NEUROSCIENCE AND

BIOBEHAVIORAL
REVIEWS

PERGAMON Neuroscience and Biobehavioral Reviews 23 (1999) 673–685

www.elsevier.com/locate/neubiorev

Neurobiology of mother–infant interactions: experience and central

nervous system plasticity across development and generations
A.S. Fleming a,*, D.H. O’Day b, G.W. Kraemer c
a
Department of Psychology, University of Toronto at Mississauga, Mississauga, Ontario, Canada L5L 1C6
b
Department of Zoology, University of Toronto at Mississauga, Mississauga, Ontario, Canada L5L 1C6
c
Department of Kinesiology, Harlow Primate Laboratory, University of Wisconsin, Madison, WI 53715, USA
Received 6 March 1998; received in revised form 19 November 1998; accepted 8 December 1998

Abstract
The optimal coordination between the new mammalian mother and her young involves a sequence of behaviors on the part of each that
ensures that the young will be adequately cared for and show healthy physical, emotional, and social development. This coordination is
accomplished by each member of the relationship having the appropriate sensitivities and responses to cues that characterize the other.
Among many mammalian species, new mothers are attracted to their infants’ odors and some recognize them based on their odors; they also
respond to their infants’ vocalizations, thermal properties, and touch qualities. Together these cues ensure that the mother will nurse and
protect the offspring and provide them with the appropriate physical and stimulus environment in which to develop. The young, in turn, orient
to the mother and show a suckling pattern that reflects a sensitivity to the mothers odor, touch, and temperature characteristics. This article
explores the sensory, endocrine, and neural mechanisms that underlie this early mother–young relationship, from the perspective of, first, the
mother and, then, the young, noting the parallels between them. It emphasizes the importance of learning and plasticity in the formation and
maintenance of the mother–young relationship and mediation of these experience effects by the brain and its neurochemistry. Finally, it
discusses ways in which the infants’ early experiences with their mothers (or the absence of these experiences) may come to influence how
they respond to their own infants when they grow up, providing a psychobiological mechanism for the inter-generational transmission of
parenting styles and responsiveness. q 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Maternal behavior; Brain plasticity; Development; Maternal experience; Olfaction; Somatosensation; Hormones; MPOA; Amygdala; c-fos; Signal
transduction; PKC; CaMBPs; Maternal deprivation; Rat; Monkeys; Humans

1. Introduction
Non-human mammalian mothers typically display a
stereotyped set of behavioral responses to their newborn.
They exhibit species-characteristic ways of transporting,
holding, feeding, and grooming the young, and of protecting
them from the predators and other dangers [1]. For instance,
the prospective mother rat constructs a nest before giving
birth. She aids the birth by pulling individual pups from the
vaginal canal, severs the umbilicus, eats the placenta, cleans
the pups, and carries them one-by-one in her mouth to the
nest. In the nest, she continues to lick the pups, especially
their anogenital regions, and eventually adopts a nursing
posture over them. In return, mammalian neonates exhibit
behavior that is even more stereotyped and rigid than mater-
nal behavior. This includes orchestrated orienting responses
* Corresponding author. Tel.: 11-905-828-3961; fax: 11-905-569-
4326.
E-mail address: afleming@credit.erin.utoronto.ca (A.S. Fleming)
0149-7634/99/$ - see front matter q 1999 Elsevier Science Ltd. All rights reserved.
PII: S0149-763 4(99)00011-1
towards the mother, seeking and attachment to her teats, and
emission of sound and odor signals that elicit maternal
responses (crying, squealing, urination, and so forth). The
reciprocal exhibition of maternal behaviors and newborn
signaling promotes physiological and immunological resi-
lience, physical maturation, and species-typical social and
emotional development in the young (see [2–8]). Ulti-
mately, reciprocal mother–infant behaviors increase the
probability that the young will survive and, beyond survival,
will mate and successfully rear their own offspring. In this
article, we show how these behavior patterns, previously
viewed as fixed and stereotyped, are in fact quite plastic,
and depend on brain structure and function that was substan-
tially influenced by experience at the time of birth and over
the life-span.
As shown in Fig. 1, the development of the capacity to
both express and modify maternal behavior patterns in
adulthood may depend on mechanisms that were themselves
activated and later tuned by early experiences. The interac-
tion between the newborn and the mother alters basic
674 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685

Fig. 1. Schematic showing factors that affect the newborn infant’s response to the mother and mother’s response to infants. In this ‘Intergenerational’ model,
we describe the hypothesized transmission of experiences received by the infant (F1 generation) in the nest and in relation to their own mothers on the quality of
mothering the offspring show towards their offspring (F2 generation) when they grow up. The assumption is that the transmission of experience effects persists
across generations, from generations F1 to F2 to F3, etc. Influences experienced by the developing offspring are determined in part by their genetic makeup, by
uterine experiences, by hormones (both pre- and post-natally), and by present context in the nest and with mother and/or siblings. Experiences alter the
psychobiology of the offspring, changing their subsequent neuroanatomy, chemistry, endocrinology, and, hence, behavior. These offspring, then grow up and
gain experiences throughout their lives which, together with their earlier experiences, will determine how they respond to their offspring.

mechanisms of behavioral expression in both. How the
mother responds determines, in part, how the neurobiologi-
cal and behavioral changes in the infant proceeds. Changes
in an infant may eventually play out as to how the individual
will respond to the offspring as an adult, and so on.
