nagasawa oxitocin mother infant

REVIEW ARTICLEpublished: 28 February 2012

doi: 10.3389/fnhum.2012.00031

Oxytocin and mutual communication in mother-infantbondingMiho Nagasawa , Shota Okabe , Kazutaka Mogi and Takefumi Kikusui*

Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Kanagawa-ken, Japan

Edited by:Bert Timmermans, UniversityHospital Cologne, Germany

Reviewed by:Rebecca Elliott, University ofManchester, UKJack van Honk, Utrecht University,Netherlands

*Correspondence:Takefumi Kikusui, Department ofAnimal Science and Biotechnology,Azabu University, 11771Fuchinobe, Chuoh-ku, Sagamihara,Kanagawa-ken 2525201, Japan.e-mail: [email protected]

Mother-infant bonding is universal to all mammalian species. In this review, we describethe manner in which reciprocal communication between the mother and infant leadsto mother-infant bonding in rodents. In rats and mice, mother-infant bond formation isreinforced by various social stimuli, such as tactile stimuli and ultrasonic vocalizations(USVs) from the pups to the mother, and feeding and tactile stimulation from the motherto the pups. Some evidence suggests that mother and infant can develop a cross-modalsensory recognition of their counterpart during this bonding process. Neurochemically,oxytocin in the neural system plays a pivotal role in each side of the mother-infant bondingprocess, although the mechanisms underlying bond formation in the brains of infants hasnot yet been clarified. Impairment of mother-infant bonding, that is, deprivation of socialstimuli from the mother, strongly influences offspring sociality, includingmaternal behaviortoward their own offspring in their adulthood, implying a non-genomic transmissionof maternal environment, even in rodents. The comparative understanding of cognitivefunctions between mother and infants, and the biological mechanisms involved inmother-infant bonding may help us understand psychiatric disorders associated withmother-infant relationships.

Keywords: mother-infant, bonding, oxytocin, maternal behavior

INTRODUCTIONSympathy is much strengthened by habit. In however com-plex a manner this feeling may have originated, as it is one ofhigh importance to all those animals which aid and defend oneanother, it will have been increased through natural selection;for those communities, which included the greatest number ofthe most sympathetic members, would flourish best, and rearthe greatest number of offspring (Charles Darwin, Descent ofMan, 1871).

During the process of mammalian evolution, animals devel-oped sympathetic neural and behavioral systems, in which forexample, weak and helpless member of individuals are protectedand nurtured by other group members. This phenomenon ismostly clearly observed in mother-infant relationship, such asmother infant bonding (Broad et al., 2006).

Social bonds like mother-infant bonding are hypothetical con-structs and cannot be measured directly. However, there are sev-eral behavioral and physiological measures that have been used asindices of social bonding, including increased physical proximity(Hennessy, 1997), behavioral distress, or elevated corticosteroidlevels following separation from the bonding partner (Ziegleret al., 1995; Norcross and Newman, 1999). Social bonding hasnot yet been clearly defined, but it has been proposed that socialbonding can be distinguished neurochemically from social affili-ation, in which corticosteroid elevation does not occur followingseparation (DeVries, 2002). Moreover, subsequent reunion withconspecific animals ameliorates separation distress or aversiveexperiences. This phenomenon is termed as social buffering

(Kikusui et al., 2006); its effect depends on the degree of affiliationwith the partner and is strongest with the bonding partner, suchas that seen in the dyad of mother-infant.

Mother-infant bonding is unique with respect to its influenceon the offsprings future. This idea was first suggested in humansby Bowlbys attachment theory (Bowlby, 1969). Subsequently,many psychological and animal research studies have reportedthat child abuse or childhood neglect are correlated with severe,deleterious long-term effects on the childs cognitive, socio-emotional, and behavioral development (Hildyard and Wolfe,2002). The developmental effects of mother-infant bonding havealso been indicated experimentally in non-human primates. Forexample, in a study by Winslow et al. (2003), mother-reared andhuman nursery-reared monkeys were subjected to a novel envi-ronment with or without a cage mate. The monkeys reared bytheir mothers exhibited a reduced cortisol response when a socialpartner was available, whereas nursery-reared monkeys did not.In nursery-reared monkeys, social contact, such as allogroom-ing and inter-male mounting, was drastically reduced. Thesefindings suggest that the social buffering effect is impaired asnursery-reared monkeys had experienced less social contact in anovel environment. Thus, impairment of mother-infant bondingstrongly influences offspring sociality in human and non-humanprimates (Agid et al., 1999; Heim and Nemeroff, 2001), althoughdetails of the underlyingmechanisms are not yet fully understood.Additionally, because the bonding formation is established duringthe process of social communication between mother and infants,social cognition has a pivotal influence on the bonding process

Frontiers in Human Neuroscience www.frontiersin.org February 2012 | Volume 6 | Article 31 | 1

HUMAN NEUROSCIENCE

Nagasawa et al. Neurobiology of mother-infant bonding

(Ross and Young, 2009). However, little information has beenobtained regarding the role of each social cue in the formationof bonds.

