Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Abstract

Children form a strong attachment to their caregiver-even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues-a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.E arly-life trauma is associated with compromised neurobehavioral development and vulnerability to later-life psychiatric disorders like depression (1-5). Long-lasting effects of infant trauma relevant to depression include disruptions in social behavior, alterations in the serotonin (5-HT) system, and amygdala dysfunction (2, 5-8), which have been replicated by animal models (9-15). Paradoxically, trauma-linked cues-even those associated with abusive attachment-can elicit strong attraction and feelings of comfort in humans (16,17). Furthermore, a lifelong attraction to trauma-linked cues has also been demonstrated in rodent models of infant trauma, which suggests that sensory cues learned during infancy alter adult behaviors and amygdala activity (12,18,19).To explore the enduring effects of infant trauma and the mechanisms underlying their modulation by infant trauma-linked cues, we used an odor-learning paradigm during the sensitive period for attachment learning in rat pups, postnatal (PN) days 8-12, which is characterized by rapid and robust odor-preference learning that extends to aversive stimuli (14,(20)(21)(22). Specifically, we used infant olfactory classical conditioning in which a novel peppermint odor is paired with a mild shock (0.5 mA, 1s) to produce a preferred odor that functions behaviorally as a maternal odor and results in neural activation comparable with that induced by natural maternal odor (20,(23)(24)(25). During the sensitive period, low endogenous levels of corticosterone (CORT) and attenuated shock-induced CORT release prevent the infant amygdala from exhibiting the learning-induced plasticity required for avoidance learning (1...

Repetitive neonatal pain and reduced maternal care alter brain neurochemistry

“…Further, male pain‐exposed rats revealed increases in hippocampal GABA and glutamate levels that were not observed in pain‐exposed females. These findings are in line with previous findings demonstrating that pain exposure in the neonatal rat pup is capable of influencing neurochemistry in a sex‐dependent manner (Rincon‐Cortes et al, ; Victoria, et al, ). Further, we produced a translational novel model that reduces maternal contact/comfort following painful procedures, and this approach does not augment maternal care after dams and pups are reunited.…”

The Neurobiology of Attachment: From Infancy to Clinical Outcomes

“…In very young rat pups, it has been shown that the HPA axis is nonfunctional during postnatal days 4-14 (Rincon- Cortes et al, 2015). This lack of cortisol inhibits any fear response, allowing the rat pups to attach to their mothers during this developmental phase.…”

“…Oxytocin and social interaction have been shown to decrease cortisol levels, demonstrating that even at this early stage, physical connection between a mother and her infant has an important effect on brain development and neuroplasticity (Heinrichs, Baumgartner, Kirschbaum, & Ehlert, 2003). Furthermore, adults with insecure attachment show a hyper-reactive HPA axis and cortisol response to acute stress, demonstrating that these effects are long lasting (Quirin, Pruessner, & Kuhl, 2008).In very young rat pups, it has been shown that the HPA axis is nonfunctional during postnatal days 4-14 (Rincon- Cortes et al, 2015). This lack of cortisol inhibits any fear response, allowing the rat pups to attach to their mothers during this developmental phase.…”

Unique neurobiology during the sensitive period for attachment produces distinctive infant trauma processing

“…When rat pups are exposed to the odor-shock model of early-life maltreatment from PN3 to PN8, their social behavior toward their mother is normal in measures of nipple-attachment and choices toward her odor in a Y-maze (Raineki et al, 2012; Rincón-Cortés et al, 2015). However, an injection of CORT (modeling a heightened stress environment) in PN8 pups revealed a hyperactive amygdala and strong deficits in social behavior toward the mother (i.e., fewer choices toward a maternal odor and less time nipple-attached (Raineki et al, 2012)).…”