Faculty Bibliography

Sleep quality varies widely across individuals, especially during normal aging, with impaired sleep contributing to deficits in cognition and emotional regulation. Sleep can also be impacted by a variety of adverse events, including childhood adversity. Here we examined how early life adverse events impacted later life sleep structure and physiology using an animal model to test the relationship between early life adversity and sleep quality across the life span. Rat pups were exposed to an Adversity-Scarcity model from postnatal day 8-12, where insufficient bedding for nest building induces maternal maltreatment of pups. Polysomnography and sleep physiology were assessed in weaning, early adult and older adults. Early life adversity induced age-dependent disruptions in sleep and behavior, including lifelong spindle decreases and later life NREM sleep fragmentation. Given the importance of sleep in cognitive and emotional functions, these results highlight an important factor driving variation in sleep, cognition and emotion throughout the lifespan that suggest age-appropriate and trauma informed treatment of sleep problems.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.

It is well-established that children from low-income, under-resourced families are at increased risk of altered social development. However, the biological mechanisms by which poverty-related adversities can "get under the skin" to influence social behavior are poorly understood and cannot be easily ascertained using human research alone. This study utilized a rodent model of "scarcity-adversity," which encompasses material resource deprivation (scarcity) and reduced caregiving quality (adversity), to explore how early-life scarcity-adversity causally influences social behavior via disruption of developing stress physiology. Results showed that early-life scarcity-adversity exposure increased social avoidance when offspring were tested in a social approach test in peri-adolescence. Furthermore, early-life scarcity-adversity led to blunted hypothalamic-pituitary-adrenal (HPA) axis activity as measured via adrenocorticotropic hormone (ACTH) and corticosterone (CORT) reactivity following the social approach test. Western blot analysis of brain tissue revealed that glucocorticoid receptor levels in the dorsal (but not ventral) hippocampus and medial prefrontal cortex were significantly elevated in scarcity-adversity reared rats following the social approach test. Finally, pharmacological repletion of CORT in scarcity-adversity reared peri-adolescents rescued social behavior. Our findings provide causal support that early-life scarcity-adversity exposure negatively impacts social development via a hypocorticosteronism-dependent mechanism, which can be targeted via CORT administration to rescue social behavior.

Attachment-related learning (that is, forming preferences for cues associated with the parent) defies the traditional rules of learning in that it seems to occur independently of apparent reinforcement¹-young children prefer cues associated with their parent, regardless of valence (rewarding or aversive), despite the diversity of parenting styles². This obligatory attraction for parental cues keeps the child nearby and safe to explore the environment; thus, it is critical for survival and sets the foundation for normal human cognitive-emotional behaviour. Here we examined the learning underlying this attraction in preschool-age children. Young children underwent an aversive conditioning procedure either in the parent's presence or alone. We showed that despite disliking the aversive unconditioned stimulus, children exhibited a behavioural approach for conditioned stimuli that were acquired in the parent's presence and an avoidance for stimuli acquired in the parent's absence, an effect that was strongest among those with the lowest cortisol levels. The results suggest that learning systems during early childhood are constructed to permit modification by parental presence.

Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence-analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.

Children's development is largely dependent on caregiving; when caregiving is disrupted, children are at increased risk for numerous poor outcomes, in particular psychopathology. Therefore, determining how caregivers regulate children's affective neurobiology is essential for understanding psychopathology etiology and prevention. Much of the research on affective functioning uses fear learning to map maturation trajectories, with both rodent and human studies contributing knowledge. Nonetheless, as no standard framework exists through which to interpret developmental effects across species, research often remains siloed, thus contributing to the current therapeutic impasse. Here, we propose a developmental ecology framework that attempts to understand fear in the ecological context of the child: their relationship with their parent. By referring to developmental goals that are shared across species (to attach to, then, ultimately, separate from the parent), this framework provides a common grounding from which fear systems and their dysfunction can be understood, thus advancing research on psychopathologies and their treatment. Expected final online publication date for the Annual Review of Clinical Psychology Volume 15 is May 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Children reared in impoverished environments are at risk for enduring psychological and physical health problems. Mechanisms by which poverty affects development, however, remain unclear. To explore one potential mechanism of poverty's impact on social-emotional and cognitive development, an experimental examination of a rodent model of scarcity-adversity was conducted and compared to results from a longitudinal study of human infants and families followed from birth (N = 1,292) who faced high levels of poverty-related scarcity-adversity. Cross-species results supported the hypothesis that altered caregiving is one pathway by which poverty adversely impacts development. Rodent mothers assigned to the scarcity-adversity condition exhibited decreased sensitive parenting and increased negative parenting relative to mothers assigned to the control condition. Furthermore, scarcity-adversity reared pups exhibited decreased developmental competence as indicated by disrupted nipple attachment, distress vocalization when in physical contact with an anesthetized mother, and reduced preference for maternal odor with corresponding changes in brain activation. Human results indicated that scarcity-adversity was inversely correlated with sensitive parenting and positively correlated with negative parenting, and that parenting fully mediated the association of poverty-related risk with infant indicators of developmental competence. Findings are discussed from the perspective of the usefulness of bidirectional-translational research to inform interventions for at-risk families.

