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NPAS4+ Neuronal Ensembles: Mechanisms of Reward-Cue Associations and Relapse-Like Behavior

Award Number: K99DA064784
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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NPAS4+ Neuronal Ensembles: Mechanisms of Reward-Cue Associations and Relapse-Like Behavior - PROJECT SUMMARY Substance use disorders (SUDs) directly affect over 48 million individuals in the United States, many of whom remain prone to relapse even after prolonged periods of abstinence. Associations between drug reward and environmental cues are a fundamental component of this vulnerability, often triggering a return to drug-seeking behavior. However, the underlying neurobiological mechanisms, and thus ideal targets for successful therapeutic intervention, remain elusive. Expression of Neuronal PAS Domain Protein 4 (NPAS4), an activity-regulated transcription factor, is induced following cocaine conditioning in a select ensemble of cells within the nucleus accumbens (NAc), a brain region heavily implicated in the early reinforcing effects of drugs of abuse and drug- seeking behavior. This ensemble is composed primarily of medium spiny neurons (MSNs) expressing either D1 (D1-MSNs) or D2 (D2-MSNs) dopamine receptors and is required for the expression of cocaine conditioned place preference (CPP). D1- and D2-MSNs collectively regulate net basal ganglia output, with activity in D1- MSNs promoting and activity in D2-MSNs opposing drug-related behavior. Activity in the NPAS4-positive ensemble is also required for the cue-induced reinstatement of sucrose seeking, suggesting this small population of cells is preferentially engaged by both natural- and drug-reward learning processes to facilitate future reward seeking. However, how and why the NPAS4+ ensemble is required for reward-cue associations and whether there are reward type-specific ensemble characteristics remains unknown. Thus, the Aims outlined in this proposal will test the role of the NPAS4-positive ensemble in cue-reinstated cocaine seeking, evaluate the calcium transient dynamics of the NPAS4-positive vs. NPAS4-negative neurons throughout a multi-phase sucrose and cocaine self-administration paradigm, and identify cell type-specific subpopulations within the NAc NPAS4-positive ensemble critical to sucrose and cocaine seeking behavior. These experiments employ cutting- edge in-vivo imaging techniques in awake, behaving animals trained to self-administer for intravenous cocaine, an assay considered the gold-standard for substance use research. Further, the use of a novel transgenic mouse model enabling the investigating of cell type-specific ensemble subpopulations will provide unprecedented insight into how heterogenous ensembles facilitate behavior. Overall, the innovative approach and comprehensive experimental design of these Aims will increase our understanding of how the NAc NPAS4+ ensemble encodes behaviorally relevant reward-cue associations and identify potential subpopulations that preferentially encode this information, findings which will set the table for future studies aimed at elucidating drug-selective neuroadaptations and activity dynamics that underlie prepotent drug-cue associations which often trigger relapse events in SUD patients attempting to remain abstinent.


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 = $211,680 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	7/16/2026	NEW	$211,680
														Subtotal = $211,680

Grand Total All Awards = $211,680

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NPAS4+ Neuronal Ensembles: Mechanisms of Reward-Cue Associations and Relapse-Like Behavior

Award Number: K99DA064784

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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