2. Reciprocity in the mother–young relationship
2.1. Mothers learn about and from their infants: role of
sensory, hormonal, and neural influences
Experiences acquired while mothers are with their infants
influence their willingness to care for the young. In many
primate species (including humans), prior experiences of
holding and carrying the young either during adolescence
(siblings) or after a previous birth can have profound effects
on how competent or motivated females care for their
offspring (humans, [9]; marmosets, [10], rhesus macaques,
[11–13]; vervet monkeys, [14]). In some species, absence of
pre-pubertal experience with younger siblings results in
first-time mothers who neglect or even eat their infants
[10]. Postpartum maternal experience can also affect
mothers’ subsequent responsiveness to these same offspring
at a time when the hormones of parturition are no longer
behaviorally effective. In species that respond selectively to
their own infants, to the exclusion of other infants (e.g.
sheep mothers, ewes), mothers rapidly learn to identify
their own infants based on their odor characteristics. In
species that do not show selectivity (e.g. rats), the early
postpartum experiences with the litter helps to maintain
maternal responsiveness to young during subsequent lacta-
tion. Although processes of learning are likely to be
involved in both types of experience, the mechanisms
mediating mothers’ recognition of individual infants are
somewhat different from those that mediate the effects of
experience on maternal responsiveness in general.
2.1.1. Maternal experience affects individual recognition of
offspring
Under the influence of parturitional hormones ewes who
have just given birth may initially nurse any lamb, but they
soon learn to recognize their own lamb by its odor [15].
Once an ewe has smelled her lamb’s odor (usually the
mother’s own amniotic fluid), she butts away alien-smelling
lambs and permits to nurse only her own lamb. Her recogni-
tion requires only a few minutes of exposure to the lamb to
form [15]. In humans also, new mothers come to recognize
their own infants’ odors, cries and tactile characteristics
[16–18]. They do so even with very brief exposure to the
features of the infant during the first few postpartum days.
Mothers who nurse their infants sooner after birth and/or
who keep their faces in close proximity to their infants while
holding them (hence acquiring more olfactory experience)
 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
are both more attracted to their infants’ body odors and
come to recognize them more easily [9].
We now have a substantial understanding of the endo-
crine mechanisms that mediate the enhanced responsiveness
to offspring normally seen in the mother at parturition (see
[1,19,20]). Endocrine and neurochemical mechanisms regu-
lating the expression of maternal behavior intersect or over-
lap with those that activate or prime discriminate learning
mechanisms. In most mammals that have been studied, the
hormones that activate maternal responsiveness to young in
general are those that change at the time of parturition.
These include a period of elevated progesterone during
pregnancy, followed by its pre-parturitional decline
[20,21,106]; a late pregnancy rise in circulating estradiol
and pituitary prolactin; and a rise with parturition in oxyto-
cin [20,21]. In ewes, a variety of hormones and neuropep-
tides including estradiol, oxytocin, endogenous opioid
peptides, and corticotrophin releasing hormone (CRH) are
elevated at parturition and act in synergy with cervical
stimulation (which occurs during the birth of the lamb and
stimulates oxytocin release) to enhance the learning of the
new lamb’s odors [15]. The catecholamines norepinephrine
(NE) and dopamine (DA), along with glutamate and g-
amino-butyric acid (GABA) and nitric oxide are also
released or synthesized within the olfactory bulbs at this
time. In addition, levels of brain NE at parturition are higher
in multiparous than in primiparous ewes [22]. Hence, the first
maternal experience may prime (or sensitize) the neurochem-
ical mechanisms regulating the formation of specific discrimi-
nation of subsequent offspring. At parturition, release of these
neurochemicals facilitates changes in brain mechanisms
underlying the recognition process [15,22–24].
Consolidation of the association between the mother’s
birthing stimuli (cervical dilation) and attraction to the
lamb’s odor appears to involve changes in the olfactory
bulb cytoarchitecture and synaptic efficiency [22–24] and
possibly, amygdala, and hypothalamic processes as well.
The importance of these limbic and hypothalamic sites for
the onset and maintenance of maternal behavior is most
evident in the research on rodents (see the following).
2.1.2. Maternal experience affects maternal responsiveness
In contrast to the many species that require early pre-
pubertal or subadult caretaking experience to show adequate
mothering, female rats under laboratory conditions, and
with no prior experience with rat pups, usually care
adequately for their first litter. Female rats who have not
given birth usually withdraw from or avoid pups, so changes
surrounding the birthing process must alter this pre-potent
response. The inexperienced mother rat builds a nest, gives
birth, and then gathers, licks, and nurses her young under the
influence of changing levels of circulating steroidal and
protein hormones (see [1,20]). The hormones associated
with lactation may also contribute to the patterning of
nursing after parturition [27]. However, the later persistence
of a motivation to care for the young seems not to be
675
hormonally regulated. Once the maternal behavior has
been exhibited it persists for a number of weeks in the
absence of parturitional hormones [28,29]. Hence, for the
new mother, care of offspring appears to depend on hormo-
nal activation of neural mechanisms that express maternal
behavior. Once this has happened the hormones are no
longer required.
Pup stimuli have intrinsic effects on the female nervous
system. Virgin rats can be induced to become maternal
through repeated exposure to pups over five to seven days
[30]. Maternal behavior is exhibited most rapidly towards
pups when the parturitional hormones are present, however.
When interacting with the young, the hormonally influenced
maternal rat associates how the pups smell, feel, and sound
with motor responses involved in picking up and moving
pups and adopting a crouch posture over them. Through
concurrent hormone changes and exposure to pups, the
mother becomes habituated to their odors and other novel
aspects that would usually activate fear and withdrawal
[31,32]. Unlike mother sheep who learn the individual
odors of their lambs, rodent mothers do not develop indivi-
dual pup recognition. They respond to their own and other
litters of the same age in much the same way. Parturitional
hormones enhance the attractiveness of pups and their odors
[31] and facilitate maternal learning [33]. Pups become
considerably more reinforcing to the dam once she has inter-
acted with them and become experienced. In fact, mothers
exhibit preferences for visual environments that have been
associated with pups in only two trials [34]. Maternally
experienced females show enhanced bar-pressing for deliv-
ery of pups by comparison to the inexperienced females
[35].
