactin-deficient animalsexhibit some s possible that this enhanced response may receptor knockout model, deficiencywith a in ( 72 ll maternalll induce behaviour atdoses that are les enhanced topups responsiveness for an pparently more sensitive to prolactin sensitive toprolactin during more pparently well as other central sites of prolactin action,prolactin sites of as othercentral well ) ) . Using localised injections into the MPOA,the into injections Using localised . . ( 64-66 our, this response is much in enhanced ismuch response this our, ( 59 ( 67 ) ) . Furthermore, prolactin induces prolactin Furthermore, . . Prolactin onmaternal. actions ) . The critical role of prolactin in +/- mice, and an even more and an mice, ( ( ( 68 69 73 ( ) ) 71 ) , and increased and , . These findings . . There. are high ) increases as a ( 76 ) . Accepted Article Tip39 is encoded by asingle gene, which does not express any other known peptide topographically pathway very similar release mediates suckling-induced prolactin lactating mothers was purified as the ligand of the then orphan parathyroid 2 hormone receptor (Pth2r) details More on this cell disclosed identificationgroup were following the ofa newly region the neuropeptide discovered in pathway reaching this area. mediatedThus, the ofsuckling behaviour by motivation be also may effect and a on maternal reflex milk-ejection theblocked this area the zona incerta ventromedial to the medial geniculate body tegmentum mesencephalic reflex arcascends lateral throughand entersthe milk-ejection the Lesionpathway maternalfunction. andmicrostimulation studies specific suggested with that neurones isworthmenti oxytocinmagnocellular behavioursmaternal suckling for the input whetherobscure remains oxytocin neuronesproject magnocellular to the MPOA tomediate suggesting interaction of these for thepotential important lactation hormones. Whileit prolactin receptors maternal-fetal signallingissue,[in this role for Oxt intheinitiation rather thethan maintenance of maternal care care been shown that preoptic of injection an Oxt re MPOAinto the where it aneuromodulatory Ithas may have influence onMPOA neurones. neurones th blood reachespreoptic ventromedial to the medial geniculate body medial geniculate the to ventromedial inthelactatingintralaminar posterior mothers of pubertal development the end brain by Tip39 is expressed in2 thalamic and apontine si This isbyarticle protected reserved. copyright. Allrights reflex ejection of the milk part suckling as suprao paraventricular and hypothalamic the of pi posterior the issecreted(Oxt) Oxytocin in behaviours of maternal maintenance the to contributing inputs Neuronal critical for the normal expression Prolactin-induced neurogenesis inthesubv ( 81 ) and mood adaptations inrats thisissue, adaptations [in mood and ( 94 ( 87 ) , suggesting relay of the, suggesting of relay pathway ) and both acutelyresponsiveare chronically and prolactin to of maternal post behaviour partum rough the blood-brain barrier, Oxt is also released directlyreleased Oxt isalso barrier, blood-brain rough the ( 97 ) . Tuberoinfundibular peptide of 39 residues (Tip39) (Tip39) peptide of39residues Tuberoinfundibular . entricular zone duringentricular pregnancyearly ( ( ( 86 ( tuitary from terminals of magnocellular neurones of magnocellular tuitary terminals from 101 93 80 ( ( 100 89 ceptor antagonist blocked the onset of maternal ) complex immediately complex the thalamus (PIL) of ) ]. Interestingly, oxytocin neurones express oxytocin neurones ]. Interestingly, ) and c-fos expressionand c-fos in wasdetected here te andalmost completely the disappears from ) . Although isnotlikely the it Oxtfrom that ptic nuclei (PVN and SON) in responsetonuclei SON) in ptic and (PVN ) and the medial and paralemniscal nucleus , the anatomical pathway from nipples to anatomical pathway, the from ) . It is, however,. It induced dramaticallyin oning as it is the best-studied ascending best-studied isthe oning asit ( 82 ) ]. Other reports have confirmed reports a have confirmed Other ]. in this position. The same or a same or The thisposition. in ( 90-92 ( ) 78,79 . Excitotoxic . lesions of ) . ( 83-85 ( 77 ) , and in ) ( isalso 95,96 ( ( ( ( 102 98 88 99 ) ) ) ) ) . . , .

Accepted Article PIL PIL However, neurones activatedby highintensity Since ultrasonic vocalization may Prl evoke This isbyarticle protected reserved. copyright. Allrights can enhanceresponsiveness maternal responses preoptic of toevokingthe ventral bymaystimulation the bodysurface contribute pups also the mother's ventral body surface on movementsposture, byperforming pupcrawls supine nipple the "stepping" reaching to a a other Stimuli than suckling may reach also MPOA the to tocontribute the maintenance of responsiveness.maternal An receptorV1a expression andits direct pharmacologicalinhibitionimpaired it local of while blockade care, improved maternal lactating rats MPOA the of within receptors behaviourmaternal MPOA in the during PVN during neurones suckling in is increased expression geneAvp ma the in located vasopressin (Avp) neurones ( number of brain regions activatedare following suckling, as determined by Fos expression ( to the previously relayidentified for duringsuckling information ejection milk chemoarchitectonic and Fosactivational analysis as well were Pth2r knock-outmice heterozygous show weight reduced gain in during lactation an affectingwithout serum levels prolactin place ofconditioned formation a preference inmothers, the lactatingthe MPOA blocked into motivation becausemicroinjection virus aPth2r of role inmaternal antagonist a expressing studies (Fig.transection 2) preopticto the area hasdemonstratedbeen tracer using injections pathway and retrograde antagonist Pth2r by a prolactin suckling-induced release blockade bynear of complete demonstrated the suckling withlabelled areTip39 expression Foswith responseto induced neurones in of majority gray vast The periventricular thalamus. the site of inthe expression of its but notthethird 109 101,105,107,108 ( ) 119 . For example, suckling information may reach the MPOA via the activation of arginin- of activation the via MPOA the reach may information suckling example, For . It is also conceivableIt thatsuckling also is reaches A routes. MPOA information the byother ) are candidates to convey information to the MPOAto the candidatesto convey are information ( ( 101,102 ( 115 101 ) ) . In addition, a specific. pups,vocalization, auditory from ultrasonic the input . The projection of Tip39 neurones in the PIL to the arcuate nucleus but neuronesthePILof arcuate also Tip39 in tothe Theprojection . ) . ) . The active role of Tip39 in mediating the suckling reflex was was reflex suckling the mediating in Tip39 of role active The . ( 103-105 ( 114 ) . Tip39 projection of The fibres tothe MPOA. plays a ) . Thus, listed experiments,in theabove . somatosensory ( 116 ( 105 ) ( in a synergistic way with odour inputs synergistic in waywith odour a release, hormonal mediationa ispossible 112 ) . Further, pupsof. mice Further, lacking thePth2rgene acoustic input inacoustic input thecorresponding areato the alysis of pup movement showed afterthat gnocellular subdivision of the PVN.Indeed, the subdivision of gnocellular ) experiment where the where pups experiment wildtype of as of the PIL suggest that this the PILsuggest area correspondsof that . Furthermore, up-regulation of Avp V1a up-regulation . Furthermore, ( 105 ( 106 ( ) 110,111 suggesting the the suggesting existence ) . Cytoarchitectonic, Cytoarchitectonic, . ) ( . Avp is released 81,113 ) . ( ( 117 118 ) ) . . Accepted Article and/or tachykinin 2 neurones bu activated Fos-positive all almost cellsand are Fos-positiveexpress with neurones. Amylin ne ovariectomized, behaviourally-sensitized rats these canoccur neurones pregnancy absenceof example in stimulation, for the in hormone demonstrated in a V-shaped distribution pattern in coronal sections with the 3 sections withthe coronal pattern in distribution V-shaped in demonstrated a was neurones of the activity technique, this Using separation. previous following returned theexamines typical experiment Therefore, a taken away. the is when reduced litter is which area, preoptic c-fos activitythe strong in basal c-fosusing method the performed were resolutionallowing cellular based on 2-deoxyglucosec-fos, MPOA elevated likely inthe activity is their is activation behaviour. brain Still, maternal as The electrophysiological MPOA activity hasnot beeninvestigated of neurones relation to in Alterations of neuronal activity and gene nuclei ( in role a therefore, might play dams and rat means that about 40% of that 40%of meansc-fos-expressingneurones about containEsr1 expressing Esr1-positive cells.of About 10% ofdistribution estrogenreceptor alpha(Esr1) expressing overlaps neurones c-fos with This isbyarticle protected reserved. copyright. Allrights tomotherhood transition during the sensitizationmaternal process ratsin responsivenessrodents in Rather, emphasizedbehaviours. been the regulation have the inputs olfactory in maternal of visual have stimuli not been experimentally pathway,of neuronal a vocalizationby ultrasonic which canreach the MPOA. In contrast, neurones are GABA-ergicneurones are neurones but they appear torepresent a diverse group of cells. About half of the activated commissure.anterior information is Limited available on labelledthe characteristics of the subdivision theventral bed uptothe the of terminalis dorsolaterally stria nucleus in of alsoFos-positivehigh neuronesare density of being middle. the Ventrally, in manyneurones labelled intheare nucleus. medial Apreoptic 37,122 ( 123 ) . Odour information reaches the MPOA via the medial and cortical amygdaloid medial and cortical via the MPOA reachesthe Odour information . ( 132 ) . ) . Similarly, a portion of activated neur of a portion Similarly, . ( 51 ) . Furthermore, about half. Furthermore, of the activated neurones contained Avp ( 1 ) . The role of . Therole olfactory has been input shown tochange during the ( 129 ( ) 124 and many of these are projectionneurones are these of many and ( ) 121 andfMRItechniques ( 120 ) . Initially aversive pup odours become attractive to. Initiallybecome pup odours aversive expressionthe in maternal preoptic area ) . Theodours valence ofpup seems tochange Fos immunoreactivity pattern after the litter is the litter after Fos immunoreactivity pattern the maintenance of maternal responsiveness of maintenance the supported tosignificantly maternal induce ( 131 cells cells activatedare by pupwhich exposure, t still represent only a subset of Fos-positive of onlyrepresent Fos-positive subset t a still urones have asthe distribution urones a similar dorsolateral to this area and also further also tothis and area dorsolateral ) . Someneuropeptide markers also co- ones contained galanin,ones contained neurotensin, ( 125 ) . Themost detailed studies ( ( 109,126-128 130 ) . The of activation . ) . There is a rd ( ventricle 34

