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Development of the hypothalamic-pituitary-adrenocortical (HPA) axis was examined using salivary cortisol levels assessed at wake-up, midmorning, midafternoon, and bedtime in 77 children aged 12, 18, 24, 30, and 36 months, in a cross-sectional design. Hierarchical linear modeling (HLM) analyses were used to characterize cortisol production across the day and to examine age-related differences. Using area(s) under the curve (AUC), cortisol levels were higher among the 12-, 18-, and 24-month children than among the 30- and 36-month children. For all five age groups, cortisol levels were highest at wake-up and lowest at bedtime. Significant decreases were noted between wake-up and midmorning, and between midafternoon and bedtime. Unlike adults, midafternoon cortisol levels were not significantly lower than midmorning levels. Over this age period, children napped less and scored increasingly higher on parent reports of effortful control. Among the 30- and 36-month children, shorter naps were associated with more adultlike decreases in cortisol levels from midmorning to midafternoon. Considering all of the age groups together, effortful control correlated negatively with cortisol levels after controlling for age. These results suggest that circadian regulation of the HPA axis continues to mature into the third year in humans, and that its maturation corresponds to aspects of behavioral development.

Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight, and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. Birth weight data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at transcription factor binding sites, was associated with birth weight. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.

Animal studies reveal that early deprivation impairs regulation of the hypothalamic-pituitaryadrenocortical (HPA) axis, potentially increasing vulnerability to stressors throughout life. To examine early deprivation effects on basal HPA axis activity in humans, basal cortisol levels were examined in 164 internationally adopted children who had experienced varying degrees of preadoption deprivation. Duration of institutional care, age at adoption, and parent ratings of preadoption neglect indexed a latent factor of Deprived Care. Adoption measures of height and weight standardized to World Health Organisation norms indexed a latent factor of Growth Delay that was viewed as another reflection of deprivation. Cortisol samples were collected 3.3-11.6 years postadoption (Md = 7.3 years) at home on 3 days approximately 30 min after wakeup and before bedtime. Both early a.m. levels and the decrease in cortisol across the day were examined. A structural equation model revealed that preadoption Deprived Care predicted Growth Delay at adoption and Growth Delay predicted higher morning cortisol levels and a larger diurnal cortisol decrease.Children who are neglected and abused early in life are at heightened risk for physical and mental disorders (Cicchetti & Toth, 1995). There is currently considerable interest in understanding how adverse early care influences brain development and contributes to individual differences in vulnerability (e.g., Cicchetti & Tucker, 1994). Animal studies of the impact of early adverse experiences on the hypothalamic-pituitary-adrenocortical (HPA) system provide a compelling explanatory model (e.g., see Graham, Heim, Goodman, Miller, & Nemeroff, 1999;Heim, Owen, Plotsky, & Nemeroff, 1997). However, their applicability to human development remains uncertain. Glucocorticoids (cortisol in primates, corticosterone in rodents) are hormones produced by the HPA axis that are essential both for maintaining homeostasis and adapting to physical and psychological stressors (de Kloet, Rots, & Cools, 1996;Sapolsky, Romero, & Munck, 2000). Although increases in glucocorticoids above basal levels are typically examined in research on stress, basal levels also contribute importantly to stress vulnerability and resilience (Sapolsky et al., 2000). According to the allostatic load model (McEwen, 1998), the HPA system supports adaptation to stress through increasing or decreasing its basal set points and responsiveness. These changes, although permitting individuals to continue to function, carry a risk or allostatic load that increases vulnerability to physical and mental disorders. Indeed, both Address correspondence and reprint requests to: Megan R. Gunnar, Institute of Child Development, 51 East River Road, University of Minnesota, Minneapolis, MN 55455; gunnar@umn.edu. HHS Public AccessAuthor manuscript Dev Psychopathol. Author manuscript; available in PMC 2018 March 22. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript chronically elevated and chronically suppressed basal gluco...

Preschool-aged children (n = 274) were examined in the laboratory to assess behavioral and cortisol responses to nonsocial and social threat. Parents also responded to scales on the Children’s Behavior Questionnaire reflecting exuberant approach to novel/risky activities (reversed scored) and shyness. Multi-method measures of Nonsocial and Social Inhibition were computed. Parents and children were observed engaging in a series of interactive tasks and the Emotional Availability scales were scored for parental sensitivity, nonintrusiveness, non-hostility, and structuring. These scores were factored to yield one measure of Parenting Quality. Analyses revealed that Nonsocial and Social Inhibition could be distinguished and that associations with cortisol response were stressor specific. Moderation analyses revealed that parenting quality buffered cortisol elevations for extremely socially, but not nonsocially inhibited children. These findings are consistent with evidence that sensitive, supportive parenting is an important buffer of the HPA axis response to threat in infants and toddlers, and extends this finding to the preschool period.