As with other types of learning, the integrity and resili-
ence of maternal learning/memory varies with frequency
and duration of exposure and the interval between exposure
and test. If new mothers are separated from their young and
not permitted to interact with them at all, their maternal
responsiveness declines over the first postpartum week.
By 10 days postpartum, the mother withdraws from the
foster pups much as the naive females would [36]. However,
if permitted as little as two hours of contact with the pups on
day 1 postpartum, the mother rat shows very active maternal
response to the foster pups presented 10 days later [36].
Initial maternal learning depends primarily on somato-
sensory and chemosensory modalities. If new mothers are
rendered anosmic and cannot smell pups and are also unable
to acquire somatosensory stimulation of the ventrum and
mouth regions (due to application of anesthetic onto or
into these regions), pups are not licked or retrieved
[37,38]. Maternal olfactory and somatosensory processing
is necessary for pups to acquire reinforcing value, and for
the mother to retain responsiveness to pups over long peri-
ods of separation [37,39]. As an example, presenting
mothers with pups scented with an artificial odor results in
preferential attraction to that odor in an odor preference task
and preferential maternal treatment of similarly scented (as
676 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685

Fig. 2. Functional neuroanatomy mediating maternal and related behaviors in mammals. Neuroanatomical structures include olfactory bulbs, amygdala
(medial (Me), cortical (CORT), central (Ce), and basolateral (BASOLAT), nuclei, nucleus accumbens, bed nucleus of the stria terminalis (BNST), medial
preoptic area, midbrain, and parietal cortex. Relevant neurochemistry includes the catecholamines, norepinephrine (NE), and dopamine (DA), the neuropep-
tides, g-amminobutyric acid (GABA), N-methyl-d-aspartate (NMDA) and opioids.

opposed to ‘otherly’-scented) pups in tests 10 days later. In
order to continue the caring of pups after the hormonal
effects have subsided, the mother must continue to find
them attractive. Hence, mechanisms of reinforcement,
learning and memory are recruited. Hormones may facili-
tate the relationship, but learning factors maintain it. Facili-
tated postpartum learning also occurs in olfactory-social
contexts which are not related to pups, indicating that the
general learning processes are recruited [40].
The combined role of hormonal changes and sensory
experience in promoting maternal behavior and learning is
fairly well understood [9,29]. Until recently, however, there
has been virtually no understanding of which neuroanato-
mical and neurochemical systems are responsible for the
experiential modification of maternal behavior. One
approach was to investigate the neurochemical systems
that are known to be involved in the mediation of learning
and memory in other functional contexts that involve affec-
tive changes. As with other types of learning, maternal
learning requires protein synthesis for its consolidation.
Injection of protein synthesis inhibitors (e.g. cyclohexi-
mide) into the ventricles of the brain after exposure to
pups for three hours blocks the long-term retention of the
behavior [41]. NE mechanisms are also involved as b-nora-
drenergic blockers administered after this exposure block
the long-term effects whereas isoproterenol, an NE agonist,
enhances the retention [42]. Finally, the development of
maternal conditioned place preference using pups as rein-
forcing stimuli is blocked by a-flupenthixal, a DA antago-
nist [34]. Our particular interest, though, is in the relation
between learning systems and maternal systems [29,43].
As there is a considerable overlap of maternal learning
with more general conditioning and learning reinforcement
mechanisms and we know some of the neuroanatomical
systems underlying aspects of general learning per se, a
next step was to determine the role of these brain structures
and those in the ‘maternal circuit’, in the acquisition and
retention of maternal experience. For instance, work on the
supraoptic nucleus shows that, with suckling experience in
the lactating animal, there occur changes in the structural
and functional properties of supraoptic neurons. These
neurons release oxytocin in response to suckling stimulation
and are necessary for the milk letdown reflex. [44]. Modney
and Hatton [44] found two kinds of change associated with
the end of pregnancy and the initiation of nursing. One
involves the formation of new (double) synapses on the
cell body and dendrites of the supraoptic nucleus, while
the other involves the increase in electrical coupling
among these same oxytocinergic supraoptic neurons.
These changes very likely contribute to the synchronized
activity in these oxytocin cells prior to milk ejection. Of
particular interest in this context are the additional findings
that some of these modifications also appear in virgin
animals induced to become maternal through long-term
exposure to pups, but who did not receive suckling stimula-
tion. Instead, there is evidence that olfactory and/or other
chemosensory stimulation derived through licking and
retrieving of pups may induce these changes in the virgin
[44,45]. The time course of these effects in the nursing
animal may be relevant; some synaptic changes are rever-
sible, but apparently others are more permanent. Such long-
term structural changes could provide a possible basis for
the findings that, once dams have had some nursing experi-
ence, distal olfactory and other exteroceptive pup cues come
to elicit the conditioned release of oxytocin in the absence of
suckling [46].
 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
Fig. 3. Potential signal transduction pathways leading to maternal c-fos
expression. Maternal hormones, neurotransmitters and pup stimulation (e.g.
olfactory) can activate many receptor complexes. This leads to the eleva-
tion of neuronal calcium levels and the stimulation of protein kinase C
(PKC). Calcium activates calmodulin (CaM), which in turn stimulates a
wide range of calmodulin binding proteins (CaMBPs) such as CaM-depen-
dent kinases. These kinases and PKC each phosphorylate specific upstream
elements that ultimately lead to the expression of c-fos. As part of transcrip-
tional complexes, such as AP-1, c-fos could then activate gene expression
that underlies maternal behaviour.
