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date: 16 December 2019

Developmental Consequences of Trauma on Brain Circuits

Abstract and Keywords

Traumatic experiences can be challenging at any age, but recent evidence has highlighted the trauma experienced from an attachment figure as particularly detrimental. Fear, or threat, conditioning is a major experimental paradigm that has uncovered the neurobiology of trauma processing. This controlled paradigm has enabled us to understand the changing neurobiology of trauma processing as well as the developmental importance of caregiver presence during trauma. Maternal presence buffers the infant during brief trauma exposure, although repeated trauma in her presence programs the enduring trauma effects on the neurobiology of cognition and emotion. We review the data on innate and learned fear responses across development and describe the interaction between trauma and attachment in early life when threatening cues are processed by the attachment circuitry, rather than fear circuitry, within the brain. This approach can provide insight into age-specific treatments and interventions following infant trauma in the presence of a caregiver.

Keywords: Trauma, threat, fear, attachment, amygdala, development, stress, sensitive period, infant, maternal care

Introduction

Experiencing trauma at any stage of development can have detrimental effects on brain and behavior, although trauma experienced in early life, especially when associated with the caregiver, can have more profound and enduring effects on cognition and emotion (Andersen & Teicher, 2008; De Bellis & Thomas, 2003; Landers & Sullivan, 2012; Levine, 2005; Plotsky et al., 2005; Roth, Zoladz, Sweatt, & Diamond, 2011; Sanchez, Ladd, & Plotsky, 2001). Here we review developmental effects of this socially anchored trauma and consider the unique features of the developing social brain that produce specific deleterious outcomes in infancy that continue across the lifespan.

The developing brain is not simply an underdeveloped version of the adult brain. First, brain development is protracted in altricial species, such as humans and rodents, and it is important to understand whether brain areas involved in the adult’s response to trauma are functional in early life. As will be reviewed herein, the neural network responsive to trauma in adults is immature in early life. Second, while the adult brain is functionally optimized for such tasks as procuring food, finding mates, and self-preservation, the primary function of the altricial infant brain is to form an attachment to the caregiver who can provide these key resources (Salzen, 1970). This is linked to the developmental niche of the infant, who is not sufficiently independent to acquire these resources alone. Thus, the infant’s response to trauma changes over the course of development, with the human infant and infants of other altricial species gradually developing the sensory, motor, and cognitive abilities necessary for self-preservation.

The young altricial brain is also undergoing programming: early life is a highly plastic time when experience can profoundly influence cognitive and emotional development. This plasticity is optimal for adapting the brain to fit diverse environments to enhance survival. However, this flexibility can also be deleterious; repeatedly experiencing trauma in early life, especially when associated with the attachment figure, can disrupt development and potentially initiate a developmental pathway that will result in maladaptive cognitive or emotional outcomes. Finally, many of the effects of early life trauma are not expressed until a later stage of development or are revealed only in certain circumstances, such as during periods of high stress (Ainsworth, 1969; Gunnar, Quevedo, & De Kloet, 2007; Landers & Sullivan, 2012; Raineki, Cortés, Belnoue, & Sullivan, 2012). Thus, understanding how the uniquely functioning infant brain responds to trauma and how trauma influences immediate and later-life functioning is a complex task. However, this developmental approach can provide insight into age-specific treatments and interventions for early-life trauma.

Adult Trauma Neurobiology and Fear (Threat) Conditioning

We briefly introduce adult trauma neurobiology literature to provide a template for understanding how the trauma neural network changes over development. The trauma literature indicates that trauma processing is ubiquitous in the brain, although the amygdala, hippocampus, and prefrontal cortex (PFC) have been highlighted (Fragkaki, Thomaes, & Sijbrandij, 2016; O’Doherty, Chitty, Saddiqui, Bennett, & Lagopoulos, 2015). Importantly, most trauma victims recover from their trauma experience, with approximately only 3% failing to recover to develop debilitating anxiety disorders and/or post-traumatic stress disorder (PTSD; American Psychiatric Association, 2013; Breslau & Kessler, 2001). Thus, resilience is the typical response to trauma. Becoming one of the small percentage of individuals who fail to show resilience to trauma exposure is associated with experiencing more severe and/or repeated traumatic events, such as terrorism or combat. Failing to show resilience to trauma is also linked to alterations in the brain’s trauma processing network, including impaired function of the ventromedial PFC (vmPFC), amygdala, and hippocampus (Bremner, 2002; Bryant et al., 2008; Etkin & Wager, 2007; Felmingham et al., 2006; Jorge, 2015; Kemp et al., 2007). Many paradigms have been used to explore the neurobiology of anxiety and trauma, and, as expected, both increases and decreases in brain functioning of these brain areas have been documented (Bauer, Wieck, Lopes, Teixeira, & Grassi-Oliveira, 2010; Bryant et al., 2008; De Bellis & Thomas, 2003; Etkin & Wager, 2007; Fonzo, Huemer, & Etkin, 2016; Fragkaki et al., 2016). Additional research suggests that the victims’ experiences with trauma, especially if that experience is associated with the caregiver (i.e., child maltreatment), is a critical factor in producing diverse individual responses to trauma.