) . The Accepted Article have altered expression levels in microarray study that suggested number ofa process of maternal Erkin the their functions andtherole suggestingmice in maternal be induced to also found Rad andSpry1B, were Fos of elements regulatory 2downstream as well (Erk), regulatedkinase signal extracellular by the be regulated canalso Fosto Fosand B, similar which, NGF1-B, factor, Another transcription selectively deficient inmaternalresponsiv expressing neurones, co-expression is likely the numberof Fos B-immunoreactiv ( c-fo pattern to similar a in MPOA in the expression MPOA. levelwith inthe altered Anot neuronaThe expression of anindicatorc-fos is of Gene expressional changes in functionsof these cell groups remain todisclosed be in studies. future This isbyarticle protected reserved. copyright. Allrights mothers in nucleus neuromodulators. The expression of level Oxt is neuropeptides may aroleinthe play receptor Oxt co-expression the wasfound no for butalmost receptor amyloid polypeptide – Iapp), whichamyloid polypeptide is –Iapp), exclus the growing pups. expression is related tothephysiological starving at postpartumday 10 maximal (over 19 increase) times at 5dayselevation but appeared postpartum ( hypothalamic is inthelateral expressioncells level whose reducedinmothers actually area medial preoptic nucle subcommissural and paraventricular /supraoptic nucleibe to remain established. relationship However, potential 131 141 ) ) . Fos B expression appears with some some . FosBexpression with appears . Interestingly, Mch levels in the preoptic the in Mch levels Interestingly, . Neuropeptide gene expression isincr also Another recently i Another recently maternally discovered the in wasinduced (Mch) expressionofmelanin-concentrating gene hormone The ( 138 us of mother rats rats mother us of ) , which may be related tothe whichmayrelated be , the preoptic area of mothers the preoptic areaof mothers and similarities between Oxt neurones in the inthe anterior Oxtneurones between and similarities e neurones is 3-4times lower thethan ofc-fos number ( 140 s-positive neurones in response to pup exposure pup responseto s-positiveneurones in eness suggesting rolein its this process delay but lasts longer than c-fos delay than longer lasts but ) ively inexpressed the MPOA ofrat dams . This cell group Mch from clearly is different ( 134 additional transcription transcription additional factors and co-factors execution of execution of maternal responsiveness as Mch mRNA as well as peptide levelspeptide as wereMch mRNAaswell area increased with postnatal days. Some her transcription factor, factor, expressed Fos B,is transcription her ) characteristic in this late period of nursing in lateperiod this characteristic elevated in the anterior subcommissuralin the elevated anterior nduced neuropeptide is amylin (or islet is amylin (or neuropeptide nduced l activityl butisalso a transcription factor easedthe in MPOA ofmothers. These . Interestingly, mice lacking Fos B were B lackingFos mice Interestingly, . control of maternal behaviours maternal of control (

( 137 142 ( 136 ) ) . . It is possible thatpossible Mch. Itis ) . Furthermore, a recent ( 51 ( ) 133 . The specific specific The . ) . Although . Although ( ( ( 139 135 143 ) ) ) . . . Accepted Article signaling alteredis in the postpartum period expression is also increasedin lactating rats expression receptor remains theelevated in period postpartum inthepostpartum control level period Oxt receptor expression was alsoincreased in prolactin suggested levels this that increase maternal behaviours. regions amygdala andthe receptor (neurotensin – Sort1)receptors inthe 3 butnot in someMPOA, other hypothalamic times) but significant increase was found inthe mRNA level of neurotensin and one of its ventrolateral preoptic nuclei preoptic in thepostpartum nuclei period ventrolateral (Prlr) receptor too.Prolactin maternal MPOA, relatedtomaternal behaviours orreducedthe anxiety and stress responseof lactating dams. killing Ais studylimited. maternal showedCrh that behavior actually inhibited andinduced pup- stress females compared with virgin andpregnant anddidrats notincrease inresponse further to MPOA oneabout and third of them are byactivated pupexposure elevation after parturition and its induction in induction its and parturition after elevation maternal and motivation in than behaviour, rather feeding, wassuggested by immediate its This isbyarticle protected reserved. copyright. Allrights genemicroarray study, of11904geneexpression Systemsin mothers. biologicalapproaches have amylin in theMPOA Fos-positive contain 27% of neurones neurones are labelledw amylin 90%of Indeed, The distribution of amylin similarneurones is toof that maternally active neurones area maternal preoptic the in times) 25 (over level in itsexpression increase largest the expression between mother motherandpup-deprived Previously, amylinwas only in found the pancreas ( 148 In MPOA, corticotropin releasing corticotropin In MPOA, hormone releasing Neurones containing theneuroten neuropeptide Apart from Apart from neuropeptides, some hormonere ( We have changesWe have in on thelimited of information proteins other gene level expression 149 ) . The available information on the functionon the The available information . ) .It remains to be elucidated whether the ( 146 ) . It has also been Ithasalso that demonstrated . endogenous neurotensin ( 112,152 ( 84,113 maternally sensitized control female rats control sensitized female maternally is result the direct of activation neuronal ) the MPOA during parturition, but returned to but returned the MPOA parturition, during . In recentcontrast, a study suggested Oxtthat Ina this times. questionaddressed onlyfew a ith Fos in response to pup exposure, butonly pupexposure, to ithFosresponse in levels were elevated in the ventromedial and intheventromedial elevated levels were ( 147 s wascompared between lactating mothers ( ) 144 (Crh) was expression higher in lactating . ) rats identified gene amylin asthe with rats ( reported alteration in isCrh expression suggesting neurotensin of role a in 150 of elevated Crh inthematernal MPOA ceptors elevated have levelsin the ) sin are sindistributed are inall parts ofthe . A microarray study comparing gene gene comparing study microarray A . ) . Pharmacological manipulation of manipulation Pharmacological . ( 132 ( ) 51 . A. role of amylin in ( 137 ) . A small (about 1.5 ) . AVP. receptor ( 132 ( ( ( 151 145 143 ) . ) ) ) . . . Accepted Article This isbyarticle protected reserved. copyright. Allrights wane and after input orhormonal neuronal involved For genes. genes,some the expression changes may berelated to continuous temporal to pa theprecise establish important of maternallyexpressedidentifyrolegenes the the above discussed microarray arestudies not kn hydroxytryptamine (serotonin) receptor 2A are genes with altered maternal expression 5- 1 mu(Oprm1), and Cypx1b1a,gene opioid glucocorticoid-related receptor, non-maternal females dopaminefound that receptor (Dat), D4(Drd4), transporter dopamine ( significantlywere oxidesythasedecreased nitric 1 and subunit epsilon (Gabre), receptor, upregulated in while level the mothers, of angitensin 1converting GABA(Ace), enzyme A glutamate-ammonia ligase (Glul), Oxtr, and supp 7PCR, were validated assignificantly altered. B leukemia/lymphomacell 2(Bcl2), in overrepresented were procedureproved gene enrichment that set single expression changed significantly in the maternal preoptic area andcont mice between mother area preoptic medialgene35557 targets the expressionof compared in which microarray study, recent B, Ngf1-B, Spry1behaving inbothparentally Rad, and induced males and females transcription Fos c-fos, the factors: reported which study, microarray in another examined was above)described other genes further but analysed werenot delivery. studyimmediately This after the identified maternal neuropeptide amylin (as with compared rats lactatingmaternal female kinasethatbeen has recently suggested tosilence synuclein at the synapse development including Cited2 and Plk2.Cited2 is a Cbp/p30 mothers transduction pathways, neuroimmune factors, ( and virgin mice female in thehypothalamus (including theMPOA) andnucleus accumbens 137 153 ) ) . Several genes belonging growto neuropeptides, . Another recent study microarray mo . Another comparing The distribution, temporal course of induction, and function, of thegenes ofand of induction,by temporalcourse distribution, function, identified The genestudyAnother microarray investigated ( 153 ( ) 154 . Unfortunately, qRT-PCRverification. genes, wasreported only afew for ) but still does not have an established neural function. Plk2 is a polo-like polo-like anestablished neural function. doesnothave a Plk2is butstill the altered gene list list gene altered the rol females, found 734 annotated genes, whose genes, 734 annotated females, found rol ( in the MPOA andin MPOA itssubdivisions.the It is equally and mitochondrial genes were induced in mother rats that mother rats were deprived pups of their 137 tterns of the gene expression gene the tterns of maternally of weaning of the pups. thematernal pups. However,weaning of s implicated in disorders with social deficits deficits social with indisorders implicated s own yet. Thus, studiesare needed further to own yet. 0-interacting transactivator required transactivator required during 0-interacting ressor ofcytokine signalling (Socs2) were ) expression exclusively in the MPOA of of MPOA the in exclusively expression . Among the 13 genes tested with qRT- tested with genes 13 Amongthe . th factors, receptors,of signalth factors, elements ther and maternally behaving andmaternally withther rats ( 143 ) ( . The dorsal part of MPOA of dorsal . The part 137 ) . Subsequentmodular . ( 155 ) . ( 136 ( 156 ) . A ) . Accepted Article or DNA as stable and permanent,not is accurate Similarly, classification of asacetylation dynamic andreversible, butmethylation ofhistones but this view isnot always supportedby data [for a thoughtful discussion see example, itis tempting specific tolink modifications states with on/off of transcription,gene For insufficient. are activity transcriptional on remodelling chromatin of consequences becomemodifications research, of increasingan area that clear it is generalizations the about bindingDNA proteins methylated of recruitment remodelling; cytosine tightensmethylation structure chromatin the and canresult in increasing transcription factor access toDNAsequences. DNA is a target for itself also their proteins, charge "loosening" histone of bind factor transcription altering DNA) and/or structure of remodelling the chromatin(thestrength between histones of association and Post-translational modifications tohistone and DNA methyltransferases met (DNMTs) add (HATs) groups addacetyl toproteins, histon epigenome regulated is by theenzymatic activity ofproteins. Histone acetyltransferases gene expression tocontrol genome Thesealso be by modified methylation. of level "epigenetic the abovethe marks"exist modifications to histones such as acetylation and canoccur,methylation and DNA itself can DNAcomplex of compactly hist coiled around possibility modificationsgenetic One regulatechromatin isthat networks involvedin is interactions. Chromatin thethe mother-infant of the reorganization MPOA during initial responsivenessinfants to maternal of long-lastingmaintenance the abovesupport phenotype described neuronal maternal responsivenesspoor results in rearinglitter, experience of the a the damage occurs after even MPOA, that to when damage because care maintenance maternal of the the gene within support MPOA expression likely This isbyarticle protected reserved. copyright. Allrights described whichabove, regulate maternal res transition intoThe motherhood with isassociated expression geneMPOA,the changes within responsiveness Epigenetic mechanisms thatex the control changes. expression gene long-term with be accompanied may which responsiveness remains elevated for a longpe ( 158-162 ) .