In the present review, we describe the manner in which mutualcommunication between mother and infant leads to mother-infant bonding in rodents. We emphasize the significance of theconserved oxytocin neural system in mother-infant bond infor-mation, with several studies having shown that oxytocin playsa fundamental role in establishing this bond (Kendrick, 2000;Young et al., 2001; Wang and Aragona, 2004; Young and Wang,2004). Other neurotransmitters that regulated social bonding,such as opioids and dopamine are also important, however, wewould concede these issues in other articles. We also review theeffects of deprivation of mother-infant bonding, by studying theconsequences of early weaning on neurobehavioral developmentin rodent offspring. Intensive maternal care has evolved and hasbeen preserved, uniquely in mammals, and it is highly proba-ble that mother-infant bonding is universal to all mammalianspecies. These comparative points of view provide insights intothe biological significance ofmother-infant bonding inmammals;a comparative understanding of the developmental consequencesof this bonding and its underlying mechanisms, even in rodents,may help in our treatment or prevention of disorders associatedwith child abuse or childhood neglect (Agid et al., 1999; Heim andNemeroff, 2001).

SOCIAL CUES FROM INFANTS TO MOTHERAlthough rodent pups have limited thermoregulatory and phys-ical capabilities during the first 1 or 2 postnatal weeks, theyproduce a variety of signals to their mother, such as olfactoryand auditory signals (Levy et al., 2004; Ehret, 2005). These socialcues play a very important role of facilitating maternal care andensuring formation of the mother-infant bond.

Ultrasonic vocalizations (USVs) are among the repertoire ofauditory outputs from rodent pups. When infant rodents are iso-lated from their mother and/or littermates, they cool rapidly andemit USVs (Branchi et al., 2001; Ehret, 2005). The incidence ofpup USVs generally increases during the first 67 days of life.These vocalizations peak around day 8, after which they start todecrease, finally disappearing at 2 weeks after birth (Elwood andKeeling, 1982). Although vocalizations ranges differ between miceand rats, (the range of mice was approximately 3080 kHz, andthat of rats was approximately 3050 kHz), many studies haveshown that pup USVs could stimulate maternal behavior suchas searching for/retrieving pups in both species (Brown, 1973;Branchi et al., 2001). In a previous study, we showed that mothermice responded to pup USVs reproduced by ultrasonic speakers,but they did not respond to other synthesized ultrasounds suchas double-duration USVs (Uematsu et al., 2007), indicating thatmother mice can recognize the specific pattern of pup USVs inorder to retrieve their pups and return them to the nest. Moreover,we showed that social experiences such as mating or parent-ing enhanced both retrieving behavior and the responses to pupUSVs (Okabe et al., 2010). These results indicate that the mothermice showed specific responsiveness to pup USVs, and this soundcontributed to the induction of maternal behavior. Interestingly,electrophysiological studies reported that the auditory cortex of

mother mice showed specific activation in response to pup USVs,as compared to non-experienced (those having never had a lit-ter) female mice (Liu and Schreiner, 2007; Cohen et al., 2011).Therefore, maternal behavior expression can be at least partiallyregulated by functional changes in the sensory cortical representa-tion of pupUSVs.However, there is a critical missing link betweencortical responses to pupUSVs and expression of maternal behav-ior, which is probably regulated by neurons in the medial preopticarea (mPOA) of the hypothalamus (Numan, 2007).

Olfactory cues from pups were also found to be extremelyimportant in stimulating maternal behavior in rodents. Therehave been many studies showing the behavioral or neuralresponses to pup odor, and it was shown that the role of olfac-tory inputs in maternal behavior is different between rats andmice (Levy et al., 2004). In rats, olfactory stimuli clearly inhibitmaternal behavior before parturition, a phenomenon termedneophobia. After parturition, however, mother rats drasticallychange their behavior; they develop a high level of responsivenessto olfactory cues from their pups, and show intensive maternalbehavior toward pups (Fleming et al., 1989; Kinsley and Bridges,1990). This suggests that the experience of partum and the hor-monal changes accompanying pregnancy and partum induce thismaternal behavior. Once they start displaying maternal behav-ior, mother rats show a high preference for bedding soiled bypups over clean bedding (Kinsley and Bridges, 1990). In addi-tion, when the pups heads were rubbed with their anogenitalsmears and the anogenital areas were cleaned, the dams lickedonly the head region (Brouette-Lahlou et al., 1991), suggestingthat odors emitted from the anogenital area stimulate licking andgrooming behavior in the mother rats. Although the behavioralevidence clearly shows that olfaction plays an important orga-nizational role in the induction of maternal behavior, lesionsof the main and the accessory olfactory system, or preventingaccess to the olfactory cues from the pups, produces contra-dictory or inconsistent results. Several studies have shown thatpup retrieval was somewhat impaired by lesions to the olfac-tory mucosa caused by zinc sulfate (Benuck and Rowe, 1975).However, other studies showed that these manipulations did notdecrease maternal behavior (Jirik-Babb et al., 1984; Kolunie andStern, 1995). Similarly, removal of the vomeronasal organ, suchas vomeronasal nerve cuts or olfactory bulbectomy, did not fullydisrupt maternal behavior (Jirik-Babb et al., 1984; Morgan et al.,1992). These results suggest that, in rats, olfaction is not cru-cial for the successful care of pups since the anosmic motherapparently easily compensates for the loss of this sensory input.

