i An update to this article is included at the end

Developmental Cognitive Neuroscience 25 (2017) 145–159

Contents lists available at ScienceDirect

Developmental Cognitive Neuroscience

journal homepage: http://www.elsevier.com/locate/dcn

Early life adversity during the infant sensitive period for attachment:
Programming of behavioral neurobiology of threat processing and
social behavior
Maya Opendak a,b,∗ , Elizabeth Gould c , Regina Sullivan a,b
a
Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
b
Child Study Center, Child & Adolescent Psychiatry, New York University School of Medicine, New York, USA
c
Department of Psychology, Princeton University, Princeton, NJ, USA

a r t i c l e i n f o a b s t r a c t

Article history: Animals, including humans, require a highly coordinated and flexible system of social behavior and threat
Received 30 April 2016 evaluation. However, trauma can disrupt this system, with the amygdala implicated as a mediator of these
Received in revised form 3 January 2017 impairments in behavior. Recent evidence has further highlighted the context of infant trauma as a criti-
Accepted 4 February 2017
cal variable in determining its immediate and enduring consequences, with trauma experienced from an
Available online 16 February 2017
attachment figure, such as occurs in cases of caregiver-child maltreatment, as particularly detrimental.
This review focuses on the unique role of caregiver presence during early-life trauma in programming
Keywords:
deficits in social behavior and threat processing. Using data primarily from rodent models, we describe the
Development
Threat
interaction between trauma and attachment during a sensitive period in early life, which highlights the
Amygdala role of the caregiver’s presence in engagement of attachment brain circuitry and suppressing threat pro-
Social behavior cessing by the amygdala. These data suggest that trauma experienced directly from an abusive caregiver
Dominance hierarchy and trauma experienced in the presence of caregiver cues produce similar neurobehavioral deficits, which
are unique from those resulting from trauma alone. We go on to integrate this information into social
experience throughout the lifespan, including consequences for complex scenarios, such as dominance
hierarchy formation and maintenance.
© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2. Developmental trajectory of brain areas important for social behavior and threat processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3. Infant social interaction: importance of the caregiver as regulator of brain and behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4. The infant attachment circuit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
5. Maternal control over stress hormones: social buffering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
6. Attachments formed to abusive caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
7. Stress uncovers latent consequences of early-life trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
8. Amygdala involvement in social behavior throughout the lifespan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9. Implications for complex social behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
10. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

∗ Corresponding author at: Emotional Brain Institute, Nathan Kline Institute, New York University Langone Medical Center, 1 Park Ave. 8th Floor, New York, NY 10016,
USA.
E-mail address: [email protected] (M. Opendak).

https://doi.org/10.1016/j.dcn.2017.02.002
1878-9293/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.
0/).
146 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159

1. Introduction following abusive caregiving in rodents. Finally, we will discuss

the long-term consequences of these atypical attachment-trauma
We have known for half a century that the brain and behav- experiences for behavior in highly complex social scenarios in the
ior of altricial species, including humans and rodents, continues wild.
to develop after birth, and that genetics and experience interact
to guide the intricate process of constructing the brain (Andersen
and Teicher, 2008; De Bellis and Thomas, 2003; Fisher, 1955; 2. Developmental trajectory of brain areas important for
Landers and Sullivan, 2012; Levine, 1957, 2005; Mainardi et al., social behavior and threat processing
1965). This open system enables early-life experiences to sculpt the
brain and optimize behaviors to more closely fit diverse environ- The effects of early life experience on the brain involve changes
ments to enhance survival (Bock et al., 2014). However, this same at nearly every level of analysis, from cellular signaling to behav-
open system can permit developmental perturbations to produce ioral expression. Indeed, through the decades, countless brain
vulnerability to psychiatric disorders and maladaptive behaviors regions and nearly every neurotransmitter have been implicated
that reduce access to resources, especially during critical periods in the etiology of psychopathology following early life experi-
for programming complex cognition and behavior (Andersen and ences, including changes in receptors, epigenetics, brain structure,
Teicher, 2008; Opendak and Sullivan, 2016). In particular, trauma the microbiome, immune system, and homeostasis maintenance
experienced from a caregiver during a sensitive window in early (Andersen and Teicher, 2008; Bale, 2015; Blakemore and Mills,
life can produce life-long deficits in threat processing and social 2014; Callaghan et al., 2016; Drury et al., 2012; Gold et al., 2016;
behavior across many species (Amaral, 2003; Callaghan et al., 2014; Green et al., 2016; Halevi et al., 2016; Hartley and Lee, 2015;
McEwen, 2003; Moriceau et al., 2006; Tang et al., 2014; Tzanoulinou Heim and Binder, 2012; Humphreys et al., 2016; Kane et al., 2016;
and Sandi, 2017; Zeanah et al., 2003). Modeling this in rodents sug- Kennedy et al., 2016; Knudsen, 2004; Lawler et al., 2016; Nelson
gests that repeated pairing of cues associated with the caregiver et al., 2014; Pechtel et al., 2014; Poulos et al., 2014; Puetz et al.,
and with trauma can disrupt the typical developmental trajectory 2016; Reuben et al., 2016; Troller-Renfree et al., 2016; Umemori
of brain areas important for both forming attachments and learning et al., 2015; Werker and Hensch, 2015; Zannas and Binder,
about threat (Opendak and Sullivan, 2016; Raineki et al., 2012). In 2014; Zeanah and Sonuga-Barke, 2016). Research on rodents
particular, we have observed that trauma experienced in the pres- and nonhuman primates promptly identified the hypothalamic-
ence of the caregiver has similar neurobehavioral consequences pituitary-adrenal (HPA) axis as one mediator for how experience
as trauma experienced directly from an abusive caregiver; these disrupts development (Rincon-Cortes and Sullivan, 2014; Sanchez,
socially anchored traumas produce unique and profound effects 2006). This system is involved in the body’s response to allostatic
that go beyond those of trauma alone. load; chronic over-activation of the HPA axis in response to early life
Understanding trauma effects and the importance of a social trauma can produce long-term adaptations in the stress response,
context on brain development has been challenging, not only and these changes are thought to underlie the development of dis-
because the process of building a brain is complex, but because orders such as PTSD, depression, and anxiety (Graham et al., 1999).
many of the effects of early life perturbations are often not While the HPA axis has remained a focus as the mediator of early life
expressed until a later stage of development (Ainsworth, 1969; trauma, additional mechanisms have been implicated in the com-
Gunnar et al., 2007; Landers and Sullivan, 2012; Raineki et al., plexity of early life experiences on brain programming, including a
2012). Threat processing has been a major focus in studying disor- critical role for learning (Moriceau et al., 2006).
dered attachment because of the link between trauma and aberrant Although it is beyond the scope of this review to describe brain
detection of danger, vigilance, and regulation of emotion in men- development in detail, a few basic concepts are helpful for the
tal illness in children and adults (Bremne and Vermetten, 2001; present discussion (for additional reading on brain development,
Caron et al., 2015; Cirulli et al., 2009; Drury et al., 2012; Elzinga see Casey et al., 2005; Houston et al., 2014). First, the brain con-
et al., 2003; Jedd et al., 2015; Teicher et al., 2003; Tottenham and tinues to develop throughout early life, with different brain areas
Sheridan, 2009). We rely on animal research to highlight mecha- each having their own trajectory of development and matura-
nisms, which has shown that caregiver abuse in early life produces tion (Berdel et al., 1997; Brummelte and Teuchert-Noodt, 2006;
structural and functional changes in the amygdala and a changed Chareyron et al., 2012a,b; Cunningham et al., 2002; Ehrlich et al.,
threat system (Bagot et al., 2009; Bock et al., 2014; Caldji et al., 1998; 2012; Knudsen, 2004; Van Eden and Uylings, 2004; Wakefield
Ivy et al., 2008; Maestripieri et al., 1999; Raineki et al., 2012; Roth and Levine, 1985). Brain areas important for basic physiological
and Sullivan, 2005; Sanchez et al., 2001; Tang et al., 2014). Drury functions are certainly mature at birth, but continue to mature
et al. (2015) have recently written a review comparing different and develop more complex connections with other brain areas
animal models used to assess mechanisms of early life adversity and within themselves (Rinaman et al., 2011). Regions involved
(Drury et al., 2015). in complex behaviors and higher-order functioning, including the
Although there is a broad literature documenting multiple forms amygdala, hippocampus, and prefrontal cortex (PFC), are more
of early-life trauma across many species, the focus of this review delayed in maturation, although recent evidence suggests spe-
will be species-atypical abusive maternal care using data from cific functions of each of these brain regions have their own
rodent models. While translating rodent data to humans can be developmental trajectories. For instance, hippocampus-dependent
challenging, the attachment system and its response to trauma contextual fear learning emerges around postnatal (PN) day 23 in
have considerable convergence between species. Indeed, stud- rodents (Raineki et al., 2010a), while other hippocampal dependent
ies in rodents, primates, and humans have identified a sensitive learning behaviors emerge either before or after this age (Ainge
period in early life during which abusive care from an attachment and Lanston, 2012; Moye and Rudy, 1987; Pugh and Rudy 1996;
figure interacts with heightened neural plasticity to program long- Stanton, 2000). Traditional measures of neural maturation, such
term impairments in social behavior through effects on amygdala as long-term potentiation (LTP), a presumed measure of synaptic
development (Opendak and Sullivan 2016; Humphreys and Zeanah plasticity, emerge over a week earlier than contextual fear learn-
2015; Drury et al., 2015). We will begin to review attachment- ing (Ainge and Langston, 2012; Bekenstein and Lothman, 1991;
trauma effects on amygdala development with an exploration of Harris and Teyler, 1983; Swann et al., 1990; Wilson, 1984) and
neurobiology of attachment in typical rearing conditions. We will do not highlight the distinct behavioral trajectories of specific
then expand our discussion to disordered attachments that form hippocampal-dependent behaviors. Furthermore, some brain areas
 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159 147