The response to trauma engages much of the same neural circuitry used to learn about threatening or fearsome cues. For this reason, we focus here on fear (threat) conditioning as the primary experimental paradigm to explore the neural substrate of trauma processing (Dunsmoor, Kroes, Braren, & Phelps, 2017; Garfinkel et al., 2014; Jovanovic et al., 2014; Kessler et al., 2012; LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998; Pattwell et al., 2012; Rabinak, Mori, Lyons, Milad, & Phan, 2017; Tallot, Doyere, & Sullivan, 2016; Thomas et al., 2001). The fear (threat) conditioning procedure involves the pairing of an initially neutral stimulus (conditioned stimulus, CS) with a stimulus that has an inherent biological threat (unconditioned stimulus, US) such as a painful shock or an intense, harsh sound. After one or several CS–US pairings, the CS comes to evoke conditioned responses (CR) related to defense against the threat, which were once only evoked by the threatening US (Lonsdorf et al., 2017). This paradigm has contributed to a better understanding of the basic network used to process threat and trauma because it produces rapid, robust learning, provides control over the experience, and can be used across development and across species.

The neurobiology of this learning is well documented from animal models and overlaps with brain areas critical in trauma processing, including the amygdala, hippocampus, and PFC. In the typical response of the brain during fear/threat conditioning, information about the auditory or olfactory CS and the painful somatosensory US converge on the basolateral nucleus of the amygdala (BLA) to produce neural activity, but after repeated pairings, the CS presentations alone are capable of eliciting BLA activity (Fanselow, 1994; Fanselow & LeDoux, 1999). The BLA sends information to the central nucleus of the amygdala, which then relays this information to hypothalamic, brainstem nuclei and other sites for engaging autonomic responses such as increased heart rate, blood pressure, and respiration; “freezing” behavior; acoustic startle; and stress hormone release. These, in turn, coordinate an adaptive behavioral response in response to the CS (Galatzer-Levy et al., 2014). Surrounding contextual and environmental information is also processed during fear learning by the hippocampus, a brain region with a major influence on fear learning and expression. Projections from the cornu ammons region 1 (CA1) of the hippocampal formation to the amygdala BLA are implicated in processing contextual information about threatening stimuli (Rosas, Todd, & Bouton, 2013). The vmPFC (prelimbic/infralimbic cortex in rodents) is involved in decision-making and is thought to provide top-down inhibition of amygdala function to modulate fear learning (Bechara, Damasio, Damasio, & Lee, 1999; Bechara, Tranel, & Damasio, 2000). This occurs, for example, when additional presentations of a cue trained as a CS are no longer paired with an aversive US in a training paradigm designed to extinguish learned associations—the basis for exposure therapy in clinical settings. This extinction process is thought to require inhibition from the hippocampus and vmPFC to prevent the amygdala from persistently responding to a neutral cue to produce a fear response (Milad, Orr, Pitman, & Rauch, 2005; Milad & Quirk, 2002). Indeed, failure to update learned associations is thought to underlie the persistent fearful responses to neutral cues observed in individuals with PTSD (Etkin & Wager, 2007; Koenigs & Grafman, 2009).

Individuals with a history of trauma who failed to show resilience and have developed anxiety disorders show deficits in fear conditioning (Duits et al., 2015; Holmes & Singewald, 2013; Kroes, Schiller, LeDoux, & Phelps, 2016; Lissek et al., 2005; Novak et al., 2016). Specifically, these patients show structural and functional changes in a wide variety of brain areas, including the amygdala, PFC, and hippocampus. Volumetric analyses in adults with PTSD indicate decreases in the size of the amygdala and hippocampal formation, as well as changes in cortical thickness (Jelicic & Merckelbach, 2004; Sussman, Pang, Jetly, Dunkley, & Taylor, 2016). In addition, functional magnetic resonance imaging (fMRI) data show that adults exposed to trauma exhibited heightened amygdala reactivity to both fearful and neutral cues, which has been attributed to decreased inhibitory input from the vmPFC (Etkin & Wager, 2007; Garfinkel et al., 2014; Jorge, 2015; Nakagawa et al., 2016; Woon, Sood, & Hedges, 2010). Other brain areas associated with the processing of emotional stimuli, including the insula and anterior cingulate cortex, also demonstrate changes in activation to emotional stimuli in adults with PTSD (Etkin & Wager, 2007). There is also some indication that anxiety patients exhibit aberrant responses to signals that predict safety cues (a CS that predicts the shock will not be delivered) (Duits et al., 2015). Finally, stimuli previously paired with unconditioned aversive cues continued to produce behavioral and amygdala responses when these associations were experimentally dissociated through extinction. In other words, these adults showed impaired ability to extinguish learned fear associations (Davis & Whalen, 2001; Garfinkel et al., 2014; Kim et al., 2011; Marin et al., 2016; Milad et al., 2007; Phelps & LeDoux, 2005; Rauch et al., 2000; Schiller, Levy, Niv, LeDoux, & Phelps, 2008; Thomas et al., 2001; for a summary of these network changes, see Figure 1).