Olfactory stimuli appear to play a more significant role in micethan in rats. Mother mice failed to show any maternal behaviorfollowing bulbectomy, or anosmia induced by either nasal irri-gation of zinc sulfate or by depletion of noradrenaline withinthe main olfactory bulb (Levy et al., 2004). Moreover, Wangrecently showed that type 3 adenylyl cyclase (AC3), which is oneamong a multigene family of odorant receptors, knockout moth-ers did not show any pup retrieving or nest building behaviorat all (Wang and Storm, 2010). From these lesion and geneticdeletion studies, it can be surmised that olfactory stimuli areessential for the induction and maintenance of maternal behav-iors in mice. Interestingly, in female mice which had a previous



maternal experience, pup-killing induced by peripheral anosmiawas prevented (Seegal and Denenberg, 1974), indicating that theprimiparous mother depends profoundly on olfactory informa-tion for the induction of maternal behavior, as compared withthe multiparous mother. However, experienced mother mice areable to use multiple sensory inputs and compensate for the loss ofone type of sensory cues and still show maternal behavior.

In both mice and rats, maternal behavior is not regulated by asingle sensory input. Mothers can use both auditory and olfactorycues to identify and locate their pups. For example, rat motherscan detect pupUSVs, and these pupUSVs serve as a potent stimu-lus for the induction of maternal retrieving behavior, particularlywhen presented together with pup odors (Farrell and Alberts,2002). Therefore, the integration of multisensory stimulus inputsfrom pups triggers discrimination and retrieving of pups. Cohenrecently showed that exposure to pups body odor enhances theneuronal response to pup USVs in the primary auditory cortex ofmother mice (Cohen et al., 2011). Additionally, they showed thatthe pup retrieving behavior of mother mice decreased when thepups were washed with warm water (Cohen et al., 2011).

In summary, multisensory stimuli from pups activates the fullrange of maternal behavior, although there are no current reportsof direct anatomical or neural mechanisms that could explainthis multisensory integration. Further studies of the neurobio-logical mechanisms for the integration of olfactory, auditory, andother social stimuli may lead to a better understanding of the roleof sensory modalities to induce maternal behavior, which wouldstrengthen the bond between mothers and their pups.

SOCIAL CUES FROMMOTHER TO INFANTThe neonatal infants are innately attracted to their mother. Forinstance, odors emitted from the nipple area have a specific char-acter that attracts both rodent and human new-born infants(Porter and Winberg, 1999). Therefore, the infant can suckle thenipple just after the birth after which infant animals can recog-nize their own mother using chemicals cues, probably becausethe infant can memorize the mothers individual odors associ-ated with suckling (Moriceau and Sullivan, 2004). This type ofodor memory is regulated by the neuropeptide oxytocin (Nowaket al., 2000, 2011). Oxytocin is released in the infant brain whilesuckling, and it acts on the olfactory bulb. In the olfactory bulb,oxytocin can enhance memory-related neural activation throughlong-term potentiation (Fang et al., 2008). Therefore, odors fromthe mother have a fundamental ability to attract her infants.

Physical and tactile stimuli from mother to infants have beenindicated to have a great impact on infant brain development. Thepioneer study in this field was conducted by Dr. Meaneys groupatMcGill University. They found that rat pups that received inten-sive tactile stimulation, such as licking and grooming from theirmother, showed lower stress responses during their adulthood(Liu et al., 1997; Meaney, 2001). Pups raised by higher licking andgrooming mothers had a higher level of glucocorticoid receptorexpression in the hippocampus, and showed an enhanced neg-ative feedback ability along the hypothalamus-pituitary-adrenalaxis of stress responses. Such tactile stimulation releases 5HTin the hippocampus of pups, which epigenetically modulates theCpG islands of glucocorticoid receptors (Weaver et al., 2004a,b).

These effects of tactile stimulation are most important just afterbirth, because the epigenetic changes of DNA methylation aredetermined within the first three days of the neonatal period.However, themother-infant relationship during the later neonatalperiod also produces a long-lasting modulation of infant behav-ior, implying that not only the tactile stimulation, but other socialcues frommother to infant have a significant role on the develop-ment of pups (Kikusui and Mori, 2009; Curley et al., 2010; Mogiet al., 2011).

