in however complex a manner this feeling may have originated , as it is one of high importance to all those animals which aid and defend one another , it will have been increased through natural selection ; for those communities , which included the greatest number of the most sympathetic members , would flourish best , and rear the greatest number of offspring  ( charles darwin ,  descent of man , , animals developed sympathetic neural and behavioral systems , in which for example , weak and helpless member of individuals are protected and nurtured by other group members . this phenomenon is mostly clearly observed in mother - infant relationship , such as mother infant bonding ( broad et al . , 2006 ) . social bonds like mother - infant bonding are hypothetical constructs and can not be measured directly . however , there are several behavioral and physiological measures that have been used as indices of social bonding , including increased physical proximity ( hennessy , 1997 ) , behavioral distress , or elevated corticosteroid levels following separation from the bonding partner ( ziegler et al . , 1995 ; norcross and newman , 1999 ) . social bonding has not yet been clearly defined , but it has been proposed that social bonding can be distinguished neurochemically from social affiliation , in which corticosteroid elevation does not occur following separation ( devries , 2002 ) . ( kikusui et al . , 2006 ) ; its effect depends on the degree of affiliation with the partner and is strongest with the bonding partner , such as that seen in the dyad of mother - infant . mother - infant bonding is unique with respect to its influence on the offspring 's future . this idea was first suggested in humans by bowlby 's attachment theory ( bowlby , 1969 ) . subsequently , many psychological and animal research studies have reported that child abuse or childhood neglect are correlated with severe , deleterious long - term effects on the child 's cognitive , socio - emotional , and behavioral development ( hildyard and wolfe , 2002 ) . the developmental effects of mother - infant bonding have also been indicated experimentally in non - human primates . ( 2003 ) , mother - reared and human nursery - reared monkeys were subjected to a novel environment with or without a cage mate . the monkeys reared by their mothers exhibited a reduced cortisol response when a social partner was available , whereas nursery - reared monkeys did not . in nursery - reared monkeys , social contact , such as allogrooming and inter - male mounting , these findings suggest that the social buffering effect is impaired as nursery - reared monkeys had experienced less social contact in a novel environment . thus , impairment of mother - infant bonding strongly influences offspring sociality in human and non - human primates ( agid et al . , 1999 ; heim and nemeroff , 2001 ) , although details of the underlying mechanisms are not yet fully understood . additionally , because the bonding formation is established during the process of social communication between mother and infants , social cognition has a pivotal influence on the bonding process ( ross and young , 2009 ) . however , little information has been obtained regarding the role of each social cue in the formation of bonds . in the present review , we describe the manner in which mutual communication between mother and infant leads to mother - infant bonding in rodents . we emphasize the significance of the conserved oxytocin neural system in mother - infant bond information , with several studies having shown that oxytocin plays a 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 , we would concede these issues in other articles . we also review the effects of deprivation of mother - infant bonding , by studying the consequences of early weaning on neurobehavioral development in rodent offspring . intensive maternal care has evolved and has been preserved , uniquely in mammals , and it is highly probable that mother - infant bonding is universal to all mammalian species . these comparative points of view provide insights into the biological significance of mother - infant bonding in mammals ; a comparative understanding of the developmental consequences of this bonding and its underlying mechanisms , even in rodents , may help in our treatment or prevention of disorders associated with child abuse or childhood neglect ( agid et al . , 1999 ; heim and nemeroff , 2001 ) . although rodent pups have limited thermoregulatory and physical capabilities during the first 1 or 2 postnatal weeks , they produce a variety of signals to their mother , such as olfactory and auditory signals ( levy et al . , these social cues play a very important role of facilitating maternal care and ensuring formation of the mother - infant bond . . when infant rodents are isolated from their mother and/or littermates , they cool rapidly and emit usvs ( branchi et al . these vocalizations peak around day 8 , after which they start to decrease , finally disappearing at 2 weeks after