# Effects of air pollution/maternal stress on microglial sculpting of social circuits

> **NIH NIH K99** · DUKE UNIVERSITY · 2022 · $95,319

## Abstract

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. During the
K99 phase of this proposal, in Aim 1, I propose to further my training in the analysis of the gut microbiome to
ask 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, I propose to
learn in vivo optogenetic techniques to test whether activation of the mesolimbic dopamine reward pathway is
sufficient to restore social behavior following DEP/MS. During the R00 phase, in Aim 3, I will use the techniques
acquired during the K99 phase to determine whether changes in the gut microbiome are responsible for changes
in social behavior and dopamine signaling in DEP/MS offspring. Moreover, I will use the preliminary data
gathered in Aim 1 to ask what potential metabolites or molecular mechanisms might be altered following
DEP/MS. Finally, I 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 providing me with new training in
cutting-edge techniques such as in vivo optogenetics and metagenomic sequencing. Thus, it will help me to
establish my own independent line of work and the preliminary d...

## Key facts

- **NIH application ID:** 10462810
- **Project number:** 5K99ES033278-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Caroline Jackson Smith
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $95,319
- **Award type:** 5
- **Project period:** 2021-08-06 → 2023-01-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462810

## Citation

> US National Institutes of Health, RePORTER application 10462810, Effects of air pollution/maternal stress on microglial sculpting of social circuits (5K99ES033278-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462810. Licensed CC0.

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