Neurobiobehavioral Underpinnings of Intergenerational Obesity

Abstract Maternal obesity is a major public health problem affecting 20 million women in the United States and accounting for 22 to 42% of the prevalence of childhood obesity. Currently, 1 in 8 children aged 2-5 years old have obesity, increasing their risk for obesity and chronic disease during the lifecourse. Rodent and non-human primate models demonstrate that in utero exposure to maternal obesity and high-fat diet can alter fetal development of mesocorticolimbic circuitries that regulate inhibitory control and reward sensivity, leading to obesogenic behaviors. However, a critical knowledge gap is the neurobiology underlying intergenerational obesity in humans. The extend to which maternal obesity programs central regulation of food intake and related behaviors is unknown. The first 1,000 days, the period from conception to age two, is critical for the prevention of childhood obesity. Therefore, an understanding of neurobiological and behavioral underpinnings during this window of developmental plasticity will inform an innovative approach to childhood obesity prevention. This proposal will address current knowledge gaps through two complimentary studies: In study 1, a secondary analysis of a deeply-phenotyped pre-birth cohort (5R01MH113883), we will (1) determine the impact of pre-pregnancy obesity on newborn regulatory behaviors and brain connectivity in networks supporting reward sensitivity and inhibitory control and (2) determine whether variation in newborn self-regulation and brain connectivity is associated with body mass index z-score trajectories from birth to two years. We will also design an innovative pilot study (study 2) to evaluate the extent to which neonatal brain connectivity measures and maternal obesity are associated with longitudinal changes in eating behaviors and self-regulation from birth to two years. In both studies, analysis of gestational neurotrophic adipokines and dietary inflammation will provide further insight into potential metabolic targets. This will be the first study in humans to use prenatal dietary assessments, advanced multimodal imaging, infant neurobehavior assessments, and longitudinal growth modelling, while leveraging the biology of adipocytes, to comprehensively characterize a neurobiobehavioral model of intergenerational obesity. Through a rigorous career development plan, the candidate will build on her strong research foundation and achieve five training goals: (1) gain in-depth knowledge of the neurobiology of eating behaviors and develop skills in neuroimaging acquisition/analysis; (2) acquire knowledge and skills in inflammatory/adipokine biomarker assessment methodologies; (3) broaden knowledge in dietary assessment tools and analysis; (4) strengthen skills in causal mediation analyses; (5) master assessments of early markers of self-regulation and executive function. By the end of the training period, the candidate will position herself uniquely to achieve her goal of becoming an R01-funded independent investigator leading an innovative multidisciplinary research program investigating the neurocognitive basis of intergenerational obesity and potential metabolic targets during pregnancy.