DESCRIPTION (provided by applicant): Exposure to severe trauma in childhood such as physical or sexual abuse represents one of the most pervasive and pernicious stressors in society. Its sequelae, which may endure over the entire lifespan, include depression, PTSD, endocrine and immune function dysregulation, obesity, substance abuse, and also increased likelihood of subsequent exposure to trauma in adulthood. Moreover, emerging evidence suggests the long shadow cast by childhood trauma may not be restricted to only the lifespan of this vulnerable population of abused women, but also may be transmitted to another yet even more vulnerable population - their children - who then go on to exhibit an increased prevalence of neurodevelopmental and psychiatric disorders. Thus, a vicious cycle of perpetuation and possible amplification may become established. The prevailing view is that the intergenerational transmission from mother to child of the effects of maternal exposure to childhood trauma likely occurs after her child's birth via the effects of maternal dysfunctional states and behaviors (e.g. low maternal sensitivity, depression). We postulate that the process of intergenerational transmission may start earlier during the highly sensitive period of fetal development. In the current proposal we focus on the newborn child's brain stress circuit morphology and connectivity as the outcome of primary interest and on CT-related alterations in the maternal-placental-fetal (MPF) endocrine and immune stress biology as the proximate pathway of transmission. We propose to conduct a prospective, longitudinal study from early gestation till the neonatal period in a population-based cohort of approximately 200 mother-child dyads. We will collect serial measures of stress biology in early, mid and late pregnancy to characterize the endocrine (CRH, cortisol) and immune (CRP, IL-6) milieu at each trimester as well as their trajectories across gestation. We will acquire newborn brain scans to quantify the volumes of fronto-limbic regions (hippocampus, amygdala, prefrontal cortex) and their structural and functional connectivity as the primary outcomes of interest. Causal pathway models will be used to assess whether the effects of maternal CT exposure on her newborn's brain and mediated by MPF stress biology. Among CT+ women we will delineate the relative importance of psychiatric/psychological, behavioral and biophysical states and conditions in modulating the effects of CT exposure. This project addresses scientific and public health issues of critical importance. Our results will reveal new information about the health status of vulnerable populations and shed light on the mechanisms of intergenerational cycles of vulnerability. Our findings may suggest new avenues for early identification of at-risk individuals, as well as for th subsequent development and testing of prevention and intervention strategies to limit the intergenerational perpetuation of poor health and disadvantage. Study results will be disseminated through scientific publications and presentations at scientific conferences as well as at advanced training events for medical and social work personnel.

PUBLIC HEALTH RELEVANCE: The goal of this study is to determine in a population of mother-child dyads whether and how maternal exposure to severe trauma in her own childhood could influence the development of her baby's brain during her pregnancy and her baby's intrauterine life. It is important to understand more about the transgenerational (mother-to-child) transmission of the effects of maternal exposure to childhood trauma from an individual as well as public health perspective because this new knowledge may suggest new ways for early identification of at-risk individuals, as well as guide the subsequent development and testing of prevention and intervention strategies to limit the intergenerational perpetuation of poor health and disadvantage.