likely encode information at one age but affect behavioral expres- 2012). Evidence from rodent studies on development of the amyg-
sion at another (Moye and Rudy, 1987; Pattwell et al., 2012; Poulos dala and hippocampus show a similar developmental time course;
et al., 2014). both regions demonstrate considerable growth during the initial
Emerging evidence also suggests brain areas can have unique postnatal period and become functionally mature in normal rearing
function in early life, such as the important role of locus coeruleus conditions at PN10 and PN23, respectively (Chareyron et al., 2012b;
(LC) norepinephrine (NE) in attachment that is described below Raineki et al., 2010a,c). These ages reflect significant developmental
(Landers and Sullivan, 2012). Neurochemicals, too, can have milestones in rats: although no consensus exists mapping rodent
age-specific effects, such as the switch between excitation and inhi- age onto human age, weaning around PN23 is considered a marker
bition by GABA at birth (Ben-Ari, 2014). The changing roles of other of early or peri-adolescence in infant rats, while PN0-PN9 is thought
molecules across development are less clear: while oxytocin has to represent infancy (Andersen, 2003; Sullivan and Holman, 2010).
a demonstrable role in prosocial behavior and maternal care in As will be discussed further, these first ten days represent a sen-
adults (Calcagnoli et al., 2015; Frijling et al., 2016; Johnson and sitive period for forming attachments. Although the amygdala,
Young, 2015; Lee et al., 2007; Marlin and Froemke, 2017; Nelson hippocampus, and PFC are robustly involved in trauma process-
and Panksepp, 1998; Shamay-Tsoory and Abu-Akel, 2016), its role ing during adulthood, their involvement in processing early-life
in very early life and the sensitive period for attachment remains trauma is complex, due to their limited functional unavailability
unclear (Nelson and Panksepp, 1998; Parr et al., 2016; Sannino and/or immaturity at this age.
et al., 2017). Finally, the numerous connections among brain areas
can be further delayed in maturation so that feedback systems
that form complex loops of bidirectional information processing
become functional at a later age. Thus, as we consider how early 3. Infant social interaction: importance of the caregiver as
life trauma can impact a child, it is important to consider when regulator of brain and behavior
brain areas implicated in adult trauma processing are function-
ally mature and functionally connected to other brain areas. As Understanding the role of a caregiver relies on a rich historical
will be shown below, processing of trauma in early life is differ- literature that has demonstrated the importance of the relation-
ent from processing such information in adulthood (Gunnar et al., ship between a child and a caregiver across a variety of species – a
2007; Opendak and Sullivan, 2016; Teicher et al., 2003). relationship primarily understood in terms of attachment. Animal
The amygdala-hippocampus-PFC circuit is crucial for threat research has provided clear evidence of the critical role of early
detection and many forms of social behavior, but the matura- life attachment in programming cognitive and emotional health.
tion and connectivity between these brain regions develops slowly Specifically, seminal works by Niko Tinbergen, Konrad Lorenz, and
over early life in humans (Casey et al., 2005; Gee et al., 2013; John Hinde characterized how the newly hatched chick attached
Graham et al., 1999; Malter Cohen et al., 2013; Skuse et al., 2003; (imprinted) to the parent (Hess, 1962) within a temporally lim-
Tottenham, 2012; Tottenham and Sheridan, 2009), nonhuman pri- ited sensitive period. Around the same time, Harry Harlow and his
mates (Bachevalier and Loveland, 2006; Chareyron et al., 2012a,b; colleagues were working with rhesus monkeys and assessing the
Lavenex and Banta Lavenex, 2013; Sanchez et al., 2001; Skuse et al., effects of being reared without a mother but providing basic food,
2003) and rodents (Brummelte and Teuchert-Noodt, 2006; Holland water and warmth (Harlow and Harlow, 1965). This work clearly
and Gallagher, 2004). The amygdala is considered to be the critical highlighted the importance of the infant’s social interactions with
structure involved in the formation and storage of conditioned fear the mother during a sensitive period in development since, without
associations (Davis et al., 1994; Phelps and LeDoux, 2005), but it has the caregiver, infants showed emotional and cognitive disabilities
a role in many emotional functions, including those unrelated to that were reminiscent of human children reared in inadequate
fear, such as social odor processing and assessing hedonic value of orphanages without an attachment figure (Gunnar et al., 2015;
stimuli (Holland and Gallagher, 2004; Maren and Fanselow, 1996; Humphreys and Zeanah, 2015; Levin et al., 2015; Teicher et al.,
Phelps and LeDoux, 2005; Royet et al., 2000). It has been suggested 2016).
that neonatal amygdala connectivity correlates with fear responses Attachment to a caregiver during a sensitive window is of
at six months of age in human infants (Graham et al., 2016). Further- paramount importance to altricial infant survival due to the infant’s
more, volumetric analysis indicates that amygdala volume peaks greatly reduced ability to acquire food, protection, and warmth.
in pre-adolescence (Uematsu et al., 2012). The PFC works with Furthermore, during early life, the infant relies on the caregiver for
the amygdala to regulate complex decision-making, particularly in regulation of basic physiology, ranging from vital functions, such
functions relevant to threat processing and social behavior, but the as heart rate and respiration, to emotional regulation. Caregiver
developmental trajectory of this region is not fully understood. The regulation of the infant’s emotional state is seen during perfunc-
PFC subarea orbitofrontal cortex (OFC), which plays an important tory caregiving, such as by soothing a crying infant or by smiling
role in assessing the hedonic value of odors (Anderson et al., 2003; at or tickling an infant to increase arousal. In turn, this stimulation
Gottfried et al., 2002; Rolls, 2015; Zald and Pardo, 1997), is postu- of the infant’s sensory systems changes physiology; for example,
lated as functional by the time a child is two or three years old, while soothing a stressed infant can lower stress hormone levels (Gunnar
the anterior cingulate (ACC) and medial PFC (mPFC) are thought to and Quevedo, 2007; Gunnar et al., 2007; Hofer, 1994; Sarro et al.,
possibly become functional around four months and as early as four 2014a,b). In typically developing children, this caregiver regula-
years, respectively (Allman et al., 2001; Gee et al., 2013; Graham tion of infant physiology has been shown to be critical for a child’s
et al., 2015). interaction with the world, including reduction of fear, response
The hippocampus is a region with diverse functions, including to novelty, and learning (Humphreys and Zeanah, 2015; Gee et al.,
the ability to remember specific information about events, such 2013; Nachmias et al., 1996). In turn, this system appears to be com-
as where and when events occurred. These functions appear to promised in children with early life trauma. Specifically, neglectful
develop around two years old in children, but show great improve- and/or abusive caregiving has been associated with poor regulation
ment over the next four years (Gomez and Edgin, 2015; Lavenex and of infant physiology and is correlated with disrupted developmen-
Banta Lavenex, 2013). Since the child’s hippocampus is difficult to tal trajectories related to social behavior and threat processing
image using brain scanning techniques, data on hippocampal func- (Gunnar et al., 2007; Mikics et al., 2008; Nemeroff, 2004; Rincon-
tional emergence does not exist, although hippocampal growth Cortes and Sullivan, 2014). These effects have little to do with
rates appear to peak around 9–11 years of age (Uematsu et al., the level of sensory stimulation of the infant, as this varies across
148 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159