birth ( elwood and keeling , 1982 ) . although vocalizations ranges differ between mice and rats , ( the range of mice was approximately 3080 khz , and that of rats was approximately 3050 khz ) , many studies have shown that pup usvs could stimulate maternal behavior such as searching for / retrieving pups in both species ( brown , 1973 ; branchi et al . , 2001 ) . in a previous study , we showed that mother mice responded to pup usvs reproduced by ultrasonic speakers , but they did not respond to other synthesized ultrasounds such as double - duration usvs ( uematsu et al . , 2007 ) , indicating that mother mice can recognize the specific pattern of pup usvs in order to retrieve their pups and return them to the nest . moreover , we showed that social experiences such as mating or parenting enhanced both retrieving behavior and the responses to pup usvs ( okabe et al . , 2010 ) . these results indicate that the mother mice showed specific responsiveness to pup usvs , and this sound contributed 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 litter ) female mice ( liu and schreiner , 2007 ; cohen et al . , 2011 ) . therefore , maternal behavior expression can be at least partially regulated by functional changes in the sensory cortical representation of pup usvs . however , there is a critical missing link between cortical responses to pup usvs and expression of maternal behavior , which is probably regulated by neurons in the medial preoptic area ( mpoa ) of the hypothalamus ( numan , 2007 ) . olfactory cues from pups were also found to be extremely important in stimulating maternal behavior in rodents . there have been many studies showing the behavioral or neural responses to pup odor , and it was shown that the role of olfactory inputs in maternal behavior is different between rats and mice ( levy et al . , 2004 ) . in rats , olfactory stimuli clearly inhibit maternal behavior before parturition , a phenomenon termed neophobia . after parturition , however , mother rats drastically change their behavior ; they develop a high level of responsiveness to olfactory cues from their pups , and show intensive maternal behavior toward pups ( fleming et al . this suggests that the experience of partum and the hormonal changes accompanying pregnancy and partum induce this maternal behavior . once they start displaying maternal behavior , mother rats show a high preference for bedding soiled by pups over clean bedding ( kinsley and bridges , 1990 ) . in addition , when the pups ' heads were rubbed with their anogenital smears and the anogenital areas were cleaned , the dams licked only the head region ( brouette - lahlou et al . , 1991 ) , suggesting that odors emitted from the anogenital area stimulate licking and grooming behavior in the mother rats . although the behavioral evidence clearly shows that olfaction plays an important organizational role in the induction of maternal behavior , lesions of the main and the accessory olfactory system , or preventing access to the olfactory cues from the pups , produces contradictory or inconsistent results . several studies have shown that pup retrieval was somewhat impaired by lesions to the olfactory mucosa caused by zinc sulfate ( benuck and rowe , 1975 ) . however , other studies showed that these manipulations did not decrease maternal behavior ( jirik - babb et al . similarly , removal of the vomeronasal organ , such as vomeronasal nerve cuts or olfactory bulbectomy , did not fully disrupt maternal behavior ( jirik - babb et al . , 1984 ; morgan et al . these results suggest that , in rats , olfaction is not crucial for the successful care of pups since the anosmic mother apparently easily compensates for the loss of this sensory input . mother mice failed to show any maternal behavior following bulbectomy , or anosmia induced by either nasal irrigation of zinc sulfate or by depletion of noradrenaline within the main olfactory bulb ( levy et al . , 2004 ) . moreover , wang recently showed that type 3 adenylyl cyclase ( ac3 ) , which is one among a multigene family of odorant receptors , knockout mothers did not show any pup retrieving or nest building behavior at all ( wang and storm , 2010 ) . from these lesion and genetic deletion studies , it can be surmised that olfactory stimuli are essential for the induction and maintenance of maternal behaviors in mice . interestingly , in female mice which had a previous maternal experience , pup - killing induced by peripheral anosmia was prevented ( seegal and denenberg , 1974 ) , indicating that the primiparous mother depends profoundly on olfactory information for the induction of maternal behavior , as compared with the multiparous mother . however , experienced mother mice are able to use multiple sensory inputs and compensate for the loss of one type of sensory cues and still show maternal behavior . in both mice and rats , for example , rat mothers can detect pup usvs , and these pup usvs serve as a potent stimulus for the induction of maternal retrieving behavior , particularly