Using quite a different approach we used the c-fos immu-
nocytochemistry to assess which brain areas are activated
during the acquisition and retention of a maternal experi-
ence.
3. Correlates of maternal behavior at the intra-cellular
level
3.1. Fos as a neuroanatomical marker of maternal
experience
Fos is a protein produced by a class of immediate early
genes known as c-fos oncogenes that are present in brain
neurons and activated by a variety of stimulus situations and
behavioral states [47]. Acting with another proto-oncogene
protein, Jun, as part of the AP-1 transcription factor, Fos can
operate directly as part of the transcriptional apparatus to
direct gene transcription or it can act by binding to enhancer
elements to affect the gene regulation [48]. Therefore, c-fos
immunocytochemistry can be used as a tool to determine
which brain sites are activated when an animal first responds
maternally, acquires an experience, and then retrieves the
memory [43,49–52]. Moreover, the physiological relevance
of Fos for maternal behavior is suggested by the recent
observation that c-fos-knockout mice fail to show adequate
maternal behavior under circumstances in which it would
normally be seen in the wild-type mouse [53].
If an animal is maternally active for the first time,
enhanced c-fos expression is found in a number of brain
regions including the medial pre-optic area (MPOA), the
677
bed nucleus of the stria terminalis, the medial, cortical
and basolateral nuclei of the amygdala, the nucleus accum-
bens, the olfactory and somatosensory cortices, and the pre-
frontal cortex [51,52]. Fig. 2 shows the functional neuroa-
natomy mediating the maternal and related behaviors. Some
of these sites are clearly part of the final common path for
the expression of maternal behavior (e.g. MPOA,
[29,43,55]). Others mediate stimulus salience and effect
(medial and cortical amygdala, see [56,57]), and processes
of learning, memory and reinforcement (pre-frontal cortex,
basolateral amygdala, nucleus accumbens, see [51,58]).
Others participate in sensory processing (cortical and
medial amygdala, parietal and olfactory cortices [56,59].
Only a few of these sites are activated at retention testing.
When re-exposed either to pups themselves or to pup-asso-
ciated conditioned cues (an environment or stimulus paired
with pups), the only sites that are more active in the experi-
enced than the inexperienced animal are the MPOA, the
basolateral amygdala and the parietal cortex [50]. Experi-
ential effects of performing maternal behavior and receiving
pup stimulation in the postpartum mother are the basis for
maintaining maternal behavior when hormonal effects have
waned. MPOA lesions produce severe deficits in both the
hormonal and experiential components of maternal behavior
[43]. The transition from hormonal to non-hormonal regula-
tion of maternal behavior, therefore, is probably dependent
on MPOA mechanisms.
4. Effects of experience on signal transduction
components
Although c-fos expression is clearly enhanced with the
expression of maternal behavior and experience, it is not
known whether this protein is necessary for the behaviors
to be expressed and, if so, what role they play. As our
interest lies in understanding the regulatory events that initi-
ate maternal behavior and experience, we have started to
determine how c-fos expression is regulated by up stream
regulators of maternal behavior, and to determine what
function the expressed proteins serve. In mammalian cells,
there are numerous signaling pathways that can lead to c-fos
expression [60]. One approach to dissect the major signaling
pathways in specific regions of the rat brain is to immuno-
localize selected proteins from those pathways, and then to
determine if they are present during and are linked to the
maternal behavior. Two major components of calcium-
mediated signaling pathways that lie upstream to c-fos
expression were examined: protein kinase C (PKC) and
calmodulin binding proteins (CaMBPs; Fig. 3). At least
two of the protein hormones involved in the expression of
maternal behavior, oxytocin and prolactin, can produce
intracellular neuronal increases in calcium levels, leading
to the activation of PKC and CaMBPs [61]. PKC can be
activated by diverse signaling pathways, including via G
protein-linked phospholipases, receptor tyrosine kinases
678 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
and non-receptor tyrosine kinases [62,63]. While numerous
PKC forms of the protein exist (isozymes), the brain-speci-
fic PKC isozyme (PKC gamma) is a typical C kinase that is
activated by calcium ions and diacylglycerol and undergoes
developmental increases in the rat brain [63]. PKC is impli-
cated in long-term potentiation (a neuronal model of
memory) as well as in learning, memory, and plasticity
processes [64,65], PKC can also act as an upstream regula-
tor of AP1 (c-fos/c-Jun) expression [48,66].
Immunocytochemical assay of a number of different PKC
isozymes indicates that there is a considerable overlap in the
regional and temporal pattern of expression of PKC and Fos
protein in mother rats exposed to offspring [67]. There are
also some incongruities in their patterns of expression that
may be informative. For example, enhanced staining of both
PKC and Fos protein is observed in the MPOA and the
parietal cortex after maternal experience with pups [32]. If
the pups are removed, enhanced PKC will still be observed
in the mother four days later but Fos staining would have
diminished by then. Active stimulation by pups or pup-asso-
ciated conditioned cues is necessary to reinduce enhanced c-
fos expression, and this occurs rapidly but is also relatively
short-lived. The relation between the PKC and Fos results
suggest that maternal experience initially stimulates
enhanced PKC synthesis and an activation of the c-fos
gene in the maternal system (e.g. MPOA). In the absence
of pup stimuli, maternal PKC remains elevated for a consid-
erable period, but c-fos gene activation declines. As PKC
sits upstream in the biochemical cascade leading to c-fos
activation, enhanced PKC resulting from past experience
with pups would permit rapid activation of the c-fos gene
in relation to new pup stimuli in the experienced female.