Although the specific cues from mother to infant have notyet been identified, the most well studied model is a maternaldeprivation paradigm. When mutually strongly bonded moth-ers and young are separated prematurely, bouts of reinstatementbehavior such as locomotion (searching) and distress vocalsare exhibited by both the mother and the young, interspersedwith periods of energy-conserving depression in most mam-mals (Panksepp, 2004), indicating the importance of mother-infant bonding across species. Bowlby referred to these phases asprotest and despair, respectively (Bowlby, 1969). The impactof deprivation of mother-infant bonding is not temporary, andthe effects can be observed much later in life. In rat and mousemodels, maternally deprived animals show higher anxiety andstress responses, as well as lower learning and memory abili-ties in their adulthood (Levine, 1967; Plotsky and Meaney, 1993;Plotsky et al., 1993; Liu et al., 2000), suggesting that the epige-netic modulation of the brain function by maternal deprivationhas long-lasting effects. We have studied the effects of early wean-ing, where the animals are weaned one week earlier than normal,and found that early weaned mice and rats showed higher lev-els of anxiety-related behaviors, as well as higher stress responsesin their adulthood, even though no growth retardation wasobserved (Kikusui et al., 2004; Kikusui and Mori, 2009; Mogiet al., 2011). These results show that not only the early neonatalperiod, but also the mother-infant relationship in the later lac-tating period, has a profound impact on brain development inthe infant.

When early-weaned male mice are grouped together, highlevels of agonistic behavior, accompanied by an elevation in glu-cocorticoid levels were found (Nakamura et al., 2008). In youngmale elephants, following the loss of their mothers and otherfamily members due to poaching, unusually violent behavior hasbeen attributed to the termination of social interaction with olderelephants, including parents, and the loss of behavioral inhi-bition that would normally result from the presence of oldermales (Slotow et al., 2000). The critical role of older males innormal social development was clearly shown when researchersre-introduced older bulls to quell the young males violence, andhyperaggression and abnormally early musth cycles (periods ofsexual activity and hormonal shifts) both ceased. Scott and Fuller(1965) studied behavioral development in dogs, and found thatthe socialization period, during which puppies stop suckling butcontinue to live with their parents, was crucial to their behavioraland social development. The social cues from mother or adult tojuvenile animals responsible for these phenomena has not beendetermined, and we should consider the influence of social envi-ronment on the development of normal brain function in juvenileanimals.



NEUROENDOCRINE REGULATION OF MOTHER-PUPINTERACTIONSFemale rats or mice that have never given birth usually with-draw from or avoid pups, and it has been intensively studiedhow neuroendocrine changes at parturition act to enhance theneural mechanisms responsible for maternal behavior, such asthose occurring in the mPOA of the hypothalamus (Numan andStolzenberg, 2009). A great deal of evidence suggests that the oxy-tocin neuroendocrine system plays a key role in the initiationof maternal behavior following birth. It is now clear that oxy-tocin, which is synthesized in the neurons of the hypothalamus(specifically in the paraventricular nucleus [PVN] and supraop-tic nucleus), is released not only into the general circulation fromthe posterior pituitary, but centrally during vaginal stimulationand parturition, to act upon oxytocin receptors widely expressedthroughout the central nervous system (Forsling, 1986; Barberisand Tribollet, 1996; Gimpl and Fahrenholz, 2001). Moreover,maternal behavior was found to be greatly impaired in post-parturient rats that received PVN lesions during pregnancy (Inseland Harbaugh, 1989), and in female rats administrated an oxy-tocin antagonist immediately after parturition (van Leengoedet al., 1987). Furthermore, oxytocin receptors proliferate in manyforebrain areas including the mPOA, ventromedial hypothala-mus, and bed nucleus of the stria terminalis of female rats at thetime of partition (Jirikowski et al., 1989; Pedersen et al., 1994).These alterations in oxytocin receptor expression may be partiallyresponsible for the induction of maternal behavior, since intra-ventricular and mPOA infusion of oxytocin induces a rapid onsetof maternal behavior in virgin female rats (Pedersen and PrangeJr, 1979; Pedersen et al., 1994).

In rodent mothers, the maintenance of maternal behavior isdependent on stimuli from the pups. If new mothers are sepa-rated from their pups and not permitted to interact with them,their maternal responsiveness declines over the first postpartumweek (Orpen and Fleming, 1987). Among the various pup stim-uli, physical contact is thought to play an important role in themaintenance of maternal behavior. Suckling of the nipple is arepresentative stimulus in lactating females, because suckling isknown to stimulate oxytocin release not only into the periph-eral circulation to cause milk ejection, but also into the brain(Neumann et al., 1993). Several types of tactile stimuli such astouch or massage-like stroking and warmth have also been shownto stimulate oxytocin release in rats; however, these are not associ-ated with lactation physiology (Uvnas-Moberg et al., 1993; Agrenet al., 1995).