Trauma experienced in early life has unique neurobehavioral outcomes related to later life psychiatric sequelae. Recent evidence has further highlighted the context of infant trauma as critical, with trauma experienced within species-atypical aberrations in caregiving quality as particularly detrimental. Using data from primarily rodent models, we review the literature on the interaction between trauma and attachment in early life, which highlights the role of the caregiver's presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. Together these data suggest that infant trauma processing and its enduring effects are impacted by both the immaturity of brain areas for processing trauma and the unique functioning of the early-life brain, which is biased towards forming robust attachments regardless of the quality of care. Understanding the critical role of the caregiver in further altering early life brain processing of trauma is important for developing age-relevant treatment and interventions.

Learning, memory, and emotional regulation are all modulated by sleep. Sleep influences on neural circuit function and plasticity occur in all mammalian brain regions examined to date, including the noncanonical olfactory system, suggesting sleep disruption could have wide-ranging consequences on behavior and cognition. New evidence suggests that sleep disturbances during early development can have particularly insidious and long-lasting consequences. In particular, work from our lab and others suggests that early-life adverse events can disrupt sleep across the life span, thus contributing to a variety of negative cognitive and behavioral outcomes. These findings raise the possibility that interventions targeting sleep may have therapeutic value for children or adults exposed to early-life adverse events. Here, we describe sleep and sleep ontogeny and then describe the role of sleep in normal and pathological brain function. Finally, we explore how early-life adverse events and sleep disturbances may reciprocally interact to produce a range of psychopathological outcomes.
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Within the infant-caregiver attachment system, the primary caregiver holds potent reward value to the infant, exhibited by infants' strong preference for approach responses and proximity-seeking towards the mother. A less well-understood feature of the attachment figure is the caregiver's ability to reduce fear via social buffering, commonly associated with the notion of a "safe haven" in the developmental literature. Evidence suggests this infant system overlaps with the neural network supporting social buffering (attenuation) of fear in the adults of many species, a network known to involve the prefrontal cortex (PFC). Here, using odor-shock conditioning in young developing rats, we assessed when the infant system transitions to the adult-like PFC-dependent social buffering of threat system. Rat pups were odor-shock conditioned (0.55 mA-0.6 mA) at either postnatal day (PN18; dependent on mother) or 28 (newly independent, weaned at PN23). Within each age group, the mother was present or absent during conditioning, with PFC assessment following acquisition using ¹⁴C 2-DG autoradiography and cue testing the following day. Since the human literature suggests poor attachment attenuates the mother's ability to socially buffer the infants, half of the pups at each age were reared with an abusive mother from PN8-12. The results showed that for typical control rearing, the mother attenuated fear in both PN18 and PN28 pups, although the PFC [infralimbic (IL) and ventral prelimbic (vPL) cortices] was only engaged at PN28. Abuse rearing completely disrupted social buffering of pups by the mother at PN18. The results from PN28 pups showed that while the mother modulated learning in both control and abuse-reared pups, the behavioral and PFC effects were attenuated after maltreatment. Our data suggest that pups transition to the adult-like PFC social support circuit after independence from the mother (PN28), and this circuit remains functional after early-life trauma, although its effectiveness appears reduced. This is in sharp contrast to the effects of early life trauma during infancy, where social buffering of the infant is more robustly impacted. We suggest that the infant social buffering circuit is disengaged by early-life trauma, while the adolescent PFC-dependent social buffering circuit may use a safety signal with unreliable safety value.