Rodent Model of Infant
Attachment Learning and Stress
Tania L. Roth3
Regina M. Sullivan1,2
1Emotional Brain Institute
Nathan Kline Institute for
Psychiatric Research and Child
& Adolescent Psychiatry
New York University School of Medicine
140 Old Orangeburg Road
Orangeburg, NY 10962
2Department of Zoology
University of Oklahoma
3Department of Neurobiology and
Evelyn F. McKnight Brain Institute
University of Alabama at Birmingham
ABSTRACT: Here we review the neurobiology of infant odor learning in rats, and
discuss the unique role of the stress hormone corticosterone (CORT) in the learning
necessary for the developing rat. During the first 9 postnatal (PN) days, infants
readily learn odor preferences, while aversion and fear learning are attenuated.
Such restricted learning may ensure that pups only approach their mother. This
sensitive period of preference learning overlaps with the stress hyporesponsive
period (SHRP, PN4–14) when pups have a reduced CORT response to most
stressors. Neural underpinnings responsible for sensitive-period learning include
increased activity within the olfactory bulb and piriform ‘‘olfactory’’ cortex due to
heightened release of norepinephrine from the locus coeruleus. After PN10 and with
the decline of the SHRP, stress-induced CORT release permits amygdala activation
and facilitates learned odor aversions and fear. Remarkably, odor preference and
attenuated fear learning can be reestablished in PN10–15 pups if the mother is
present, an effect due to her ability to suppress pups’ CORTand amygdala activity.
Together, these data indicate that functional changes in infant learning are modified
by a unique interaction between the developing CORT system, the amygdala, and
maternal presence, providing a learning system that becomes more flexible as pups
mature. ? 2010 Wiley Periodicals, Inc. Dev Psychobiol 52: 651–660, 2010.
Keywords: mother–infant interactions; olfactory bulb; norepinephrine; attach-
ment; imprinting; locus coeruleus; amygdala; learning; classical
conditioning; corticosterone; stress; fear
‘‘There is continuity in development, such that the
organization at one stage provides the basis for
organization at the next succeeding stage. This
does not mean, however, that all processes persist
throughout life, nor does it mean that behaviors
must remain stable across stages. On the contrary,
development is essentially a dynamic process that
promotes reorganization and adaptation across
exquisitely designed to identify, learn, and remember
experiences with their caregivers. Indeed, infants readily
learn an attraction to their mother’s odor, which ensures
that infants will exhibit approach behaviors toward the
mother in order to receive the food, protection, and
warmth needed for survival. Perinatal learning of
maternal odor is required forpups to approach the mother
and attach to her nipples for nursing (Pedersen & Blass,
1982), though somatosensory cues from the nipple are
also required for these behaviors (Polan & Hofer, 1999;
Stern, 1997). The maternal odor continues to be learned
throughout the postnatal period (Cheslock, Varlinskaya,
Petrov, & Spear, 2000; Pedersen, Williams, & Blass,
1982), presumably since the mother’s odor can be altered
with her diet (Leon, 1992). Overall, infant behavior is
Kaner, 1980; Leon, 1992), and, as will be discussed here,
this early attachment process is facilitated by infants’
enhanced ability to learn preferences and their decreased
ability to learn aversions or fear. Presumably, this
constrains infants to form only preferences to caretakers.
Received 24 November 2010; Accepted 25 June 2010
This article is a contribution to a Special Issue of Developmental
Psychobiology, 52(7), 2010, entitled ‘‘Seymour Levine’s Legacy: The
Infant’s World and its Consequences.’’
Tania L. Roth’s present address is Department of Psychology,
University of Delaware, Newark, DE.
Correspondence to: S. Moriceau
Published online 20 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI 10.1002/dev.20482
? 2010 Wiley Periodicals, Inc.
