Early Trauma PDF

REVIEW ARTICLE
published: 21 March 2014

doi: 10.3389/fendo.2014.00033
Early life trauma and attachment: immediate and enduring

effects on neurobehavioral and stress axis development
Millie Rincón-Cortés 1,2,3 * and Regina M. Sullivan 1,2,3
1
Department of Neuroscience and Physiology, Sackler Institute for Graduate Biomedical Sciences, New York University School of Medicine, New York, NY, USA
2
Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, New York, NY, USA
3
New York University Child Study Center, Department of Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, USA
Edited by: Over half a century of converging clinical and animal research indicates that early life
Nikolaos P. Daskalakis, Icahn School
experiences induce enduring neuroplasticity of the HPA-axis and the developing brain.
of Medicine at Mount Sinai, USA
This experience-induced neuroplasticity is due to alterations in the frequency and inten-
Reviewed by:
Aniko Korosi, University of sity of stimulation of pups’ sensory systems (i.e., olfactory, somatosensory, gustatory)
Amsterdam, Netherlands embedded in mother–infant interactions. This stimulation provides “hidden regulators”
James A. Carr, Texas Tech University, of pups’ behavioral, physiological, and neural responses that have both immediate and
USA
enduring consequences, including those involving the stress response. While variation in
*Correspondence:
stimulation can produce individual differences and adaptive behaviors, pathological early
Millie Rincón-Cortés, Sullivan
Laboratory, New York University Child life experiences can induce maladaptive behaviors, initiate a pathway to pathology, and
Study Center, Department of Child increase risk for later-life psychopathologies, such as mood and affective disorders, suggest-
and Adolescent Psychiatry, New York ing that infant-attachment relationships program later-life neurobehavioral function. Recent
University School of Medicine, 1 Park
evidence suggests that the effects of maternal presence or absence during this sensory
Avenue, New York, NY 10016, USA
e-mail: millie.rinconcortes@ stimulation provide a major modulatory role in neural and endocrine system responses,
med.nyu.edu which have minimal impact on pups’ immediate neurobehavior but a robust impact on
neurobehavioral development. This concept is reviewed here using two complementary
rodent models of infant trauma within attachment: infant paired-odor-shock conditioning
(mimicking maternal odor attachment learning) and rearing with an abusive mother that
converge in producing a similar behavioral phenotype in later-life including depressive-like
behavior as well as disrupted HPA-axis and amygdala function. The importance of maternal
social presence on pups’ immediate and enduring brain and behavior suggests unique pro-
cessing of sensory stimuli in early life that could provide insight into the development of
novel strategies for prevention and therapeutic interventions for trauma experienced with
the abusive caregiver.
Keywords: infant-attachment, maternal programming, development, amygdala, social behavior, rodent models,
stress
INTRODUCTION in maternal care during infancy program individual differences

Both animal and human research demonstrate that early life expe- in behavioral and endocrine responses to stress in rodents and
riences interact with genetics to program the central nervous humans; although pathological experiences, including abuse and
and endocrine systems, including the hypothalamus–pituitary– neglect, produce vulnerability to later-life psychiatric disorders (7,
adrenal (HPA)-axis (1–5). Infant experiences typically occur 27–37).
within the context of the mother and the quality of caregiving Here, we focus on infant experiences and the effects of early life
by the mother, determined by the patterning and intensity of stress and HPA-axis activation as experienced within the mother–
maternal stimulation of pups’ sensory systems, is a key regula- infant dyad, as well as the pups’ attachment to the caregiver
tor of HPA-axis neuroplasticity in the neonatal period (6–10). and learning about the caregiver. We review two complementary
Dissecting the mother–infant dyad has characterized maternal rodent models of infant trauma within attachment: infant paired-
control over infant brain and behavior through “hidden regu- odor-shock conditioning and rearing with an abusive mother,
lators” present during mother–infant interactions (11, 12). Lack which converge in producing a similar neurobehavioral pheno-
or loss of typical parental stimulation is a potent stressor dur- type in later-life consisting of depressive-like behavior as well
ing early life (13, 14), and removal of these hidden regulators as disrupted HPA-axis and amygdala function, thus enabling us
through maternal deprivation, modulation of maternal behavior, to explore both the immediate and enduring effects of abusive
and/or traumatic interactions with the mother, produce imme- attachment as well as role of the HPA-axis and the stress hormone
diate changes in pups and result in wide-spread dysregulation corticosterone (CORT). Although infant trauma resulting from
of physiological and behavioral responses during development abusive attachment affects neural substrates of stress vulnerabil-
(15–26). Within the range of typical parenting, normal variations ity and resilience, these can be engaged by sensory cues learned
www.frontiersin.org March 2014 | Volume 5 | Article 33 | 1