when presented together with pup odors ( farrell and alberts , 2002 ) . therefore , the integration of multisensory stimulus inputs from pups triggers discrimination and retrieving of pups . cohen recently showed that exposure to pups ' body odor enhances the neuronal response to pup usvs in the primary auditory cortex of mother mice ( cohen et al . , additionally , they showed that the pup retrieving behavior of mother mice decreased when the pups were washed with warm water ( cohen et al . , 2011 ) . in summary , multisensory stimuli from pups activates the full range of maternal behavior , although there are no current reports of direct anatomical or neural mechanisms that could explain this multisensory integration . further studies of the neurobiological mechanisms for the integration of olfactory , auditory , and other social stimuli may lead to a better understanding of the role of sensory modalities to induce maternal behavior , which would strengthen the bond between mothers and their pups . the neonatal infants are innately attracted to their mother . for instance , odors emitted from the nipple area have a specific character that attracts both rodent and human new - born infants ( porter and winberg , 1999 ) . therefore , the infant can suckle the nipple just after the birth after which infant animals can recognize their own mother using chemicals cues , probably because the infant can memorize the mother 's individual odors associated with suckling ( moriceau and sullivan , 2004 ) . this type of odor memory is regulated by the neuropeptide oxytocin ( nowak et al . oxytocin is released in the infant brain while suckling , and it acts on the olfactory bulb . in the olfactory bulb , oxytocin can enhance memory - related neural activation through long - term potentiation ( fang et al . , 2008 ) . therefore , odors from the mother have a fundamental ability to attract her infants . physical and tactile stimuli from mother to infants have been indicated to have a great impact on infant brain development . they found that rat pups that received intensive tactile stimulation , such as licking and grooming from their mother , showed lower stress responses during their adulthood ( liu et al . pups raised by higher licking and grooming mothers had a higher level of glucocorticoid receptor expression in the hippocampus , and showed an enhanced negative feedback ability along the hypothalamus - pituitary - adrenal axis of stress responses . such tactile stimulation releases 5 ht in the hippocampus of pups , which epigenetically modulates the cpg islands of glucocorticoid receptors ( weaver et al . these effects of tactile stimulation are most important just after birth , because the epigenetic changes of dna methylation are determined within the first three days of the neonatal period . however , the mother - infant relationship during the later neonatal period also produces a long - lasting modulation of infant behavior , implying that not only the tactile stimulation , but other social cues from mother to infant have a significant role on the development of pups ( kikusui and mori , 2009 ; curley et al . , 2010 ; mogi et al . , although the specific cues from mother to infant have not yet been identified , the most well studied model is a maternal deprivation paradigm . when mutually strongly bonded mothers and young are separated prematurely , bouts of reinstatement behavior such as locomotion ( searching ) and distress vocals are exhibited by both the mother and the young , interspersed with periods of energy - conserving depression in most mammals ( panksepp , 2004 ) , indicating the importance of mother - infant bonding across species . bowlby referred to these phases as  protest  and  despair ,  respectively ( bowlby , 1969 ) . the impact of deprivation of mother - infant bonding is not temporary , and the effects can be observed much later in life . in rat and mouse models , maternally deprived animals show higher anxiety and stress responses , as well as lower learning and memory abilities in their adulthood ( levine , 1967 ; plotsky and meaney , 1993 ; plotsky et al . , 1993 ; liu et al . , 2000 ) , suggesting that the epigenetic modulation of the brain function by maternal deprivation has long - lasting effects . we have studied the effects of early weaning , where the animals are weaned one week earlier than normal , and found that early weaned mice and rats showed higher levels of anxiety - related behaviors , as well as higher stress responses in their adulthood , even though no growth retardation was observed ( kikusui et al . , 2004 these results show that not only the early neonatal period , but also the mother - infant relationship in the later lactating period , has a profound impact on brain development in the infant . when early - weaned male mice are grouped together , high levels of agonistic behavior , accompanied by an elevation in glucocorticoid levels were found ( nakamura et al . , 2008 ) . in young male elephants , following the loss of their