cultures without producing deficits in caregiver regulation (Choi, Malkova et al., 2010; O’Connor and Cameron, 2006; Raper et al.,
1995; Welles-Nystrom et al., 1994). 2014; Sanchez, 2006; Sanchez et al., 2015; Suomi, 2003).
The effects of inadequate and abusive care on the etiology of A rich literature has identified a unique learning circuit involved
neurobehavioral deficits remain poorly understood, although ani- in the formation of attachment across a variety of species, although
mal models have attempted to add some insight into this complex the neurobiology of attachment has mostly been described using
issue (Gunnar et al., 2015; Hennessy et al., 2006, 2009; Hostinar rodents. Infant rodents, called pups, can neither hear nor see until
et al., 2014; Opendak and Sullivan, 2016; Raineki et al., 2010b; the third week of life, and olfaction is the main sensory system used
Roth et al., 2013; Sarro et al., 2014a,b; Sullivan et al., 2011; Sullivan for interactions with the caregiver (in contrast to newborn humans,
and Holman, 2010). When drawing parallels between work in who use all of their sensory systems) (Ehret, 1976; Weber and
humans and animal models, it is important to clarify that ani- Olsson, 2008). Specifically, maternal odor is of paramount impor-
mal studies typically model this attachment–trauma within the tance to pups’ survival, as they rely on this odor cue for nipple
framework of either harmful or species-atypical input (e.g. abusive attachment, proximity seeking, and social behavior. Without these,
caregiving) or absence of expected input (e.g. maternal deprivation, pups cannot access nourishment, thermoregulation, or maternal
decreased maternal care) (Champagne et al., 2008; Francis et al., care. Indeed, pups without the ability to smell rarely survive as
2002; Tottenham, 2012; Tottenham and Sheridan, 2009). Similarly, they frequently fail to nipple attach and can become malnourished
trauma studies in children distinguish between the neurobehav- (Landers and Sullivan, 2012).
ioral effects of abuse, neglect, and trauma that is not associated with The incredibly complex process of caregiver-infant interaction
a caregiver (Bowlby, 1984; Bremner, 2003; Maestripieri and Carroll, was long considered to be innate and guided by a pheromone (Blass
1998; Neigh et al., 2009). For instance, data from children raised and Teicher, 1980; Distel and Hudson, 1985; Leon, 1983). How-
in institutional care typically reflects the consequences of neglect, ever, research has indicated that learning is of major importance
rather than abuse (Humphreys and Zeanah, 2015). Although these for activating behavioral systems that are age-relevant and biologi-
various subtypes of early-life trauma produce divergent adult out- cally predisposed towards preference for maternal odor. In rat pups,
comes, research using animal models and clinical populations this learning process begins in the prenatal environment, where
highlights the amygdala’s involvement in the etiology of psy- amniotic odors can guide nipple attachment as soon as pups are
chopathology (Raineki et al., 2012; Sitko et al., 2014; Teicher et al., born. Even a neutral odor can acquire the valence of a maternal
2016; Tzanoulinou and Sandi, 2017). By modeling attachment in odor if placed into the amniotic fluid a few days before birth, sug-
normal and abusive circumstances, we can explore some of the gesting the odor itself is arbitrary for both rats and mice (Hepper
neural mechanisms by which early life attachment programs social and Cleland, 1998; Leon, 1992; Logan et al., 2012; Pedersen and
and threat processing throughout the lifespan. Blass, 1982; Smotherman and Robinson, 1987; Sullivan and Leon,
1986; Sullivan and Wilson, 1991). Once pups are born, a new mater-
nal odor can be rapidly learned; a novel odor (e.g. peppermint)
4. The infant attachment circuit placed either on the mother or in the air surrounding her will read-
ily take on the properties of maternal odor (Cheslock et al., 2000;
The infant learns about the smell, sight, touch, sound and taste Roth and Sullivan, 2005; Sullivan et al., 1990). Outside the nest, if
of the caregiver during social interactions. Once learned, these sen- a neutral odor is paired with warmth, milk, or stroking – stimuli
sory cues from the caregiver are preferred and help regulate infant designed to mimic maternal behavior– this odor acquires the value
behavior and physiology. How the infant learns about the care- of a new maternal odor that is not only preferred, but can support
giver relies upon the unique neurobiology of the infant brain for nipple attachment and prosocial behavior in the absence of a natu-
attachment learning, which is describe below as identified in infant ral maternal odor (Roth et al., 2013; Roth and Sullivan, 2005; Roth
rodents. A useful framework in which to understand the changing and Sullivan, 2006; Sullivan et al., 1986). This is especially impor-
learning circuitry of the young brain is to understand that the brain tant to ensure a robust attachment, given the fact that a dam’s odor
must continuously morph to accommodate the specific behavioral can change with her diet and is dependent on gut bacteria (Leon,
niche at each stage of development. For example, the young infant 1983, 1992).
does not need a brain that supports learning behaviors to gather During the first ten days of life, the learning process for new
food from the environment or procure a receptive mate; rather, maternal odors in rat pups occurs through a relatively simple
the brain is designed to learn about the caregiver and show proso- neurobiological substrate. At this early age, learning-associated
cial behaviors toward the caregiver that will engage the caregiver plasticity occurs within the olfactory bulb, the first relay station for
to provide those resources needed for survival (Bowlby, 1978; Hess, olfactory processing. This process requires that an odor is paired
1962). As the child matures, he or she gains adult-like functioning with copious amounts of NE (Sullivan et al., 2000b, 1992; Yuan
for different tasks at different ages and this is presumably sup- et al., 2000). The sole source of the NE to the olfactory bulb is
ported by transitions in brain morphology and function. the LC, and this structure’s unique physiology during early life is
Given that an altricial infant’s attachment to a caregiver is essential for neonatal odor approach learning. In particular, the
critical for survival, the attachment circuit was likely shaped by large amounts of NE required for this attachment-related plasticity
evolutionary pressures to ensure attachment formation occurred, results from the failure of the infant LC to show habituation or to
regardless of the quality of caregiving received. Indeed, John turn itself off via auto-inhibition (as occurs in older pups and adults)
Bowlby’s Attachment Theory described the infant brain of altri- (Nakamura et al., 1987; Winzer-Serhan et al., 1996). In addition, the
cial species as designed to support attachment to the caregiver, olfactory bulb undergoes a host of anatomical and physiological
even when the quality of care is compromised or abusive, during changes reflecting enhanced responding to the learned maternal
a temporally defined sensitive period (Bowlby, 1965, 1978). This odor (Raineki et al., 2009; Roth and Sullivan, 2006; Sullivan et al.,
feature of attachment formation is supported by clinical and epi- 1990; Yuan et al., 2002). It is important to note that both natu-
demiological literature indicating that abused children frequently ral maternal odor and a learned artificial maternal odor generate
long to be reunited with their abusive attachment figure after sep- the same responses from the olfactory bulb (Raineki et al., 2010c;
aration and placement in a safe home (Ainsworth, 1969; Perry and Roth and Sullivan, 2005). The olfactory bulb axons of mitral cells
Sullivan, 2014). This has been modeled in a variety of species includ- project directly to the piriform cortex (Haberly, 2001; Schwob and
ing birds, non-human primates, dogs, and rodents (Cirulli et al., Price, 1984; Swanson and Petrovich, 1998; Wilson and Stevenson,
2009; Goursaud and Bachevalier, 2007; Harlow and Harlow, 1965; 2003); this region plays a key role in assigning the hedonic value
 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159 149