Although exteroceptive social cues from pups, such as infantsodors or vocalizations, may not have as strong an effect on thedevelopment of nurturance as physical stimuli (Stern, 1983), theydo play an important role in making mothers seek their pups outandmaintain proximity. The infants odors are used as not only anattractive signal to mothers, as described in previous sections, butalso for themothers recognition of their own infants (Ostermeyerand Elwood, 1983). As described above for rats, infants odorshave been shown to be quite aversive to females before partu-rition and lactation, whereas on the boundary of parturition,these odors become very potent attractive stimuli (Levy et al.,2004). This change in the mothers responsiveness is governed by

hormonal changes at parturition, and it is suggested that the oxy-tocin system participates primarily in this process. Pregnancy andparturition enhance the sensitivity and neural firing in the olfac-tory bulb in rats, and oxytocin infusion directly into the olfactorybulb increases the firing frequency and spontaneous excitatorypostsynaptic currents in granule cells (Yu et al., 1996) via bothpre- and postsynaptic mechanisms, a process integral to olfactoryrecognition memory (Engelmann et al., 1998; Dluzen et al., 2000;Osako et al., 2001). Similar to the responsiveness to pup odors,the response to pup USVs has also been shown to be far morepronounced in mothers than in nave females (Koch and Ehret,1989; Okabe et al., 2010); however, the neuroendocrine mecha-nisms responsible for this change in response to pup USVs hasnot been elucidated.

Oxytocin-induced maternal behavior is reinforced by infantsinnate attachment behaviors, i.e., vocalization or milk sucklingfor sustenance. Interestingly, it has been suggested that the oxy-tocin neuroendocrine system is also involved in these behaviorsin infants. Central administration of oxytocin has been foundto reduce the frequency of isolation-induced USV in young ratpups (Insel and Winslow, 1991), suggesting a possible role forcentral oxytocin in the affective calm response infants displayduring social contact. Central oxytocin also induces paw suckingin neonatal rats (Nelson and Alberts, 1997). These innate attach-ments regulated by oxytocin ensure the infants physical develop-ment, and the subsequent development of adequate attachmentbehaviors accompanied by growth of the pup. In return, ade-quate attachments maintain maternal behaviors in response topup stimuli.

SOCIAL EXPERIENCE MODULATING THE MOTHER-PUPINTERACTIONMaternal behavior is regulated by genetic and epigenetic back-grounds. Regarding epigenetic modulations of maternal behavior,non-genomic transmission has been indicated in a rat model(Champagne et al., 2001; Champagne and Meaney, 2001; Weaveret al., 2004a). As described above, pups that received higher lev-els and more intensive care from their mother in turn showedhigher licking and grooming behavior toward their own offspringafter delivery (Francis et al., 1999a,b). This behavioral transmis-sion was persistent even when the pups were cross-fostered toother mother rats; that is, when pups born to the lower lickingand grooming mother were cross-fostered to the higher lickingand grooming mother, they showed higher maternal care to theirown pups (Francis et al., 1999a,b). This transmission was clearlydemonstrated by the epigenetic modification of the estrogenreceptor genes in the mPOA in the hypothalamus (Champagneet al., 2001; Champagne and Meaney, 2001). The female rats thatreceived higher licking and grooming behavior from the mothershowed higher estrogen receptor expression in the same cells thatalso express oxytocin receptor. Estrogen receptor activation actsto induce oxytocin receptor expression, therefore, higher estrogenreceptor expression results in higher oxytocin receptor expres-sion. The oxytocin system in the mPOA is associated with theinduction of maternal behavior (Pedersen et al., 1994). Therefore,these epigenetic modulations are plausible candidates to cause theindividual differences in maternal behavior.



Early-weaned females also showed lower maternal behaviorwhen they became mothers (Kikusui et al., 2005). This may bebecause the early-weaned females were deprived maternal care inthe third week of the postnatal period, resulting in lower mater-nal behavior in their adulthood. Although the responsible socialcues frommother to infant mice in this model was not identified,it is suggested that not only the early neonatal period, but alsomother-infant interactions during the late lactating period canepigenetically modulate the maternal behavior. Another inter-esting model to aid our understanding of the significance ofsocial experience in the late neonatal period is the alloparentalcare experience in juvenile animals. For example, if the juvenileshave a chance to show maternal or paternal-like behavior towardtheir younger siblings (termed alloparental care), they will showhigher levels of nursing behavior toward their own offspring laterin life (Riedman, 1982). These phenomena are widely observedin mammals, but detailed analyses have focused mainly on pri-mates (Quiatt, 1979). In humans, similar mechanisms have beensuggested, but not clearly defined (Hrdy, 1999).