Rincón-Cortés and Sullivan Early life trauma and attachment
during infancy (i.e., artificial or natural maternal odor), which models have provided some insight into the mechanisms by
have the ability to normalize adult neurobehavioral dysregulation which disruptions in parental care alter the development of stress
stemming from early life trauma. response systems (92, 93), which may contribute to our under-
standing of resilience following infant trauma (62, 94–98). For
ATTACHMENT example, research using animal models of maternal deprivation in
Attachment is a psychosocial process referring to the deep and rodents and non-human primates parallel human imaging stud-
enduring emotional bond that connects two individuals across ies suggesting that disruptions in infant-attachment also produce
space and time, with an individual deriving security from physi- long-term alterations in the limbic system and the stress axis that
cal and psychological contact with the attachment figure (38–40). may compromise the development of emotion- and attention-
Attachment requires experience-dependent learning of the sen- regulatory systems, which has been used to explain the heightened
sory stimuli associated with infant–caregiver interactions, and a risk of behavioral and affective disorders in human children expe-
strong attachment to the caregiver is crucial for survival in altri- riencing adverse parental care (13, 31, 32, 75, 93, 99–108). Overall,
cial species, including humans (41–48). In children, attachment these studies demonstrate that parental care affects the matura-
is characterized by specific behaviors such as seeking proximity tion of these brain areas and offers potential sites to understand the
to the caregiver, whom provides a sense of safety and security damaging effects of early life abuse on subsequent neurobehavioral
for the infant (49–51). Like humans, infants from altricial species development (31, 70, 71, 74, 84, 94, 109–115). For these reasons,
also exhibit attachment related behaviors to their caregiver shortly we employ rodent models of abusive attachment and study the
after birth that elicit nurturing and attachment from the care- infant’s immediate response to trauma as well as the neurobiolog-
giver, which entails responding appropriately to the infant’s needs ical sequelae leading to later-life neurobehavioral dysregulation to
by providing nourishment, protection, and warmth necessary for better understand the infant mechanisms that initiate the pathway
survival (51–53). Thus, infant-attachment is an adaptive and rec- to later-life psychopathologies.
iprocal process consisting of a dynamic and complex exchange of
mother–infant behavioral interactions that enhance the infant’s THE STRESS-HYPORESPONSIVE PERIOD AND MATERNAL REGULATION
chance of survival by maintaining contact with the caregiver. OF THE HPA-AXIS
The mother–infant attachment bond is among the strongest In rats, infant-attachment occurs within a unique developmen-
social attachments formed by most mammals (54). As such, tal context – the stress-hyporesponsive period (SHRP) – during
human infants seek proximity to and maintain contact with the which neonates show low basal plasma concentrations of CORT
caregiver despite the quality of care they receive (55), including and reduced stress-reactivity, as indexed by limited adrenocor-
attachment to an abusive caregiver. This paradoxical phenomenon ticotropic hormone (ACTH) and CORT responses to stressful
also occurs in dogs, chicks, and non-human primates, suggesting stimuli compared to older animals, as well as low levels of corti-
a phylogenetically preserved system (32, 41, 43, 56–63). From an costeroid binding globulin (CBG), which regulates glucocorticoid
evolutionary perspective, attachment to an abusive caregiver is (GC) access into the brain (92, 116–123). Thus, the neuroen-
thought to be adaptive because it provides immediate benefits, docrine stress response of the neonatal rat is characterized by
as the infant still has access to some care (48, 64). Albeit infant attenuated hormonal responses and altered gene regulation in
organisms are biologically predisposed to attach to their caregiver response to stress compared to adults due to hyporesponsiveness
and possess behavioral systems that allow them to rely on these at all levels of the HPA-axis, namely: (1) a blunted pituitary ACTH
bonds for survival (38), clinical and preclinical studies suggest that secretion, resulting from a combination of immaturity of neural
adverse parental care compromises brain development and has inputs to the corticotropin releasing hormone (CRH) neurons,