to a learned odor stimuli in a region-specific manner. In particular, Wilson, 1994). The mother also begins to socially buffer the stress
the anterior piriform is activated by odors learned during this sen- response, in a manner similar to that seen in adults. Specifically, at
sitive period, while the posterior piriform is engaged in response PN10, stressful stimuli begin to produce a more immediate increase
to learned odor in older pups and adults (Moriceau and Sullivan, in pups’ CORT levels, and the presence of the mother completely
2006; Moriceau et al., 2006; Roth and Sullivan, 2005). The sensi- blocks its release (Moriceau et al., 2006; Stanton and Levine, 1990;
tive period terminates when pups are around 10 days old, as the Suchecki et al., 1993). Research has begun to explore the specific
LC becomes more adult-like: NE release is greatly restricted due to neural mechanisms involved in social buffering (Hennessy et al.,
the development of recurrent collaterals that quickly self-inhibit 2006, 2009, 2015; Moriceau et al., 2006; Shionoya et al., 2007).
the LC’s response. After the sensitive period, NE takes on a modu- It has been shown that in infant rodents, social buffering by the
latory role in odor learning that is more similar to what has been mother greatly attenuates stress hormone release by the HPA axis
described in adult rats (Ferry and McGaugh, 2000). at the level of the hypothalamic paraventricular nucleus (PVN),
Human infants also show learning of caregiver cues across mul- through suppression of NE afferents from medullary A1/A2 nora-
tiple sensory modalities (DeCasper and Fifer, 1980; Sullivan et al., drenergic neurons (Shionoya et al., 2007)–a system identified in
2011), which enables them to form attachments to adoptive par- adults (Ziegler and Herman, 2002). This social buffering by the
ents and caregivers of either sex. Although it remains unclear mother has profound effects on whether pups have access to the
whether learning in human infants is the same as the rodent, NE attachment learning neural circuitry: the maternal social buffering
plays a critical role in bond formation in numerous species (Nelson can reopen pups sensitive period for attachment between the ages
and Panksepp, 1998; Numan and Young, 2016), suggesting it is a of PN10-15. In particular, during this transitional sensitive period,
phylogenetically conserved system. Notably, NE levels are very high maternal presence can modulate whether pups learn to avoid or
in humans at birth and over the first two years of life (Lagercrantz prefer an odor paired with shock; this process depends on amygdala
and Bistoletti, 1977). Further work will be necessary to determine serotonin and CORT levels (Moriceau et al., 2006) (Fig. 2).
whether humans engage the same neural circuitry as rodents in After PN15, pups show a rapid transition to independence and
forming attachments to a caregiver and whether the child’s brain by weaning age (∼PN23), they show stress-induced activation of
is predisposed towards forming odor preferences at this age. the HPA axis similar to adult-like levels. At this age, the relative
ability of the mother to decrease the pups’ adult level stress hor-
mone response is greatly reduced and leaves pups with significant
5. Maternal control over stress hormones: social buffering CORT levels (Levine et al., 1988; Stanton and Levine, 1990; Suchecki
et al., 1993; Upton and Sullivan, 2010). The human literature also
Once the attachment figure’s smell, sight, sound, touch and taste suggests that, with further maturation, maternal presence loses
are learned, these cues take on the role of regulating the brain and some value to socially buffer children beginning to enter adoles-
behavior. A crucial factor mediating the effects of early-life attach- cence (Gee et al., 2014; Hostinar et al., 2015; Sanchez et al., 2015;
ment on adult outcomes is how well the caregiver can regulate Sandi and Haller, 2015) which is consistent with the animal litera-
stress reactivity in the infant. As noted above, maternal cues reg- ture (Barr et al., 2009; Ditzen and Heinrichs, 2014; Hennessy et al.,
ulate a wide variety of neurobehavioral functions (Hofer, 1994). 2015; Kiyokawa et al., 2004; Sanchez et al., 2015; Shionoya et al.,
Social buffering is a phenomenon that has been observed in myr- 2007; Sullivan and Perry, 2015; Takahashi et al., 2013).
iad species and throughout the lifespan and describes the reduction
of both the stress response and release of stress hormones (Ditzen
and Heinrichs, 2014; Hennessy et al., 2009; Hostinar et al., 2015; 6. Attachments formed to abusive caregivers
Kikusui et al., 2006; Sanchez et al., 2015; Sullivan and Perry, 2015;
Takahashi et al., 2013). This has been demonstrated in children, The quality of care an infant receives from the caregiver, while
for whom maternal presence dampens cortisol reactivity to threats preserving attachment, does alter how well the caregiver can regu-
even when they behaviorally exhibit fear (Nachmias et al., 1996). late the infant’s physiology. For instance, highly stressed caregivers
Social buffering of the infant is a dynamic process that wanes have a reduced capacity to socially buffer children (Ainsworth and
as individuals across species mature and become independent Bell, 1970; Gunnar et al., 2007, 1996; Nachmias et al., 1996). In spite
(Gee et al., 2014; Levine, 2001; McCormack et al., 2009; Sanchez, of this, throughout the animal kingdom, young, including humans,
2006; Stanton and Levine, 1990; Suchecki et al., 1995; van Oers form attachments to abusive caregivers (Harlow and Harlow, 1965;
et al., 1998) (Fig. 1). For example, at birth, rat pups have a func- Hess, 1962; Rajecki et al., 1978; Salzen, 1970; Stanley, 1962).
tional HPA axis, although it soon becomes hypo-responsive and This abuse-related attachment appears phylogenetically conserved
not activated by most painful stimuli, a period of life termed the across species, including chicks that form attachments after being
stress hypo-responsive period (SHRP) (Dallman, 2000; Stanton shocked during imprinting (Hess, 1962; Rajecki et al., 1978; Salzen,
and Levine, 1985). Since no stress response occurs, we have tra- 1970), dogs (Stanley, 1962), and monkeys raised with a wire sur-
ditionally viewed social buffering as nonfunctional or irrelevant rogate that inflict pain (Harlow and Harlow, 1965). More recent
in infants.Although the specific time-course is unknown, there work has modeled abusive caregiving in nonhuman primates and
appears to be a similar stress hypo-responsive period in human again shows that infants retain strong preferences for the abusive
children. Studies show that infants begin to exhibit dampened cor- caregiver (Maestripieri et al., 1999; O’Connor and Cameron, 2006;
tisol reactivity during the first year of life (6–12 months) (Gunnar Sanchez et al., 2001; Suomi, 2003). Attachments to an abusive or
and Donzella, 2002; Gunnar et al., 2015). Although the duration of negligent caregiver may have short-term advantages, e.g. there is
this period is unknown, basal cortisol remains at low levels through neonatal access to care, but long-term consequences associated
the preschool period (Grunau et al., 2004; Watamura et al., 2004). with compromised threat processing and emotion expression.
At PN10 in rodents, the SHRP begins to wane and we begin to see Due to the unique neurobiology of the infant brain that is biased
increases in CORT release in response to shock and other stressful towards forming attachments, traumatic cues during the sensitive
stimuli in pups (Sullivan and Holman, 2010). It is also the age at period for attachment are processed within the attachment cir-
which pups transition from crawling to walking and begin to leave cuitry rather than the threat processing circuitry. Again, the rodent
the nest and nibble solid foods (Galef, 1981). As mentioned above, literature provides some clues to understanding why this occurs.
the LC takes on more adult-like functioning at this age (Moriceau Our lab employs an abuse paradigm in which the mother rat is
and Sullivan, 2004; Nakamura and Sakaguchi, 1990; Sullivan and provided insufficient bedding to build a nest for the pups. Under
150 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159