Another primary route for calcium function is via calmo-
dulin (CaM) and theCaMBPs to which it binds and modu-
lates. Upon activation by Ca 21, CaM was shown to regulate
c-fos expression but the specific CaMBPs that mediate this
expression have not been identified [68]. However, the
CaMBP, CaM-kinase II has been implicated in models of
neuronal plasticity [69]. In addition, certain kinases and
calcineurin (CaM-dependent protein phosphatase 2B), a
major brain protein, regulate transcription factor phosphor-
ylation upstream of Fos expression [70]. Cells also contain
dozens of CaMBPs many of which mediate neurotransmitter
release [71]. Previous studies have identified only a handful
of the many CaMBPs in brain and other tissues of the rat.
Rather than focusing upon one or two known CaMBPs,
analysis of the pattern of changes in the total population
of these proteins during maternal behavior has been a fruit-
ful approach in elucidating the role of these important cellu-
lar regulators. A gel overlay technique with recombinant
calmodulin (35S-VU1-CaM) reveals over two dozen
CaMBPs, a number in keeping with the known population
extant in mammalian and other eukaryotic cells [72]. Analy-
sis of the quantitative changes in the CaMBP profiles
reveals that there is a decrease in several CaMBPs asso-
ciated with the onset of maternal behavior. Western blotting
has further revealed the absence of calcineurin from the
MPOA but not other regions of the maternal brain (O’Day
et al., unpublished results). These changes and differences
are localized only to the MPOA suggesting that there may
be calcium-regulated signaling pathways that are specifi-
cally associated with maternal behavior and plasticity. The
goal now is to characterize these CaMBPs to gain further
insight into their possible functions.
5. A functional neuroanatomy of maternal experience
These studies not only reveal some of the basic molecular
mechanisms underlying maternal processes, but also help to
elucidate the neuroanatomy that underlies the acquisition
and retention of maternal experience (see Fig. 2). A role
for the MPOA, the limbic system, the olfactory and soma-
tosensory systems in the initiation and retention of maternal
behavior is consistent with more general learning, memory,
and emotional functions of these structures.
Beyond this it is known that the MPOA contains receptors
for the hormones that activate both the motoric and motiva-
tional aspects of maternal behavior [28,55]. Lesions of the
MPOA eliminate maternal retrieving and nest-building as
well as instrumental responding for pup-delivery in an oper-
ant apparatus [35,43]. Electrical stimulation of this area has
opposite effects [55]. Of all the brain structures studied from
a molecular perspective, the MPOA undergoes the most
robust and substantial change with maternal experience.
MPOA function is substantially altered by experience, and
such alterations may play a role in the facilitated maternal
behavior seen in the experienced animals. The hormonal
responsiveness of the MPOA increases with increasing
parity [21]. Moreover, electrical stimulation of this brain
site is more effective in promoting maternal behavior in
experienced as opposed to inexperienced animals [55]. In
short, it appears that the MPOA is involved not only in the
initial expression of maternal behavior, but also in retaining
and mediating the effects of maternal experience and parity
on the subsequent expression of the behavior.
Other central nervous system structures clearly mediate
the sensory aspects of maternal behavior (e.g. parietal cortex
and ofactory bulbs), being activated when the animals sniffs,
licks, mouths and crouches over the pups [38]. The parietal
cortex also appears to be changed by maternal experience,
an effect that is consistent with evidence that this sensory
receiving area is plastic and re-organizes in relation to
experience in adult rodents. For example, in comparison
to the non-lactating postpartum females, lactating (and
hence more experienced) females have an expanded region
of the cortex activated by stimulation of the ventral teat
region [73]. What this probably means is that cortical
mechanisms change in relation to experience; and subse-
quent experiences are almost certainly processed differently
than were the initial experiences.
A role for amygdaloid nuclei in the expression and
 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
retention of maternal behavior has alsobeen demonstrated.
Areas in the medial and cortical amygdala receive olfactory
input and are believed to mediate avoidance responses to
odors or have anxiogenic actions more generally. Indeed,
these amygdalar mechanisms inhibit the expression of
maternal behavior in virgin animals. Lesions of these nuclei
or of pathways that project from the amygdala to the MPOA
in the virgin animal permit rapid maternal responding to
pups and reduce fear responses to odors in other contexts
(see [9,32,43,55]).
The enhanced activation of the basolateral amygdala with
maternal experience is consistent with the observation that
this structure receives extensive primary or secondary input
from all the relevant sensory modalities, thereby serving as a
point of convergence where the formation of associations
may occur [52,56,59,74]. Walsh et al. [52] demonstrated
that the combined chemosensory and somatosensory desen-
sitization in maternally-behaving animals produces an addi-
tive reduction in basolateral amygdaloid activity (reflected
in c-fos expression). Moreover, lesions of this region elim-
inate the development of a conditioned place preference for
pups and disrupt the postpartum expression of maternal
behavior [35]. Not surprisingly, given its role in reinforce-
ment [58,75], DA depletions or lesions of the nucleus
accumbens also disrupt the consolidation of maternal
memories [28]. Hence, the combined activation of basolat-
eral and nucleus accumbens in response to pup stimuli, and
the effects of lesions in reducing the maternal responsive-
ness, suggest that the basolateral amygdala and nucleus
accumbens form an interconnecting neural loop that
mediates the formation of associations between biologically
relevant events (pup stimuli and maternal behavior, in this
instance) [56].
The effects of maternal experience on the basolateral
amygdala and on the parietal cortex reflects the general
properties of these two structures (systems) that are
recruited by many types of learning. Experience-related
activation of MPOA seems to be specific to maternal beha-
vior, however. Perhaps it makes sense that in mammals, as
in birds [4,6], the long-term effects of memory should be
most clearly seen in the very system that normally underlies
the expression of the behavior.
6. Intergenerational effects: Does how one was mothered
influence subsequent mothering?
6.1. The infant becomes experienced through the mother
Among mammals, the maternal and nest contexts provide
a rich learning environment for the developing young.