Social experience affects not only neonates or juveniles, butalso adult rodents in terms of maternal behavior. Unlike lactat-ing mothers, most sexually and parentally nave adult rodentsavoid physical contact with pups when they are first introducedto them (Terkel and Rosenblatt, 1971). Particularly noticeablein rats, [although juvenile and premature rats (1842 days old)will approach pups and initiate physical contact with unfamiliarpups], inexperienced adult rats show clear avoidance or attack-ing behavior toward unfamiliar pups (Terkel and Rosenblatt,1971). However, after 58 days of continuous cohabitation withdonor pups, they first become tolerant of proximate contact withpups, and then start caring for the pups, which includes licking,retrieving, crouching, and nest building (Rosenblatt, 1967). Thiscohabitation effect is termed pup sensitization. Once becomingfully parental by pup sensitization, virgin female rats can main-tain a high level of parental responsiveness for several weeks afterseparation from pups (Bridges and Scanlan, 2005).

In mice, virgin females are often said to be spontaneouslyparental like postpartummothers, because a cohabitation periodof only 30min can induce parental care behavior (Gandelman,1972). At the first time of exposure to the pups, female mice sniffthe pups from a distance with their eyes closed, and then inves-tigate the pups. During these bouts of investigation, the virginfemale runs between the pup and the nest, apparently showing anapproach-avoidance conflict. In addition, their retrieving latencydecreases with repetition of the presentation of donor pups,indicating that previous parenting experience enhances parentalbehavior (Ehret et al., 1987). Once they become parental throughpup sensitization, they seldom revert to rejecting pups, at leastduring successive daily pup exposure. Therefore, parental expe-rience can develop the parental responsiveness in a long-lastingmanner in rodents.

Reproductive experiences such as mating, pregnancy, and par-turition are also important factors for expression of maternalbehavior. Graber showed that even uterine distention can shortenthe onset latency of maternal behavior in rats (Graber and Kristal,1977). Similar to Grabers study, in our previous study, matingexperience facilitates maternal behavior in female mice. However,

our results also showed that the additional experience of parent-ing is necessary for the complete induction of maternal behaviorin female mice (Okabe et al., 2010).

These social experiences are all accompanied by the releaseof oxytocin, not only from the posterior pituitary, but alsothrough central release in order to act upon oxytocin receptorswidely expressed throughout several brain regions. Interestingly,increases in oxytocin levels have been measured both centrallyand peripherally following genital and cervical stimulation inseveral species including rodents and ruminants (Kendrick andKeverne, 1992; Sansone et al., 2002). In addition, tactile or nipplesuckling stimuli can stimulate the release of oxytocin (Uvnas-Moberg et al., 1993; Agren et al., 1995), which is similar physicalcontact to that experienced during pup sensitization. Therefore, itis possible that pup sensitization as well as sexual experience couldfacilitate maternal behavior through activation of the oxytocinsystem in the brain, particularly the MPOA in the hypothalamus.

IMPLICATIONS FOR HUMANMOTHER-INFANTINTERACTIONSIn experimental animals, it has been shown that oxytocin stronglyinfluences maternal care, and the prosocial effects of oxytocinhave been widely recognized (Francis et al., 2000; Williams et al.,2001; Caldwell and Young, 2006). However, the neuroendocrino-logical research of mother-infant relations in humans is nowbeing progressively undertaken, although it remains unclear howoxytocin links mother-infant relationship and post-growth off-spring. In this section, we review the current research on theeffects of oxytocin in mother-infant relationships in humans.

Human research on the role of oxytocin in mother-infantrelations is divided into two types. One type involved the investi-gation of the association between the mothers oxytocin levels andmaternal behavior or degree of attachment, and the other typeinvolved examining the influence of parental care experienced bythe infants on their oxytocin levels. In the first type, maternal oxy-tocinergic status from pregnancy to early postnatal was evaluated.Levine et al. (2007) assayed plasma oxytocin levels in the first andthird trimesters of pregnancy and the first postpartum month,and the subjects completed a psychological scale (Maternal-FetalAttachment Scale; MFAS) in the third trimester. Although therewas no significant correlation between oxytocin levels duringpregnancy and MFAS scores, the group having increasing oxy-tocin patterns during pregnancy tended to show higher MFASscores. Feldman et al. (2007) examined maternal plasma oxytocinlevels at the same points as those used in Levines study alongwith analysis of maternal representations and maternal behaviorsin the first postpartum month. Oxytocin levels in early preg-nancy and postpartum correlated significantly with attachmentrepresentation and maternal behaviors, such as gaze at infants,affectionate touch, and frequent infant checking. Feldman andcolleagues also focused on mother-infant behavioral synchronyand showed a correlation between maternal salivary and plasmaoxytocin levels and affection synchrony (Feldman et al., 2010,2011). Strathearn et al. (2009) conducted an interview with preg-nant women and divided them according to their attachmentstyle; that is, mothers with a secure attachment style and thosewith an insecure-avoidant attachment style. At sevenmonths after



birth, they assayed maternal serum oxytocin within a short timeof mother-infant interaction, and found that oxytocin levels wereincreased significantly in the secure mother group. Gordon et al.(2010) examined both maternal and paternal plasma oxytocinlevels after a period of interaction with their infants, and foundthat maternal oxytocin levels correlated with affectionate par-enting behavior and paternal levels correlated with stimulatoryparenting behavior. These results suggest the presence of a clearpositive relationship between mothering style and attachment,and oxytocin activity in mothers.