Such attachment learning has a wide phylogenetic
representation and appears to enable altricial animals to
easily form a repertoire of proximity-seeking behaviors
toward the primary caregiver, regardless of the quality of
care they receive. For example, in avian imprinting, a
chick will continue to follow its caregiver even while
being shocked (Hess, 1962; Salzen, 1970). A similar
experiment in dogs has shown that puppies will display
strong attachment to a handler who provides rough
treatment or neglect (Rajecki, Lamb, & Obmascher,
1978). Additionally, nonhuman primates and human
children will also demonstrate strong attachment to an
abusive caregiver (Harlow & Harlow, 1965; Helfer,
Kempe, & Krugman, 1997; Maestripieri, Tomaszycki, &
Carroll, 1999; Sanchez, Ladd, & Plotsky, 2001).
We have hypothesized that the infant rat learning
system is designed to ensure that pups will learn an
approach response towards and preference for the
mother, regardless of whether she is associated with
pain or pleasure (Hofer & Sullivan, 2001). We refer
to this period of attachment learning as the ‘‘sensitive
period.’’ Furthermore, it is worthwhile to note that
postpartum mothers of various mammalian species also
display a sensitive period for learning about offspring
(Brennan & Keverne, 1997; Insel & Young, 2001;
Keverne & de la Riva, 1982; Marlier, Schaal, &
Soussignan, 1998; Moffat, Suh, & Fleming, 1993; Okere
& Kaba, 2000; Pissonnier, Thiery, Fabre-Nys, Poindron,
& Keverne, 1985). Much like that of the infant, mother
learning requires unique neural circuitry to facilitate odor
preferences, approach responses, and nurturing behavior
toward offspring (Brennan & Keverne, 1997; Insel &
Young, 2001; Le ´vy, Gervais, Kindermann, Orgeur, &
In just 3 short weeks, rat pups are transformed into
independent organisms with the maturation and experi-
ence to survive on their own. These 3 weeks represent
a time of transition from maternal dependence to
independence that uniquely characterizes the dramatic
reorganization and adaptation of learning required of the
infant. In this review, we discuss the neural basis that
enables pups to transition between readily learning
preferences within the context of attachment to learning
fear. One prominent characteristic of learning after
postnatal day (PN) 10 is the amygdala’s dependence
on stress-induced corticosterone (CORT) release. Indeed,
the ontogeny of infant stress responsiveness and the
hypothalamic–pituitary–adrenal (HPA) system develop-
ment were two major foci of Seymour Levine’s devel-
opmental work. As will be evident below, Levine’s
contributions to developmental psychobiology have
certainly been instrumental in helping us understand
the neurobehavioral basis of infant attachment and the
ontogeny of fear learning.
NEUROBIOLOGY OF INFANT RAT ODOR
During the infant sensitive period, PN1–9, pups display
an enhanced capacity for preference learning. We have
shown that learned odor preferences (conditioned via
either positive or aversive stimuli paired with an
unfamiliar odor) during this period are in part due to
strong noradrenergic input to the olfactory bulb from the
locus coeruleus (LC). Infant acquisition (learning) is
disrupted if norepinephrine (NE) receptors are blocked in
the bulb (Sullivan, Zyzak, Skierkowski, & Wilson, 1992)
or if the LC is pharmacologically destroyed (Sullivan,
Wilson, Lemon, & Gerhardt, 1994). Presentations of an
odor with the activation of olfactory bulb NE b-receptors
produce odor preference learning (Sullivan, Stackenwalt,
Neve, & McLean, 2003). Additionally, we have shown
that NE is required for the maintenance of the prolonged
mitral cell response characteristic of sensitive-period
learning (Wilson, Sullivan, & Leon, 1987).