Fig. 1. Transitions in learning across early development. Using a fear conditioning paradigm of odor-shock presentations has enabled us to uncover a developmentally unique
learning system in pups that typically supports attachment learning. Data indicate that during the sensitive period for attachment learning (PN < 9), low CORT levels block
amygdala plasticity to prevent pups from learning amygdala-dependent fear/threat. Instead, this learning paradigm activates the attachment learning neural circuit involving
elevated NE (thick gray arrow) to produce approach responses to the odor (Moriceau et al., 2006). The odor also takes on qualities of the maternal odor to support nipple
attachment and enhance prosocial behaviors to the mother. In pups older than PN9, this fear conditioning paradigm accesses the amygdala to support fear/threat learning
if the pup is alone. A critical feature of this learning is that shock induces activation of the HPA axis and CORT release, which is necessary for the young amygdala to learn.
However, if the mother is present, she socially buffers the pup’s stress response, and pups revert to sensitive period learning and learn an odor preference (red dashed line).
This mother-controlled switch between fear and attachment learning is mediated through the mother’s ability to control pups CORT (Sullivan, in press). A more adult-like
fear learning system, which cannot be switched on/off by CORT develops by PN15. Environmental variables that control pups’ CORT level, such as receiving CORT from a
stressed mother via milk, environmental manipulations that increase pups’ CORT (abusive rearing) or the mother’s ability to socially buffer the pups (compromised in abusive
mothers), have the potential to modify the age of these transitions and whether a pup learns fear or attachment (Moriceau et al., 2006; Perry and Sullivan, 2014; Raineki
et al., 2012; Shionoya et al., 2007; Sullivan and Holman, 2010). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article.)