longstanding effects in stress-responsive neurobiological systems, (2) decreased pituitary peptide content or decreased sensitivity to
including the HPA-axis, neurotransmitter systems, as well as cor- CRH stimulus; and (3) an adrenal gland hyporesponsive to cir-
tical and limbic structures such as the prefrontal cortex, amygdala, culating ACTH levels (18, 119, 121, 124–130). Accumulating evi-
and hippocampus (65–75). Moreover, traumatic early life expe- dence suggests that human infants exhibit a period of dampened
riences involving the caregiver increase the risk for a wide-range cortisol reactivity analogous to the rodent SHRP, which develops
of deleterious mental health and behavioral outcomes, including gradually over the course of the first year of life (~6–12 months),
developmental psychopathology, affective, and mood disorders although it remains unclear how long it extends (131–135). In
(37, 72, 76–86). Therefore, perturbations in infant-attachment both humans and rodents, the SHRP is thought to protect the
appear to induce immediate neurobiological changes that shape developing brain from the detrimental effects of elevated HPA-axis
subsequent development and lead to neurobehavioral dysregu- activity and excess GC exposure, and the sensitivity and respon-
lation associated with compromised emotionality and increased siveness from the caregiver appears critical in maintaining low
vulnerability to psychopathology during later-life, suggesting that cortisol activity and controlling the offspring’s physiological and
the quality of an infant’s first social relationships programs the behavioral responses to stressors during this period (3, 30, 32, 68,
infant’s emotional and cognitive capabilities to adapt to later-life 100, 122, 127, 129, 136–140).
environments. However, the SHRP during development appears to be stres-
Despite the fact that childhood abuse remains a major public sor specific, since the HPA-axis is fully capable of responding to
health concern (87–91), the mechanisms by which infant trauma stimuli that may be considered stressful to a neonatal rat such
initiates the pathway to psychopathology are poorly understood, as cold or saline injection (141–145). Indeed, the HPA-axis and
although the stress axis is evidently implicated. However, animal CORT receptors are functional at birth, but are modulated by
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the sensory stimulation provided by the mother (100, 119, 126, to learn and develop a preference for the mother’s odor, which is
146–152). Moreover, the mother is able to directly regulate the diet dependent and can change postnatally (47, 170–174). Since
pups’ CORT levels through hidden regulators embedded in typical rat pups are born deaf and blind, they must rapidly learn their
mother–infant interactions, such as the sensory, motor, nutrient, mother’s odor, which conveys distal and proximal information
and thermal events associated with caregiving, which exert regu- about the mother’s location, and helps the pups orient to the
latory influence over the infant’s immediate and long-term behav- mother, approach her and elicit care (169, 175). The maternal
ioral and physiological responses by affecting sleep-wake states, odor is critical in guiding infant-attachment; without it, pups show
cardiac rates, and HPA-axis function (6, 10–12, 17, 129, 153, 154). reduced contact with the mother, are unable to nipple attach and
Removal of maternal sensory stimulation during the SHRP, such exhibit low survival rates (25, 176). Moreover, any neutral odor
as that occurring when the pups are separated from the mother for can acquire properties of the natural maternal odor and act as a
a prolonged period of time (i.e., maternal deprivation paradigm), new maternal odor by simply being placed on the mother, in a
increases CORT secretion (16), elevates CORT levels in pups (11, cage during mother-infant interactions (177–182) or learned in
12, 129), and enables higher CORT/ACTH responses to acute stress classical conditioning paradigms (i.e., odor-stroke, odor-shock)
(15, 19, 100, 145, 155). Importantly, these changes are similar to performed outside the nest in the absence of the mother (111, 165,
those induced by normal variations in maternal care (i.e., maternal 171, 183–188).
high/low licking paradigm) (7, 27, 29) as well as atypical or abu- Our lab uses infant olfactory classical conditioning in which an
sive maternal care (20, 144, 156), suggesting that the hypothalamic artificial odor (i.e., peppermint) is paired with a 0.5 mA shock
mechanisms controlling physiological stress responses in the pup as a rodent model of abusive attachment. While the adult rat