mothers and other family members due to poaching , unusually violent behavior has been attributed to the termination of social interaction with older elephants , including parents , and the loss of behavioral inhibition that would normally result from the presence of older males ( slotow et al . , 2000 ) . the critical role of older males in normal social development was clearly shown when researchers re - introduced older bulls to quell the young males ' violence , and hyperaggression and abnormally early musth cycles ( periods of sexual activity and hormonal shifts ) both ceased . scott and fuller ( 1965 ) studied behavioral development in dogs , and found that the socialization period , during which puppies stop suckling but continue to live with their parents , was crucial to their behavioral and social development . the social cues from mother or adult to juvenile animals responsible for these phenomena has not been determined , and we should consider the influence of social environment on the development of normal brain function in juvenile animals . female rats or mice that have never given birth usually withdraw from or avoid pups , and it has been intensively studied how neuroendocrine changes at parturition act to enhance the neural mechanisms responsible for maternal behavior , such as those occurring in the mpoa of the hypothalamus ( numan and stolzenberg , 2009 ) . a great deal of evidence suggests that the oxytocin neuroendocrine system plays a key role in the initiation of maternal behavior following birth . it is now clear that oxytocin , which is synthesized in the neurons of the hypothalamus ( specifically in the paraventricular nucleus [ pvn ] and supraoptic nucleus ) , is released not only into the general circulation from the posterior pituitary , but centrally during vaginal stimulation and parturition , to act upon oxytocin receptors widely expressed throughout the central nervous system ( forsling , 1986 ; barberis and 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 ( insel and harbaugh , 1989 ) , and in female rats administrated an oxytocin antagonist immediately after parturition ( van leengoed et al . , 1987 ) . furthermore , oxytocin receptors proliferate in many forebrain areas including the mpoa , ventromedial hypothalamus , and bed nucleus of the stria terminalis of female rats at the time of partition ( jirikowski et al . , 1989 ; these alterations in oxytocin receptor expression may be partially responsible for the induction of maternal behavior , since intraventricular and mpoa infusion of oxytocin induces a rapid onset of maternal behavior in virgin female rats ( pedersen and prange jr , 1979 ; pedersen et al . if new mothers are separated from their pups and not permitted to interact with them , their maternal responsiveness declines over the first postpartum week ( orpen and fleming , 1987 ) . among the various pup stimuli , physical contact suckling of the nipple is a representative stimulus in lactating females , because suckling is known to stimulate oxytocin release not only into the peripheral circulation to cause milk ejection , but also into the brain ( neumann et al . , 1993 ) . several types of tactile stimuli such as touch or massage - like stroking and warmth have also been shown to stimulate oxytocin release in rats ; however , these are not associated with lactation physiology ( uvnas - moberg et al . , 1993 ; agren et al . , 1995 ) . although exteroceptive social cues from pups , such as infant 's odors or vocalizations , may not have as strong an effect on the development of nurturance as physical stimuli ( stern , 1983 ) , they do play an important role in making mothers seek their pups out and maintain proximity . the infant 's odors are used as not only an attractive signal to mothers , as described in previous sections , but also for the mother 's recognition of their own infants ( ostermeyer and elwood , 1983 ) . as described above for rats , infant 's odors have been shown to be quite aversive to females before parturition and lactation , whereas on the boundary of parturition , these odors become very potent attractive stimuli ( levy et al . , this change in the mother 's responsiveness is governed by hormonal changes at parturition , and it is suggested that the oxytocin system participates primarily in this process . pregnancy and parturition enhance the sensitivity and neural firing in the olfactory bulb in rats , and oxytocin infusion directly into the olfactory bulb increases the firing frequency and spontaneous excitatory postsynaptic currents in granule cells ( yu et al . , 1996 ) via both pre- and postsynaptic mechanisms , a process integral to olfactory recognition memory ( engelmann et al . , 1998 ; similar to the responsiveness to pup odors , the response to pup usvs has also been shown to be far more pronounced in mothers than in nave females ( koch and ehret , 1989 ; okabe et al . , 2010 ) ; however , the neuroendocrine mechanisms responsible for this change in response to pup usvs has not been