Unique properties of the LC appear to be responsible
for infant preference learning. In effect, the LC of a
sensitive-period pup is characterized by prolonged
stimulus-evoked excitation, which prompts release of an
enormous amount of NE (Nakamura, Kimura, & Saka-
guchi, 1987). This isin contrast tothe LC of an older pup,
in which there is a much shorter evoked physiological
response and thus smaller release ofNE(Nakamuraetal.,
the sensitive period is associated with the functional
emergence of LC a2 inhibitory autoreceptors and the
downregulation of LC a1 excitatory autoreceptors
(Nakamura et al., 1987; Pieribone, Nicholas, Dagerlind,
& Hokfelt, 1994; Scheinin et al., 1994). To test whether
these developmental changes in LC autoreceptors are
important for ending pups’ rapid preference learning,
we recreated neonatal levels of these LC autoreceptors’
activity in older pups to reproduce the largeNE release of
younger pups. Specifically, after stimulating the LC with
intra-LC cholinergic infusion, combined with drugs that
blocked the autoinhibition (a2 antagonists) and enhanced
the autoexcitation (a1 agonists), we successfully rein-
(Moriceau & Sullivan, 2004b). These data suggest that
functional changes in the LC support termination of the
rapid and robust preference learning period.
Though early-life learning is characterized by odor
preference learning, infants during this developmental
readily learn an odor preference even when an unfamiliar
odor has been paired with an aversive stimulus, such as
Moriceau, Roth, and Sullivan
.5mA foot-shock or tail pinch (Camp & Rudy, 1988;
Haroutunian & Campbell, 1979; Moriceau & Sullivan,
2006; Moriceau, Wilson, Levine, & Sullivan, 2006; Roth
& Sullivan, 2005; Spear, 1978; Sullivan & Hall, 1988;
Sullivan, Hofer, & Brake, 1986; Sullivan, Landers,
Yeaman, & Wilson, 2000). At the end of the sensitive
period, similarly to older animals, pups readily learn to
avoid unfamiliar odors paired with the same aversive
stimuli (Blozovski & Cudennec, 1980; Camp & Rudy,
1988; Collier, Mast, Meyer, & Jacobs, 1979; Goldman &
Tobach, 1967; Haroutunian & Campbell, 1979; Moriceau
& Sullivan, 2006; Moriceau et al., 2006; Myslivecek,
1997; Stehouwer & Campbell, 1978; Sullivan, Landers,
et al., 2000).
Shock-induced preference learning during the sensi-
tive period is likely not due to the pups’ inability to feel
pain since unconditioned responses to shock vary little
Spear, 1985; Fitzgerald, 2005; Shair, Masmela, Brunelli,
& Hofer, 1997; Stehouwer & Campbell, 1978; Sullivan,
Landers, et al., 2000). Also, pups’ inability to learn
aversions or fear is not limited to olfactory-cued fear
conditioning, as other learning paradigms that produce
learned fear in older animals (such as passive avoidance
and inhibitory conditioning) do not readily do so in infant
rats (Bialik, Pappas, & Roberts, 1984; Blozovski &
Cudennec, 1980; Camp & Rudy, 1988; Collier & Mast,
1979; Myslivecek, 1997).
Due to the known role of the amygdala in supporting
learned fear in older animals (Cahill, Weinberger,
Roozendaal, & McGaugh, 1999; Debiec & LeDoux,
2006; Fanselow & Gale, 2003; Fanselow & LeDoux,
Doyere, Cain, & LeDoux, 2007), we have examined
whether the amygdala mediates the developmental
transition that permits pups’ emergence of avoidance
uptake and cfos immunohistochemistry), we have found
that the amygdala only appears to be involved in odor-
shock conditioning when this conditioning is able to
support odor avoidance acquisition—that is, when the
sensitiveperiod has ended (Moriceau et al., 2006; Roth &
Sullivan, 2005; Sullivan,Landers,etal., 2000; Sullivan&
Wilson, 1993, 2003).