are regulated by elements of maternal care. Taken together, these responds to shock with a robust CORT response, the neonatal
findings suggest that maternal deprivation, variations in maternal rat does not (9, 100, 189). Unlike older animals, which readily
care, and abusive maternal care influence the development and learn odor aversions to painful stimuli paired with an odor, rat
function of the HPA-axis (8, 9, 30, 112, 114, 157–160). In summary, pups actually exhibit an odor preference and approach the odor
maternal stimulation modulates the infant’s HPA-axis and main- (111, 165, 190–193). This odor preference, however, is not due to
tains the SHRP, although potent stressors involving disruptions the inability of pups to feel pain, since the pain threshold varies lit-
in maternal stimulation (i.e., cold, maternal deprivation, atypical tle during the neonatal period and pups emit vocalizations to the
maternal care) can activate the HPA-axis and override maternal shock, suggesting that they are experiencing distress (165, 190,
control of the SHRP. 194–197). Instead, infant paired-odor-shock conditioning pro-
duces a new artificial maternal odor that acquires the ability to
ATTACHMENT LEARNING DURING A SENSITIVE-PERIOD IN regulate pup behaviors typically controlled by the maternal odor;
RAT PUPS it induces proximity-seeking/approach responses in pups (distal
Infants possess a predisposition to approach the mother as well cues), guides mother–infant interactions by facilitating contact
as specific sensory cues associated with her care, such as her odor with the mother and nipple attachment (proximal cues), and acti-
and vocalizations (161, 162). Within an evolutionary context, the vates the same neural circuitry as the natural maternal odor (25,
infant-attachment system serves to establish a preference for the 111, 165, 169), suggesting that this odor has comparable quali-
mother regardless of whether or not she is associated with pain ties to the natural maternal odor. Importantly, infant odor-shock
or pleasure (48, 64). This type of survival-dependent learning is conditioning is a useful experimental paradigm for understanding
known as imprinting, has wide phylogenetic representation, and is how early life trauma (i.e., pain-shock) can support and maintain
temporally confined to a sensitive-period in development (50, 161, attachment and provide insights into the particular ways the infant
163) typically involving a hypofunctioning HPA-axis – the prin- brain processes painful stimuli and its relationship to the endur-
cipal pathway of the mammalian stress response that regulates ing effects of this experience due to the well documented neural
the production of GCs (cortisol in humans, CORT in rodents) circuitry underlying this type of learning (198–202). Three brain
(40, 164). In rats, we refer to this period of enhanced attach- structures have been shown to play a role in the neonatal rat’s
ment/preference learning as the “sensitive-period,” or postnatal sensitive-period for enhanced odor learning: the olfactory bulb
(PN) days 1–9 (see Figure 1). As we will discuss below, sensitive- (OB), the noradrenergic locus coeruleus (LC), and the amygdala
period learning is due to the pup’s unique learning circuit, pre- (50, 203).
sumably one sculpted through evolution to provide infants with
the neural circuitry required to survive and maximize attachment NEUROBIOLOGY OF INFANT-ATTACHMENT AND THE ROLE OF
to a caregiver (48). THE HPA-AXIS IN TERMINATING ATTACHMENT LEARNING
Intriguingly, the sensitive-period for attachment learning in Neonatal odor learning produces changes in the OB, which can
rat pups overlaps with the SHRP, suggesting that low levels of be induced both naturally in the nest and experimentally in con-
CORT and reduced HPA-axis responsiveness may contribute to the trolled learning experiments outside the nest (182, 186, 204–210).
neonate’s unique neural circuitry for attachment learning. How- For example, both natural and learned odors produce a simi-
ever, in order for infant-attachment to occur, the rat pup must lar enhancement of OB responding during the sensitive-period,
first learn to identify the caregiver and exhibit the social behaviors which has been assessed through a variety of techniques includ-
necessary for survival such as orienting to and approaching the ing 2-deoxy-glucose (2-DG) uptake, c-Fos immunoreactivity (ir),
caregiver, grasping the nipple and nursing (50, 168, 169). Infant- CREB phosphorylation, electrophysiology, and optical imaging
attachment learning in rodents revolves around the pup’s ability (205–208, 211–214). Thus, olfactory-based attachment learning

