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Illuminating Neurobiological Adaptations of Afferent Projections to the Lateral Habenula During Aversion-Resistant Alcohol Consumption

Award Number: F31AA031597
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/05/2024
PERIOD OF PERFORMANCE END DATE: 02/04/2028

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Illuminating Neurobiological Adaptations of Afferent Projections to the Lateral Habenula During Aversion-Resistant Alcohol Consumption - RESEARCH SUMMARY Alcohol use disorder (AUD) accounts for the largest percentage of active substance use disorders. One prominent trait of AUD is compulsive use despite adverse consequences. Previous work has found that animals who drink alcohol in excess display diminished lateral habenula (LHb) activity, a brain region widely acknowledged to participate in aversive behaviors, suggesting that LHb hypoactivity may be an integral factor in compulsive alcohol use. However, mechanisms that contribute to these reductions in LHb activity have not been fully explored. Comprehensive assessment of LHb plasticity in preclinical models of AUD through the measurement of afferent neurotransmission dynamics could offer potential insight into a neurobiological basis for the reduced LHb activity observed in aversion resistance. One afferent region of particular interest is the ventral pallidum (VP). Recent findings have shown that VP glutamate (VPGlu) neurons, which project extensively into the LHb, contribute to adaptive constraint of natural reward consumption and reduction of drug-seeking actions. Yet, there remains a significant knowledge gap concerning potential alterations of LHb-projecting VP neurons that arise in response to the development of aversion-resistant alcohol use. Clarifying the changes that occur in both multiregional and VP-specific afferent input is necessary to improve our understanding of physiological alterations preventing normative aversive behavior in aversion-resistant drinking. Thus, the broad goal of the proposed work is to elucidate neurobiological adaptations of LHb afferent projections during compulsive alcohol consumption. The primary objective of this proposal is twofold: first, to investigate the impact of alcohol use on afferent neurotransmission into the LHb during aversion resistant alcohol consumption, and second, to explore the significance of VP-to-LHb projections in this behavior. Given that afferent input from several distinct brain regions has been shown to influence aversive behavior and alcohol misuse, I hypothesize that LHb afferent neurotransmission is adaptably dysregulated in animals that exhibit aversion resistant alcohol use, which may be due in part to changes in activity of VP inputs. To test this hypothesis, I will use in vivo fiber photometry to record neurotransmitter activity in the LHb and optogenetics to manipulate VP-to-LHb projections during aversion-resistant alcohol consumption alongside histological techniques to quantify neurochemical content of LHb projections. Experiments proposed here will advance our understanding of the neural mechanisms underlying aversion-resistant alcohol use, establishing a foundation for future research examining LHb-associated neural circuitry in compulsive alcohol use. Throughout this proposal, I will gain valuable training in the execution of behavioral neuroscience experiments, in vivo neurotransmitter recording methods, neuronal manipulation techniques, histological processing, and advanced computational strategies. This project will allow me to build a firm foundation for a successful career as an independent investigator.


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 = $47,804 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Alcohol Research Programs	001	3	3/27/2026	NON-COMPETING CONTINUATION	$576
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Alcohol Research Programs	000	3	2/2/2026	NON-COMPETING CONTINUATION	$47,228
														Subtotal = $47,804

Issue Date FY: 2025 ( Subtotal = $47,228 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Alcohol Research Programs	000	2	4/22/2025	NON-COMPETING CONTINUATION	$46,664
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Alcohol Research Programs	001	2	6/5/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $47,228

Issue Date FY: 2024 ( Subtotal = $46,664 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Alcohol Research Programs	002	1	5/1/2024	NEW	$1,280
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Alcohol Research Programs	001	1	2/5/2024	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Alcohol Research Programs	000	1	2/5/2024	NEW	$45,384
														Subtotal = $46,664

Grand Total All Awards = $141,696

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Illuminating Neurobiological Adaptations of Afferent Projections to the Lateral Habenula During Aversion-Resistant Alcohol Consumption

Award Number: F31AA031597

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/05/2024

PERIOD OF PERFORMANCE END DATE: 02/04/2028

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