Developmental Consequences of Trauma on Brain Circuits

Figure 1Effects of PTSD on functional circuitry involved in fear learning. Research in clinical populations has shown that individuals with PTSD following trauma show functional and volumetric changes in brain areas involved in processing fear, including the amygdala, PFC, and hippocampus. These changes are shown here in parallel with baseline roles of the amygdala, PFC, and hippocampus during fear learning. This summary reflects data collected from behavioral and fMRI assays in humans.

It is clear that the pathological response to trauma seen in patients is associated with considerable individual differences, including both increased and decreased neural activity and volume in myriad brain areas. One promising approach to understanding this diverse literature is the consideration of a patient’s past history of trauma, as well as the testing demands (Duits et al., 2015; Fonzo et al., 2016; Lissek et al., 2005). Considerable literature highlights a clear association between childhood maltreatment and later-life anxiety disorders and PTSD, and suggests these infant experiences alter the developmental programming of brain areas used to process trauma (Bremner, 2002; Fonzo et al., 2016; Milani, Hoffmann, Fossaluza, Jackowski, & Mello, 2017). The purpose of this review is to go beyond infant programming to ask, “Why does child abuse have particular influence over later-life response to trauma?”

The Developmental Neurobiology of Trauma

Traumatic experiences in infants and young children can include maltreatment from the caregiver, sexual abuse, and witnessing family violence, among many others. A child’s response to trauma is variable; while some children exhibit acute anxiety and PTSD, others’ responses lie dormant until later life. The sources of this variability are not fully understood, but it is clear that trauma’s effects are dependent upon the child’s age during the trauma experience, the type of trauma, and the support system available to the child (Eth, Silverstein, & Pynoos, 1985). The clinical picture is further complicated by the difficulty of diagnosing clinically relevant responses to traumas. For example, anxiety is well documented to be present in early life; however, an early form may be expressed through separation anxiety (separation from the caregiver) or fear of strangers, and then developmentally transition into generalized anxiety disorder with maturation. Documenting the presence of PTSD in children remains more challenging, although it is now included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5): as a subtype of PTSD specific to preschool children, based on research involving children as young as one year old through six years old (American Psychiatric Association, 2013; Scheeringa, 2016).

We understand little about the neurobiology of early life trauma, partly due to its complex clinical expression, but also because of ethical and technical difficulties with imaging the human brain. The issue is further complicated by the changing behavioral expression to both innate threats and learned threats supported by the protracted development of brain areas supporting the detection of threats, neural processing of threats, and the behavior responses to threats, all of which are reviewed later. A basic understanding of the ontogeny of threat processing in early life will provide insight into developing age-specific insights and treatments for trauma.

Developmental Neurobiology of Innate Threat

In children, the fear response emerges around eight months of age, specifically expressed with fear of heights and fear of strangers. This closely coincides with the emergence of crawling, when dangerous situations might be encountered (Freedman, 1961; Schaffer & Emerson, 1964), although the infant’s previous locomotor experience may play a role (Adolph, Kretch, & LoBue, 2014; Dahl et al., 2013). Questioning when the adult-like neural circuit for threat processing becomes involved in these early-life expressions of fear remains challenging, but some progress has been made. For example, we know that the amygdala is critical for emotional responses to the widened eye (prominent white sclera) generated during fear (Whalen et al., 2004); this response is present in seven-month-old infants (Jessen & Grossmann, 2015; Jones, Laurens, Herba, Barker, & Viding, 2009). This is consistent with more recent fMRI research suggesting that stronger amygdala-vmPFC connectivity at birth is associated with heightened fear at six months of age (Graham et al., 2016). It appears unlikely that the hippocampus is involved: behavioral studies suggests hippocampal function emerges around two years of age, although there is great functional improvement over the next four years (Chareyron, Lavenex, Amaral, & Lavenex, 2012; Gomez & Edgin, 2015; Lavenex & Banta Lavenex, 2013). This parallels the morphological development of the hippocampus, which grows rapidly up to two years of age, but continues to develop throughout adolescence (Qin et al., 2014; Uematsu et al., 2012). Finally, the developmental trajectory of the PFC subareas, brain areas critical for higher order functioning, is protracted: functional emergence of the anterior cingulate cortex (ACC) is thought to occur at around four months, the orbitofrontal cortex (OFC) at approximately two or three years old, and medial PFC (mPFC) at around four years (Allman, Hakeem, Erwin, Nimchinsky, & Hof, 2001; Anderson et al., 2003; Gee et al., 2013; Gottfried, Deichmann, Winston, & Dolan, 2002; Graham et al., 2015; Rolls, 2015; Zald & Pardo, 1997). The child’s brain continues to develop well into adolescence, with different brain areas each having their own developmental trajectory (for review, see Casey, Tottenham, Liston, & Durston, 2005). This suggests that the neural response to threatening cues and trauma continues to undergo changes throughout early life (Berdel, Morys, & Maciejewska, 1997; Brummelte & Teuchert-Noodt, 2006; Chareyron, Lavenex, Amaral, et al., 2012; Chareyron, Lavenex, & Lavenex, 2012; Cunningham, Bhattacharyya, & Benes, 2002; Ehrlich, Ryan, & Rainnie, 2012; Jagalska-Majewska et al., 2003; Knudsen, 2004; Van Eden & Uylings, 2004; Wakefield & Levine, 1985).

