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Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors

Award Number: R00AA030089
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2025
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors - PROJECT SUMMARY Adolescent binge drinking hijacks the developing brain, resulting in long-lasting increases in neuroinflammation which are paralleled by decreases in hippocampal neurogenesis and deficits in learning and memory-related tasks. Unlike adult alcohol exposure, the cellular and behavioral effects of adolescent binge drinking do not recover following periods of abstinence, suggesting that alcohol exposure across adolescence permanently disrupts the brain’s developmental trajectory. However, while prior research has focused on the underlying mechanisms driving this loss and restoration of newborn hippocampal neurons, no research has investigated how adolescent intermittent ethanol (AIE) impacts the ability of surviving hippocampal neuroprogenitor cells (NPCs) to appropriately integrate into adult hippocampal circuitry. Newborn neurons assimilate into dentate circuitry in an activity dependent manner which is sensitive to shifts in the balance between neuronal excitation and inhibition as well as neuroinflammatory signaling. Any disruption in this integration could have profound consequences on learning and memory functions as granular cells are a gatekeeper for downstream activation of hippocampal circuitry. To test the impact of adolescent alcohol on network integration of developing neurons, we will use a reporter mouse line (DCX-CreERT2/tdtomato) which was developed to specifically tag and then fate-map NPCs across their lifespan. This technique will allow us to track how alcohol impacts the ability of adolescent maturing neurons to effectively integrate into mature dentate circuitry. By combining this transgenic model with 5-ethynyl-2'-deoxyuridine, we will test whether adolescent alcohol exposure induces adult innate immune gene expression preferentially in adolescent-maturing NPCs and glia, and we will also test whether AIE impairs formation of dendritic arborization in adolescent-maturing NPCs (AIM 1/K99). We will then test whether adolescent alcohol impairs the electrophysiological properties of these adolescent-maturing NPCs in adulthood (AIM 2/K99). As it remains unclear whether maturational changes in adolescent maturing neurons mediate cognitive-behavioral deficits, we will test whether AIE disrupts immediate early gene expression in adolescent-maturing NPCs following reversal learning in the Morris water maze, novel object recognition memory, and social dominance behaviors in adulthood (AIM 3/K99). Finally, while preliminary data suggest that anti-inflammatory interventions can reverse neurogenic and behavioral deficits after AIE in both sexes, whether anti-inflammatory pharmacological interventions (e.g., indomethacin) can similarly restore morphological and physiological maturation, circuit integration, and innate immune gene expression in adolescent-maturing NPCs in adulthood is unknown (AIM 4/R00). Collectively, these experiments will provide critical insight into the impact of adolescent alcohol on the resulting phenotypic fate and circuit regulation of surviving NPCs in both sexes.


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 = $249,000 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT WILMINGTON	601 S COLLEGE RD	WILMINGTON	NC	28403	NEW HANOVER	USA	Alcohol Research Programs	001	4	3/3/2026	NON-COMPETING CONTINUATION	$249,000
2026	2025	UNIVERSITY OF NORTH CAROLINA AT WILMINGTON	601 S COLLEGE RD	WILMINGTON	NC	28403	NEW HANOVER	USA	Alcohol Research Programs	000	3	12/17/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT WILMINGTON	601 S COLLEGE RD	WILMINGTON	NC	28403	NEW HANOVER	USA	Alcohol Research Programs	001	3	7/21/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2025	UNIVERSITY OF NORTH CAROLINA AT WILMINGTON	601 S COLLEGE RD	WILMINGTON	NC	28403	NEW HANOVER	USA	Alcohol Research Programs	000	3	7/8/2025	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $498,000

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Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors

Award Number: R00AA030089

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2025

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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