FIGURE 1 | The neural circuitry underlying pup attachment learning present at this age, pups will revert back to preference learning and the neural
changes over development. During the earliest days of life, pups have a circuitry of the sensitive-period. Thus, the mother’s presence socially buffers
sensitive-period in which odor-shock conditioning produces an odor pups (i.e., attenuates pups shock-induced CORT release) and pups learn a
preference. At 10 days of age, pups begin the transitional sensitive-period, preference. As pups mature and enter the post-sensitive-period, odor-shock
when pups endogenous CORT levels have increased sufficiently to enable conditioning induces amygdala-dependent fear and odor avoidance learning
amygdala-dependent fear/avoidance learning. However, with the mother (25, 165–167).
in neonatal rats is associated with the acquisition of odor-specific infant amygdala plasticity and avoidance learning (Figure 1) (201,
neural changes in the OB, which can only be acquired during the 218, 241).
sensitive-period, and are retained throughout development (111, Indeed, the natural increase of stress-induced CORT release
201, 215–218). marks the end of sensitive-period learning (165, 201, 203, 238),
Infant rats (PN1–9) readily learn an odor preference to neu- which has been demonstrated experimentally by increasing CORT
tral odors paired with pleasant (i.e., milk, stroking) (47, 171, 179, systemically (3 mg/kg, i.p.) or through intra-amygdala CORT
183–185, 219) or painful stimuli, such as 0.5 mA shock or tail infusions (50–100 ng) prior to odor-shock conditioning, which
pinch (111, 165, 190, 191, 201), which is partly due to a uniquely enables sensitive-period pups to learn an odor aversion and exhibit
large noradrenergic input to the OB from the LC, the sole source learning-evoked neural activity (i.e., enhanced 2-DG uptake)
of norepinephrine (NE) for the OB (220, 221), which prompts in the amygdala, while preventing the acquisition of learning-
abundant release of NE into the OB (203, 222). Furthermore, induced changes in the OB (201, 238, 241, 242). In contrast, CORT
the neonatal LC shows prolonged stimulus-evoked excitation and depletion (via adrenalectomy or social buffering, discussed below)
greater NE release to odors during the sensitive-period compared in PN12 pups results in shock-induced odor preference learning
to later-life due to the immaturity of the LC alpha-2 inhibitory and acquisition of OB neural changes. Thus, within the context of
autoreceptors, which functionally emerge around PN10 and cause paired-odor-shock conditioning, CORT appears to play a modu-
a shift from prolonged excitatory alpha-1 mediated responses to latory role on infant learning by switching whether the amygdala
inhibitory alpha-2 mediated responses, resulting in brief excitation learns attraction or avoidance: if CORT is low, pups learn a pref-
due to inhibited LC firing and decreased NE output (203, 222– erence to an odor paired with shock due to a lack of amygdala
227). Importantly, NE release from the LC is both necessary and involvement; if CORT is high, the amygdala is activated by odor-
sufficient for odor preference learning during the sensitive-period shock conditioning and pups learn an avoidance. Recently, we have
(228–232). identified a role for amygdala dopamine (DA) in mediating these
Experimental evidence indicates a lack of amygdala participa- infant learning transitions, as conditions that block aversion/fear
tion in the neural circuitry underlying infant paired-odor-shock learning are associated with downregulated DA function (243).
conditioning during the sensitive-period, as suggested by amyg- Altogether, these findings suggest that neonatal rat pups have
dala lesions, 2-DG, and c-Fos-ir (111, 201, 203, 216, 232), although unique learning capabilities that aid olfactory-based attachment
the amygdala is strongly implicated in adult classical conditioning to the mother, which are dependent on low levels of CORT.
(198–200, 202, 233). These data suggest that the infant amygdala In summary, the infant learning circuit is characterized by an
is not part of the sensitive-period learning circuit during which enhanced ability to learn odor preferences to aversive stimuli, due
aversions are difficult to learn because of its failure to exhibit the to a hyper-functioning LC, as well as a decreased ability to learn
plasticity required for this type of learning (234–236), although the odor aversions that may interfere with proximity-seeking during
amygdala is responsive to odors and other environmental stimuli the sensitive-period due to a hypo-functional amygdala, suggest-
by PN10 (165, 201, 237). Like the infant amygdala, the infant HPA- ing that the infant brain is specialized for maximizing attachment
axis is limited in function, resulting in reduced shock-induced to a caregiver (Figure 1) (41, 165, 186, 221, 225, 229, 234, 235, 244–
CORT release during the neonatal sensitive-period (189), which 247). As the sensitive-period ends, owing to the natural emergence
limits pups’ ability to acquire learned odor aversions (201, 238). of CORT, odor aversions can be learned because of changes in the
Endogenous CORT levels increase gradually and reach a critical infant learning circuit, including maturation of LC autoinhibition,
level by PN10 (92, 136, 239, 240), at which time stressful or painful which reduces NE release and greatly attenuates rapid odor pref-
stimuli are able to elicit a sufficient CORT response that permits erence learning, but also due to the functional emergence of the