Other mammals similarly fail to show the species-specific threat response of fleeing/freezing to innately threatening stimuli in very early life. Research using these animal models has helped further identify the neurobiological substrate of the ontogeny of fear learning. Indeed, environmental or age-specific defense behaviors are present at different stages in development for many altricial species. For example, in rabbits, freezing/fleeing in response to a hawk’s flying overhead emerges at independence from the mother (Pongrácz & Altbäcker, 2000). In addition, infant birds respond to a shaking nest (associated with a predator landing on the nest) by freezing; this behavioral response transitions to escaping as the ability to fly emerges (Kuhlmann, 1909). Finally, rat pups do not show the classic response of freezing to threat seen in adult humans and rodents: fearful responses emerge at post-natal day 10 (PN10), when walking develops and they begin to take brief excursions outside the nest (Takahashi, 1994)Woods & Bolles, 1965). The functional emergence of the amygdala occurs at the same age and has been shown to be causally responsible for the emergence of this behavior, although threat behavior continues to develop as the amygdala continues to mature (Barnet & Hunt, 2006; Hunt, Richardson, & Campbell, 1994; Moriceau, Roth, Okotoghaide, & Sullivan, 2004; Perry, Al Ain, Raineki, Sullivan, & Wilson, 2016; Sullivan et al., 2000).

In rodents, emerging evidence also suggests that brain areas can have unique functions in infancy, such as the important role of locus coeruleus (LC) in attachment that is described later (Landers & Sullivan, 2012). Neurochemicals have also been shown to have age-specific effects, such as gamma amino-butyric acid (GABA)-ergic neurons switching between excitation and inhibition at birth in humans and other species (Ben-Ari, 2014). Other neurotransmitters also show a developmental switch in function. For example, oxytocin plays a demonstrable role in prosocial behavior and maternal care in adults (Calcagnoli et al., 2015; Frijling et al., 2016; Johnson & Young, 2015; Lee, Brady, Shapiro, Dorsa, & Koenig, 2007; Marlin & Froemke, 2016; Nelson & Panksepp, 1998; Shamay-Tsoory & Abu-Akel, 2016), yet its role in very early life remains unclear, and increased oxytocin may have adverse effects on the infant (Nelson & Panksepp, 1998; Parr et al., 2016; Sannino, Chini, & Grinevich, 2016). Additionally, high levels of serotonin in early life are associated with the programing of anxiety and depression, while its adult role is alleviation of these same behaviors (Suri, Teixeira, Cagliostro, Mahadevia, & Ansorge, 2015). Developmentally regulated neurotrophins, such as brain-derived neurotrophic factor (BDNF), have also been shown to differentially modulate fear expression across the lifespan (Dincheva, Lynch, & Lee, 2016). Finally, the functional connectivity between brain areas is often delayed during maturation. Thus, as we consider the impact of early life trauma on the child or brain programming, it is important to consider the structural and functional maturity of brain areas involved in processing fear. As we will show, trauma processing by the brain changes during development (Gunnar et al., 2007; Opendak & Sullivan, 2016; Teicher et al., 2003).

The Sensitive Period for Attachment: Threat Learning Paradigm Engages Attachment Learning in Infancy

A critical aspect of understanding the neurobiology of trauma processing across development is understanding what is learned from the threat experience. From a developmental perspective, key areas used in fear (threat) learning show protracted development and, as we will review, compromise early life learning about threat. In rodents, amygdala-dependent learning does not occur in infant rats younger than 10 days of age (Rudy & Cheatle, 1977) because the amygdala is not engaged (Sullivan et al., 2000). This has been demonstrated using the fear conditioning paradigm described before, in which an odor cue (CS) is paired with a mild foot-shock (US). The inability of a paired cue–pain procedure to produce fear learning is not due to pups’ inability to detect the aversive stimulus or feel pain, as noxious stimuli readily elicit pup escape responses (Barr, 1995; Collier & Bolles, 1980; Emerich, Scalzo, Enters, Spear, & Spear, 1985; Stehouwer & Campbell, 1978). When eight-day-old rat pups received odor–shock pairings, they learned to approach the odor predicting the shock rather than show the typical adult behavior of freezing to the odor CS. Moreover, learning the odor association engaged the same neural circuitry used for learning their mother’s odor (Perry et al., 2016). In fact, the odor predicting the shock was shown to support nipple attachment and social interactions with the mother, effectively replacing her learned odor. These data showed that, remarkably, threat conditioning fails to engage the threat system—instead, it had engaged the neural circuitry supporting attachment.