( ( 163 51,157 ) . The placementof epigenetic markson the association with negatively charged DNA, and and DNA, charged negatively with association e deacetyltransferases (HDACs) remove them, ing. Histone acetylation neutralizes the positivethe ing. neutralizes Histone acetylation protein tails regulate gene transcription by protein tails regulate genetranscription ponsiveness. Furthermore, ) riod of time following maternal experience, following maternal riodof time ( . A critical question. Acritical how is the alterations in hyl DNA. of cytosine residues groups tothe pression of genes involved in maternal in maternal genes involved pression of that repress gene transcription. As chromatin genethat repress transcription. 165,166 one proteins. Numerousone proteins. post-translational ) . these in alterations ( 164 ) ]. ]. Accepted Article transcriptional activities required maternal memory.for line ofresearch This may help clarify stabilize initiate and that modifications chromatin the opportunityto identify activity, affords experience-dependent changes inmaternal responses appearbe regulated to by Crebbp-HAT consistent were [manuscript underreview, alsosee experience a maternal after tested 1-month novelpups scattered endsofa from the T-maze far backnest. mice were totheWhen re- than postpartum females. Maternal motivation latencyby wasmeasured the toretrieve of experience,amounts maternal such that was not statistically motivationmaternal different ( may experience of maternal consolidation Creb-mediatedrequires transcription gene maternalis consolidated, experiencethat as idea the with Consistent memory? of maternal the maintenance and/or maternal experience If chromatin remodelling isa final common pathway through hormones which and of consolidation the involvedin also it responsiveness, is activate maternal experience chromatin by remodelling a interaction), mother-infant activity during estrogen at recept coactivator a is (Crebbp factors acetylation is logicala candidate mechanism because Crebbp canbe onby hormonalturned activating binding HAT enzymes, such(Crebbp). CBP-mediated Creb as histone protein This isbyarticle protected reserved. copyright. Allrights virginthatmice show maternal responsiveness gein Crebbp and increases mice virginfemale support signallingpathways and Erk Creb of the strikinglyof on MPOA responseseffects produce similar maternal idea, this of In support HATs. of recruitment through beforesurge estradiol whichthe of activates birth just maternal involves behaviour see review [for pathways pups sensoryrepeated hormones, from inputs neurones toinfant respond One (Fig. stimuli 3)? possibility is inthethat absence pregnancyof experienti factors(hormonal, different which signalling pathways 171,174

If dynamic regulation of acetylation and methylation occur in response to responsecell andmethylationregulation occurin acetylation dynamic of If ) . In the absencehormones, pregnancy Inthe of . ( 165,166 ( 167 ( 165,166,168 ) ) , is chromatin remodelling a final common pathway through commonpathway final a remodelling is chromatin , ]. Intracellular signalling cascades affect histone acetylation by ) . Thus, Thus, it. certainly is the possible thatmechanism ( nd regulates gene expression inMPOA nd regulates expression neurones gene nd/or HDACi treatment, pup retrieval responses 173 al) producelong-term al) changes in way the MPOA maternal responsiveness and both postpartum in maternal estradiol and dopamine D1 receptor stimulation stimulation dopamineestradiol and D1receptor involve Crebbp-mediated involve in other forms of learning; maternal learning maternal of learning; forms in other ( and are bothpostpartum seenne in expression 136,153,171-173 ) . Recent . Recent evidence supports idea the that the HDAC potentiated inhibition sub-threshold ultimately stimulate the same molecularsame the ultimately stimulate ors) as well asexperiential factors(neural ors) aswell ( 29 ) ]. Importantly, the fact that fact the Importantly, ]. ) . ( histone acetylation histone 169,170 ) . Activation Activation . Accepted Article signature that underliesMPOA. plasticityin that the signature workto identify needed the epigenetic is Future maternal experience. involvement in gene MPOA of expressionregulation firststep are in the toward understandinga epigenetic Thus, the data linking histone to acetylation in ofmodifications learning estradiol facilitation elucidated andmemoryhasbeen depends ontheCrebbp HAT activity of This isbyarticle protected reserved. copyright. Allrights increased formation memory amygdala, increased histone acetylation the consolidation of long-term this memories [in issue, hasbodydynamically research linked of driven epigenetic to mechanismschanges underlying thesupport the might of regulation ideaepigenome dynamic that the Finally, although long-lasting in changes MPOA neuronesthatsustain motivationmaternal is new, growing a ofberegulationtranscriptional in involved these genes under[manuscript review]. toEsr2 Crebbp recruited is 4). Furthermore, (Fig. withexperience consolidation coincides maternal maze, suggesting theirup-regulation these gene expression changes are Importantly, totightly responses maternal linked onthe T- sub-threshold experience increases the expression of Crebbp, Esr2, andOxt virgin mice in experience consolidationmaternal behaviour maternal of development inthe role an important playsof Esr1expression regulation example, epigenetic duringmaternal lear alterations tobediscovered. havenovel yet However, that targets experimentalevidence of epigenetic involved behaviour, such asthose describedin maternal includingabove as as Tip39, well vasopressin receptor (Avp), andvasopressin behaviour: beta estrogenreceptor oxytocin (Esr2), oxytocinreceptor (Oxtr), (Oxt), maternal for relevant as of thegenes identified some increases the of experience expression expression of genes associated with maternal thecare in ForMPOA. example, maternal an HDACi not only affects behavioural responses toward pups but also potentiates the that regulatory mechanism transcriptional is a histoneacetylation Consideringthat allows for increased transcription of particular ge expression. how neuronal initial inputs (hormonal and experi