Fig. 2. Timeline of attachment learning and the effects of early life maltreatment on later-life social and emotional behavior in the rat model of trauma associated with
attachment. Early infants will learn attachment regardless of the quality of care, while slightly older infants (PN10-PN15) will either learn to fear a traumatic associated
stimulus when away from the mother or learn an attachment if acquisition takes place with the mother. Testing later in life shows that only the early life trauma associated
with attachment will lead to lifelong amygdala-dependent behavioral deficits, such as poor social behavior (onset prior to weaning) and depressive-like behaviors (onset
post- weaning (Raineki et al., 2012; Raineki et al., 2010b; Sevelinges et al., 2011; Sullivan et al., 2000a,b). In adulthood, early trauma produces enhanced aggression (Marquez
et al., 2013) and impaired threat response (Perry, in press).

these circumstances, the mother becomes highly agitated and fre- with pain appears similar to typical attachment within the nest, as
quently builds and re-builds her nest. In the process, she mistreats noted below, stress can uncover infant neurobehavioral problems
the pups, behaviors that include stepping on pups, dragging them consistent with disordered attachment (Raineki et al., 2010b).
across the cage floor, and transporting them inappropriately, induc- Although this naturalistic maternal abuse paradigm is highly
ing pain-related vocalizations in pups (Roth and Sullivan, 2005; informative, its complexity makes it difficult to assess the mech-
Moriceau et al., 2009). Pairing this painful maternal care with a anisms linking low resources and neurobehavioral pathology.
novel peppermint odor does not activate the important survival Therefore, we complement this model with a classical condition-
circuit within the brain to support aversion learning. Rather, pups ing paradigm to mimic abusive attachment. Just as new maternal
not only learn to approach this odor, but this odor takes on the qual- odors can be learned when a previously neutral odor is paired
ities of maternal odor to support nipple attachment and prosocial with stimuli evoking maternal care, such as milk or stroking, we
behaviors (Roth and Sullivan, 2005; Sullivan et al., 1986; Sullivan paired an odor with a moderately painful foot-shock (0.5 mA) or
et al., 2000a). This learning can occur rapidly, within as little as tail-pinch; this produced an odor preference in young pups (Camp
10–30 min. While the behavioral output of attachment formation and Rudy, 1988; Haroutunian and Campbell, 1979; Spear, 1978;
 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159 151

Sullivan et al., 1986); we later showed this procedure also produces children in the absence of physical evidence. In parallel with obser-
a new maternal odor that pups prefer (Raineki et al., 2012). The vations of latent abuse-related deficits in rodents and non-human
inability of the paired odor-pain procedure to produce fear learn- primates, many of the effects of early life trauma on children’s
ing is not due to pups’ inability to detect the aversive stimulus or mental health appear to be delayed until they begin to transi-
feel pain. Noxious stimuli readily elicit <PN9 pup escape responses tion into adolescence (Bachevalier and Loveland, 2006; Bachevalier
and the pain threshold does not appear to change as shock switches et al., 2001; Callaghan et al., 2014; Goursaud and Bachevalier,
from supporting preference to supporting aversion learning (Barr, 2007; Goursaud et al., 2014; Machado and Bachevalier, 2003;
1995; Collier and Bolles, 1980; Emerich et al., 1985; Stehouwer and Raper et al., 2014; Tottenham and Sheridan, 2009). However,
Campbell, 1978). As described above, the pup’s olfactory bulb, ante- stress can uncover deficits associated with trauma that may oth-
rior piriform cortex, and a hyper-functioning LC work together to erwise be hidden, as demonstrated by Mary Ainsworth’s Strange
generate enhanced odor preference learning despite adversity. Crit- Situation Test. In this procedure, repeatedly removing children’s
ically, shock presentations that are not paired with an attachment caregiver and introducing a stranger was necessary to reveal behav-
odor fail to produce the same neurobehavioral sequelae as either ioral impairments marking disordered attachment (Ainsworth,
abusive care or paired odor-shock treatment (Raineki et al., 2012). 1969; Crittenden, 1992; Nachmias et al., 1996). This can also be
As mentioned above, termination of the sensitive period for modeled in rodents: pups that were exposed to abuse in the
attachment at PN10 in typical rearing conditions is primarily due low bedding procedure and repeated odor-shock pairings form
to increasing levels of CORT and functional emergence of the amyg- a disordered attachment to the mother, expressed in decreased
dala (Sullivan and Holman, 2010). While CORT levels naturally approach behavior towards the maternal odor, less nipple attach-
increase at PN10, the environment readily changes pups CORT ment, and amygdala hyperactivity if given CORT injections before
levels, providing environmental control of the sensitive period testing (Raineki et al., 2012). The CORT injection in pups models
for attachment termination. Specifically, increasing CORT during a high-stress environment, which appears necessary to uncover
the sensitive period, either via rearing with an abusive mother, neurobehavioral deficits before weaning. Importantly, this CORT
or through pharmaceutical manipulations (systemic injections or injection did not disrupt social interaction or activate the amygdala
by intra-amygdala microinfusions), can prematurely end sensitive in pups reared with a nurturing mother, nor was there evidence of
period learning. Indeed, the amygdala is mature enough to support disordered attachment in pups that received only shock trauma or
threat learning in pups as young as PN6, provided sufficient levels unpaired odor-shock training. Taken together, these findings sug-
of corticosterone are available within the amygdala (Debiec and gest that repeatedly experiencing trauma associated with caregiver
Sullivan, 2014; Moriceau et al., 2004, 2009; Moriceau and Sullivan, cues during the sensitive period for attachment has a unique neu-
2004, 2006). Pups reared by an abusive mother during the SHRP ral signature, producing latent changes in amygdala function to
receive CORT through her milk and her ability to socially buffer this program emotionality and social behavior throughout the lifespan.
CORT elevation is compromised; when these pups are trained on
a peppermint odor-shock conditioning paradigm outside the nest
at PN7, they will learn an aversion through amygdala-dependent 8. Amygdala involvement in social behavior throughout
mechanisms (Moriceau et al., 2004; Raineki et al., 2010b). Simi- the lifespan
larly, pups reared with a normal nurturing mother but trained on
a 5-day odor-shock conditioning procedure during the SHRP will In humans, the amygdala is implicated in social behavior in
learn an aversion to the odor if they receive CORT injections before adults (Thomas et al., 2001), as well as during development (Skuse
each training session (Raineki et al., 2010b,c). It is important to note et al., 2003; Tottenham and Sheridan, 2009). Furthermore, research
that, although abused pups or pups injected with CORT can learn has shown that humans with disorders associated with social
arbitrary odor aversions (eg. peppermint) via premature amygdala behavior deficits, such as Autism and Williams Syndrome, show
engagement, they will nevertheless always show a preference for amygdala abnormalities (Baron-Cohen et al., 2000; Bachevalier
the maternal odor. As will be discussed further, this preference et al., 2000; Critchley et al., 2000; Howard et al., 2000; Pierce
accompanies a disordered, rather than typical, attachment. et al., 2001; Haas et al., 2009; Paul et al., 2009). Moreover, studies
Although abuse and repeated odor-shock fails to produce an in nonhuman primates demonstrate that adult monkeys without
aversion to maternal odor, these manipulations generate latent amygdalae display inappropriate social behavior (Amaral, 2003;
changes in amygdala function that emerge around weaning age. Baron-Cohen et al., 2000; Bliss-Moreau et al., 2011; Brothers et al.,
Importantly, direct abuse from the caregiver and pairing of the 1990; Emery et al., 2001; Malkova et al., 2010).
maternal odor with shock produce indistinguishable neurobehav- While the amygdala is also implicated in social behavior in
ioral outcomes. Amygdala-dependent deficits are expressed in a children (Tottenham and Sheridan, 2009), its role is less clear. Stud-
task-specific manner: amygdala hyperactivity underlies decreased ies on abused and neglected children, as well as children with
social exploration in adolescence and depressive and anxiety-like PTSD, indicates changes in the response to threatening faces (Pine
behavior in adulthood (Fig. 2), in parallel with impaired ability et al., 2005; Pollak et al., 2000). The most dramatic developmen-
to learn aversions to threat and blunted amygdala activation dur- tal differences were first observed in non-human primates, where
ing fear conditioning (Raineki et al., 2012; Sevelinges et al., 2007, infant amygdala lesions lead to decreased fear response to normally
2011, 2008). These results parallel clinical studies showing a role threatening stimuli and an enhanced response to novel social situ-
for amygdala dysfunction in psychiatric sequelae in adults with a ations (Amaral, 2002, 2003). This parallels work showing impaired
history of attachment trauma, resulting from abuse and/or neglect, threat assessment in abused rats with amygdala dysfunction (Perry,
during childhood (Callaghan et al., 2014; Teicher et al., 2003). Santiago, & Sullivan, in press) and rats that were stressed during
peripuberty (Marquez et al., 2013).
The rodent literature allows for more precise manipulations of
7. Stress uncovers latent consequences of early-life trauma specific amygdala nuclei. Social behavior in adult rodents appears
to rely on the medial amygdala (Rasia-Filho et al., 2000). It has
Across many species, many of the effects of infant abuse remain been shown that c-Fos expression, an indirect marker of neu-
latent until peri-adolescence (Adriani and Laviola, 2004; Amaral, ral activation, increases in the medial amygdala following social
2003; Andersen and Teicher, 2008; Bauman et al., 2006; Costello encounters and maternal behavior in rodent models (Fleming et al.,
et al., 2003). For this reason, it can be difficult to identify abused 1994; Kirkpatrick et al., 1994). Medial amygdala activation is also
152 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159

