Our nation has experienced a recent surge in the prevalence of childhood neuropsychiatric disorders. Mounting evidence indicates that exposure to environmental risk factors such as inflammation during critical periods of fetal development contribute to this increase; however the mechanisms for this association remain largely unknown. Rodent studies provide strong evidence that maternal obesity causes a heightened inflammatory response and subsequent long-term changes in offspring brain development and behavior. However, the critical periods for development of many of the neural systems that regulate behavior are different between rodents and primates (postnatal vs. in utero, respectively). The effects of maternal obesity- induced inflammation on the behavior of juvenile offspring have not been examined in a primate species. In accordance with the NIMH new strategic plan and Research Domain Criteria (i.e. RDoC), this proposal examines the consequences of maternal obesity-induced inflammatory responses on negative valence symptoms in offspring using a non-human primate (NHP) model. Negative valence symptoms are a core component dimension of several developmental neuropsychiatric disorders, and are often a primary factor that prompts families to seek clinical services. We hypothesize that exposure to inflammation induced by maternal obesity impact the development of neural circuits critical in behavioral regulation and subsequently alter offspring behavior. Considering that two-thirds of pregnant American women are overweight or obese, this may be one of the most common and influential environmental risk factors for behavioral disorders. Using our NHP model, we have demonstrated that maternal obesity causes activation of inflammatory pathways in the placenta and fetal brain. NHP offspring exposed to inflammation induced by maternal obesity have decreased brain serotonin and exhibit increased anxious, aggressive, and repetitive behavior, and reductions in social behaviors. As such, this model is ideal to examine the influence of inflammatory factors induced by maternal obesity on negative valence symptoms (anxiety and aggression). We propose that maternal obesity increases offspring exposure to inflammation, which leads to perturbations in the serotonin system, induces atypical brain connectivity, and increases risk for behavioral abnormalities.
Aim 1 defines the long-term impact of exposure to inflammation induced by maternal obesity on offspring temperament and behavior.
Aim 2 uses functional brain imaging to identify target regions for histochemical studies and observe the effect of inflammation induced by maternal obesity on brain wide functional neural networks. The use of this non-invasive technique allows our findings to be readily translatable to humans.
Aim 3 identifies the site- specific changes in neuroanatomy that underlie the alterations in functional brain imaging and behavioral abnormalities. The proposed studies are fundamental to understanding the impact of inflammation induced by maternal obesity on the behavioral regulation of the next generation.

Public Health Relevance

The rates of child behavioral disorders (such as autism spectrum disorders and attention deficit hyperactivity disorder) have risen dramatically during the past decade. Recent studies indicate that exposure to maternal obesity and inflammation during development increases the risk of developing a childhood mental disorder; however, the mechanisms for this association remain largely unknown, and thus it is critical to examine the impact of maternal obesity-induced inflammation during pregnancy on offspring's brain development and behavior. The proposed set of studies uses a nonhuman primate model, behavioral assays, and functional brain imaging to examine the consequences of exposure to maternal obesity-induced inflammation on offspring brain development and behavior.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Zehr, Julia L
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Oregon Health and Science University
Primate Centers
United States
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