The goal of this proposal, is to discover prenatal determinants of post-natal behavioral precursors, emerging in the first 36 months after birth, of neurodevelopmental and psychiatric disorders. Epidemiological studies have demonstrated an association between developmental exposure to maternal obesity, gestational diabetes, and hypertension and increased incidence of neurodevelopmental disorders; however, the mechanisms for this association remain largely unknown. Our own work, using non-human primate models, demonstrates causal effects on offspring temperament, operating via changes in inflammation and neurotransmitter synthesis and relate behaviorally to negative valence, supporting the timeliness of a more focused, prospective human study to isolate potential mechanisms. From the RDoC perspective, we therefore prioritize the negative valence domain, which our conceptual framework also places as central to developmental risk in very early life. We also secondarily consider key modulating domains, including positive valence, social processes, and cognitive systems. Working from a liability x experience model, and considering emerging concepts of developmental programming, we highlight two powerful but insufficiently understood environmental inputs in early development: maternal obesity and poor antenatal nutrition. We hypothesize that maternal obesity and poor nutrition alter the in-utero milieu that offspring are exposed to during fetal development resulting in increased exposure to inflammatory factors. Those, in turn, alter brain development (not directly evaluated here) and ultimately behavior (which we study carefully). The overarching hypothesis is that increased exposure to inflammatory factors during fetal development predicts alterations in infant negative valence, shaping a cascade of behavioral development that increases the outcomes related to ADHD, irritability, and behavioral risk for psychiatric disorder. To address this hypothesis, a powerful yet novel combination of a well-established infant/toddler behavioral characterization is coupled with detailed measurements of the nutritional, metabolic, inflammatory, and hormonal profile of the in-utero environment. We also examine selected postnatal moderators and other relevant RDoC-dimensions, in line with our model.
Aim 1 evaluates the extent to which in humans' developmental exposure to maternal obesity and/or poor maternal nutrition predicts offspring infant and toddler behavior, in particular negative affectivity.
Aim 2 examines changes in the in-utero environment induced by maternal obesity and poor nutrition and tests the hypothesis that increased exposure to inflammation during development underlies the behavioral changes in the offspring.
Aim 3 examines the hypothesis that the programming of offspring behavior via maternal obesity-induced inflammation is moderated by the nutrients and hormones that offspring are exposed to during fetal development. Results will clarify mechanistic routes to psychopathology.

Public Health Relevance

Child developmental and learning problems like ADHD, place heavy, often lifelong burdens on families, as well as on the nation's educational, health care, and justice systems. New evidence suggests that inflammation during pregnancy due to maternal obesity and poor diet may cause developmental disruption for the child, but studies to confirm this are needed. This study will characterize changes in the nutritional, metabolic, inflammatory, and hormonal profile of the in-utero environment associated with maternal obesity and poor nutrition, determine which factors are the strongest predictors of alterations in infant and toddler behavior associated with neurodevelopmental disorders, and set the stage for new approaches to prevent or treat child mental health problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH117177-02
Application #
9762210
Study Section
Psychosocial Development, Risk and Prevention Study Section (PDRP)
Program Officer
Zehr, Julia L
Project Start
2018-08-15
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239