Conversely, Feldman et al. (2010) examined infants salivaryoxytocin levels following parent-infant interaction, and foundthat parent and infant oxytocin levels were significant corre-lated both pre-interaction and post-interaction. Moreover, underconditions of high levels of affect behavioral synchrony in theparent-infant interaction, infants whose parents had high oxy-tocin levels had significantly higher oxytocin level than infantswhose parents had relatively low oxytocin levels. A recent studyshowed that social vocalization from the mother to the daugh-ter stimulates oxytocin release and reduces stress responses inhumans (Seltzer et al., 2010). These results suggest that socialsignals from the mother stimulate the oxytocin system in infants.

However, Fries et al. (2005) elucidated a relationship betweeninfants oxytocin levels and early negative experiences. They mea-sured urinary oxytocin levels of children aged approximately4 years who had experienced early neglect and institutionaliza-tion. Although the children were adopted into new families, theiroxytocin levels tended to be lower than in children who werereared by their biological parents. Moreover, Gordon et al. (2008)reported that plasma oxytocin levels of young adults had a sig-nificant correlation with their maternal and paternal care, whichwas measured by self-report (Parental Bonding Instrument).Meinlschmidt and Heim (2007) targeted young adults who hadexperienced early childhood trauma by divorce or separationof parents at an age of less than 13 years. They measured sali-vary cortisol levels after the nasal administration of either oxy-tocin or placebo. In the control group, oxytocin administrationdecreased cortisol levels; however, this was not the case in thedivorce/separation experienced group. Heim et al. (2009) exam-ined the effects of early-life adversity on oxytocin activity in thecentral nervous system in adult women. Oxytocin concentrationsin cerebrospinal fluid (CSF) in maltreated women decreased ascompared to healthy controls. These studies suggested that qual-ity of parental care during the juvenile period might influenceoxytocinergic function over a longer duration, until adulthood.

In humans, the behavior of oxytocin can be measured mainlyin the periphery, such as the plasma, saliva, and urine (Amicoet al., 1987; Carter et al., 2007). Moreover, human interactionsare extremely complex and encompass various individual differ-ences. These factors may prove to be an obstacle for elucidatingthe precise influences of oxytocin in humans. On the other hand,research on humans can make use of psychological introspectivemethods that allow to map out behavior and feelings in moredetail. Moreover, recent fMRI research has begun to investigatethe relationship between oxytocin-related areas in the central ner-vous system and social stimuli involved in bonding (Strathearnet al., 2009; Riem et al., 2011). The research in humans may

be able to provide a new viewpoint on the role of oxytocin inmother-infant relationships using a combination of endocrino-logical, behavioral, and psychological methods.

The comparison of rodent and human studies is valuablefor translational research in this field. In the rodent models,the release of oxytocin in the amygdala was increased by socialolfactory cues in mice (Ferguson et al., 2001), and oxytocinadministration to lactating mother rats activated the brain areaincluding the olfactory system and amygdala, as detected by fMRI(Febo et al., 2005). Therefore, the oxytocin system ismainly actingon the olfactory circuit. The release of oxytocin in the amygdala,which is the higher brain area of olfactory circuit, also enhancesthe effect on dopamine transmission in the nucleus accumbens,which is essential for social bonding (Broad et al., 2006). On theother hand, in monkeys and humans, it was found that socialvisual cues, such as gazing, activated the oxytocin systems. Thus,the sensory inputs that stimulate oxytocin in the brain are differ-ent in rodents and primates. Interestingly, visual cues in monkeysactivate neurons in the amygdala (Morris et al., 1996; Gothardet al., 2007), implying that the amygdala is the key region for thesocial signal circuit. There is a possibility that similar mechanismsmay underlie bonding in both humans and rodents, neverthelessthe nature of the cues that can stimulate oxytocin has shifted overthe course of evolution (Broad et al., 2006).

CONCLUSIONWe have presently described the mutual communication betweenmother and infants, and discussed the manner in which thistype of communication creates a fundamental bonding betweenmother and infant. Although the social cues used by humanbeings are not so clearly defined, vocal and visual stimuli fromboth mother and infants to others seem important. Moreover,tactile stimulation between mother and infants is a basic commu-nicative tool that is used to bond with each other. Further studiesare required to clarify these issues in humans. The summarizedrole of the oxytocin system in reciprocal communication is shownin Figure 1.