Mothers not only learn about their offspring; but the
offspring also gain experiences during the pre-weaning
period that affects their adjustment to the mother and later
on to their own offspring.
679
6.1.1. Short-term experience effects
For instance, rat pups develop an attraction to the chemo-
sensory characteristics of mother’s ventrum and first
attaches to the nipples based on prior intrauterine experi-
ence with the amniotic fluid [76]. Attraction is often
followed by the development of nipple-preferences. In
fact, kittens develop a preference for a particular nipple or
nipple location on the mother’s ventrum. Seeking the ideal
nipple position is based on experiences with the tactile and
thermal characteristics of the mother’s ventral surface [77].
In rats, the expression of food preferences is based on
experiences acquired during the infant’s exposure first to
the mother’s milk, then her odors (which are partially
dependent on her diet), then to food particles remaining in
the vicinity of the mother’s mouth and on her fur, and
finally to following the mother to a food site [78–81].
More subtle discrimination by weaned animals of nutri-
tious versus nutritionally deficient foods is also based
on learning [82].
The behavioral effects of early experiences occurring in
the maternal nest are mediated by neurochemical and
neuroanatomical mechanisms that have been substantially
changed by early experiences [2–3,83–85]. As an example,
the recognition of the rat mother’s specific odor by pups
occurs in conjunction with licking of the pups by the mother
[86]. Formation of the association between licking and
maternal odor depends on licking induced activation of
the midbrain nucleus, the locus coeruleus (LC), whose
axons terminate in the olfactory bulbs and release the neuro-
transmitter, NE [86]. Recognition of maternal odor involves
both the neurochemical and cellular cytoarchitectural
changes in the olfactory bulb [86,87]. Development of an
attraction and preference for maternal odors (over other
odors in the environment), depends on central processing
of olfactory information by the limbic structure, the amyg-
dala. More generally, processing of the olfactory bulb inputs
by amygdalar mechanisms determines the salience of olfac-
tory stimuli and the nature of affective responses to them
[86]. The neuropeptides (oxytocin and opioids) may also
play a role in the infant rat’s early affiliative behaviors in
the nest and in the infant’s attraction to maternal odors [25–
26,85,88]. The proclivity of rat pups to approach and attach
to the mother is heavily dependent on the experiential
effects on olfactory and limbic mechanisms that mediate
attraction to and recognition of the mother and her environ-
ment.
6.1.2. Long-term experience effects
Postpartum experiences with the mother and nest influ-
ence the development of the infant prior to weaning.
Concurrent early olfactory experiences (mothers’ odors)
and somatosensory experiences (being nursed, licked, etc.)
also appear to have long-term effects on the infants as they
grow. For instance, infant rats who received more touch and
licking stimulation from the mother in the nest show a
higher level of pup-licking as juveniles and as adults
680 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
when presented with new-born pups, by comparison to less
stimulated infants; moreover, recent studies indicate that the
quality of the infants’ nest experience may well affect their
later behavior with their own offspring (Natterer, Lovic,
Shah, and Fleming, in preparation). Similar early maternal
stimulation in the nest also produces a dampening of the
offspring’s emotional reactivity to novelty and stress when
they become adults [89]. Reductions in stress reactivity are
attributable in part to the increased density of hippocampal
glucocorticoid receptors. These receptors normally mediate
negative feedback effects of circulating adrenal glucocorti-
coids following hypothalamic-pituitary-adrenal (HPA) acti-
vation. Stimulation-induced changes in thyroid function and
brain serotonin system activity early in the postpartum
period are also involved in these long-term hippocampal
effects [90]. Hence, long-term changes in brain mechanisms
that modulate the stress reactivity in offspring are produced
by natural variations in mothering behavior. To the degree
that many interactions with offspring are stressful, this may
canalize some aspects of the way individuals respond to
their own offspring later on. In species in which mothers
develop individual recognition of their offspring, as in
sheep, the same or similar mechanisms used to promote
attachment of the young female to her mother, are re-acti-
vated when she gives birth and exhibits recognition and
attachment to her own offspring. This transfer of biological
effects of early rearing experience to later maternal respon-
siveness and behavior may be especially evident when
considering species in which the parent is intimately
involved with disciplining or socialization of offspring, as
in non-human primates.
In rhesus monkeys, measures of HPA axis activity in
mothers and offspring are positively correlated [91]. In
vervet monkeys, there is substantial evidence that the style
of mothering exhibited by adult daughters is similar to the
style of mothering shown by their mothers [14]. Vervet
monkey mothers who engage in a high level of mother–
infant ventral contact have daughters who also show high
mother–infant contact. Abusive patterns of maternal care
span generations as well, and the incidence of abuse varies
across matrilines in pigtail macaques [14]. One cannot, of
course, identify the mechanism underlying the intergenera-
tional similarity based on these correlations. Similarity
could be due to consistent (genetically pre-programmed)
personality styles or due to the effects of observing the
mother’s interactions with younger siblings. Using multi-
variate analyses in which these alternate influences were
assessed, however, Fairbanks [14] demonstrated that the
manner in which the infants were mothered did indeed
exert an effect on their adult mothering behavior. Among
humans, it is commonly assumed that there are often inter-
generational similarities in maternal behavior. We have not
yet found a longitudinal study that conclusively documents
substantial and significant commonalties in specific prac-
tices of mother–daughter maternal behavior, however.
Rather, the long-term longitudinal story has to be pieced
together based on findings of multiple short-term studies
and there are missing pieces to the puzzle.
What has been investigated is the relationship between
maternal and infant attachment style, and later personality
of the infant-as-young-adult and attachment style of their
infants. The results of short term longitudinal studies indi-
cate that (1) the emotional quality of mothers’ responsive-
ness to infants is related to the infants’ attachment style, (2)
infants’ attachment style in turn is related to social and
affiliative aspects of adult personality, and (3) these adult
personality styles are related to responsiveness to infants
[92–94].
