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Ethanol-induced dysregulation of the astrocyte glucocorticoid system

Award Number: R01AA033112
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: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Ethanol-induced dysregulation of the astrocyte glucocorticoid system - Project Summary Alcohol use disorder (AUD) is highly comorbid with depression and anxiety disorders, particularly in women. Co- occurring AUD and major depressive disorder (MDD) may reduce treatment efficacy and reduce the ability to maintain abstinence. Both AUD and MDD are associated with heightened stress responsivity and salience of aversive stimuli. This may be mediated by dysregulation of the glucocorticoid system, including alterations in cortisol signaling at the glucocorticoid receptor. Cortisol (CORT; corticosterone in rodents) signaling at the glucocorticoid receptor (GR) contributes to stress and aversion responsivity and risk assessment. GR is tightly negatively regulated by the chaperone protein FKBP51, which is implicated in depression, anxiety, and substance use disorders. Following alcohol exposure or chronic stress, FKBP51 is upregulated, leading to sequestration of GR in the cytoplasm and reducing sensitivity to CORT. FKBP51 inhibition or knockout reduces ethanol intake in male, but not female, animals, and inhibition blunts stress-induced reinstatement of cocaine seeking in both males and females in low hormonal states. Astrocyte activity broadly appears to contribute to alcohol-related behaviors and dependence. In particular, the astrocyte GR system contributes to aversion-related behaviors. We have previously shown that chronic intermittent ethanol (CIE) exposure via vapor inhalation – a mouse model of ethanol dependence – perturbs both the astrocyte system and aversion-related behaviors. CIE reduced astrocytic GFAP expression in the nucleus accumbens (NAc) of female, but not male mice, and reduced resilience to reward seeking under reward-aversion conflict in female mice. Our preliminary data indicate that chemogenetic activation of astrocytic Gq signaling in the NAc can restore resilience in CIE-exposed females. However, the impact of CIE on astrocyte glucocorticoid signaling is not fully characterized, and it remains to be determined whether targeting the astrocyte signaling system is sufficient to reverse ethanol-induced impairments in aversion-driven drinking and aversion-avoidance. Thus, experiments in this proposal will test the overarching hypothesis that CIE exposure dysregulates the astrocytic glucocorticoid system and that targeting astrocyte signaling will reverse CIE-induced deficits in aversion avoidance and aversion-induced drinking. Specific Aim 1 will characterize the interaction of ethanol exposure (CIE) and aversive experience on cell type-specific expression of glucocorticoid system targets including GR, FKBP51, and SGK1 in NAc neurons and astrocytes. Specific Aim 2 will test the hypothesis that modulating NAc astrocyte activity broadly using a chemogenetic strategy, or selectively modulating FKBP51 inhibition, will reverse CIE-induced increases in aversion avoidance. Specific Aim 3 will determine whether these manipulations suppress aversion-driven ethanol drinking. Together, these experiments are expected to provide a thorough understanding of the interactive impact of chronic alcohol exposure and aversion on glucocorticoid systems, with implications for the development of novel therapeutic strategies for both AUD and MDD comorbidity.


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 = $450,372 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Alcohol Research Programs	000	1	7/17/2026	NEW	$450,372
														Subtotal = $450,372

Grand Total All Awards = $450,372

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Ethanol-induced dysregulation of the astrocyte glucocorticoid system

Award Number: R01AA033112

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: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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