The oxytocin system may play a pivotal role in bonding for-mation. In animal models, it has been clearly shown that mother-infant bonding is mediated by the oxytocin systems, particularlyin ewes (Kendrick, 2004). As described above, experiences ofsocial and affiliative interactions, such as parenting and mating,stimulate the oxytocin system. The oxytocin then enhances theirown parenting behavior toward their infants, indicating that thereis a positive loop of oxytocin and parenting behavior in individ-uals. If the infants receive higher levels of parenting care, theiroxytocin system is stimulated and makes them seek more contactwith their parent. During parenting, animals show increased oxy-tocin related to infant attachment behavior. Thus, there is also apositive loop of attachment-parenting behavior via the oxytocinsystem on each side of infant-mother dyad. Moreover, if the infantreceives higher parenting behavior, they will develop an enhancedoxytocin system and oxytocin-related behaviors in their adult-hood, such as parenting and social affiliative behaviors. Therefore,there is also a positive loop of parenting/affiliative behavior thatcrosses generations. This idea is schematically represented inFigure 2.



FIGURE 1 | Summary of the role of the oxytocin system in reciprocalcommunication. Central oxytocin release is stimulated by multiplesensory signals, such as olfactory, auditory, visual, and physical inputs.In particular, physiological stimuli are known to induce oxytocin systemactivation in mammals. When oxytocin release is increased in the central

nervous system, many sensory, physiological, and behavioral functionsare enhanced. Maternal as well as affiliative behaviors areenhanced by oxytocin. Additionally, negative responses, such aspain, stress endocrine, and anxiety behaviors are diminished byoxytocin.

FIGURE 2 | A schematic illustrating the positive loop of social bondingcontrolled by oxytocin. The mother mouse becomes pregnant and then atpartum, certain hormonal changes occur (1). After delivery, new-born infantsshow attachment behavior toward the mother (2). The hormonal changesrelated to partum and attachment behavior from the infant stimulate therelease of centrally acting oxytocin (OT) (3). OT in the maternal brainfacilitates parenting behavior toward the pups (4). This parenting behavior

also stimulates infant OT release in the brain (5). Therefore, there is a clearpositive loop of OT release in the mother-infant dyad. Once the motherexperiences parenting, her maternal behavior is persistently maintained(6) positive loop in individuals. Intensive parenting care stimulates the infantsbrain development (7), which in turn brings about higher OT and parentingactivities in their adulthood (8). This intensive care is also non-geneticallytransmitted to the next generation (positive loop in the generation).

Oxytocin is of vital importance for the induction of maternalbehavior as well as for social cognition (Young and Wang, 2004).Dissociating the role of oxytocin in bond formation and in socialcognition is likely to be difficult, but it is plausible that oxytocinmay act as the master mediator in recognizing the object of thebonding-partner and connecting to each other. This classic neu-ropeptide, seen in a wide variety of vertebrate species includinghumans, has a fascinating character, which may be vital to under-stand the biological significance of bonding, from evolutional andethological points of view (Young and Wang, 2004).

Despite the difficulties involved in measuring oxytocin activityin the human brain, as well as standardizing environments andexperiences, and considering genetic diversity among humans,there have been some fascinating results obtained in the fieldof mother-infant relationship in humans. We have recentlyfound that human-dog interaction stimulates oxytocin release in

humans, with this being particularly related to the dogs initia-tion of gaze communications (Nagasawa et al., 2009). This typeof study will shed further light on the nature of the biologicalbonding system in humans, including inter-species bonding likehuman-dog connections. We are only at the starting point ofthe journey to reveal neuronal mechanisms involved in humancognition and bonding formation.

ACKNOWLEDGMENTSThis work was financially supported by Grants-in-Aid forScientific Research from the Ministry of Education, Culture,Sports, Science, and Technology of Japan (#14760187, #23248049#23132510 to Takefumi Kikusui and #23780301 to KazutakaMogi) and Promotion and Mutual Aid Corporation for PrivateSchools of Japan, Grant-in-Aid for Matching Fund Subsidy forPrivate Universities.



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Conflict of Interest Statement: Theauthors declare that the researchwas conducted in the absence of anycommercial or financial relationshipsthat could be construed as a potentialconflict of interest.

Received: 23 December 2011; paperpending published: 30 January 2012;accepted: 10 February 2012; publishedonline: 28 February 2012.Citation: Nagasawa M, Okabe S, MogiK and Kikusui T (2012) Oxytocinand mutual communication in mother-infant bonding. Front. Hum. Neurosci.6:31. doi: 10.3389/fnhum.2012.00031Copyright 2012 Nagasawa, Okabe,Mogi and Kikusui. This is an open-access article distributed under the termsof the Creative Commons AttributionNon Commercial License, which per-mits non-commercial use, distribution,and reproduction in other forums, pro-vided the original authors and source arecredited.


Oxytocin and mutual communication in mother-infant bondingIntroductionSocial Cues from Infants to MotherSocial Cues from Mother to InfantNeuroendocrine Regulation of Mother-Pup InteractionsSocial Experience Modulating the Mother-Pup InteractionImplications for Human Mother-Infant InteractionsConclusionAcknowledgmentsReferences

nagasawa oxitocin mother infant

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