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Epigenetic Regulation of Microglia Dopamine System Interactions

Award Number: F31DA057116
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/13/2023
PERIOD OF PERFORMANCE END DATE: 03/12/2026

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Epigenetic Regulation of Microglia Dopamine System Interactions - ABSTRACT Adolescence is a time of increased risk and reward seeking behaviors, and 74% of adults with a substance use disorder initiated use by 17 years of age, with many drugs of abuse acting through the dopamine (DA) system. This makes understanding DA system development in adolescence of great importance to uncover the etiology substance use disorders. In the rat, adolescence is a critical window of circuit refinement in the nucleus accumbens (NAc), a dopamine (DA) rich brain region associated with reward. Microglia, the resident immune cell of the brain, not only provides neuroimmune support but prunes synapses and receptors. We recently demonstrated in rats that dopamine d1 receptor (D1r) peaks in adolescence and declines into adulthood, and this decline occurs via a microglial-dependent phagocytic mechanism in males but not females. Importantly, this downregulation of D1r in the NAc mediates termination of adolescent social play behavior in males. It is not known what regulates microglial pruning behavior in the NAc. It is known that microglia phagocytosis across brain regions due to chromatin remodeling altering transcriptional accessibility of required genes. Moreover, microglial phagocytosis of synapses has been demonstrated to be dependent on neuronal activity. My central hypothesis is that NAc microglial chromatin reorganization throughout adolescent development regulates genomic accessibility and expression of phagocytic genes, mediating D1r phagocytosis directing social behavior in males. I predict this occurs in a DA activity-dependent manner. To test these hypotheses, in Aim 1 I will characterize genomic accessibility and gene expression with microglia, correlating phagocytic gene accessibility expression through across adolescent development. This will provide a novel baseline characterization of microglia through development and between sexes, potentially identifying sensitive periods of dynamic gene regulation. In Aim 2 I will determine if dopaminergic signaling to the NAc is required for typical microglial phagocytic activity and chromatin organization, impacting social behavior. This will demonstrate whether microglial pruning of dopamine receptors during adolescence is dependent on neuronal activity and has consequences for behavior. Collectively these data allows for powerful future directions investigating effects of drugs of abuse on microglial development and function


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: 2025 ( Subtotal = $41,559 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Drug Use and Addiction Research Programs	000	3	3/17/2025	NON-COMPETING CONTINUATION	$41,559
														Subtotal = $41,559

Issue Date FY: 2024 ( Subtotal = $41,559 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Drug Use and Addiction Research Programs	001	2	5/2/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Drug Use and Addiction Research Programs	000	2	2/2/2024	NON-COMPETING CONTINUATION	$40,279
														Subtotal = $41,559

Issue Date FY: 2023 ( Subtotal = $40,279 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Drug Use and Addiction Research Programs	000	1	3/10/2023	NEW	$40,279
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Drug Use and Addiction Research Programs	001	1	3/10/2023	NEW	$0
														Subtotal = $40,279

Grand Total All Awards = $123,397

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Epigenetic Regulation of Microglia Dopamine System Interactions

Award Number: F31DA057116

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/13/2023

PERIOD OF PERFORMANCE END DATE: 03/12/2026

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