PROJECT SUMMARY Autism spectrum disorder (ASD) currently affects 1 in 59 children in the United States, 80% of whom are male, and is characterized primarily by impaired social interaction/communication. Prenatal exposure to air pollution has been implicated in the etiology of ASD, as well as many other neuropsychiatric disorders. However, the mechanisms by which air pollution alters the development of social circuits in the brain remains unknown. Importantly, there are large social disparities in environmental toxin exposure whereby marginalized communities bear the greatest burden of exposure. Using a novel mouse model that combines an environmental toxin (diesel exhaust particles; DEP) with an ethologically relevant maternal stressor (resource deprivation; MS), our preliminary data show that these exposures in combination, but neither alone, induce robust deficits in social interaction in male, but not female offspring. This is line with a model in which maternal psychosocial stress unmasks vulnerability to environmental toxins in offspring. ASD is increasingly recognized as a whole-body disorder. Gastrointestinal symptoms and changes in the composition of the gut microbiome are present in more than 50% of individuals with ASD. Studies using animal models suggest a causal link between the gut microbiome and social behavior, but this has not been studied in the context of environmental toxins. In Aim 1 of this proposal, we will test whether cross-fostering of DEP/MS pups at birth can prevent shifts in the gut microbiome (assessed using metagenomic sequencing). The dopamine system supports social interaction, is sensitive to microbial signaling, and my preliminary data suggests is down-regulated following DEP/MS exposure. Thus, in Aim 2, we will test whether activation of the mesolimbic dopamine reward pathway is sufficient to restore social behavior following DEP/MS. Finally, in Aim 3, we will determine whether changes in the gut microbiome are responsible for changes in social behavior and dopamine signaling in DEP/MS offspring. Moreover, we will use the metagenomic data gathered in Aim 1 to ask what potential metabolites or molecular mechanisms might be altered following DEP/MS. Finally, we will ask whether microglia, the resident immune cells of the brain, play a key role in mediating these microbiome-driven changes. Together, these experiments will elucidate the ways in which pollutants and stress synergize to produce dysregulation of the gut-brain axis and deficits in social behavior. This proposal will significantly advance my career development by helping me to launch my independent research career and the preliminary data obtained herein will serve as a foundation for future R01 funding.

Project Narrative Air pollution represents one of the largest public health burdens world-wide and is associated with increased risk of many neuropsychiatric disorders that are characterized by social dysfunction, including autism spectrum disorder (ASD). This project seeks to understand how prenatal exposure to a combination of air pollution and maternal stress (which unmasks vulnerability to environmental toxins) synergize to produce dysbiosis of the gut microbiome, and consequently, disruption of the neuro-immune mechanisms that regulate social behavior. The results of these experiments will answer outstanding questions about the relationship between the gut microbiome and the social brain and how this is impacted by environmental toxin exposure.