Scientific interest in intergenerational effects has also
been driven by efforts to understand the mechanisms under-
lying the abnormal by comparison to normal psychosocial
development. In social primates, the importance of early
mothering in determining how the daughters will mother
is clearly demonstrated under the conditions in which
female offspring are partially or completely deprived of
early mothering. For instance, rhesus monkeys can be reared
with same aged peers rather than mothers (peer-reared
monkeys) [79,95–98]. When peer-reared monkeys become
mothers as adults, they are more likely to reject or abuse
their infants than monkeys reared by their biological
mothers (mother-reared monkeys). The mechanisms that
mediate this effect are not understood. The idea that peer-
reared monkeys are generally poor mothers because they are
deprived of ‘learning how to mother’ from their own mother
cannot entirely explain their deficits in maternal behavior.
Some peer-reared monkeys are perfectly adequate mothers,
but the proportion of who are not considerably exceeds that
observed in mother-reared monkeys. As no peer-reared
monkey has experience with maternal care, the range of
variation in peer-reared maternal behavior cannot be
explained by early variation in learning how to mother.
In general, how the individual copes with environmental
change and stress may vary with how they cope with chal-
lenges presented by offspring. By comparison to mother-
reared monkeys, peer-reared monkeys are behaviorally
over-reactive to stressors such as competitive social inter-
actions or forced separation from their social group [79,95–
98]. The peer-reared monkey is both more likely to be inor-
dinately aggressive in social altercations, and more inactive
and withdrawn when isolated apart from its accustomed
social group. They exhibit chronically lower levels of
brain catecholamine (CA) system activity, but then have
exaggerated increases in brain CA activity when stressed
[79,95–98]. Their HPA axis activity is also chronically
reduced, somewhat paradoxically, in relation to what
seems to be CA system hypersensitivity, their HPA axis
response to stressors is blunted [95]. In addition, there are
lawful relations between neurochemical and neuro-
endocrine levels and behavior in mother-reared monkeys,
and these relations are less prominent or simply absent in
juvenile peer-reared monkeys [97]. Hence, in rhesus
monkeys, one persisting effect of maternal deprivation is a
 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
neurobiological disorganization which is accompanied by a
relative inability to cope behaviorally or physiologically
common social stressors later in life [99]. Among such stres-
sors would be caring for offspring, and as noted before,
peer-reared mothers are substantially more likely to reject
or abuse their infants.
Although the neurobiological effects of complete mater-
nal deprivation have not been studied in humans, it is known
that children reared in orphanages in Romania exhibit
disrupted physiological, sensory-motor, emotional, and
cognitive development reminiscent of that observed in
socially isolated rhesus monkeys [98,103]. There is also
substantial evidence that infants who received abusive or
neglectful parenting may face difficulty in parenting their
own offspring. Approximately 30% of children who were
abused or neglected during their early lives come to abuse
and/or neglect their own children many years later (versus a
base rate of 5% for non-abused children, see [104,105]). The
intergenerational effect may be that children who have been
abused develop personalities as adults, lacking in self-
knowledge and empathy for their own children’s pain and
misfortune, and also fail to cope with the many challenges
presented by the child. These effects are probably reduced or
prevented if the abused child subsequently, or concurrently,
has affiliative social experiences with a caring individual.
This is likely to be the reason why 70% of abused children
do not go on to be abusive themselves as parents [100,104,
105].
Based on our understanding of experience effects on brain
in other animals, it is also possible that children who have
been severely neglected or abused have experienced neuro-
logic changes which result in altered affective, perceptual
and cognitive function during development. Such changes
are more than likely to affect how they perceive and respond
maternally to their own offspring, how they approach mater-
nal care responsibilities initially, and how they are able to
learn or modify maternal care practices. Such conclusions
may not be controversial, or not as controversial as they
would have been decades ago when maternal behavior
was generally accepted as a hard-wired aspect of female
brain function. The major theoretical issue then is under-
standing why this aspect of brain function which is critical
for species survival is so malleable.
7. A functional analysis: plasticity and development of
species-typical behavior
Plasticity in behavioral mechanisms is not unique to
mammalian mother–young interactions, but is exhibited
across species and in a number of developmental contexts
(e.g. song-learning, food caching, food preference develop-
ment, imprinting, mate selection [4,5,7,8,82,101,102]. What
might be the adaptive, and hence selective value of plasti-
city and dependence on learning, rather than ‘hard-wiring’
of innate behavioral control mechanisms for mother–infant
681
recognition, attachment, and caregiving? Plasticity permits
a certain latitude or flexibility in the relevant features that
enable the offspring to identify the mother, and for the
mother to identify her offspring. On the one hand, olfactory
cues and other characteristics of the rodent mother may vary
depending on her sources of food and dietary regimen.
These resources vary geographically, and over days,
weeks, and seasons, and consequently are not necessarily
the same for all of her litters or even pups within a litter.
Hence, the pup’s expression of attachment behaviors cannot
be locked on a pre-determined and invariant set of salient
maternal characteristics. On the other hand, variation in
maternal diet and environmental effects on maternal pre-
parturitional physiology, may affect infant odors, body
size and conformation, and neonatal behavior. Successive
offspring will differ in genotype as well as phenotype. If
expression of maternal behaviors were narrowly locked to
invariant neonatal characteristics, then the diversity of
offspring nurtured and thus surviving would also be narrow.
