Developmental and Enduring Metabolic Adaptations to Early Life Stress

• In Event: 2-068 - Social Origins of Developmental Risk for Mental and Physical Illnesses

Integrative Statement

Early life stress (ELS) during sensitive periods of development can result in allostatic load that contributes to both acute and enduring impact on mental and physical well-being. The lifelong responses to early adversity that disrupt physiological processes that underlie cognitive, social and emotional functions are hypothesized to be due to allostatic load, which generates early adaptive changes that attempt to compensate for the challenges, but long term may result in altered cellular functions, particularly in susceptible circuits. In a rodent model that results in maternal fragmented care during the first postnatal week, previous studies have demonstrated altered neuronal morphology and neurochemical alterations that appear to be most sensitive to ELS, including hippocampus, prefrontal cortex and amygdala. Enduring cognitive and emotional regulatory dysfunction also occur. Little is known about the broader impact of ELS on molecular systems, the differential susceptibility of males and females to ELS, and how these findings might have broader implications in human infants. An unbiased assessment of molecular disruptions was performed using comparative proteomics in male and female mice raised in a limited resource paradigm during the first postnatal week. Ontological informatics analyses and ANOVA were used to identify changes in specific molecular pathways, with cellular and organelle physiological assays to validate molecular changes. The broader implications of these animal model results were examined in a longitudinal study of human infants in the first year of life, recruited from a community clinic, for which measures were performed to examine attention, through high resolution eye tracking, brain maturation by high density EEG, and a molecular biomarker of potential allostatic load, by measurement of oxidative stress. Proteins involved in mitochondrial function were the most changed group in both male and female mice. The number of differentially expressed proteins increased with age post-ELS, with more than 100 in each sex changed. While the impact of ELS on mitochondrial function was shared across sexes, the patterns of dysfunction based on Seahorse physiological assays of isolated mitochondrial respiration were different. In males and females after the first week ELS period, respiration in mitochondria isolated from hippocampus increased compared to care as usual control group (p<.01). In adults, mitochondrial from male hippocampi exhibited normal respiratory capacity, but females exhibited a robust reduction in mitochondrial function (p<.01). Regression analyses of oxidative stress in human infants revealed a small group that exhibited increased isoprostane levels and which may be related to maternal perceived stress and specific attention and EEG profiles.These results in mice and humans indicate that early life stress can disrupt basic metabolic capacities that may be related to altered brain maturation and life-long dysfunction. Sex-related differences in response suggest broad vulnerabilities, but may result in different adaptive strategies for dealing with allostatic load caused by atypical adult-infant interactions. The metabolic dysfunction that causes mitochondrial functional changes provide a potential target for interventions that may be able to restore normal developmental physiological homeostasis.

Author

• Pat R. Levitt, University of Southern California
  Presenting Author