As further evidence of its limited role in infant
induced conditioned odor preference (Moriceau et al.,
2006; Sullivan & Wilson, 1993). In contrast, amygdala
lesions in older pups prevent them from learning a
conditioned odor aversion (Maren, 1999; Moriceau et al.,
ability of sensitive-period pups to exhibit amygdala long-
term depression (LTD) furthersuggests thattheamygdala
is not participating in infant learning (Thompson,
Sullivan, & Wilson, 2008). Altogether, these data suggest
that the lack of amygdala participation in circuitry
mediating sensitive-period learning is key to an infant’s
increased capacity to learn a preference. While we first
& Morys, 2000; Berdel, Morys, & Maciejewska, 1997;
Bhattacharyya, & Benes, 2002; Morys, Berdel, Jagalska-
Majewska, & Luczynska, 1999; Nair & Gonzalez-Lima,
1999) was responsible for its lack of participation,
recent studies have since suggested that the amygdala
is sufficiently mature to respond to stimuli during the
sensitive period (Thompson et al., 2008). Rather, it is
increasing CORT levels that play a crucial role in the
emergence of fear learning and in the participation of
the amygdala after the sensitive period (Barr et al.,
2009; Moriceau & Sullivan, 2006; Moriceau et al., 2006;
Shionoya, Moriceau, Bradstock, & Sullivan, 2007;
CORTICOSTERONE, AMYGDALA ACTIVITY,
AND THE ONTOGENY OF FEAR
Our interest in CORT was initiated by two areas of
research. First, work showing that pups’ ontogenetic
at the same age as learned fear (?PN10) and is controlled
preference/attachment learning overlaps with an infant
which pups’ CORT levels are lower than normal and
remain either unaffected or are minimally increased by
stressors (Grino, Paulmyer-Lacroix, Faudon, Renard, &
Anglade, 1994; Levine, 2001; Rosenfeld, Suchecki, &
Interestingly, CORT response is functional at birth
(Arai & Widmaier, 1991; Martin, Cake, Hartmann, &
provided by the mother during nursing and grooming
seems to control the pups’ low CORT levels (Levine,
1962; Stanton & Levine, 1990; Van Oers, De Kloet,
Whelan, & Levine, 1998). Indeed, sensitive-period pups
show increases in CORT in response to intense stressors
be returned to normal low levels with replacement of
maternal sensory stimulation or maternal presence
(Avishai-Eliner, Yi, Newth, & Baram, 1995; Levine,
2001; Walker, Scribner, Cascio, & Dallman, 1991).
Additionally, functional CORT receptors are already
Developmental Psychobiology Attachment, Stress, and Learning
present throughout the brain, including within the
amygdala (Alexis, Kitraki, Spanou, Stylianopoulou, &
Sekeris, 1990; Diorio, Viau, & Meaney, 1993; Kitraki,
Alexis, Papalopoulou, & Stylianopoulou, 1996; Rose-
nfeld, van Eekelen, Levine, & de Kloet, 1993).
Studies utilizing presentations of predator odor have
helped provide a causal link between CORTresponsivity,
amygdala activation, and the ontogeny of natural or
unlearned fear. We and others have shown that during the
SHRP, predator-odor presentations fail to elicit a CORT
Tanapat, & Cameron, 1997; Moriceau, Roth, Okotog-
haide, & Sullivan, 2004; Takahashi, 1994; Wiedenmayer
& Barr, 2001; Wiedenmayer, Magarinos, McEwen, &
Barr, 2005). Furthermore, these researchers showed that
increasing neonatal CORT levels prior to presentation of
of CORT in older pups blocks amygdala responsivity to
the male odor presentations, and thus fear expression.
Together, these data highlight the importance of CORTin
changes in the developing CORT system facilitate the
transition between sensitive-period preference learning
and postsensitive-period fear conditioning.