elucidated . oxytocin - induced maternal behavior is reinforced by infants ' innate attachment behaviors , i.e. , vocalization or milk suckling for sustenance . interestingly , it has been suggested that the oxytocin neuroendocrine system is also involved in these behaviors in infants . central administration of oxytocin has been found to reduce the frequency of isolation - induced usv in young rat pups ( insel and winslow , 1991 ) , suggesting a possible role for central oxytocin in the affective  calm  response infants display during social contact . central oxytocin also induces paw sucking in neonatal rats ( nelson and alberts , 1997 ) . these innate attachments regulated by oxytocin ensure the infant 's physical development , and the subsequent development of adequate attachment behaviors accompanied by growth of the pup . in return , adequate attachments maintain maternal behaviors in response to pup stimuli . maternal behavior is regulated by genetic and epigenetic backgrounds . regarding epigenetic modulations of maternal behavior ,  non - genomic transmission  has been indicated in a rat model ( champagne et al . , 2001 ; champagne and meaney , 2001 ; weaver et al . , 2004a ) . as described above , pups that received higher levels and more intensive care from their mother in turn showed higher licking and grooming behavior toward their own offspring after delivery ( francis et al . this behavioral transmission was persistent even when the pups were cross - fostered to other mother rats ; that is , when pups born to the lower licking and grooming mother were cross - fostered to the higher licking and grooming mother , they showed higher maternal care to their own pups ( francis et al . this transmission was clearly demonstrated by the epigenetic modification of the estrogen receptor genes in the mpoa in the hypothalamus ( champagne et al . , 2001 ; champagne and meaney , 2001 ) . the female rats that received higher licking and grooming behavior from the mother showed higher estrogen receptor expression in the same cells that also express oxytocin receptor . estrogen receptor activation acts to induce oxytocin receptor expression , therefore , higher estrogen receptor expression results in higher oxytocin receptor expression . the oxytocin system in the mpoa is associated with the induction of maternal behavior ( pedersen et al . , 1994 ) . therefore , these epigenetic modulations are plausible candidates to cause the individual differences in maternal behavior . early - weaned females also showed lower maternal behavior when they became mothers ( kikusui et al . , 2005 ) . this may be because the early - weaned females were deprived maternal care in the third week of the postnatal period , resulting in lower maternal behavior in their adulthood . although the responsible social cues from mother to infant mice in this model was not identified , it is suggested that not only the early neonatal period , but also mother - infant interactions during the late lactating period can epigenetically modulate the maternal behavior . another interesting model to aid our understanding of the significance of social experience in the late neonatal period is the alloparental care experience in juvenile animals . for example , if the juveniles have a chance to show maternal or paternal - like behavior toward their younger siblings ( termed alloparental care ) , they will show higher levels of nursing behavior toward their own offspring later in life ( riedman , 1982 ) . these phenomena are widely observed in mammals , but detailed analyses have focused mainly on primates ( quiatt , 1979 ) . in humans , similar mechanisms have been suggested , but not clearly defined ( hrdy , 1999 ) . social experience affects not only neonates or juveniles , but also adult rodents in terms of maternal behavior . unlike lactating mothers , most sexually and parentally nave adult rodents avoid physical contact with pups when they are first introduced to them ( terkel and rosenblatt , 1971 ) . particularly noticeable in rats , [ although juvenile and premature rats ( 1842 days old ) will approach pups and initiate physical contact with unfamiliar pups ] , inexperienced adult rats show clear avoidance or attacking behavior toward unfamiliar pups ( terkel and rosenblatt , 1971 ) . however , after 58 days of continuous cohabitation with donor pups , they first become tolerant of proximate contact with pups , and then start caring for the pups , which includes licking , retrieving , crouching , and nest building ( rosenblatt , 1967 ) . once becoming fully parental by pup sensitization , virgin female rats can maintain a high level of parental responsiveness for several weeks after separation from pups ( bridges and scanlan , 2005 ) . in mice , virgin females are often said to be  spontaneously parental  like postpartum mothers , because a cohabitation period of only 30 min can induce parental care behavior ( gandelman , 1972 ) . at the first time of exposure to the pups , female mice sniff the pups from a