amygdala, all of which enable the plasticity required for aversion and the sensitive-period for attachment learning. In addition, this
learning (50, 165, 223, 225, 229, 232, 241). procedure results in striking changes in the expression and activ-
ity patterns of key regulatory elements of the neuroendocrine
MATERNAL MODULATION OF HPA-AXIS FUNCTION AND stress response, which result in persistent alterations of HPA-axis
SENSITIVE-PERIOD DURATION function such as elevated basal GC concentrations, impaired GC
Empirical evidence suggests that social support is a powerful mod- feedback, and modifications in CRF-receptor regulation (20, 25,
ulator of individual differences in response to potentially stressful 114, 156, 174). Since the mother serves as a primary link between
events in both humans and animals (248–253). In rodents, mater- the environment and the infant, environmentally driven alter-
nal presence is known to blunt CORT release to stressful and ations in maternal care could transduce an environmental signal to
painful stimuli in older pups (>PN12) through olfactory and the pups, alter the development of central CRF systems activating
somatosensory cues (9, 148, 152, 166, 167, 254, 255). The process behavioral, endocrine and autonomic responses to stress, as well
by which the presence of a social companion and/or social sen- as systems regulating CRF and HPA-axis activity, which may serve
sory cues can dampen HPA responses to stressors (i.e., decrease to increase or decrease stress-reactivity in the offspring, so that it
CORT levels) is termed “social buffering” and has been reported in mirrors that of the mother.
humans and other species (139, 249, 250, 253, 256–259). Our lab
has identified a transitional sensitive-period in pups from PN10– IMMEDIATE AND ENDURING EFFECTS OF EARLY LIFE STRESS
15, during which odor-shock conditioning produces either olfac- Responses to stressors, or conditions that threaten or are per-
tory preference or aversion in infant rats depending on social con- ceived to threaten physiological equilibrium, are mediated by the
text (166, 260). In the absence of the mother, paired-odor-shock activation of stress-responsive neurobiological systems that help
conditioning yields a learned odor avoidance that is accompanied preserve allostasis, or stability through change, thereby making
by amygdala activation. However, maternal presence is able to sup- the stress response an essential endocrine mechanism for survival
press amygdala activity and block aversion learning induced by (268–270). Stressors, which can include psychological and physi-
odor-shock conditioning, indicating that maternal presence reen- cal challenges, increase the amount of hypothalamic CRF that is
gages the sensitive-period attachment circuitry to reinstate odor released into the anterior pituitary gland, stimulating ACTH secre-
preference learning through modulation of CORT (see Figure 1), tion in the anterior pituitary and resulting in GC production in
and therefore CORT regulation of amygdala activity. Importantly, the adrenal gland (268, 271, 272). GCs facilitate the mobilization
these animal data are consistent with the principles of attach- of substrates for energy sources, potentiate the release of cate-
ment theory (38), in which access to a secure base provided by cholamines, and enhance cardiovascular tone while suppressing
the attachment figure reduces the probability of HPA/CRF stress “non-essential systems” for immediate survival, such as immu-
reactions that could have unfavorable long-term consequences on nity, growth, and reproduction (273–276). Stress-induced HPA-
brain development (9, 137, 261). axis activation is associated with acute release of stress-related
Yet, human parental care is disturbed under conditions of neuropeptides, hormones, and neurotransmitters, including NE,
chronic stress (262), which can be modeled in rodents by creating serotonin (5-HT), and DA, in cortical and limbic structures (21, 27,
an abnormal rearing environment that alters maternal behavior 277–289). Although acutely elevated GCs help orchestrate physi-
(20, 23, 111) and mimics the effects of a stressful environment as a ological and behavioral responses that promote allostasis, chronic
risk factor for potentiating infant abuse, including humans (62, 77, activation of the HPA-axis, and prolonged elevations of GCs and
263, 264). Because bedding type and volume are important com- CRF increase the risk of stress-related disorders and psychological
ponents of the dam’s nesting environment, limiting the amount illnesses during later-life (269, 290–292).
of bedding available constitutes a continuous stressor for the dam The effects of HPA-axis activation depend on multiple factors,
and her pups, disrupts mother–pup interactions, and alters the including the developmental stage in which the insult occurs, num-
development of the pup’s HPA-axis by reducing the frequency of ber of exposures, and type of adversity (71, 293–297). Numerous
positive maternal behaviors (i.e., licking, grooming, nursing) and behavioral, endocrine, and clinical studies have shown that vari-
increasing the frequency of negative maternal behaviors that are ous early life stressors cause a premature increase in CORT levels
painful to the pup and elicit vocalizations, such as stepping, drag- (129) that produces profound alterations in growth and develop-
ging, and rough handling of the pups (20, 25, 111, 156, 188, 265). ment and negatively affects mental health (40, 72, 135, 298, 299).
Thus, one could conceptualize a stressed dam as a poor regulator, Moreover, repeated exposure to early life stressors, both physical
which is supported by findings showing that ICV infusion of cor- and psychological, induce changes in endocrine (HPA-axis), neu-
ticotropin releasing factor (CRF) reduces maternal responsivity rotransmitter (DA, 5-HT), and brain memory systems, including
(266). the hippocampus, amygdala, and PFC that persist throughout the
Furthermore, because maternal stimulation of pups modulates life-span (8, 67, 101, 300, 301). Furthermore, the HPA-axis is mod-
pups’ endogenous CORT, maternal care quality alters sensitive- ulated by limbic and cortical regions such as the amygdala, hip-
period duration. Pups reared with a stressed mother (i.e., poor pocampus, and the PFC (269, 302), which enable the activation of
regulator) exhibit a precocious emergence of CORT, which is stress responses by psychosocial stressors (303–307). Importantly,
delivered through the mother’s milk (267), that facilitates aver- the timing of early life stress may affect brain regions undergoing
sion learning and engages the amygdala, as indexed by increased specific growth spurts during that time (308, 309), so that brain
odor-shock-induced amygdala neural activity (188), suggesting regions rich in GC receptors and characterized by extended PN
that experience with a stressed mother prematurely ends the SHRP development, such as the amygdala, hippocampus, and PFC, are