To investigate this relationship, we gave sensitive-
period pups either systemic or intra-amygdala CORT
either of these approaches enabled sensitive-period pups
to learn an odor aversion. As summarized in Table 1,
neural assessment of their brains by 2-deoxyglucose
uptake indicated that the learning had evoked significant
activity within the amygdala (Sullivan, Landers, et al.,
2000).Inturn,we canextendthe ageatwhich odor-shock
conditioning produces an odor preference and prevent
amygdala activity by eliminating endogenous CORT in
older pups, through either removal of its source, the
adrenal glands, or administration of the CORT receptor
antagonist, RU 38486 (Moriceau & Sullivan, 2004a,
2006). Preventing the increase of CORT by adrenalec-
tomy has also been shown to delay the emergence of
learned fear with aversive conditioning (Bialik et al.,
1984; Collier etal.,1979).Thisdevelopmentaleffectisin
sharp contrast to CORT effects on learning in adults,
where it only modifies how well a behavior is learned
(Corodimas, LeDoux, Gold, & Schulkin, 1994; Pugh,
and the consequent lack of significant amygdala activity
during the sensitive period appear to prevent pups from
learning aversions or avoidances to odors associated with
the mother. Levine and his colleagues have demonstrated
that sensory stimulation from the mother is responsible
for maintaining low CORT levels during the SHRP
stimulationduringthe SHRP,suchasthat occurring when
of time (24hr), produces significant elevations in CORT
levels (Levine, 2001). Aberrant maternal care in the rat
will produce similar effects (Gilles, Schultz, & Baram,
1996). Furthermore, maternal presence in older pups
(>PN12) can blunt CORTrelease to stressful and painful
stimuli (Stanton & Levine, 1990; Stanton, Wallstrom, &
Table 1. Odor-Shock Conditioning in Rat Pups
Sensitive period (PN1–9) Conditional sensitive period (PN10–15)
CORT increase (systemic
or intra-amygdala CORT)Saline
CORT reduction (maternal presence,
adrenalectomy, amygdala CORT
Anterior piriform cortex
Posterior piriform cortex
Note. The table summarizes our understanding of the brain regions supporting sensitive period (PN1–9) odor preference learning and conditional
measured by 2-deoxyglucose uptake within the olfactory bulb and anterior piriform ‘‘olfactory’’ cortex. There is no significant activity within the
with significant activity within the amygdala and posterior piriform cortex. Maternal presence during odor-shock conditioning in PN12 pups decreases
responsivity,andpermitsodorpreference learning.Note,thisisthesameneuralcircuitryresponsibleforPN8preferencelearning(Moriceau& Sullivan,
2006; Moriceau et al., 2006; Raineki, Shionoya, Sander, & Sullivan, 2009; Sullivan, Landers, et al., 2000). PN¼postnatal day.
Moriceau, Roth, and Sullivan
Levine, 1987; Suchecki, Rosenfeld, & Levine, 1993).
remarkable ability of the mother to suppress CORTlevels
even during stress in PN14 and PN21 pups. The sensory
cues capable ofbluntingthe stress-inducedCORTrelease
appear to be olfactory and somatosensory (Barr et al.,
2009; Moriceau & Sullivan, 2006; Shionoya et al., 2007;
Stanton & Levine, 1990; Suchecki et al., 1993; Wieden-
in CORT levels due to social sensory cues has since been
referred to as ‘‘social buffering’’ (Hennessy, Kaiser, &
Sachser, 2009; Kikusui, Winslow, & Mori, 2006), and
has been shown to exist in humans and other animals
(DeVries, Glasper, & Detillion, 2003; Kirschbaum,
Klauer, Filipp, & Hellhammer, 1995; Thorsteinsson &
The finding that maternal presence blunts CORT
release to stressful and painful stimuli in older pups
(Stanton & Levine, 1990; Stanton et al., 1987; Suchecki
et al., 1993), prompted us to examine whether maternal
presence in older pups (PN10–15) is capable of
We found that indeed maternal presence blocked fear
learning (aversion) in response to odor-shock condition-
ing, as well as prevented significant amygdala activation
and permitted significant olfactory bulb activation
(Moriceau & Sullivan, 2006). Furthermore, systemic or
intra-amygdalaCORTinfusions allowedthe pupstolearn
odor aversions in the presence of the mother (Moriceau
& Sullivan, 2006). As depicted in Table 1, our results
indicate that maternal presence in PN10–15 pups
reengages the attachment circuitry during learning,
effectively preventing them from acquiring an odor
aversion or fear. The ability of maternal presence to
reengagethe attachmentcircuitryappears toendatPN15,
as PN16 pups still learn an odor aversion even in the
presence of the mother (Upton & Sullivan, 2010). Based
upon these data, we now define PN10–15 as a ‘‘condi-
tional sensitive period,’’ in which odor preference
learning and attenuated fear learning can be reestablished
if the mother is present.