associated with rodent parental behavior, which is blocked by in several factors, including aggression, stress reactivity, social
lesioning this nucleus (Ferguson et al., 2002; Gobrogge et al., 2007; behavior, and “home-field advantage”, or benefits for residents
Kirkpatrick et al., 1994). While the medial amygdala has a promi- versus intruders (Barnett, 1958; Sapolsky, 2005; So et al., 2015).
nent role in social behavior, the basolateral, central and cortical Although the neurobiology of forming a stable hierarchy is incredi-
amygdala nuclei have also been implicated (Katayama et al., 2009). bly complex and involves myriad brain regions, several brain areas
As will be discussed below, these nuclei form part of a functional have been identified as key mediators of social dominance, such as
circuit with the hippocampus and vmPFC that is critically engaged the vmPFC, ventromedial hypothalamus, ventral hippocampus, and
in complex forms of social behavior. amygdala (Bauman et al., 2006; Rosvold et al., 1954; So et al., 2015;
It is important to note that while social behavior in adult rats Watanabe and Yamamoto, 2015; Wong et al., 2016). These regions
involves the amygdala and can be a behavioral measure used to have been implicated in aggression-seeking behavior, social recog-
reveal those adults with early life trauma, in rat pups, it is only nition, and memory for social position. Importantly, the basolateral
during periods of heightened stress (eg. heightened CORT levels) amygdala inhibits the ventral hippocampus during social interac-
combined with early life trauma that social behavior deficits and tion (Felix-Ortiz et al., 2016; Felix-Ortiz and Tye, 2014; Gunaydin
heightened amygdala neural activity can be uncovered. This sug- et al., 2014). Interestingly, dominance has been linked with levels of
gests that the amygdala is not involved with social behavior in corticotropin response factor (CRF) mRNA in the medial amygdala
infancy and its activation can, in fact, impair social behavior at this in mice (So et al., 2015).
age. Compromised amygdala function in animals with a history of
caregiver abuse during the sensitive period for attachment may
have highly maladaptive consequences with respect to social posi-
9. Implications for complex social behavior tion (Fig. 3). For instance, global impairments in social behavior
may pre-dispose abused rats to a lifetime of subordination, result-
Aberrant processing of social and threatening cues stemming ing in not only a lack of rewards afforded to dominants, but also
from amygdala dysfunction is a hallmark of psychiatric sequelae increased stress and illness in some types of hierarchies (Blanchard
following early-life abuse and neglect (Levin et al., 2015; Teicher et al., 1995; Sapolsky, 2005). On the other hand, increased aggres-
et al., 2003; Troller-Renfree et al., 2016; Zeanah and Gleason, 2015). sion may lead to dominance in some abused animals. However,
As individuals mature, increasingly complex social demands may heightened anxiety and/or depressive-like behavior may prevent
multiply the consequences of impaired social behavior, amplifying these same animals from maintaining their social position, result-
stress and even compromising welfare. Exploring these complex ing in a chronically unstable hierarchy that can produce profound
social arrangements in animal models can provide insight into changes in adult brain plasticity for all members (Green et al., 2013;
the mechanisms underlying long-term effects of social deficits and Opendak and Gould, 2015; Opendak et al., 2016; Weathington et al.,
identify therapeutic targets for attachment trauma in early life. 2012). Furthermore, caregiver abuse decreases sexual motivation
Dominance hierarchies provide one example of a complex social in adult rodents (Raineki et al., 2015), suggesting that these ani-
arrangement determined by individual differences that can result mals may fail to engage receptive females, a benefit of dominance
from early life experience. In the wild, rats are among a wide vari- in typically-reared individuals (Blanchard et al., 1995; Blanchard
ety of species that naturally form dominance hierarchies as a result et al., 1988; White et al., 1986).
of competition for limited resources (Sapolsky, 2005). This can be Rats with a history of caregiver abuse show impaired response
simulated in the laboratory using a visible burrow system, a semi- to a salient predator odor threat and amygdala dysfunction,
naturalistic enclosure that replicates many of the challenges and suggesting that maintenance of a social hierarchy may also be
opportunities of group-living in nature; in this setting, rats rapidly compromised in these animals (Perry et al., in press) (Fig. 3).
form stable dominance hierarchies (Fig. 3) (Blanchard et al., 1995, Specifically, these abused rats may fail to show subordination to
1988; Opendak et al., 2016). A rich literature has described the an established dominant, leading to prolonged injurious fighting
effects of life in a dominance hierarchy on its members, including and precluding their timely access to limited resources (Blanchard
measures of behavior, hormones and physiology (Blanchard et al., et al., 1995; Blanchard and Blanchard, 1989). Indeed, rats that were
1995; Hardy et al., 2002). These studies have focused on differ- stressed during adolescence show persistent aggression towards
ences between dominants and subordinates within the aggressive larger intruders in the resident-intruder paradigm, against whom
Long Evans (LE) rat strain. The factors that contribute to social a more optimal strategy may be to show submission (Marquez
position are complex, but the consequences of stratification can et al., 2013). Avoiding the dominant involves multiple learned cues,
be dramatic for an animal’s quality of life. When LE rats form a including social odor, and has been linked with adult-born neu-
dominance hierarchy within a laboratory enclosure, it has been rons in the hippocampus (Lagace et al., 2010) and oxytocin receptor
shown that subordinate rats have elevated levels of CORT com- mRNA in the medial amygdala (Timmer et al., 2011). A role for the
pared to dominants and can be prone to illness and weight loss due amygdala in this process is further supported by data in non-human
to chronic stress (Blanchard et al., 1995; Hardy et al., 2002). Subor- primates showing impaired responses to fearful stimuli follow-
dinate rats show a decrease in overall activity and social behaviors, ing infant amygdala lesions (Amaral, 2003; Bauman et al., 2006;
including aggression and sexual advances. In addition, they show Marquez et al., 2013).
an increase in a range of defensive responses to the dominant male Abuse-related impairments in amygdala function may have
(Blanchard et al., 1995, 2001). Furthermore, subordinates exhibit implications for other social behaviors as well. As mentioned
increases in the relative sizes of adrenal glands and spleen and previously, rats that were abused during the sensitive period
decreases in the sizes of the thymus and testes than dominants. for attachment show decreased social exploration in adulthood
In contrast, dominants enjoy preferential access to resources, as (Raineki et al., 2015). Specifically, they exhibit decreased prefer-
well as increases in markers of adult-brain plasticity. Specifically, ence for interacting with a conspecific over an empty container in
dominant rats show enhanced adult neurogenesis in the ventral a classic three-chamber test (Crawley, 2004). A variation on this
dentate gyrus of the hippocampal formation, an effect that also has test involves comparison between a novel conspecific and a famil-
been shown in baboons (Kozorovitskiy and Gould, 2004; Peragine iar conspecific; at baseline, rats tend to prefer to interact with
et al., 2014; Wu et al., 2014). the novel rat. This behavior has been shown to be affected by
When animal size and previous agonistic experience are equiva- specific social experiences within a dominance hierarchy. In par-
lent, social stratification emerges from small individual differences ticular, destabilization of a stable dominance hierarchy of rats by
 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159 153

