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Lateral Hypothalamus Circuits in Stress-Induced Blunting of Alcohol Aversion& Escalation of Alcohol Self-Administration

Award Number: R00AA029726
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: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Lateral Hypothalamus Circuits in Stress-Induced Blunting of Alcohol Aversion& Escalation of Alcohol Self-Administration - PROJECT SUMMARY (See instructions): Traumatic stress can lead to alcohol misuse and alcohol use disorder (AUD). In particular, avoidance coping after stress (i.e., persistent mental and/or physical avoidance of stress-related stimuli) is associated with higher rates of alcohol misuse. Using an animal model, we have shown that exposure to predator odor stress produces persistent avoidance of predator odor-paired stimuli in a subset of rats, termed ‘Avoiders’. Importantly, Avoider rats show long-lasting increases in alcohol self-administration after stress, similar to findings in humans. The neurobiology underlying this phenomenon remains an open area of investigation. This K99/R00 award includes a comprehensive career development and research plan based on Dr. Marcus Weera’s preliminary data showing that Avoider rats exhibit increased tolerance to the aversive effects of alcohol, which is hypothesized to facilitate increased alcohol self-administration in these rats. Our preliminary data also show that Avoider rats exhibit blunted activation of lateral habenula (LHb)-projecting lateral hypothalamus (LHA) neurons by aversive doses of alcohol. The scientific goal of this K99/R00 award is to test the central hypothesis that LHA-LHb neurons mediate stress-induced tolerance to alcohol aversion and stress-induced escalation of alcohol self-administration in Avoider rats via three aims. In Aim 1, we predict that Avoider rats show blunted activation of LHA-LHb and LHb neurons in response to an aversive dose of alcohol, as measured by Fos immunohistochemistry and in vivo fiber photometry. In Aim 2, we predict that in vivo chemogenetic stimulation of LHA-LHb neurons rescues stress-induced blunting of LHb activity and stress-induced tolerance to alcohol aversion in Avoider rats, as measured by in vivo fiber photometry and alcohol conditioned place aversion, respectively. In Aim 3, we predict that in vivo chemogenetic stimulation of LHA-LHb neurons rescues stress-induced blunting of LHb activity and stress-induced escalation of alcohol responding in Avoider rats, as measured by in vivo fiber photometry and operant alcohol self-administration, respectively. Results from these studies will improve our understanding of the neural circuits underlying stress-induced changes in sensitivity to alcohol’s aversive effects and in alcohol self-administration. The career development goal of this K99/R00 award is to provide the principal investigator, Dr. Marcus Weera, with additional technical training and professional development, and to help him establish an independently-funded research program. During the K99 portion of the award, under the guidance of an expert team of mentors, Dr. Weera will expand his technical repertoire to include in vivo fiber photometry. He will also search for and secure a tenure-track faculty position. During the R00 portion of the award at his new institution, Dr. Weera will use his acquired skills to build upon these studies, gathering rigorous data for submission of an R01 application. The work and training supported by this award will be critical for the PI’s successful transition to an independent research career studying the neurobiology underlying individual differences in stress and alcohol responsiveness.


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 = $244,532 )
2026	2026	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Alcohol Research Programs	000	5	1/30/2026	NON-COMPETING CONTINUATION	$244,532
														Subtotal = $244,532

Issue Date FY: 2025 ( Subtotal = $248,956 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Alcohol Research Programs	001	4	8/19/2025	NON-COMPETING CONTINUATION	$24,897
2025	2025	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Alcohol Research Programs	000	4	12/20/2024	NON-COMPETING CONTINUATION	$224,059
														Subtotal = $248,956

Issue Date FY: 2024 ( Subtotal = $364,003 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Alcohol Research Programs	001	3	3/22/2024	EXTENSION WITH OR WITHOUT FUNDS	$115,164
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Alcohol Research Programs	000	3	2/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$248,839
														Subtotal = $364,003

Grand Total All Awards = $857,491

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Lateral Hypothalamus Circuits in Stress-Induced Blunting of Alcohol Aversion& Escalation of Alcohol Self-Administration

Award Number: R00AA029726

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: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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