To summarize, the brain of the developing infant rat is
circuitry providing remarkable constraints on aversion
and fear learning. The ecological significance of this may
relate to the possible occurrence of rough handling by
the mother during normal mother–infant interactions
(i.e., stepping on pups while entering/leaving the nest and
rough pup retrieval). From an evolutionary perspective,
it would be maladaptive for pups to learn to avoid the
maternal odor in a situation where the mother is required
for milk and warmth, suggesting that this attenuated
avoidance learning ensures that pups continue to only
approach/follow the caregiver (Hofer & Sullivan, 2001).
pups are still dependent on the mother but can begin
demonstrate avoidance and fear learning to aversive
stimuli in the absence of the mother. However, the
attachment circuitry and restraint on fear learning can
be reengaged during this transitional period if the mother
is present. This suggests that older pups have a more
sophisticated learning system that enables them to
respond appropriately to learning situations dependent
on whether the mother is present or not. The data
summarized here make it clear that the ontogeny of pups’
dramatic reorganization and adaptation of learning
necessary for the developing rat.
Seymour Levine, one of the first to study the role of early
experiences in shaping stress responses, has left a lasting
response to .5mA foot-shock were measured in PN8, PN14, or
PN21 pups with or without maternal presence to assess the
ontogeny of social buffering. Immediately following 11 shock
presentations with an interval of 4min (between 12 and 2 pm),
pups were anesthetized with pentobarbital and blood was taken
from the hearts’ventricle. Shock elicits a significant increase in
(PN8). Maternal presence in PN14 and PN21 pups prevents the
her from interfering with the shock administration, as well as to
control for maternal behavior and milk letdown. The pups were,
however, free to contact the mother. Stress¼foot-shock;
Ontogeny of CORT levels. CORT levels in
Attachment, Stress, and Learning
legacy regarding the profound influence of the mother on
the development of the stress system in numerous species
(Levine, 1957, 1967; Lyons, Martel, Levine, Risch, &
Schatzberg, 1999; Morgado et al., 2008; Schmidt et al.,
2006; Stanton et al., 1987). The data outlined in this
review indicate that functional changes in infant learning
are modified by a unique interaction between the
context that depends on whether the mother is present or
While human children show remarkably similar
behavior within the realm of attachment (proximity
seeking, tolerance of pain), it is unclear if the rat
Bowlby’s (1965) use of the animal literature in the
construction of his attachment theory would argue the
likely evolutionary conservation of attachment circuitry.
Following this, it is likely the case that the humaninfant’s
brain is similarly organized to ensure rapid, robust
attachment to his or her caregiver.
The importance of a healthy and secure attachment in
humans is illustrated by the fact that securely attached
children have an increased probability of maturing into
mentally healthy adults compared to insecurely attached
children (Dozier, Peloso, Lewis, Laurenceau, & Levine,
2008; Gunnar & Quevedo, 2008). Conversely, children in
abusive attachment relationships have a greater proba-
bility of experiencing adult mental problems (Glaser,
of brain development, and it is clear that the brains’ HPA
axis and amygdala are particularly vulnerable to early
environmental influences (Dent, Smith, & Levine, 2001;
Eghbal-Ahmadi, Avishai-Eliner, Hatalski, & Baram,
1999; Francis, Caldji, Champagne, Plotsky, & Meaney,
1999; Swiergiel, Takahashi, & Kalin, 1993). Based upon
the data reviewed here, developmental insults to these
learning processes responsible for securing attachment,
thus increasing the risk for poor mental outcomes.
This work was funded by grants NIH DC009910, NSF
IOB0850527 to RMS and a Young Investigator Award from
the National Alliance for Research on Schizophrenia and
Depression to TLR.
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