distance with their eyes closed , and then investigate the pups . during these bouts of investigation , the virgin female runs between the pup and the nest , apparently showing an approach - avoidance conflict . in addition , their retrieving latency decreases with repetition of the presentation of donor pups , indicating that previous parenting experience enhances parental behavior ( ehret et al . , 1987 ) . once they become parental through pup sensitization , they seldom revert to rejecting pups , at least during successive daily pup exposure . therefore , parental experience can develop the parental responsiveness in a long - lasting manner in rodents . reproductive experiences such as mating , pregnancy , and parturition are also important factors for expression of maternal behavior . graber showed that even uterine distention can shorten the onset latency of maternal behavior in rats ( graber and kristal , 1977 ) . similar to graber 's study , in our previous study , mating experience facilitates maternal behavior in female mice . however , our results also showed that the additional experience of parenting is necessary for the complete induction of maternal behavior in female mice ( okabe et al . , 2010 ) . these social experiences are all accompanied by the release of oxytocin , not only from the posterior pituitary , but also through central release in order to act upon oxytocin receptors widely expressed throughout several brain regions . interestingly , increases in oxytocin levels have been measured both centrally and peripherally following genital and cervical stimulation in several species including rodents and ruminants ( kendrick and keverne , 1992 ; sansone et al . , 2002 ) . in addition , tactile or nipple suckling stimuli can stimulate the release of oxytocin ( uvnas - moberg et al . , 1993 ; agren et al . , 1995 ) , which is similar physical contact to that experienced during pup sensitization . therefore , it is possible that pup sensitization as well as sexual experience could facilitate maternal behavior through activation of the oxytocin system in the brain , particularly the mpoa in the hypothalamus . in experimental animals , it has been shown that oxytocin strongly influences maternal care , and the prosocial effects of oxytocin have been widely recognized ( francis et al . , 2000 ; williams et al . , 2001 ; caldwell and young , 2006 ) . however , the neuroendocrinological research of mother - infant relations in humans is now being progressively undertaken , although it remains unclear how oxytocin links mother - infant relationship and post - growth offspring . in this section , we review the current research on the effects of oxytocin in mother - infant relationships in humans . human research on the role of oxytocin in mother - infant relations is divided into two types . one type involved the investigation of the association between the mother 's oxytocin levels and maternal behavior or degree of attachment , and the other type involved examining the influence of parental care experienced by the infants on their oxytocin levels . in the first type , maternal oxytocinergic status from pregnancy to early postnatal was evaluated . levine et al . ( 2007 ) assayed plasma oxytocin levels in the first and third trimesters of pregnancy and the first postpartum month , and the subjects completed a psychological scale ( maternal - fetal attachment scale ; mfas ) in the third trimester . although there was no significant correlation between oxytocin levels during pregnancy and mfas scores , the group having increasing oxytocin patterns during pregnancy tended to show higher mfas scores . 2007 ) examined maternal plasma oxytocin levels at the same points as those used in levine 's study along with analysis of maternal representations and maternal behaviors in the first postpartum month . oxytocin levels in early pregnancy and postpartum correlated significantly with attachment representation and maternal behaviors , such as gaze at infants , affectionate touch , and frequent infant checking . feldman and colleagues also focused on mother - infant behavioral synchrony and showed a correlation between maternal salivary and plasma oxytocin levels and affection synchrony ( feldman et al . ( 2009 ) conducted an interview with pregnant women and divided them according to their attachment style ; that is , mothers with a secure attachment style and those with an insecure - avoidant attachment style . at seven months after birth , they assayed maternal serum oxytocin within a short time of mother - infant interaction , and found that oxytocin levels were increased significantly in the secure mother group . ( 2010 ) examined both maternal and paternal plasma oxytocin levels after a period of interaction with their infants , and found that maternal oxytocin levels correlated with affectionate parenting behavior and paternal levels correlated with stimulatory parenting behavior . these results suggest the presence of a clear positive relationship between mothering style