Hence, plasticity in mammalian mother–infant behavior: (a)
allows for offspring to be nurtured in widely varying envir-
onments and circumstances, and (b) provides for preserva-
tion of genetic/behavioral diversity in those offspring. Also,
by using conditioning mechanisms, a complex multimodal
stimulus (say, of an infant, who has a characteristic odor,
cry, and visual appearance) comes to be easily located and
identified based on any one of these cues. This is important
when not all the cues are present (as when the infant is
concealed within a nest or strays away from the nest or
mother).
Finally, plasticity in the maternal brain increases the
reproductive fitness by allowing experience with one infant
to modify the care of subsequent offspring in the changing
environment in which the mother lives. Among many
primate species, mothers of first infants are considerably
less competent and motivated than are mothers of subse-
quent offspring. The experiences of the multiparous female
are not limited to interactions with individual offspring.
They include somatic and physiological experiences asso-
ciated with pregnancy and parturition, as well as exposure to
infants, peers, and the larger environment and society, more
generically. This effect of parity and the associated experi-
ences usually insures that the young of an experienced
mother have an advantage in comparison to the first-born,
the young of less experienced mothers. They are more likely
to be cared for during adversity and receive more abundant
nutrition, attention, and social stimulation provided by an
older, more mature, less timid, and better socialized mother.
The mother and young usually constitute for one another the
earliest and most pervasive stimulus set present in the post-
partum environment. To the degree that the nervous system
of the infant is dependent for its development on an
extended series of interactions with a mother, deprivation
of these interactions might have adverse effects in the
proportion. Plastic brain mechanisms take time to adapt,
and their development can be adversely affected if they
682 A.S. Fleming et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 673–685
are not exposed to the expected or common set of species-
specific experiences.
8. Summary and future directions
In this article, we have described the importance of learn-
ing and plasticity mechanisms in the regulation of the
mother–young relationship. In mammals, the attraction
between mother and young, and their mutual recognition
depends on olfactory and somatosensory experiences.
Some effects of early experience are remarkably specific,
leading to recognition of, and attachment to, the mother and
siblings, and development of spatial location and food
preferences. There is a striking similarity between mechan-
isms mediating the rat pup’s recognition of maternal odors
on one hand, and the ewe’s recognition of her lamb’s odors
on the other. Recognition of the mother by infant and the
infant by mother involves the formation of an olfactory
recognition in association with somatic stimulation (cervi-
cal stimulation-ewe, or being licked, nuzzled-pup). Both
these involve somatosensory activation of the centrifugal
Locus Coeruleus NE system. This activation promotes the
formation of cytoarchitectural and synaptic changes leading
to both an increased discrimination of odors, and an asso-
ciation of odor information with somatosensory stimulation
provided either by birthing (in the case of the mother), or by
maternal grooming or cleaning (in the case of the offspring).
These processes occur within the olfactory bulb.
In mothers and offspring, NE system activation increases
the signal-to-noise ratio for odors that are present, and
promotes consolidation of neuronal changes at the cellular
and synaptic level in the olfactory bulb. Further, the initial
discrimination and its response seems to prime or sensitize
olfactory-affective systems for more rapid or efficient subse-
quent discriminations and associations. Finally, in both the
mother and the offspring, neuropeptides (oxytocin and
endogenous opioids) were shown to enhance affiliative
behaviors that are dependent on olfactory and somatosen-
sory input. Collectively, these findings suggest that comple-
mentary mechanisms mediate mother-infant affiliation in
mammals. The association of maternal odors with beha-
vioral affiliation responses in infants may well prepare the
developing nervous system for rapid expression of maternal
behavior in response to infant odors in adulthood. Stated
another way, the development of the rat pup’s ability to
discriminate maternal odor means that the neural machinery
from olfactory receptor mechanisms to more central proces-
sing was altered. This is likely to determine to some extent
how pup odors are processed and discriminated when the
pup becomes a mother.
Mothers also depend on postpartum experiences with
their young to sustain their responsiveness during lactation,
i.e. well past the period of hormonal priming. Experiences
with offspring earlier in life or after a previous birth also
enhance, refine or tune maternal responsiveness towards
subsequent offspring. Other effects of some of the same
early experiences (e.g. receiving adequate somatosensory
stimulation) are more general, leading to different patterns
of response to stressors and social stimuli. These behavioral
effects of experience are mediated by changes in brain
neurochemistry, structure, and function in both the mother
and the young.
It is important to learn which biochemical pathways are
operational in the appropriate brain regions and are tempo-
rally linked to the onset and consolidation of maternal beha-
vior. Any complex behavioral process, such as maternal
behavior is unlikely to be mediated by a single molecular
entity such as a specific PKC isozyme. Only by knowing the
functional pathways that are operational during the process
will it be possible to understand the potential interconnec-
tions and cross-talk between pathways that current research
is revealing as standard operating procedure for mammalian
cells. A complete understanding of these functional path-
ways is also essential for interpreting the results of genetic
alterations of specific components of the signaling routes.
At a different analytic level, learning and plasticity within
the mother–young context play a critical role in promoting
adaptive fitness in mammalian species per se, and this role
may be extended to non-human and human primates. In
primates, early experience and associated brain changes
clearly affect how the infants interact with the world in
general, and with their own offspring as adults. Establishing
exactly how the neurobiological changes produced by early
experiences might persistently alter the neurobiological
mechanisms providing for later maternal learning and plas-
ticity constitutes the next challenge.
Acknowledgements
Many thanks to Bernie Schiff, David Sherry, Sarah Shet-
tleworth, and Jeff Alberts and his students for their very
helpful comments on earlier versions of this manuscript.
Research and manuscript preparation supported by
M.R.C., N.S.E.R.C. and S.S.H.R.C., to A.S. Fleming, The
John D. and Catherine T. MacArthur Foundation, NIMH
(MH 40748), NICHHD (HD 23042), NIAAA (AA 10079)
to G.W. Kraemer and, N.S.E.R.C. to D.H. O’Day.
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