Understanding that the threat conditioning paradigm of odor–pain pairings produced a new maternal odor that appeared indistinguishable for the natural maternal odor prompted us to question if this same learning would occur in the nest with a mother rat hurting the pups. Rough maternal care can be induced experimentally by giving the mother rat insufficient nest-building materials (Roth & Sullivan, 2005). When this rough handling occurs for 30 minutes while a novel odor is placed in the cage, pups showed approach behaviors toward the odor outside the nest. This same effect was observed when pups received odor–shock (CS–US) conditioning outside the nest: pups approached this pain-associated odor as though it were a new maternal odor, rather than learning the odor as a threatening cue. Through these types of controlled learning experiments outside the nest using paired odor–shock conditioning, the mechanisms of attachment formation can be assessed (Johnson, Woo, Duong, Nguyen, & Leon, 1995; Moriceau & Sullivan, 2004a; Raineki, Pickenhagen et al., 2010; Roth & Sullivan, 2005; Sullivan & Leon, 1986; Sullivan & Wilson, 1991; Wilson, Sullivan, & Leon, 1987; Yuan, Harley, McLean, & Knopfel, 2002). These studies have shown that the olfactory bulb, which is the first relay station for odors entering the brain, is flooded by norepinephrine (NE) released from the LC when the mother stimulates pups through maternal behavior: a milk ejection, stepping on pups, grooming or transporting pups all produce a copious amount of NE release into the olfactory bulb (McLean & Shipley, 1991). The NE prevents the mitral cells of the olfactory bulb from habituating to continual olfactory stimulation, but also induces CREB (cyclic adenosine monophosphate [cAMP] response element-binding protein) phosphorylation (pCREB) via cAMP stimulation and ultimately supports synapse formation (Bekinschtein, Cammarota, Izquierdo, & Medina, 2008; McLean, Harley, Darby-King, & Yuan, 1999; Okutani, Kaba, Takahashi, & Seto, 1998; Sullivan, Stackenwalt, Nasr, Lemon, & Wilson, 2000; Sullivan, Wilson, & Leon, 1989; Sullivan, Zyzak, Skierkowski, & Wilson, 1992; Tao, Finkbeiner, Arnold, Shaywitz, & Greenberg, 1998; Wilson et al., 1987; Yuan, Harley, Darby-King, Neve, & McLean, 2003; Zhang, Okutani, Inoue, & Kaba, 2003). This is a common cellular cascade that supports attachment learning in many species throughout development (Carew, 1996; Carew & Sutton, 2001; Rankin, 2002).

Research on avian imprinting has provided insight into the functional implications of pups’ learning attachment instead of fear in early life odor–pain experiments (Bowlby, 1977; Salzen, 1970). Indeed, when newly hatched chicks received shocks as they were exposed to their first moving object, these chicks exhibited robust proximity-seeking behaviors (Hess, 1962; Rajecki, Lamb, & Obmascher, 1978; Salzen, 1970). A similar phenomenon of attachment despite abuse was also documented in infant dogs that were shocked while interacting with a human caregiver (Stanley, 1962) and infant monkeys that were raised with a wire surrogate that inflicted pain (Harlow & Harlow, 1965); both species demonstrated attachment behaviors toward the figure associated with pain. Attachments to abusive caregivers are observed robustly in the young of many species, including human children (Rajecki et al., 1978; Bowlby, 1977, 1984; Harmon, Morgan, & Glicken, 1984) and non-human primate infants that develop and retain a strong preference for the abusive caregiver (Harlow & Harlow, 1965; Maestripieri, Tomaszycki, & Carroll, 1999; O’Connor & Cameron, 2006; Sanchez et al., 2001; Suomi, 2003).

Bowlby noted this broad species representation of abuse-related attachment (Bowlby, 1984), suggesting that perhaps evolution has permitted an attachment neural network, which is phylogenetically conserved, that ensures that the infant brain of altricial species supports attachment to the caregiver, even when care is compromised or even abusive. In this way, cues associated with aversive experience (such as maternal odor paired with pain) fail to be conditioned as fearful or threatening; instead, they are learned as stimuli to approach. Together, these data suggest a unique neurobiology of the infant brain that processes trauma within the attachment circuitry, rather than the regions used to process trauma in adulthood.

