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Proinflammatory HMGB1 Contributions to Adolescent Alcohol-induced Reversible Epigenetic Suppression of Cholinergic Neuron Phenotype and Cognitive Deficits in Adulthood

Award Number: R01AA032804
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: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Proinflammatory HMGB1 Contributions to Adolescent Alcohol-induced Reversible Epigenetic Suppression of Cholinergic Neuron Phenotype and Cognitive Deficits in Adulthood - PROJECT ABSTRACT. Human adolescent binge drinking is associated with lasting deleterious effects on the brain, including induction of proinflammatory HMGB1 signaling, degeneration of basal forebrain cholinergic neurons (BFCNs), and impaired adult cognitive flexibility, increasing risk for later AUD development and alcohol- related dementia. BFCNs, which are crucial for cognition due to their vast projections to various brain regions (e.g., hippocampus), mature during adolescence paralleling development of executive function. Adolescent intermittent ethanol (AIE), a preclinical model of human adolescent binge drinking, recapitulates induction of proinflammatory HMGB1 signaling, reductions of BFCNs (e.g., ChAT+, TrkA+), and lasting adult cognitive deficits in adulthood. We discovered AIE-induced BFCN marker loss is reversible in adulthood through a mechanism involving increased occupancy of the epigenetic repressive marker H3K9me2 at cholinergic gene promoters. However, the mechanism underlying, and the consequences of, prolonged AIE-induced epigenetic suppression of the BFCN phenotype are unknown. Our preliminary data reveal AIE and neuroinflammation increase the H3K9 methyltransferase Ehmt2 in the adult basal forebrain, and ChAT+ BFCN loss is reversible by Ehmt2 inhibition suggesting cholinergic genes regulated by Ehmt2 could be novel targets to reverse persistent neuropathology caused by adolescent binge drinking. BFCNs are dependent on hippocampal retrograde NGF transport for maintenance of the cholinergic phenotype, which is disrupted by AIE and proinflammatory signaling. The direct contributions of basal forebrain HMGB1 signaling and reduced hippocampal NGF to reversible epigenetic suppression of the BFCN phenotype is unknown. We propose to test the overarching hypothesis that AIE induction of proinflammatory HMGB1 signaling causes reversible Ehmt2-mediated epigenetic suppression of the BFCN phenotype resulting in long-lasting adult cognitive deficits. Employing pharmacological, transgenic, and viral vector approaches, studies in Aim 1 will investigate male and female basal forebrain HMGB1 proinflammatory signaling involvement in Ehmt2-mediated epigenetic suppression of the BFCN phenotype and resulting behavioral flexibility deficits in adulthood. Employing pharmacological and NGF sequestration approaches, studies in Aim 2 will investigate contributions of AIE-induced HMGB1 proinflammatory signaling to reductions of male and female hippocampal NGF and consequent epigenetic suppression of the BFCN phenotype in adulthood. Employing pharmacological, transgenic, multiomic, and electrophysiological approaches, studies in Aim 3 will investigate the transcriptomic and chromatin accessibility changes in epigenetically suppressed BFCNs following AIE and determine HMGB1 involvement in AIE-induced alterations in physiological functioning of epigenetically suppressed BFCNs. The proposed studies on HMGB1-epigenetic regulation of BFCN phenotype and adult behavioral flexibility deficits explores novel neuroplastic mechanisms with broad therapeutic implications.


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 = $653,214 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	1	5/5/2026	NEW	$653,214
														Subtotal = $653,214

Grand Total All Awards = $653,214

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Proinflammatory HMGB1 Contributions to Adolescent Alcohol-induced Reversible Epigenetic Suppression of Cholinergic Neuron Phenotype and Cognitive Deficits in Adulthood

Award Number: R01AA032804

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: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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