Neurodevelopmental behavioral disorders, such as Autism Spectrum Disorders (ASD) or Schizophrenia, are associated with maternal infection. Maternal immune activation (MIA) models demonstrated that maternal inflammation, induced with a single injection of a viral or bacterial mimic, caused behavioral alterations in offspring. n humans, maternal infection severity tracked with increased risk of ASD, highlighting the importance of understanding underlying factors that alter inflammation. Obesity is a pervasive health issue that alters immunity, creates low-grade inflammation and maternal obesity has been linked to increased risk of ASD. Despite this, it is unknown how maternal obesity impacts MIA induced behavioral issues in offspring. Additionally, although maternal obesity results in central nervous system (CNS) inflammation, it is unknown what cells create this proinflammatory milieu. This is relevant because inflammation has been linked with altered behavior and cognition and increased brain proinflammatory cytokines have been observed in ASD. Since microglia are the primary, CNS resident immune cells, we hypothesize that maternal obesity will a) augment behavioral defects induced by MIA in offspring and b) increase and exacerbate microglial reactivity and proinflammatory functions in offspring when presented alone or as a MIA comorbidity, respectively. To address these fundamental questions we propose to 1) determine whether maternal obesity exacerbates MIA- induced neurodevelopmental behavioral changes in offspring and 2) examine the impact of maternal obesity and inflammation on microglial reactivity in offspring. Animals fed control of high fat die, to induce obesity, will be mated and subsequently injected with saline or a viral mimic, poly I:C, during gestation to induce MIA. To examine offspring behavior, we will run a variety of behavior assays that test a variety of parameters including: Open Field Assay (motor/anxiety), Elevated Plus Maze (anxiety), Social Preference (sociability) and Contextual Fear Conditioning (cognition). To elucidate the role of microglia in CNS inflammation, brains and magnetic bead purified microglia of offspring, from lean or obese dams injected with saline or poly I:C, will be assessed for inflammatory cytokines/ chemokines and molecules related to microglial activation and regulation using a combinatorial approach involving: cytokine/chemokine antibody membrane arrays, ELISAs, qPCR, Westerns and flow cytometry and assessed for microglial contribution. Over 30% of child-bearing women in the US are obese and behavioral disorders are on the rise. Our proposed work will be the first to assess obesity as a relevant comorbidity for MIA induced neurodevelopmental disorders and to specifically assess microglia as causative agents of brain inflammation under these conditions. This work will provide a critical knowledge base for assessing preventative and interventional measures (i.e. diet, exercise) readily applied to humans and define target cells /molecules for therapeutic design.

Public Health Relevance

Maternal immune activation (MIA) driven inflammation results in behavioral disorders in offspring;however, it is unclear whether maternal obesity, a prevalent comorbidity, exacerbates this process. Additionally, although brain inflammation can impact behavioral alterations, it is unknown whether increased microglial reactivity, the brain's immune cells, in offspring contribute to the etiology of disease. This proposal has far reaching implications for developing preventative, interventional and therapeutic strategies to decrease neurodevelopmental disorders induced by MIA.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
1R03MH103632-01
Application #
8676371
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Desmond, Nancy L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
City
Jacksonville
State
FL
Country
United States
Zip Code
32224