A significant proportion of variation in health outcomes and disease risk is attributable to developmental processes during fetal life in response to a variety of environmental influences. However, the precise nature of the exposure and the mechanisms by which early environmental signals influence life-long cognitive and emotional outcomes are unknown. Recent findings in rodents (Project 1) indicate that exposure to fragmented patterns of maternal signals profoundly influence emotional and cognitive outcomes already in adolescence. In the human, we have found strong evidence for the effect of maternal parameters, including anxiety and depression, on fetal, infant and child neurobehavioral outcome. Guided bv the constructive comments of the Reviewers and supported by our strong new data, we propose the novel examination of the influence of fragmented maternal emotional states and patterns of salient physiological signals during fetal life on later emotional and cognitive vulnerabilities. In strong support of a role for fragmentation of maternal signal on outcome, our prospective study [3] uncovered the novel finding that mental development of 12 month old infants is enhanced when their prenatal and postnatal exposure to maternal emotional states are consistent, even if these maternal states are depressive. Fragmented / inconsistent pre-and postnatal maternal emotional states were associated with impaired infant cognitive outcome. . Within the revised Center approach, Project 2 will interact closely with Projects 3,4 and the Computational core to 1) Test the hypothesis that fetal exposure to fragmented maternal emotional states increases vulnerabilities to cognitive and emotional deficits during infancy and (with Projects 3,4), later in life. (2) Guided by the reviewers, we will formally test if fetal exposure to fragmented patterns of maternal heart beats is a salient signal that increases vulnerabilities to cognitive and emotional deficits during infancy. (3) Test the hypothesis that inconsistency between pre- and postnatal maternal emotional states will increase the vulnerability to cognitive and emotional deficits in 1 year-old children. (4) Test the hypothesis that fetal vulnerability to fragmentation and unpredictability is sex-dependent. The comprehensively revised Project 2 will focus on several validated measures of maternal signals, explore innovative ones, arid integrate with the other projects and Cores of the revised Center. Exploiting the unique resource of a human cohort followed from fetal life to adolescence, the Project will contribute significantly to the rigorous evaluation of the role of fragmented patterns of sensory signals during fetal life on adolescent emotional and cognitive vulnerabilities

RELEVANCE A significant proportion of variation in childhood and adult health and disease risk is attributable to developmental processes during fetal life. The unparalleled growth and development exhibited by the human fetus is the most understudied transition in the human life cycle. Recent evidence indicates that fragmented maternal signals contribute to vulnerabilities to mental illness. Project 2 is the only study to examine these signals and the consequences in the human fetus.