By postnatal day 10 (PN10), the amygdala is engaged in odor–shock learning, enabling rat pups to learn to avoid an odor that is paired with shock, rather than the approach response learned by young pups (Sullivan et al., 2000). After PN10, learning about threatening cues appears to occur through the PFC-amygdala-hippocampus network observed in adults (Blair, Schafe, Bauer, Rodrigues, & LeDoux, 2001; Davis, 1997; Fanselow & Gale, 2003; Fanselow & LeDoux, 1999; Herzog & Otto, 1997; Maren, 2003; McGaugh, Roozendaal, & Cahill, 1999; Pape & Stork, 2003; Pare, Quirk, & Ledoux, 2004; Rosenkranz & Grace, 2002; Sananes & Campbell, 1989; Schettino & Otto, 2001; Sevelinges, Gervais, Messaoudi, Granjon, & Mouly, 2004; Sigurdsson, Doyere, Cain, & LeDoux, 2007), although the hippocampus does not play a role in learning about contextual cues related to threat until PN23 (Raineki, Holman, et al., 2010)

While we initially attributed the delayed functional emergence of amygdala-dependent fear learning to amygdala immaturity, pharmacological manipulations of the stress hormone corticosterone (CORT) have identified this glucocorticoid as causal in turning amygdala plasticity on and off to support fear learning. These studies have identified a Stress Hyporesponsive Period (SHRP) in infant rats, when basal CORT levels are very low and fail to increase in response to most stressors, including shock; this period maps onto the first 10 days of life in rats (Butte, Kakihana, Farnham, & Noble, 1973; Cate & Yasumura, 1975; Grino, Paulmyer-Lacroix, Faudon, Renard, & Anglade, 1994; Guillet & Michaelson, 1978; Guillet, Saffran, & Michaelson, 1980; Henning, 1978; Levine, 1962; Levine, 1967; Levine, 2001; Rosenfeld, Suchecki, & Levine, 1992; Walker, Sapolsky, Meaney, Vale, & Rivier, 1986).

At PN10, rats exhibit decreasing levels of NE and rising endogenous levels of CORT, resulting in functional emergence of the amygdala (Moriceau & Sullivan, 2006; Sullivan et al., 2000). Pups’ increase in stress hormone at this age permits the infant amygdala to show learning-induced plasticity, permitting odor–pain pairings to now activate the fear learning circuit and avoid stimuli that signal threat and danger. When the SHRP is ended prematurely through experimental increases in CORT levels, pups younger than PN10 can learn an aversion to an odor paired with shock. Specifically, systemic or intra-amygdala increase of CORT during 0.5mA odor–shock learning is sufficient to permit fear learning in pups as young as PN6, which was similar to CORT’s ability to permit threat responses to predator odor (Moriceau & Sullivan, 2004b, 2006; Takahashi, 1994). In this way, CORT acts as a switch that can engage functional plasticity in the amygdala to support acquisition of cues associated with threat.

Understanding the role of CORT in permitting threat learning enables us to consider how manipulating CORT naturally within the nest might have ecological significance. As pups begin to respond to threat with an increase in stress hormone at PN10, maternal presence can block CORT increases in response to shock, a phenomenon now termed social buffering (Hostinar, Sullivan, & Gunnar, 2014; Stanton, Wallstrom, & Levine, 1987; Suchecki, Rosenfeld, & Levine, 1993). We questioned whether a naturalistic manipulation of CORT via the mother’s presence would be as effective as our direct pharmacological manipulations of CORT during odor shock threat conditioning. Indeed, maternal presence was able to block fear learning and prevent the participation of the amygdala in learning, while reinstating the attachment learning observed before PN10 (Moriceau & Sullivan, 2006). Conversely, exposing pups as young as PN6 to the alarm odor of a fearful mother was able to increase CORT levels and support threat learning (Debiec & Sullivan, 2014). By PN15, the ability of maternal presence to block amygdala threat learning wanes, and pups learn to avoid an odor paired with shock, even if the mother is present; at this age, CORT begins to plays a more modulatory role in threat learning (Figure 2; Corodimas, LeDoux, Gold, & Schulkin, 1994; Hui et al., 2004; Pugh, Tremblay, Fleshner, & Rudy, 1997; Roozendaal, Carmi, & McGaugh, 1996; Roozendaal, Quirarte, & McGaugh, 2002; Thompson, Erickson, Schulkin, & Rosen, 2004; Upton & Sullivan, 2010).

Developmental Consequences of Trauma on Brain Circuits

Figure 2Ontogeny of fear learning in infant rodents. 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 NE 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, while attachment learning is engaged in the mother’s presence. This mother-controlled switch between fear and attachment learning is mediated through the mother’s ability to control pups’ CORT (Sullivan & Opendak, in press). A more adult-like fear learning system 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 (exogenous CORT administration and 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 & Sullivan, 2006; Perry & Sullivan, 2014; Raineki et al., 2012; Shionoya et al., 2007; Sullivan & Holman, 2010).

Children also appear to experience a period of stress hypo-responsiveness that may modulate learning about threat. For instance, infants exhibit a period of dampened stress reactivity that develops over the first year of life (6–12 months)(Gunnar & Donzella, 2002; Gunnar, Hostinar, Sanchez, Tottenham, & Sullivan, 2015), and levels of cortisol (the human analog of corticosterone) remain low through the preschool period (Grunau, Weinberg, & Whitfield, 2004; Watamura, Donzella, Kertes, & Gunnar, 2004). Fear learning is developmentally specific, as the need to be rescued while swimming prior to age seven years old was not associated with fear of swimming when measured at age 18 (Poulton, Menzies, Craske, Langley, & Silva, 1999). Moreover, aversive experiences at the dentist’s office were associated with dental fear in adults, but not in individuals younger than 18 years of age (Poulton, Waldie, Thomson, & Locker, 2001). Laboratory-based fear conditioning studies in young children show that fear conditioning increases from the preschool period to middle childhood (Gao, Raine, Venables, Dawson, & Mednick, 2010). These studies are consistent with the hypothesis that the amygdala-dependent fear system is less engaged during learning in early life than during adulthood.