acetylation, enhanceacetylation, memoryformation ( 183,184 ( 175 ) ) . Further, administration of HDAC inhibitors, which allow for allow which ofinhibitors, HDAC administration Further, . , but Esr1 expression does not seem to be modified during tobemodified doesnotseem , butEsr1 expression ning is currently available only for a subsetof For genes. available only for ningis currently ( 178-182 and Oxt gene promoters, suggesting may it promoters, Oxtgene that and (Avp1a). are othergenes Undoubtedly, also ( the ofmaternalconsolidation experience and 180 nes, it is not surprising that administration of administration surprisingthat isnot it nes, ential) ential) to come leavelasting effects ongene ) ( ( and increased Crebbphave and beenlinked to 171 ) 178-180,182,183,185-187 . More recently, a role for chromatin chromatin for role a recently, More . ) . Administration of an Administration HDACi. during ( 176,177 ) ]. In the hippocampus hippocampus ]. Inthe and ) , and this effect , and ( 188-190 ( 171 ) ) . . Accepted Article This isbyarticle protected reserved. copyright. Allrights 6 basisof Siegel HI.Hormonal behavior rat. maternal inthe DE, Agrati5 Olazabal Ferreira D, M, Pereira A, Fleming Gonzalez-Mariscal AS, Levy G, F, 3 Moses-Kolko EL, Horner MS, Phillips ML, Hi JD, editor. and Neill´s KnobilNeill Behavior. In: FMaternal Levy Fleming AS, M, 2 Numan Parental Behavior. InselTR(2003) M, Neurobiology1 Numan of New York:Springer. The References Council of New Zealand, and the Royal Society of New Zealand Marsden Fund. the KTIA AD.Program NAP_13-2-2014 for DRG was supportedby the Health Research Sciences, OTKA an K100319 research grant of Scientific theHungarian Research Fund, and Bolyai by Grant supportwas provided the HungarianJános Academy Award of of Acknowledgements maintained permanently throughtolikelythat areprocesses involve epigenetic changes. brain. is adaptation of Once maternal the of this experience the memory established, responses. Es expression tomaintainmaternal Both offspring. dependent mechanisms convergeMPOA, onthe promoting ingene changes either initiated by inputs, sensory su neural birth. of maternal care the offspring after changesHormonal during initiate pregnancy behavioural complex changes to promote Conclusions 4 Olazabal DE, Agrati4 Olazabal Ferreira D, M, Pereira A, Fleming Gonzalez-Mariscal AS, Levy G, F, 202-215. 1860-1874. approaches on maternal inmammals. motivation andexperimental N. Uriarte New theoretical M, JI, Numan Morrell Lucion AB, 37: 1875-1892. Neuroendocrinol psychophysioloyendophenotypes of postpartum Physiology of Reproduction. Oxford: Academic Press. 2006: pp. 1729-2058. 2003. substrate that supportsmate neural the of adaptation and Flexibility N. Uriarte M, Numan JI, Morrell Lucion AB, 2014:In press. rnal behavior in mammals. behavior inmammals. rnal These by extended reinforcedThese behaviours are and ckling, or by the sight, smell andsoundsofthe sight, smell ckling, orby sentially changesthese lead to the maternal pwell AE, Swain AE,Swain pwell JE. In ofsearch neural and discrupted maternalcaregiving. discrupted and Neurosci Biobehav Rev BiobehavNeurosci Ann NY Sci Acad Neurosci Biobehav Rev

1986; 1986; 474: 2013;37: 2013; J Accepted Article 15 RosenblattSiegel Hy HI. JS, 14 Siegel HI, Rosenblatt JS. Hormonalbasis of hysterectomy-induced maternalbehavior 13 Siegel HI,Rosenblatt inhib Progesterone JS. M.X.,Denenberg, V.H. Maternal 9 GandelmanR,Zarrow, betweenBehavior: Differences This isbyarticle protected reserved. copyright. Allrights by behaviorblood JS. inducedJ, maternal Maternal Rosenblatt plasmainjected 17 Terkel into 16 Siegel HI, RosenblattEstrogen-induced JS. behavior in maternal hysterectomized- Greenwald onset12 Siegel HI, Prepartum GS. of 10 FlemingKorsmit, M., AS,pups Deller, potent M.are Ratreinforcers maternal the to 8 Lee A, Clancy S, Fleming AS. rats Mother ba Mackinnon7 Stern DA. JM, Postpartum,of hormonal, maternal induction andnonhormonal 18 Moltz H, Lubin M, Leon M, Numan M. Hormonal induction of behavior maternal induction M. Hormonal inthe M, Numan Leon 18 Moltz H,LubinM, R, maternal Differences Denenberg MX, in Gandelman VH. 11 Bridges R,Zarrow 19 Bridges RS. A quantitative analysis of the rolesdosage, sequence,the AquantitativeRS. of19 Bridges analysisof of and duration 20 Orpen BG, Fleming AS. Experience with pups responding maternal sustains with postpartum in FlemingAS. Experience 20 OrpenBG, hysterectomized-ovariectomized virgin rats. effects ofestrogen andprogesterone. Psychobiology procedure. of testing a function as virginmice and mother Behav BrainRes sitesand limbic onmaternal behavior a the rat. during pregnancyrat.the in behaviorrats: in on of pups. T-mazeeffects retrieval virgin rats. rats. virgin overiectomized 127. Psychobiology Effectsanimal: dopamine ofexperience, parity, hormones, and function. responsivenesssensitized between rats. lactatingand ovariectomized nulliparous rat. nulliparousovariectomized Endocrinology re inthe estradiol andprogesterone exposure rats. rats. Physiol Behav J Comp PhysiolPsychol J Comp Physiol Psychol J Physiol Comp 1973; 3: 207-214. 1994; 22: 44-53. 1984;114: 930-940. 2000; 108: 215-231. 1987; 40: 47-54. sterectomy-induced behaviormaternal during pregnancy in Physiol Behav Horm Behav Horm Physiol Behav 1975;89:685-700. 1968; 65: 479-482. Horm Behav Horm r-press for pups: mpoaeffectsthe for ofr-press lesionsof ition of estrogen-induced maternalbehaviorition of in nd operantnd responding pup-reinforcement. for 1975; 6: 211-222. 1975; 14: 465-471. Horm Behav maternal maternal behavior in hamsters and the gulation of maternal behavior in the rat. of maternalbehaviorgulation inthe 1970; 5:1373-1377. 1975;6:237-245. Horm Behav Dev Psychobiol 1975;6: 223-230. 1976;7: 305-316. 1972; 5:123- Developmental Accepted Article 34 Numan M, Numan MJ. NumanProjection34 NumanM, sitesof medial preoptic nucleus bed of areaandventral 33 Galea Leuner LAM, SlatteryB, DA. Hippocampal plasticity period:during peripartum the Physiology andBehavior Its32 BridgesRS. roleParturition: retention in theof long termbehavior in maternal ratthe Haack,M., GK, andMarkl, H.31 Ehret determine Sex parentalexperience B., the of onset an 30 Koch M, Ehret G. Estradiol and parental experience, butnot prolactin are necessary for 29 Stolzenberg Rissman DS, EF.Oestrogen-independent, experience-induced maternal behavioural influences and development: Champagneon offspring Paternal 26 BraunK, FA. 35 Numan M, Sheehan TP. Neuroanatomical circuitry for mammalian maternal behavior. maternal mammalian for circuitry Neuroanatomical TP. Sheehan M, 35 Numan behaviorrat.28 RosenblattJS.the Nonhormonal basisof maternal in significance Functional changes ofin mammalian hormonal Ziegler TE. W, 27 Saltzman behavi and BB.Anabolicsteroids 25 Svare This isbyarticle protected reserved. copyright. Allrights MaternalBehavior:24 SternJM Sensory, Horm 23 JS,Rosenblatt Mayer AD, AL. Giordano basis duringHormonal pregnancy theonsetfor of 22 Bridges Long-term RS. of effects pregnanc onset of 21 Bridges rapid of RS.Retention Neuroendocrinol the stria terminalis neurons that Fo express ageing. and stress steroids, sex of influence behaviorininstinctive mice. 776. mouse. the in and pup-retrieving recognition ultrasound behaviour in mice. female 1512-1514. epigenetic pathways. Monogr fathers. 226. Levine editors. Psychoendocrinology.AS, San Diego: Press. Academic 1989: pp.103- rat.in the rats.primiparous N Y Acad Sci maternal behavior in the rat. rat. in the behavior maternal 1990; 102: 224-241. J Neuroendocrinol Physiol Behav 1997; 807: 101-125. 1997; 9: 369-384. Behav Biol 1977;18:487-490. J Neuroendocrinol 1975; 14: 245-249.14: 1975; J Neuroendocrinol 2014: In press. 1978; 24:113-117. Psychoneuroendocrinology Naturwissenschaften or: a preclinical re apreclinical or: y and parturition yupon maternalresponsiveness and parturition 2014:In press. onal and Neural Determinants. Neural FR, In:Brushand onal maternal behavior duringpregnancy in maternal s during maternal behavior in female rats. rats. female in behavior maternal during s J Neuroendocrinol 2011. 1989;74:47. 1988; 13: 29-46. Physiol Behav Physiol search prospectus. 2014:Inpress. Science 1989; 45: 771- 1989;45: 1967; 156: NIDA Res Ann Ann J Accepted Article This isbyarticle protected reserved. copyright. Allrights maternal and sensoryinputs pup-related of Importance MJ. Numan M, 36 Numan 48 Pereira M, Morrell JI.48 Pereira The changing the of medialpreoptic role theregulationarea ofin M, CorodimasNuman MJ, Factor47 Numan KP, 45 MV. Vasopressin-Sofroniew and neurophysi GF,44 Jirikowski JD, Pedersen Caldwell influencesoxytocin-CA, WE. Stumpf Estradiol Swanson42 Ju Studies LW, G, onthecellular Simerly RB. the bednucleiarchitecture of of Gorski propiona 41 Dodson RA.Testosterone RE, 40 Gorski RA.Sexual dimorphisms ofthebrain. 39 Gurdijan ES. The diencephalonof thealbino rat. Nursing stimulation Ferris BridgesRS, CF. M, Kulkarni P, Numan Stolberg TL, 38 FeboM, internal immediate and care inmammals: PoindronPParental G, 37 Gonzalez-Mariscal 46 Numan M. Medial preoptic area and maternal behavior in the female rat.preopticthe maternal area infemale behavior M. Medial 46 Numan and brain rat The WatsonC(2007) G, 43 Paxinos ventral bednucleus ventral of thestria of Fos-likeperformance the for immunoreactivityexpression inthepreoptic area and the stria terminalis in the rat: II. Chemoarchitecture. Chemoarchitecture. inthe rat:II. terminalis the stria 80-88. ofneurons within the themedialcentral preoptic nucleus. part 330-339. multisensory a experience. Itis sensation: than tactile more is 298. Hormones, editors. Brain andBehavior. Sa Rubin R, S, Fahrbach A, Etgen A, Arnold D, Pfaff In: in control. factors sensory 109: 135-149. Behav BrainRes pe postpartum behavioracross the maternal Neurosci preoptic and region substantia innominata disrupt maternal behavior in rats. Psychol amygdalacolchicine-treated rats. locuscoeruleus medial region, in and brainimmunoreactive systems. Academic Press. 2007. 1985; 15:347-358. 621. 1974; 87: 746-759. 1988;102:381-396. 2009; 205: 238-248. Neuroscience terminalis of postpartum rats. ofterminalis postpartum rats. J Anim Sci J Anim EM, Piers WD. Axon-sparing of WD. Piers the EM, lesions n Diego: Academic 215- Press. 2002: pp. n-immunoreactive neurons in the septal the in neurons n-immunoreactive J Comp Neurol 1988; 25: 237-248. riod: facilitation followed by inhibition. by followed riod: facilitation in stereotaxic in stereotaxic coordinates. San Diego: te administration prevents the loss of theloss prevents te administration 1985; 61Suppl 3:38-61. 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Accepted Article 57 Bridges RS,DiBiase Loundes R, DD,Dohert 58 Bridges Prolactin ofmaternal RS, behavior inrats: PM. (PRL)regulation Ronsheim 56 V, Fiedler Bluem K. ControlRepr Hormonal DenenbergS, FarooqED, SawinPB,Ross A.MaternalWilson Crary D, 55 ZarrowMX, VH, 60 Bridges RS,Numan RonsheimM, Mann PM, Stuer Friesen AM, ShiuRPC, HG, MannEndocrine PE. MC, Robertson RS, 59 Bridges Sawin Denenberg VH, Farooq A, 54 ZarrowMX, This isbyarticle protected reserved. copyright. Allrights ring dove? in the behaviorincubation induce Doesprolactin P. Brody DS, 53 Lehrman 52 Morgan Watchus JA,Fleming HD, AS. Theeffects ofelectrical stimulation of medial the Kuroda KO. M, Numan T, K, Kato S,Maruyama Nishimori Y, Yoshida T, 51 Tsuneoka Sawyer RA,Gorski CD, TerkelJ, 50 Jacobson 49 Arrati PG, CarmonaDominguez C, Beyer G,Rosenblatt C, JS. GABA receptor agonists in behavior in rats. female Comp Endocrinol stimulate maternal behavior in steroi behavior maternal in stimulate Endocrinology PRL and delays treatment bromocriptine 1961; 2:152-162. additional data on building race.Dutch-belted maternal-nest in the an rabbit: for evidence e behaviour inthe 383. Rabbit: Endocrine Control of Maternal Nest Building. Maternal Control of Rabbit: Endocrine Endocrinol maternal behavior. behavior. maternal communication between conceptus and mother: Placental lactogen stimulation of 194: 471-478. nest therat. behavior:lesions onmaternal building in retrievingand 87: 51-65. the medial preoptic area and maternal lactating behavior in rats. N Y Acad Sci rats. responsiveness in maternal female amygdala medial on andthe preoptic area 1633-1663. mouse. behavior to inthe maternal subregions inrelation and neurochemicalFunctional, of medial anatomical, area differentiation preoptic 1961; 22: 269-275. 1997; 807: 602-605. 1990;126: 837-848. 1965; 56: 186-196. 1965; 56: Neuroendocrinology Science 1985; 227:782-784. d-treated, nulliparous female rats. nulliparous female d-treated, 1996; 64: 57-64. oductive Behavior in Some Cichlid Fish. Fish. Cichlid Some in Behavior oductive ndocrine basisofndocrine maternalnestand building CH. Effects of small medial preoptic area PE, Lupini CE. infusions Central Lupini CE. prolactin PE, y PC. Prolactin stimulation of maternal stimulation y PC. Prolactin promotes thepromotes rapidonset of behavior. PB, Ross S.Maternal Behaviour in the J ReprodFertil J J CompNeurol Physiol Behav Physiol Brain Res Brain J Reprod Fertil Proceedings of Proceedings 1963; 6:375- 2013; 521: 2013;521: 1980; 2006; Gen Gen Ann J

