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The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli

Award Number: R01DA054967
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli - PROJECT SUMMARY Growing evidence suggests addiction results in part from a dominance that drug-paired cues exert over behavior. That is, when trying to remain abstinent, people with substance-use disorders (SUDs) struggle to focus on anything that is not related to drug use when reminders of drug use are present, exacerbating craving and producing relapse. We have recently uncovered a novel neural locus that appears to bias learning and behavior towards cues that are immediately related to rewards. Specifically, we have found that GABAergic neurons in the lateral hypothalamus (LH) drive learning and behavior directed to information related to rewards, while actively opposing learning about other relationships in the environment that are not immediately relevant to rewards. This is the first time one region has been found to contribute to this dissociation. We can see how a change in this balance in learning and behavior mediated by LH could contribute to addiction; increases in LH function seen following drug exposure could potentiate cue-elicited drug seeking while trying to remain abstinent, hijacking the adaptive function of LH to focus on cues that help predict rewards that likely promote survival under normal circumstances. This work will provide insight into how the pathophysiological state of addiction can contribute to relapse even during voluntary abstinence, and suggest a neural target that could drive pre-clinical work to develop treatments for SUDs. This proposal will test a novel theoretical framework to account for the influence LH has over learning. Specifically, we hypothesize that LH GABAergic neurons bias learning towards cues proximal to rewards, and away from those more distal to rewards. To test this, we have developed an innovative task taken from the cognitive neuroscience literature based on human participants, allowing us to isolate behavior and neural activity during both proximal and distal predictors of rewards in the same animal. Further, we will uncover the nature of learning about proximal cues supported by LH function. On the basis of preliminary data, we hypothesize this will involve a sensory-specific representation of reward, which allows LH to influence behavior in flexible and specific ways. Finally, our preliminary work also demonstrates that methamphetamine self-administration enhances the control that cues proximal to rewards have over behavior, and that this is also dependent on a specific reward representation. This expands our knowledge of the behavioral change that results from SUDs, standing as a counterpoint to many theories of addiction that focus on and enhancement of habitual behavior, which is without voluntary control and devoid of reward representations. On the basis of preliminary work, we hypothesize that enhancements of LH GABAergic neuronal function after drug exposure produces this effect. Accordingly, we will directly test our theory that LH GABA neurons promote a bias towards proximal cues in a specific manner, and that this function is enhanced in following drug exposure.


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 = $276,771 )
2024	2024	UNIVERSITY OF SYDNEY	RESEARCH OFFICE MAIN QUADRANGLE A14	THE UNIVERSITY OF SYDNEY				AUS	Drug Use and Addiction Research Programs	002	3	6/27/2024	NON-COMPETING CONTINUATION	$276,771
2024	2023	UNIVERSITY OF SYDNEY	RESEARCH OFFICE MAIN QUADRANGLE A14	THE UNIVERSITY OF SYDNEY				AUS	Drug Use and Addiction Research Programs	001	2	3/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,916
2024	2023	UNIVERSITY OF SYDNEY	RESEARCH OFFICE MAIN QUADRANGLE A14	THE UNIVERSITY OF SYDNEY				AUS	Drug Use and Addiction Research Programs	003	2	8/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	1	3/6/2024	NEW	-$3,916
														Subtotal = $276,771

Issue Date FY: 2023 ( Subtotal = $285,884 )
2023	2023	UNIVERSITY OF SYDNEY	LEVEL 3, ADMINISTRATION BUILDING F23	THE UNIVERSITY OF SYDNEY	NSW			AUS	Drug Use and Addiction Research Programs	002	2	7/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$285,884
2023	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	001	1	6/30/2023	NEW	$0
2023	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	1	11/30/2022	NEW	$0
														Subtotal = $285,884

Issue Date FY: 2022 ( Subtotal = $412,383 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	1	9/21/2022	NEW	$412,383
														Subtotal = $412,383

Grand Total All Awards = $975,038

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The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli

Award Number: R01DA054967

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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