The impact of early life stress on the immature primate amygdala: influence on mental health trajectories

点击翻译按钮获取中文摘要

In primates, the amygdala has a central role in learning and responding appropriately to social behaviors. Difficulty in social function is a feature of many psychiatric disorders, and early social difficulties may be a harbinger of disease onset. In both humans and monkeys, the amygdala matures in parallel with evolving social repertoires during a protracted period from infancy through young adulthood. Surprisingly, almost nothing is known of cellular changes underlying amygdala growth, or correlates with developing social behaviors. This proposal focuses on a unique group of immature neurons found in the postnatal primate amygdala (including human), and their potential for shaping social behavior over development. Importantly, these immature neurons do not exist in rodents. Along with several other groups, we have characterized immature neurons in the primate amygdala, and recently found that they are poised to mature to glutamatergic projection neurons. This finding is buttressed by recent post-mortem human data showing that mature neurons are added to specific amygdala nuclei in neurotypical children. We hypothesize that the path from immature to mature neurons in specific amygdala regions is interrupted by early life stress, and correlates with the development of atypical social behavioral outcomes. Early life adversity in the form of maternal deprivation potently alters social behavior and amygdala function in children and monkeys. We hypothesized that maternal deprivation would alter immature neuron growth trajectories, and recently used microarray analyses to specifically explore the immature neuron cells. We found strong, specific downregulation of genes governing neuroblast differentiation and migration in deprived infants, suggesting maturational disruption by early life events. We also found a correlation between the most strongly affected gene transcript (tbr1), and time spent in typical social behavior across all animals. To begin interpreting these genetic changes, we began to investigate cellular data from the same cohort (fixed hemisphere). Preliminary data suggest a reduced ratio of mature: immature neurons in maternally deprived infants, raising the possibility of slowed or reduced growth of immature neurons. In this proposal, we use archived tissue from two cohorts (infant and adolescent) to more fully explore: 1) cellular changes in immature neurons during transition from infancy to adolescence, 2) how early life stress impacts this trajectory, and 3) associated behavioral consequences. Aim 1: What is the normal trajectory of change in mature-to-immature neuron ratios between infancy and adolescence in normal control nonhuman primates? What cellular features (e.g. cell size, dendritic arborization, protein expression) track this? Does maternal deprivation alter this trajectory? Aim 2: Across all animals in each cohort (infant and adolescent), what neural maturation measures track duration (time spent) in typical social behaviors? Which behavioral developmental trajectories in each cohort are most correlated with typical neural maturation? With atypical neural maturation?