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

Award Number: R00ES033278
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/16/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Effects of air pollution/maternal stress on microglial sculpting of social circuits - 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 data obtained herein will serve as a foundation for future R01 funding.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	000	5	11/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $241,639 )
2025	2025	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	000	5	12/27/2024	NON-COMPETING CONTINUATION	$241,639
														Subtotal = $241,639

Issue Date FY: 2024 ( Subtotal = $339,265 )
2024	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	001	4	1/25/2024	SUPPLEMENT FOR EXPANSION	$91,475
2024	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	000	4	12/15/2023	NON-COMPETING CONTINUATION	$247,790
														Subtotal = $339,265

Issue Date FY: 2023 ( Subtotal = $249,044 )
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	001	3	5/9/2023	EXTENSION WITH OR WITHOUT FUNDS	$48,044
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Environmental Health	000	3	1/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$201,000
														Subtotal = $249,044

Grand Total All Awards = $829,948

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

Award Number: R00ES033278

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/16/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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