Accepted Article 71 Sjoeholm A, Bridges RS, Grattan DR, A DR, Grattan A, BridgesRS, 71 Sjoeholm Ancker van den DR, Grattan 70 AndersonGM, 69 BridgesRS, RigeroByrnes BA, EM, Yang LL,WalkerAM. Central infusionsof the AE, Herbison GrattanIC, 68 BrownRS,Kokay 67 Brown RS, Herbison AE, Grattan DR.AE, Differen Grattan Herbison 67 Brown RS, of hypothalamus the receptor DR.Increased immunoreactivity in prolactin Grattan 64 Pi XJ, 66 Bridges RS, Hays LE. Steroid-induced RS,LE. Steroid-induced alterati Hays66 Bridges gene receptor Prolactin RS. Bridges PE, 65 Mann 63 Pi XJ, Grattan DR. Distributi Grattan XJ, 63 Pi of 62 Thedistribution JI. JC,Bakowska Morrell This isbyarticle protected reserved. copyright. Allrights Atlas neurons61 BakowskaJC,of Morrell JI. the female rats. rats. female increases prolactin responsiveness in the medial preoptic area and arcuate nucleus of forebrain.the mouse neurons in female rats. rats. female re pathway-specific prolactin increasesin 142: 730-739. rats. nulliparous female steroid-primed, behavior in maternal an humanprolactinreceptor recombinant of Reproduction and toprol neuronal populations brainstem 2005; 140:10-16. estradiol. and progesterone regimen of a pregnancy-like in themedialpreoptic receptor prolactin the lactating rats. lactating rats. 462-474. estrogen-treated, ovariectomized rats. receptor in the forebrain of the female rat. female the of forebrain the in receptor Neurology prolactin receptor inthe forebrain of the female rat. 8007. AcademyUnitedNational America the of Sciences of of States the 1997; 386: 161-177. Endocrinology Endocrinology J Neuroendocrinol Brain ResBrain Res Brain Mol 2011;84:826-836. on prolactin of immunoreactivity inthebrainof receptor 2006; 147: 4688-4694. 2011; 152: 1979-1988. J Comp Neurol 1999; 11: 693-705. Journal of ComparativeNeurology 2002; 105: 136-145. nderson GM. nderson GM. Region-, neuron-, and signaling ons in mRNAons expression the in of of long form Brain Res Mol Brain Res MolBrain Res Brain sponsiveness inreproductively experienced mRNA for the short form of the prolactin theprolactin of shortform mRNAfor the that express mRNA for the long form of theof longform the for mRNAthat express actin during lactation in the mouse. the in duringlactation actin expression in the forebrain of pregnant and pregnantand of theforebrain in expression tagonist, of S179D-PRL,delay theonset W, Bridges RS. Reproductive Bridgesexperience RS. W, Effects rats: exposurearea of of female to tial changes responses hypothalamictial in of DR. Distribution of prolactin-responsive of Distribution DR. 2010; 518: 92-102. Brain Res Mol Brain Res Brain Mol Brain Res Journal of Comparative Endocrinology 2003; 116:50-58. 1990; 87:8003- 1998; 1998; 394: Biology 2001;

