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Molecular Signatures of Social Stress-Induced Escalation of Drinking

Award Number: R21AA030652
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: 05/20/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Molecular Signatures of Social Stress-Induced Escalation of Drinking - Social stress is one of the most common forms of stress experienced by humans and has been well documented to contribute to a wide variety of neuropsychiatric conditions. Exposure to repeated social defeat stress (SDS) in rodents enhances the rewarding and reinforcing effects of several drugs of abuse, including alcohol, and is a reliable predictor of future drug use. SDS is effectively modeled in animals through social defeat paradigms, where an antagonistic encounter is initiated between two animals of the same species. There is substantial overlap between brain regions that mediate the behavioral response to stressors and those that mediate drug addiction, implying shared neural circuitry. However, the precise neural mechanisms by which social stressors increase alcohol consumption are not well understood. This application will address this gap in knowledge by using a cell type agnostic approach to identify and profile the transcriptomes of cells that are activated by both SDS and alcohol exposure at single cell resolution. Using the recently developed TRAP2 (Targeted Recombination in Activated Populations) system and a mouse model for SDS-induced escalation of alcohol drinking, we examined the overlap between neural ensembles that are activated by social stress and alcohol consumption in the same animal. Our preliminary results indicate that SDS increased alcohol consumption and neuronal activation in the paraventricular thalamus (PVT) and the paraventricular nucleus of the hypothalamus (PVN), brain regions known to mediate the motivational effects of stress. We found that both stress and alcohol by themselves activate a large number of cells in the PVT and PVN. Interestingly, our results also indicate that >80% of stress-activated cells are also activated by alcohol in these brain regions. Based on these results, we hypothesize that transcriptional programs in cells that are activated by both stress and alcohol in the PVT and PVN are unique compared to those that are activated by stress alone or alcohol alone and underlie stress- induced escalation of alcohol consumption. We propose to use single nuclei sequencing to transcriptionally profile cells in the PVT and PVN that are activated by both stress and alcohol. We will then identify genes, pathways and processes that are dysregulated in these cells. We also propose to us the Library of Integrated Cellular Signatures (LINCs) to identify compounds that will reverse these transcriptional signatures and are thus predicted to prevent stress-induced escalation of alcohol consumption.


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: 2024 ( Subtotal = $189,159 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	2	5/8/2024	NON-COMPETING CONTINUATION	$189,159
														Subtotal = $189,159

Issue Date FY: 2023 ( Subtotal = $238,090 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	1	5/17/2023	NEW	$238,090
														Subtotal = $238,090

Grand Total All Awards = $427,249

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Molecular Signatures of Social Stress-Induced Escalation of Drinking

Award Number: R21AA030652

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: 05/20/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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