particularly susceptible to the long-term effects of stress (71, 92), temporary inactivation (i.e., muscimol) of amygdala function
which affects later-life memory, cognitive, executive, and affective during the FST, which normalized these behaviors to a level com-
function as well as stress-reactivity in humans (296, 297). Alter- parable to controls (26). Collectively, these findings suggest that
ations in stress-sensitive neurobiological systems, including regu- the expression of depressive-like behavior in the FST following
lation of GCs and CRF, have been posited as mechanisms through early life abuse is characterized by a hyper-functioning amygdala.
which early life stress, including inadequate/disorganized parental Thus, abusive attachment appears to disrupt the developmental
care, increases the likelihood of psychopathology by influencing trajectory of the amygdala and modify the way that it responds
HPA hyperreactivity to stressors and promoting the development to future stressors, which is supported by our work using rodent
of stress-induced illnesses throughout life (31, 40, 290, 310–312). models of early life abuse.
Early life adversity may lead to a maladaptive outcome to a Our findings are in accordance with clinical and animal liter-
given later environmental context. Depression is a common out- ature indicating that early life adversity constitutes a prime risk
come of childhood abuse, and children with a comorbid history factor for the development of psychopathologies characterized by
of depression and abuse have elevated CRF levels in the cere- dysregulated HPA-axis function (1, 5, 24, 32, 133, 319, 331–334),
brospinal fluid (313) as well as an increased ACTH response to such as mood and affective disorders (37, 93, 335, 336), which
a CRF challenge compared to children with depression without also exhibit a developmental delay (309, 337, 338) Thus, these
abuse, suggesting excessive CRF release (3, 314, 315). Additional rodent models of early life abuse allow us to explore the ontogeny
clinical evidence indicates that severe early life stressors in child- of depressive-like behavior and amygdala dysregulation, which is
hood are associated with the long-term HPA-axis disturbances in of clinical relevance because abnormal amygdala function and
depressed patients (316–319), which is supported by preclinical social behavior deficits as well as their relationship to later-life
studies of non-human primates showing that poor rearing con- depressive-like behaviors have been documented in individuals
ditions and conditions that disrupt responsive maternal care have with a history of early life abuse (71, 310, 331, 336).
a long-term impact on the neurobiology of stress and negative
emotionality (21, 31, 32, 109, 158). For example, variable foraging MODULATION OF ADULT NEUROBEHAVIORAL FUNCTION BY
paradigms that result in neglectful maternal care produce adult INFANT-ATTACHMENT RELATED CUES
offspring that are more fearful, low in dominance, have elevated An ample body of evidence suggests that the quality of infant-
levels of CRF in the CSF and high in brain levels of CRH, exhibit attachment relationships results in long-term adaptations that
persistent alterations in metabolites of 5-HT, DA, and NE, as well have the ability to program subsequent behavioral, endocrine, and
as changes in noradrenergic and serotonergic responses to stress neural function (28, 109, 261, 310, 336). Results from our lab-
(99, 320–324). Given the importance of noradrenergic and sero- oratory have shown that infant paired-odor-shock conditioning
tonergic systems in mood disorders, these findings postulate a results in reduced fear learning and attenuated related amygdala
mechanism by which early life stress may predispose an individual function, dysregulation in neural networks underlying olfactory
to later-life depression (32, 300, 325–327). learning, and depressive-like behavior during adulthood (339–
342). Importantly, attachment related sensory cues learned during
CONVERGENCE OF BOTH ABUSIVE ATTACHMENT MODELS infancy can play a critical role in modulating neurobehavioral
IN PRODUCING A DEPRESSIVE-LIKE BEHAVIORAL responses during later-life. In humans, for example, cues associ-
PHENOTYPE DURING LATER-LIFE ated with early life abuse elicit strong attraction and feelings of
Recently, our lab has demonstrated that both rodent models of comfort (343). In rodents, presentation of an artificial maternal