Although no consensus has been reached on the mapping of rodent age onto human age, data on the ontogeny of fear learning in children suggests a parallel between weaning at PN20–23, the age at which rats prepare for independence outside the nest, and various developmental milestones in children. These markers of independence include leaving home to begin school and leaving home as young adults (Callaghan & Tottenham, 2016; Gee et al., 2013; Gunnar & Donzella, 2002; Poulton et al., 1999; Tottenham, 2012; Tottenham & Sheridan, 2009). Further study will be required to determine whether the early hypo-responsivity of the stress system results in preference learning, rather than fear learning, in humans as it does in the rodent (Moriceau et al., 2006).

Processing Trauma Within the Attachment Circuit: Prolonged Exposure

As we have noted, children are fairly resilient to limited trauma exposure, and the caregiver’s presence attenuates the child’s response to trauma. However, prolonged or repeated trauma experienced with the caregiver, while maintaining attachment to the caregiver, is associated with mental health issues and compromised development (Ainsworth, 1969; Bowlby, 1984; Bremner, 2003; Callaghan, Sullivan, Howell, & Tottenham, 2014; Crittenden, 1992; Davis et al., 2014; Drury, Sanchez, & Gonzalez, 2015; Perry & Sullivan, 2014; Raineki, Moriceau, & Sullivan, 2010). From an evolutionary perspective, this suggests that an attachment system has been sculpted by evolution to ensure that attachment occurs regardless of the quality of caregiving. Understanding this paradox of prolonged trauma co-occurring with attachment has been a challenge to developmental neurobiologists for decades.

As we mentioned, pups will form an attachment to a mother that handles them roughly after she is given insufficient bedding materials to build a nest. Through controlled odor–shock pairings, we have identified that this occurs because the amygdala fails to undergo functional plasticity during brief exposures at this age (Sullivan, et al. 2000). In order to explore the long-term effects of caregiver abuse, the low bedding and odor-shock paradigms can be extended to five days (Raineki, Moriceau, & Sullivan, 2010; Roth & Sullivan, 2005). Although pups will still form an attachment to the mother, pups reared with an abusive mother in the low-shavings paradigm from PN3–8 exhibited increased CORT, heightened amygdala reactivity, and impaired attachment behaviors with the mother, suggesting that chronic stress induced premature amygdala engagement and terminated the SHRP (Raineki, Moriceau, & Sullivan, 2010).

Similarly, when pups were trained on the odor-shock paradigm outside the nest for five days, an injection of CORT (modeling a heightened stress environment) in PN8 pups revealed a hyperactive amygdala and strong deficits in social behavior towards the mother (i.e., fewer choices towards a maternal odor and less time nipple-attached (Raineki et al., 2012). These results mirror clinical data wherein stress uncovered latent neurobehavioral deficits in children with disordered attachment resulting from abuse or neglect (Ainsworth, 1969; Gunnar, Brodersen, Nachmias, Buss, & Rigatuso, 1996). Taken together, these data suggest that chronic maltreatment by an abusive caregiver or experience with repeated pairing of traumatic shock with attachment circuitry changes amygdala development so that stress produces a hyperactive amygdala that halts normal social behavior (Raineki et al., 2012; Raineki et al., 2015; Sevelinges et al., 2011).

Enduring Effects of Infant Trauma with the Caregiver

Early life trauma, especially when experienced with the caregiver, compromises emotional and cognitive development, leading to maladaptive behavioral responses such as those seen in psychiatric illness. Our understanding of mechanisms that initiate the pathway to pathology during these early life abusive experiences have been explored using animal models since the 1950s (Denenberg, 1963; Famularo, Kinscherff, & Fenton, 1992; Harlow & Harlow, 1965; Hofer, 1994; Levine, 1957; Levine, Johnson, & Gonzalez, 1985; Teicher et al., 2003). Our model of abusive caregiving in rodents shows that repeatedly experiencing pain, either from an abusive mother or through experimentally controlled shocks that engage the attachment circuit (i.e., with mother present or during attachment learning), produces neurobehavioral changes that begin in infancy and persist into adulthood (Ivy, Brunson, Sandman, & Baram, 2008; Raineki, Moriceau, & Sullivan, 2010; Raineki et al., 2012; Raineki et al., 2015; Roth, Matt, Chen, & Blaze, 2014; Sevelinges et al., 2007; Sevelinges et al., 2011; Sevelinges, Sullivan, Messaoudi, & Mouly, 2008).