and attachment , and oxytocin activity in mothers . ( 2010 ) examined infants ' salivary oxytocin levels following parent - infant interaction , and found that parent and infant oxytocin levels were significant correlated both pre - interaction and post - interaction . moreover , under conditions of high levels of affect behavioral synchrony in the parent - infant interaction , infants whose parents had high oxytocin levels had significantly higher oxytocin level than infants whose parents had relatively low oxytocin levels . a recent study showed that social vocalization from the mother to the daughter stimulates oxytocin release and reduces stress responses in humans ( seltzer et al . , these results suggest that social signals from the mother stimulate the oxytocin system in infants . ( 2005 ) elucidated a relationship between infant 's oxytocin levels and early negative experiences . they measured urinary oxytocin levels of children aged approximately 4 years who had experienced early neglect and institutionalization . although the children were adopted into new families , their oxytocin levels tended to be lower than in children who were reared by their biological parents . ( 2008 ) reported that plasma oxytocin levels of young adults had a significant correlation with their maternal and paternal care , which was measured by self - report ( parental bonding instrument ) . meinlschmidt and heim ( 2007 ) targeted young adults who had experienced early childhood trauma by divorce or separation of parents at an age of less than 13 years . they measured salivary cortisol levels after the nasal administration of either oxytocin or placebo . in the control group , oxytocin administration decreased cortisol levels ; however , this was not the case in the divorce / separation experienced group . ( 2009 ) examined the effects of early - life adversity on oxytocin activity in the central nervous system in adult women . oxytocin concentrations in cerebrospinal fluid ( csf ) in maltreated women decreased as compared to healthy controls . these studies suggested that quality of parental care during the juvenile period might influence oxytocinergic function over a longer duration , until adulthood . in humans , the behavior of oxytocin can be measured mainly in the periphery , such as the plasma , saliva , and urine ( amico et al . , 1987 ; carter et al . , 2007 ) . moreover , these factors may prove to be an obstacle for elucidating the precise influences of oxytocin in humans . on the other hand , research on humans can make use of psychological introspective methods that allow to map out behavior and feelings in more detail . moreover , recent fmri research has begun to investigate the relationship between oxytocin - related areas in the central nervous system and social stimuli involved in bonding ( strathearn et al . the research in humans may be able to provide a new viewpoint on the role of oxytocin in mother - infant relationships using a combination of endocrinological , behavioral , and psychological methods . the comparison of rodent and human studies is valuable for translational research in this field . in the rodent models , the release of oxytocin in the amygdala was increased by social olfactory cues in mice ( ferguson et al . , 2001 ) , and oxytocin administration to lactating mother rats activated the brain area including the olfactory system and amygdala , as detected by fmri ( febo et al . , the release of oxytocin in the amygdala , which is the higher brain area of olfactory circuit , also enhances the effect on dopamine transmission in the nucleus accumbens , which is essential for social bonding ( broad et al . , 2006 ) . on the other hand , in monkeys and humans , it was found that social visual cues , such as gazing , activated the oxytocin systems . thus , the sensory inputs that stimulate oxytocin in the brain are different in rodents and primates . interestingly , visual cues in monkeys activate neurons in the amygdala ( morris et al . , 1996 ; gothard et al . , 2007 ) , there is a possibility that similar mechanisms may underlie bonding in both humans and rodents , nevertheless the nature of the cues that can stimulate oxytocin has shifted over the course of evolution ( broad et al . , 2006 ) . we have presently described the mutual communication between mother and infants , and discussed the manner in which this type of communication creates a fundamental bonding between mother and infant . although the social cues used by human beings are not so clearly defined , vocal and visual stimuli from both mother and infants to others seem important . moreover , tactile stimulation between mother and infants is a basic communicative tool that is used to bond with each other . the summarized role of the oxytocin system in reciprocal communication is shown in figure 1 . central oxytocin release is stimulated by multiple sensory signals , such as olfactory , auditory , visual , and physical inputs . in particular , physiological stimuli are known to induce oxytocin