Fig. 3. Schematic of a visible burrow system for use in rodents and putative effects of early-life abuse on dominance hierarchy formation. This enclosure, adapted from
Blanchard et al. (1995), allows for a semi-naturalistic setting in which rodents can be group-housed with limited access to resources including food, water, and receptive
females. Social position can emerge from individual differences in aggression and stress reactivity. These factors may be compromised in cases of caregiver abuse in early life,
which produces enhanced aggression (Marquez et al., 2013), impaired threat response (Perry, in press), depressive and anxiety-like behavior (Raineki et al., 2012; Raineki
et al., 2015) and decreased social exploration (Raineki et al., 2015). As a result, abuse may affect formation and maintenance of a stable dominance hierarchy.

removal of the dominant reverses the social preference for nov- bility to later-life mental health disorders (Bowlby, 1984; Bremner,
elty in all community members: in the three-chamber test, rats 2003; Famularo et al., 1992; Graham et al., 1999; Nemeroff and Vale,
spend more time with a familiar conspecific. This behavior has been 2005; Pechtel et al., 2014).
linked with changes in the number of adult-born neurons (Opendak Animal models across a variety of species have allowed us to
et al., 2016). Work showing changes in novelty-seeking follow- assess the mechanisms by which caregiver abuse engenders neu-
ing early-life amygdala lesions in non-human primates (Amaral, robehavioral deficits, with programming of the stress system as
2003) suggests that social novelty preference may also be affected a point of convergence in adult outcomes (Andersen and Teicher,
in animals with a history of abuse. Given the extensive connections 2008; Denenberg, 1963; Famularo et al., 1992; Harlow and Harlow,
between the amygdala and ventral hippocampus in social inter- 1965; Hofer, 1994; Levine, 1957; Levine et al., 1985; Teicher et al.,
action and novelty-seeking (Felix-Ortiz and Tye, 2014; Gunaydin 2003). Here we have focused on two very selective models of care-
et al., 2014; Zeamer and Bachevalier, 2013), exploring these inter- giver abuse in rodents, namely, rough handling by the mother
actions in a model of amygdala dysfunction presents an exciting given low nesting resources, and repeated presentations of paired
opportunity for further research. odor-shock during the sensitive period for attachment. Both of
these manipulations produces latent changes in amygdala func-
10. Concluding remarks tion and depressive-like behavior, aberrant fear expression, and
social behavior deficits (Perry et al., in press; Raineki et al., 2010b,c;
Early life provides a sensitive window for programming lifelong Raineki et al., 2015; Roth et al., 2014; Sevelinges et al., 2007, 2011,
emotional and cognitive processing, which has profound influence 2008). Importantly, these effects are not produced when a pup
over threat-processing and social behaviors. In altricial species, this experiences shock without the mother (Sarro et al., 2014a; Tyler
period of brain development favors forming attachments to a care- et al., 2007). These results suggest that caregiver abuse during the
giver, regardless of the quality of care, in order to ensure the infant sensitive period for attachment produces a unique outcome, with
receives access to warmth, protection, and food. However, attach- the social dimension of early abuse, rather than pain alone, predis-
ments formed in threatening or traumatic contexts have unique posing amygdala development towards an impaired phenotype.
consequences for the development of social behavior and learning In the clinical population, the amygdala has also been impli-
about threat. In the clinical literature, this has been demonstrated cated in the pathogenesis of psychiatric sequelae. For instance,
in individuals with a history of abuse or disordered attachment who patients with depression also show alterations in amygdala func-
exhibit compromised fear and social behavior, as well as vulnera- tion and its connectivity with other brain areas (Elzinga et al.,
154 M. Opendak et al. / Developmental Cognitive Neuroscience 25 (2017) 145–159

2003; Frijling et al., 2016; Jedd et al., 2015; McEwen, 2003; Ressler plasticity in adult rat hippocampal dentate gyrus. Neurobiol. Learn. Mem. 92
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Bale, T.L., 2015. Epigenetic and transgenerational reprogramming of brain
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The purpose of this publisher correction is to inform readers that the Declaration of Interest statement which the publisher inadvertently
final version of the articles linked with this correction were replaced omitted from the original version.
with a corrected version in April 2019. The corrected version contains a The Publisher apologizes for any inconvenience this may cause.”

DOIs of original article: https://doi.org/10.1016/j.dcn.2017.03.006, https://doi.org/10.1016/j.dcn.2017.03.007, https://doi.org/10.1016/j.dcn.2017.04.002,

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ttps://doi.org/10.1016/j.dcn.2020.100843

Available online 28 August 2020

878-9293/© 2020 Published by Elsevier Ltd.