As we mentioned, pups that experience prolonged caregiver abuse exhibit changes in attachment behaviors and show premature amygdala engagement. These acute changes predicted later-life behavioral deficits and amygdala dysfunction. Specifically, rats with a history of maltreatment associated with the caregiver exhibited decreased sociability with peers at PN23 (Rincon-Cortes et al., 2015). This was followed by the emergence of depressive-like symptoms accompanied by a hyper-functioning amygdala in adolescence (PN45), persisting through adulthood (Figure 3; Raineki et al., 2012; Sevelinges et al., 2007; Sevelinges et al., 2011; Sevelinges et al., 2008). These results parallel clinical data suggesting that childhood dysfunctional social behavior precedes depression (Letcher, Smart, Sanson, & Toumbourou, 2009; Mason et al., 2004; Mazza, Fleming, Abbott, Haggerty, & Catalano, 2010).

Developmental Consequences of Trauma on Brain Circuits

Figure 3Effects of brief and prolonged exposure to trauma associated with a caregiver in infancy in the rat. Abusive care can be induced in a rat mother by giving her insufficient nest-building materials; pups will nevertheless form an attachment to her odor (Roth & Sullivan, 2005). The same effect is observed when pups receive pairings of a neutral odor with mild tail-shock; pups younger than PN10 form a preference for the odor as though it were a maternal odor. In these young pups, the amygdala fails to exhibit plasticity in response to threatening cues—perhaps to ensure attachment to a caregiver that can provide crucial resources. When trauma exposure with a caregiver, or caregiver odor, is prolonged, the amygdala shows premature plasticity, and stress reveals amygdala hyperactivity. Testing later in life shows lifelong amygdala-dependent behavioral deficits, such as poor social behavior (onset prior to weaning) and depressive-like behaviors (onset post-weaning) (Sullivan et al., 2000; Raineki, Moriceau, & Sullivan, 2010; Sevelinges et al., 2011; Raineki et al., 2012). In contrast, prolonged trauma without attachment results in later-life anxiety (Rincón-Cortés & Sullivan, 2014; Sarro, Sullivan, & Barr, 2014).

These behavioral impairments appear to be due to amygdala activation deficits and changes in DNA methylation in the adult amygdala (Roth et al., 2014), as well as aberrant amygdala–PFC connectivity (Yan et al., 2017). Notably, trauma, such as painful shock or tail-pinch, experienced without the engagement of the attachment circuit does not produce depression-like and social behavior deficits. Rather, pups that received mild shocks in the absence of the caregiver odor later exhibited anxiety-like behavioral deficits associated with dysfunctional amygdala GABA, but not a hyperactive amygdala (Sarro, Sullivan, & Barr, 2014; Tyler, Moriceau, Sullivan, & Greenwood-van Meerveld, 2007). Together, the divergent and specific outcomes from infant experiences of pain with and without the caregiver highlight the critical role of the caregiver in producing profound, unique neural responses to pain that initiate a specific neurobehavioral developmental trajectory.

Concluding Remarks

The role of attachment in processing trauma in young rat pups suggests that brief experiences with trauma engage social buffering by the mother, which protects pups from increasing stress hormone levels that are known to alter brain development. This system prevents young pups from learning to fear sensory cues associated with pain. Indeed, it may be adaptive: pups typically live exclusively within the nest during the first couple of weeks of life, where pain is most likely from the mother as she steps on pups entering and leaving the nest to take care of herself (e.g., eat). However, repeated experiences with trauma appear to break down this protective system and engage a developmental pathway to pathology. Indeed, caregiver-related trauma produces a more profound impact than trauma alone on cognitive and emotional processing of threat and social signals.

Our review highlights trauma with the caregiver in a rodent model, which complements the myriad other infant experience and stress models used today. These models including the maternal separation/deprivation model (prolonged removal of maternal sensory stimulation of pups), exposure to trauma (shock or CORT), brief novelty exposure outside the nest, and handling (Bagot et al., 2009; Callaghan & Richardson, 2014; Claessens et al., 2011; Daskalakis et al., 2014; Meaney, 2001; Plotsky et al., 2005; Weaver et al., 2004). These models converge in identifying the stress system as a mechanism mediating enduring adult outcomes from these models. Here, we have attempted to identify a selective infant experience: the association of trauma with or without attachment that focused on the amygdala as one causal mechanism initiating the pathway to pathology involving stress hormone levels. This developmental approach using animal models of trauma is likely to provide insight into the diverse outcomes in children following early life adversity.

Future Directions

  1. 1. Distinguish the effects of abuse from those of neglect in the pathogenesis of caregiver-associated trauma.

  2. 2. Characterize changes in threat-processing circuitry following trauma in the clinical population.

  3. 3. Determine whether children form preferences toward abusive caregivers.

  4. 4. Identify age-specific treatments and interventions for individuals experiencing trauma from a caregiver.

Acknowledgements

This work was supported by training grants T32MH019524 (supported MO), F32MH11223201 (MO), and NIH MH091451, HD083217 (RMS).

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