Accepted Article This isbyarticle protected reserved. copyright. Allrights maternalof activation ReproductiveRS. experience Bridgesand Byrnes VF, EM, 72 Scanlan 73 NR. Voci VE,Carlson Enhancement behavior maternal of andnestbuilding following 76 Melo AI, Perez-Ledezma76 Melo AI, M, Clapp Arnold E,RiveraC, JC, Fleming ofAS.Effects K,SJ, EngleTanakaM, Nakashima E, Montecinorodriguez ND, ZhaoWZ, 75 Horseman 74 Lucas Ormandy BK, CJ, Binart N, Bridges RS 77 Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, Cross JC, Weiss S. S. Weiss JC, Cross C, Geary R, Hassam H, Fujikawa E, Enwere C, Gregg T, Shingo 77 78 Larsen Grattan mito CM, DR. Prolactin-induced 79 Larsen CM, Grattan DR. Prolactin, ne Grattan DR. Larsen CM, 79 81 Pedersen CA, Caldwell JD, Walker C, Mason AyersG, GA. Oxytocin activates the Young JAOxytocLJ, JPH, Russell 80 Burbach 82 Lonstein Maguire JS, J, G,ID. Meinlschmidt adaptationsNeumann Emotion and in mood memory. memory. receptor gene produces a defect in maternal behavior. maternal in defect produces a gene receptor JPhysiol Psychol Comp systemic and diencephalic of progesterone prolactin administration inand mouse.the behavior in female rats: mother's milk makes the difference. difference. the makes milk mother's rats: female in behavior prolactin deficiencyduring early postnat the Journal gene. prolactin hematopoiesis, the disruption atargeted with of in mice E,Smith F,Markoff DorshkindK. butDefective mammopoiesis, normal 4107. prolactin. Pregnancy-stimulatedneurogenesis in the adultby femaleforebrain mediated 281-291. responses in the mother. pregnancy during is maternal early brain Immun areas. preopticand medial tegmental ventral behavior the in maternal rat of onset postpartum AcademicOxford: Press.2006: pp. Functions. In:Neill JD, Knobil Physiologyeditor. Neill´s and Reproduction. of oxytocin. gamma-aminobutyric complementary of female: and acid peripartum contributions the Behav Neurosci 2012; 26: 2012; 201-209. 1997;16:6926-6935. Behav Neurosci J Neuroendocrinol Science 2003; 117-120.299: 1994; 108:1163-1171. 1973;83:388-393. Endocrinology 2006; 120: 676-686. 2014: In press. urogenesis, andmaternal behaviors. 2010; 151: 3805-3814. in: Synthesis, Secretion, and Reproductive essential for normal postpartum normalpostpartum behavioral essential for , Kelly PA. Null mutation Kelly the prolactin PA.Null of , al periodtheal maternal development on of genesis inthe subventricular zone of the Endocrinology Horm Behav Horm 1998; 139: 4102- 1998;139: Brain Behav Brain Behav 2009; 56: 2009; EMBO Accepted Article 94 Lin SH, Miyata S, Matsunaga Kawarabaya W, S, Miyata SH, 94 Lin 90 Juss TS, Wakerley JB. Mesencephalic areas pulsatilecontrolling oxytocin release inthe 89 Ross HE, Cole CD, Y, NeumannSmith ID, Landgraf MurphyR, AZ, Young LJ. Kokay Grattan sensitivity Ostberg of RS, 88 L, DR. Differential IC, TJ, Bridges Sapsford This isbyarticle protected reserved. copyright. Allrights JS,of Knaggs th Determination GS. 92 Tindal M,91 Dubois-Dauphin E, Tribollet WE, Armstrong 87 KokayIC,PM, Bull DavisLudwig RL, Gra M, 86 Kenkel WM, Yee JR, Carter CS.Is oxytocina maternal-fetal signaling molecule at birth? oxytocin receptor central of the behavior: activation Maternal SunB. Kiyohara T, SH, 85 Lin 84 Bosch OJ, Neumann ID. Both oxytocin and vasopressin are mediators of maternal care and 83 Leng SL, Douglas G,Meddle maternal AJ.Oxytocin brain. the and 93 Hansen S, Kohler C. The importance of th S,Kohler C.Theimportance 93 Hansen prairie voles. prairie Characterization of oxytocinthe system regulating behavior affiliative infemale Neurol to prolactin action. populations hypothalamus therat of neuronal specific 2006; 290: R1216-1225. prolactin regulation of oxytocin neurons. prolactin receptor inmagnocellular oxytocin isassociatedneurons with specific immunohistochemistry. pregnant, part thebrain in mapping of 563-572. rat. suckled system in parturient rats? rats? parturient in system 293-303. action. of tosites centralaggression from release inrodents: 2008; 8:731-734. control of sexual behavior and milk ejection in the rat. the ejection in milk sexual behavior of and control ejection reflex inguinea-pig. the Neuroscience funiculus. cervicaland lateral dorsal nucleus-dorsolateral thalamic complex, columns II. Th rat. reflex the milk-ejection in the development. for Implications 2012;520: 1062-1077. J Endocrinol 1985;15: 1131-1140. 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Accepted Article 104 Palkovits M, Usdin104 Palkovits M, GB, Dobolyi Makara TB, of39 peptide A.Tuberoinfundibular theconnectionbetween neuronal Adirect GE. Hoffman UsdinTB, SnyderFK, N, 103 Szabo 106 Coutellier L, Logemann A, Rusnak M, Usdin TB. Maternal absence of the Usdin the Maternal Logemann A, M, 106 of parathyroid L, Rusnak absence Coutellier TB. I, Nagy M, Szabo LekoA,Bodnar Dobolyi105 Cservenak M, ER, Palkovits Usdin TB, GM, 102 B,Bago Varga Mogyorodi T, AG, Cserve This isbyarticle protected reserved. copyright. Allrights 101 BodnarUsdin TB, I, Cservenak M, TB. Usdin S, Irwin J, Wang 100 Dobolyi A, JS,95 Tindal Knaggs Pathways inthe GS. rat ofthe theconcernedforebrain of release with 99 Dobolyi A, Ueda H, Uchida H,H, Palkovits Ueda Uchida 99 Dobolyi A, and neuropeptide new JA.TIP39: a Kowalak MezeyE, WangT, SR, Hoare TB, 98 Usdin Expres UsdinTB. Palkovits 97 Dobolyi M, A, HaarO'Neill MB. JB, Relationship96 Wakerley between suckling-induced ter DS, the release terminate terminate hypothalamus.in neuroendocrine the zona the in fibers immunoreactive residues- 37: 62-70. this pathway arole play inthe suckling-induced prolactinrelease? andventrolateral subparafascicular arcuate may participate in maternal functions. PalkovitsUsdin M, Dobolyi TB, rat TIP39 A.Paralemniscal in dams induced is and in the suckling-induced prolactin release in rat. peptide Tuberoinfundibular of 39 residues is expression ofbrain.TIP39 in the rat 612-619. pupdevelopment. postnatal affects hormone 2receptor motivation. neuropeptide Thalamic mediatingA. of theeffects nursing onlactation maternaland prolactin. ProcAcad Natl Sci US A 39residues in of peptide nociception. tuberoinfundibular involvement of evidence for PTH2-receptor agonist from hypothalamus.PTH2-receptor agonist from 547-566. peptide of 39 residues in the ratcentral nervous system. 1978; 76:493-500. urethane-anaesthetized lactatingin the prolactin rat. and oxytocin of Brain Res Psychoneuroendocrinology 1977; 119: 211-221. 2002;99:1651-1656. J CompNeurol Brain Struct Funct 2013. Postnatal development and gender-dependent M, Usdin TB. Anatomical TB. physiological Usdin M, and nak M, Domokos D, Renner E, Gallatz K, Gallatz E, Renner DomokosD, M, nak sion and distribution of tuberoinfundibular oftuberoinfundibular distribution sion and Palkovits M, Nagy GM, NagyGM, Dobolyi A.Palkovits M, Nat Neurosci nuclei rats. non-lactating female Couldin activated duringand participates lactation activated incerta and the supraopticdecussations the incerta and Endocrinology Neurochem Res 2006; 498: 375-389. 2012;217:323-335. J Neuroendocrinol 1999;2:941-943. J CompNeurol 2010;151:5830-5840. 2010; 35: 2078-2085. Endocrine J Endocrinol J 2003; 455: 2003; 2011; 2011; 23: 2010;