abusive attachment (paired-odor-shock, abusive mother) during odor, resulting from infant paired-odor-shock conditioning, is able
infancy result in later-life depressive-like behavior in the Forced to reverse the behavioral effects of abusive attachment in rodent
Swim Test (FST), a measure of behavioral despair in rodents (328, measures of depressive-like behavior, such as the sucrose con-
329), that is accompanied by changes in amygdala function and sumption test and the FST (342). Specifically, the odor increased
preceded by disruptions in social behavior (26). When employed the latency to immobility and reduced the time spent immobile
from PN8–12, these two complementary rodent models of early in the FST, but also increased the percentage of sucrose consumed
life abuse produced a reduction in sociability, as indexed by spend- during a sucrose preference test to levels comparable to controls.
ing significantly less time in a social chamber compared to control Furthermore, these restorative effects of a learned infant maternal
animals reared with a normal mother – a behavioral pattern that odor on adult function were also observable at electrophysiological
was observable prior to weaning (PN23) and maintained in adoles- level, as odor presentation also normalized paired-pulse inhibition
cence (PN45). However, animals experiencing early life abuse only deficits in the amygdala. Collectively, these data suggest that early
showed depressive-like behavior in the FST during adolescence life experiences are able to shape adult neural circuits underlying
(PN45), as indicated by immobility – the passive state in which behavior and that adult behaviors can be modified under envi-
the animal makes only those movements necessary to keep its ronmental conditions in which learned infant cues are present.
head above water (328, 330). In addition, depressive-like behavior The discovery that infant cues can retain their value throughout
in the FST in animals experiencing early life abuse was associated the life-span and regulate later-life behaviors controlled by cir-
with increased c-Fos-ir in the basal, lateral, and central amygdala cuits implicated in emotion, learning, and social behavior is of
nuclei, suggesting that increased neural activity in these structures great interest because it provides an opportunity for interven-
may contribute to the expression of depressive-like behavior in tion and possibly correction of maladaptive outcomes related to
the FST (26). A causal relationship between amygdala function psychopathology induced by adverse early life experiences within
and depressive-like behavior in the FST was suggested through attachment. Thus, it appears that the enduring neurobehavioral

dysregulation stemming from early life abuse can be positively 11. Hofer MA. Hidden regulatory processes in early social relationships. In: Klopfer
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ACKNOWLEDGMENTS 20. Gilles EE, Schultz L, Baram TZ. Abnormal corticosterone regulation in an
This work was supported by the National Science Founda- immature rat model of continuous chronic stress. Pediatr Neurol (1996)
tion Graduate Research Fellowship (DGE-1137475) to Millie 15:114–9. doi:10.1016/0887-8994(96)00153-1
21. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-
Rincón-Cortés and NIH-MH091451, NIH-DC009910 to Regina
releasing factor neuronal systems induced by maternal deprivation. Endocrinol-
M. Sullivan. ogy (1996) 137:1212–8. doi:10.1210/endo.137.4.8625891
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REVIEW ARTICLE

published: 21 March 2014

Early life trauma and attachment: immediate and enduring

INTRODUCTION in maternal care during infancy program individual differences

www.frontiersin.org March 2014 | Volume 5 | Article 33 | 1

Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 2

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 4

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 6

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 8

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 10

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 12

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Frontiers in Endocrinology | Neuroendocrine Science March 2014 | Volume 5 | Article 33 | 14

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