system activation in mammals . when oxytocin release is increased in the central nervous system , maternal as well as affiliative behaviors are enhanced by oxytocin . additionally , negative responses , such as pain , stress endocrine , and anxiety behaviors are diminished by oxytocin . , it has been clearly shown that mother - infant bonding is mediated by the oxytocin systems , particularly in ewes ( kendrick , 2004 ) . as described above , experiences of social and affiliative interactions , such as parenting and mating , stimulate the oxytocin system . the oxytocin then enhances their own parenting behavior toward their infants , indicating that there is a positive loop of oxytocin and parenting behavior in individuals . if the infants receive higher levels of parenting care , their oxytocin system is stimulated and makes them seek more contact with their parent . during parenting , thus , there is also a positive loop of attachment - parenting behavior via the oxytocin system on each side of infant - mother dyad . moreover , if the infant receives higher parenting behavior , they will develop an enhanced oxytocin system and oxytocin - related behaviors in their adulthood , such as parenting and social affiliative behaviors . therefore , there is also a positive loop of parenting / affiliative behavior that crosses generations . this idea is schematically represented in figure 2 . a schematic illustrating the positive loop of social bonding controlled by oxytocin . the mother mouse becomes pregnant and then at partum , certain hormonal changes occur ( 1 ) . after delivery , new - born infants show attachment behavior toward the mother ( 2 ) . the hormonal changes related to partum and attachment behavior from the infant stimulate the release of centrally acting oxytocin ( ot ) ( 3 ) . ot in the maternal brain facilitates parenting behavior toward the pups ( 4 ) . therefore , there is a clear positive loop of ot release in the mother - infant dyad . once the mother experiences parenting , her maternal behavior is persistently maintained ( 6 ) positive loop in individuals . intensive parenting care stimulates the infants ' brain development ( 7 ) , which in turn brings about higher ot and parenting activities in their adulthood ( 8) . this intensive care is also non - genetically transmitted to the next generation ( positive loop in the generation ) . oxytocin is of vital importance for the induction of maternal behavior as well as for social cognition ( young and wang , 2004 ) . dissociating the role of oxytocin in bond formation and in social cognition is likely to be difficult , but it is plausible that oxytocin may act as the master mediator in recognizing the object of the bonding - partner and connecting to each other . this classic neuropeptide , seen in a wide variety of vertebrate species including humans , has a fascinating character , which may be vital to understand the biological significance of bonding , from evolutional and ethological points of view ( young and wang , 2004 ) . despite the difficulties involved in measuring oxytocin activity in the human brain , as well as standardizing environments and experiences , and considering genetic diversity among humans , there have been some fascinating results obtained in the field of mother - infant relationship in humans . we have recently found that human - dog interaction stimulates oxytocin release in humans , with this being particularly related to the dog 's initiation of gaze communications ( nagasawa et al . , 2009 ) . this type of study will shed further light on the nature of the biological bonding system in humans , including inter - species bonding like human - dog connections . we are only at the starting point of the journey to reveal neuronal mechanisms involved in human cognition and bonding formation . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
mother - infant bonding is universal to all mammalian species . in this review , 
 we describe the manner in which reciprocal communication between the mother and infant leads to mother - infant bonding in rodents . in rats and mice , 
 mother - infant bond formation is reinforced 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 mother to the pups . 
 some evidence suggests that mother and infant can develop a cross - modal sensory 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 bonding process , although the mechanisms underlying bond formation in the brains of infants has not yet been clarified . 
 impairment of mother - infant bonding , that is , deprivation of social stimuli from the mother , strongly influences offspring sociality , including maternal behavior toward their own offspring in their adulthood , implying a  non - genomic transmission of maternal environment ,  even in rodents . 
 the comparative understanding of cognitive functions between mother and infants , and the biological mechanisms involved in mother - infant bonding may help us understand psychiatric disorders associated with mother - infant relationships .