Accepted Article This isbyarticle protected reserved. copyright. Allrights common motor nipple: the gets to neonatalrat the How WP. D,Smotherman 114 Eilam ID.112 Bosch Maternal R, OJ, behaviour Neumann Pfortsch is Landgraf J, Beiderbeck DI, C P, PerksS,RJ, ShanksN, Wood 111 Windle 107 Dobolyi A,Palkovits Usdin M, TB. The TIP39-PTH2 system: unique receptor 118 Terkel J, Damassa Sawyer J,118 Terkel Damassa DA, CH. fromrats Ultrasonic cries stimulate infant prolactin S,117 NagasawaOkabe Kihara T, Kato M, T, M, KoshidaHarada N, K, Mogi Kikusui T. 116 Hashimoto H, Saito TR,Furudate S,Takahashi KW. Prolactin levels maternaland CJ,115 FlemingWalsh AS,Lee A,Magnus Neumannis an vasopressin113 BoschOJ, ID. Brain MuschBredewold Slattery OJ, W, R, 110 Bosch populationsSmith Neural MS. Chen P, 109 Li C, Kosaka T.Medioventral part 108 K, Motomura mechanisms. brainstem peptidergic cellgroupsand th the in exposed postpartumrats. somatosensory desensitization on Fos-like Psychobiol modules and their intheinvolvement expression early of motor behavior. independentof dams' trait anxiety. the in rat. terminalis stria associated vasopressin with in theme release 9: 407-414. activity. maternal during rats non-disrupted lactating female SL. Endocrine and behavioural to responses postpartum moodfor disorder. HPA activity axis impairsand maternal care in 117-129. sucklingstimulusby by asdemonstrated the cFos expression. Chem Neuroanat releaselactating in mothers. mice. Pup odorandultrasonic vocalizations synergis 312. bybehavior induced vocalizations ultrasonic of theratpup. Behav Neurosci 1998;32:57-66. Prog Neurobiol 2011; 42: 192-209. 2013; 127:432-438. Behav Neurosci J Neuroendocrinol Horm Behav 2010; 90:29-59. 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Allrights Perez124 DelCerroMC,RosenblattJS, MA, Izquierdo Johnson BM,Pacheco P,Komisaruk motherhood. expectant adapting The brain: JA. for Russell PJ, 123 Brunton 119 Campeau S, Watson Jr. SJ, Connections of 128 Fleming AS,Walsh C. Neuropsychology matern of area, regions preoptic and hypothalamus within the expression of FosSM. 127 Luckman 126 Lonstein JS,Simmons DA,Swann JM, Stern Forebrain JM. expression of due c-fos to 125 Febo M, Numan M, CF.Functional resonance Ferris magnetic imaging shows oxytocin of mediation Olfactory M. Keller 122 Levy F, 120 JS.Fleming AS,Rosenblatt Olfactory behavior of regulation maternal I. in rats. Effects of 130 Lonstein JS,Greco130 Lonstein VriesJM B,De Stern GJ, 129 Lonstein GJ. Maternal behaviJS, De Vries 121 Kinsley CH,Bridges RS. Morphine treatmen study combined with Fos expression. axis in response to audiogenic stress inrats: an anterograde andretrograde tract tracing ofactivation in nuclei putativelyinvolved rat. rat. BR. 2-deoxyglucose Brain related to levels 2008; 9:11-25. species. activates brain regionsactivates brain suckling. associated with mother-pup bonding during 331-347. preferences male for rats. pup andadult odors infemale females. olfactory removal experienced bulb in inexperiencedand lactating andcycling Neuroendocrinology c-fos activity estrogenwithin receptor al interactions. during mother-litter brainstemparturition.and during pregnancy active maternal behaviour in lactating rats. Neurosci 2000; 100:557-568. nucleus of the stria terminalis, and ventrocaudal periaqueductal gray. glutamate decarboxylase-synthesizingof neurons Brain Res Behav Brain Res Behav 2005;25:11637-11644. J Comp Physiol Psychol 1995; 696: 213-220. 2000; 72:91-101. 2009;200:336-345. Psychoneuroendocrinology 1974; 86: 221-232. J Comp Neurol J Comp some auditory-responsive posterior thalamic posterior some auditory-responsive maternal behavior in selectedmammalian behavior maternal , Blaustein JD. 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Accepted Article This isbyarticle protected reserved. copyright. Allrights 131 Kalinichev M, Rosenblatt JS, Nakabeppu Y, 133 Stack EC, Numan The133 Stack EC,M. temporalcourse Numan of potential Amylin neuropeptide anovel Cservenak is M, Dobolyi with A. ER, 132 Szabo 134 Lin S, SH,Miyata W, Weng Matsunaga Ichikawa W, J, K, Furuya Nakashima T, 138 Brooks PJ, Lund PK, Stumpf WE, Pedersen Stumpf WE, CA. OxytocinLundPJ, Messenger Acid138 Brooks PK, Ribonucleic 137 Driessen TM, Eisinger Zhao BE, C, Stevenson SA, SaulMC, SC. Gammie Genes KatoKO,136 Kuroda PontonA, T.ERK-FosBY, Meaney Uetani N, Fortin MJ, signaling in 135 BrownYe H, JR, Bronson Greenberg RT, Adefect Dikkes in P, nurturing ME. inmice 140 Knollema S, Brown ER, Vale W, Sawchenko W, Vale Brown ER, S, Knollema 140 area.medial preoptic the in levels oxytocin mRNAregulation of The PJ. 139 Brooks 141 MC,Garcia Lopez Gualillo M, O, Seoane LM, Dieguez Senaris C, RM. Hypothalamic pup-mediated maternal behavior in juvenile and adult rats. and rats. adult juvenile behavior in maternal pup-mediated immunoreactivity like involved neuronal reveals populations forebrain in differentially prolonged mother--young interactions. prolonged mother--young interactions. medial preoptic andarea otherbrainre maternal functions in the rat. 45-78. parturition and lactation. hy area, preoptic rat the FosB Fos in and Kiyohara T.Comparison theexpressiof Levels in the MedialArea PreopticLevelsIncreasedthe are in Lactation. During 2014; 15:11. deficits. social disorders with and other to autism related are phenotype expression pre showingmedial inthe altered Mol Cell Neurosci dorsal MPOA playsneurons a rolemajor in the initiation of parental behavior in mice. fosB. gene early immediate the lacking expression in lactating rats. Acid andPeptide messenger prepro-melanin-concentrating ribonucleic hormone of Relationship to maternal inbehavior rat.the 1990; 2:621-626. rat: role of prolactin. rat: roleofprolactin. the in lactation and during pregnancy mRNA MCH, prepro-orexin and NPY, of levels 2007; 36:121-131. FASEB J Neurosci Res J Neuroendocrinol FASEB J FASEB 2003; 17: 1392-1400. 2012; 26:272-281. 1998; 32:333-341. Behav Neurosci Cell pothalamus and brainstem during pregnancy, during pregnancy, and brainstem pothalamus Morrell JI. Induction of c-fos-like and fosB- and of c-fos-like JI.Induction Morrell on of two immediate early gene proteins,geneimmediate early on of two PE. Novel hypothalamic and preoptic sites preoptic hypothalamic and Novel PE. expression of c-Fos and the Fos Bwithin gions of femalegions of rats postpartum during 1996; 86:297-309. Ann N Y Acad Sci Y Acad N Ann optic area in the highlyoptic area maternal inthe social 1992; 4: 709-717. 2000; 114:609-622. J CompNeurol 1992;652: 271-285. J Neuroendocrinol BMC Neurosci 2000; 416: 2000;416:

Accepted Article 146 Driessen TM, Zhao C, Whittlinger A, Williams H, Gammie SC. Gammie Williams CNS H, Zhao Endogenous C,Whittlinger TM, 146 Driessen A, regulators145 Dobolyi Novel potential maternal A. of during adaptations lactation: 144 Leffert JD, Newgard Okamoto CB, H, Milburn JL,KL. LuskeyRat amylin: cloning and This isbyarticle protected reserved. copyright. Allrights G. Hypothalamic and SL, Aguilera Ma Lightman IngramCD, AP, Costa X, 148 da Lee G, SC,147 Gammie MA, SA, Stevenson Scotti Gessay GM. Neurotensin induced Egr-1 dams. rat143 Dobolyi in Central and itsamylin expression induction A. Donato TA,142 Rondini Bde J,Jr., Rodrigues C, 149 Pedersen CA, Caldwell JD, McGuire M,CA, McGuire Caldwell JD, 149 Pedersen 150 Pi X,Voogt JL. ofsuckling Effect on 151 Pi X, 151 X, Voogt Pi suckling-induced changes JL. Mechanisms for inexpressionof prolactin 152 Meddle SL, Bishop VR, Gkoumassi E, van Leeuwen FW, Douglas AJ. Dynamic changesDynamic AJ. Douglas FW, Leeuwen van Gkoumassi E, SL, BishopVR, 152 Meddle 154 Du J,Yang cellfunction. inhematopoieticstem YC. Cited2 153 SC, HasenGammie NS, AwadTA, Auger JessenAP, HM, Panksepp Bronikowski JB, Postpartum Period Mice. inOutbred Postpartum NeurotensinExpressionNeurotensinIsAltered of and Receptors during the peptidetuberoinfundibular 39 and amylin. 3127-3130. tissue-specific expression inpancreatic islets. 111: 1490-1500. hormone during lactation. and ofmedial preopticconnections area expression thestress-hyporesponsivein la amygdaloidcorticotropin-releasing (CRH)and CRHreceptor-1 hormone mRNA activity altered periodpostpartum is the mice. in in Mol Brain Res Mol Brain inhibits maternal behavior maternalinhibits and induces pup-killing. hypothalamus of therat. receptor receptor in the hypothalamus ofthe rat. lactating Endocrinology andactiva expression receptor in oxytocin 20: 301-307. virginrandomly cycling mice. 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Experience-dependent cell survival theExperience-dependent in D, cell LevyFleming AS. F, Chatterjee EM, 162 Akbari experience of maternal effects maternal circuit: Plasticityin the M. Korsmit 161 FlemingAS, This isbyarticle protected reserved. copyright. Allrights Leon-Guerrero J, Diazde 166 Cortes-Mendoza 165 RiccioA. Dynamic epigenetic in regulation enzymes, neurons: stimuli signaling and 164 Meaney MJ, Ferguson-Smith AC. Epigeneticregulationof neural the transcriptome: the Sweatt163 LevensonJD. Epigenetic JM, mechanisms information. memory JE. Swain The human Mayes FeldmanR, LC, of JF, X, plasticity Wang 160 Kim Leckman P, 159 Kinsley CH, KG. Reproduction-induceLambert 157 Franz JR,LeoRJ,Steuer MA,of Kristalhypothalamic MB. Effects knife cuts and Z,Kent WestwoodT, CF, Kaiguo M, Razak ShamsBelay HT, EM, S, 156 Akbari A,Schneider155 BL, Oueslati 158 Shams S, Pawluski JL, Chatterjee-Chakraborty Neuroendocrinol neuronal associatedalterations with the production care ofand offspring. transcription. transcription. Shaping plasticity: synaptic theroleof acti ratbrain. maternal Behav Neurosci postpartum rat.on Fos-Lir the limbic, structures in cortical inhypothalamic, and virgin female rats: A microarray study. expression in the medial preoptic area a Sokolowski Fleming MB, of effects The parity behaviorAS. ongenematernal and ProcAcad Natl Sci US A selective autophagic alpha-synuclein clearance suppresses and toxicity its vivo. in pathways. meaning ofthemarks. 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Behav Neurosci nd the and medialamygdalainpostpartum brain anatomy during the early postpartum brain anatomyduring early the vity-mediated vity-mediated epigenetic regulation on gene Physiol BehavPhysiol M, M, Oatley H, Mastroianni A, Fleming AS. d neuroplasticity: natural behavioural and and behavioural d neuroplasticity:natural S, Pedraza-Alva G, Perez-Martinez L.G, Perez-Martinez Pedraza-AlvaS, 2013; 127: 913-922. 1986; 38:629-640. Nat Rev J Accepted Article This isbyarticle protected reserved. copyright. Allrights 173 Jin SA. JA,Thomas SH, Blendy Cyclic response element-binding AMP is protein Neurobehavioral UetaniKO,172 Kurodabasis N, Meaney T. MJ, Kato of the impaired 171 StevensStolzenberg DS, JS, Rissman EF. improvements Experience-facilitated inpup 170 M, RosenblattNuman JS, Komisaruk BR. Medial preoptic andarea onsetof maternal 169 StolzenbergDS,McKenna Keough Hancock Numan JB, R, MJ, Numan S, M. 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Accepted Article This isbyarticle protected reserved. copyright. Allrights altera Epigenetic KM. 188 Zhao FanL,Frick Z, M. CBP Mayford Rosenfeld hist 180 Korzus MG, E, Regulation JD. DL, Sweatt Molfese MA, Trinh KD, KJ, Brown Levenson O'Riordan 179 JM, 187 Malvaez M, Sanchis-Segura187 Malvaez M, C,VoD, Ly RM, DP, of Reolon Modulation long-termWood MA.GK,AR, Barrett 186 Stefanko 185 VecseyHawk CG, JD, Lattal KM, Stein JM, Fabian Attner SA, MA, Cabrera SM, 184 F, Hollis Wang H, Dietz D, Gunjan A, Kabbaj M. The effects of repeated social defeat on Lin SH, 183 Yeh Acetylation CH, PW. Gean nuclearof inratamygdalafactor-kappaB 182 JM, MalleretAlarcon G,TouzaniK, Vr KharchenkoShevchenkoAB, OA, 181 Danilova KG, of memory consolidation.of memory component ofmemory consolidation. 2004; 279:40545-40559. hippocampus. the in formation duringmemory acetylation histone of 5037-5046. of memory long-term modulation modification. via chromatin Biol Psychiatry Biol of place cocaine-inducedpreference. conditioned modification facilitates extinction long-term depressive-like behavior ands long-term depressive-like 2004; 65:1286-1292. memory. fear of retention short-term butnot improves long-term 42: 947-959. the cognitive deficit inRubinstein-Taybi andits syndrome amelioration. acetylation,Chromatin for in LTPCBP+/- amodel impaired mice: and memory, are the inNetwork Mollusk Lucorum. Helix UponLearningin Induced is Asymmetrically 106: 9447-9452. memory for object recognition via HDAC inhibition. activation. memoryenhance andsynaptic plasticity McDonough CB,BrindlePK, Abel T, Wood 69-77. Sprague-Dawley rats. male hippocampus in J Neurosci 2010; 67: 36-43. 2007; 27:6128-6140. Proc NatlAcad SciSU A Lattal KM, Wood MA. Modulation of chromatin of chromatin Modulation KM,Lattal WoodMA. Neuron Front Behav Neurosci tions regulate estradiol-inducedtions regulate enhancement onskaya S, Ishii S, Kandel onskaya S,IshiiKandel A.ER, Barco via CREB:CBP-dependent transcriptionalvia CREB:CBP-dependent hort-term histone modifications histone inthe hort-term Identified Neurons of the Food Aversion 2004; 42:961-972. one acetyltransferase activity is a critical a acetyltransferaseis activityone Grinkevich LN.Histone H3 Acetylation Psychopharmacology (Berl) MA. HistoneMA. deacetylase inhibitors 2010; 107: 5605-5610. Proc Natl AcadSciS A U Natl Proc 2010; 4: 180. J NeurosciJ Mol Pharmacol Neuron J Biol Chem J Biol 2010;211: 2010; 30: 2010; 2009; 2004;

Accepted Article on inthe pup retrieval T-maze invirgin micewere versus postpartum adapted from were maternalexposure. experience ovary Virgin mice Datacomparing effectsof intact. the exposure was T-maze separated by 24-hours. pupretrieval oninduce themaze. Exposureto required to of HDACi experience of reducedthe an amount Administration mice. postpartum behaviour similar as in resulted (4 maze, butexperience exposures) onthe infants threshold mice with no expe experience orsub-threshold Fig. 3.Histone deacetylase (HDACi)inhibition projectionof these neurones to the MPOA. drawing The shows Tip39-expressingneurones. the represent right the Large dotson cell inthe PIL.bodies B:Tip39-immunoreactive terminals. Tip39 fibre the right represent drawingon dots MPOA. the Small in the 39residues in peptideof (Tip39) tuberoinfundibular terminals containing fibre of distribution The A: (MPOA). preoptic area medial Fig. 2.The projection the from intralaminar posterior of complex thalamusthe (PIL) tothe a prolactin-sensitive neuron. Data are from gonadotrophin-releasingsensitive hormoneneuronla immunohistochemistry using STAT5the MPOA in the lateral ventricles). Remaining panels il MPOA lateral (including vBNST) sept well as as throughout the evident extensivethe section, expression with of film shows autoradiographic labelling dots)overnumerous neurones (black This isbyarticle protected reserved. copyright. Allrights shows S Fig. 1. receptors Prolactin widelyare expressed in the MPOA. The (toppanel,figure left) Figure legends of hormone- ofregulation estrogen:epigenetic Fan The L. epigenetics ZhaoZ, KM, 190 Frick acetylationKM. histone Hippocampal MI, BoulwareFrick AM, L, Fortress Z, Fan 189 Zhao induced memory enhancement. memory induced recognition. estradiol-induced object the enhancement of recognition and object regulates 35 -labelling of prolactin receptor mRNA by in situ hybridisation, showing strong hybridisation, mRNA in situ receptor by of prolactin -labelling J Neurosci 2012; 32: 2344-2351. Epigenetics ( 67,68 lustrate prolactin-i rience (2 exposures) we (2 rience (blue counterstain)intheMPOA. Theinset um and choroid plexus (dark staining within staining within plexus (dark choroid and um testing tookplace 24hours thelast after potentiates maternalresponsiveness. Virgin ) foster each pupslasted 2hoursfor and . 2011;6:675-680. (black nuclear staining), with a prolactin- witha nuclear staining), (black belled (brown staining) as an example of example as an (brownstaining) belled nduced phosphorylation of nduced phosphorylation re not responsive tonot responsive re ( 174 ) . Accepted Article This isbyarticle protected reserved. copyright. Allrights month later[manuscript review].{Stolzenberg, 2012under #152} pup experiencethreshold pup maintains retrieva pupexperience after 24h pupretrieval expression and gene effects treatment HDACi (C)-(D) data]. [unpublished pupexperience after 5h on T-maze retrieval or pup MPOA in on expression gene HDACi-treatment effect of No (A)-(B) Fig. 4. SEM. oradapted were from control HDACi administration after maternal in onpupretrieval T-maze experience of the Data theeffects comparing l responses l 1 withalong Esr2expression ( 171 ( ) 171 . All data. All are presented Meanas ± ) . (E)-(F) HDACi during sub- during HDACi (E)-(F) .

Accepted Article This isbyarticle protected reserved. copyright. Allrights

Accepted Article This isbyarticle protected reserved. copyright. Allrights

Accepted Article This isbyarticle protected reserved. copyright. Allrights