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Cell-Type Selective Transcriptional and Mitochondrial Control of Drug Seeking

Award Number: K01DA061048
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 01/05/2026

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Cell-Type Selective Transcriptional and Mitochondrial Control of Drug Seeking - Substance use disorders comprise chronic cycles of drug use, abstinence, and relapse driven by drug-induced transcriptional and circuit adaptations in the brain. Despite consistent evidence that epigenetic chromatin modifications drive these long-term neuronal adaptations, successful druggable treatment targets have not emerged, and further understanding of mechanistic pathways from the epigenome to altered behavior are needed for novel substance use disorder therapies. This proposal examines the link between epigenetic processes, including histone deacetylase (HDAC) function and chromatin accessibility, and mitochondrial morphology and function in the context of nicotine reinforcement learning to bridge this gap. Use of nicotine, the primary psychoactive component of both tobacco and e-cigarettes, alters brain reward pathways, including inputs to spiny projection neurons (SPNs) of the nucleus accumbens (NAc). The subsequent transcriptional and morphological changes in these SPNs support electrophysiological activity driving cue-induced craving and drug- seeking behaviors that make smoking cessation difficult and contribute to nicotine use disorder. Understanding how drugs such as nicotine induce lasting molecular adaptations and alter the functioning of NAc SPNs is critical in untangling the local mechanisms promoting persistent drug use and relapse. SPN mitochondria stand out as an unexplored but likely regulator of NAc SPN adaptations to nicotine, mediating plasticity downstream of epigenetic genome modifications. This proposal uses cutting edge cell-type selective techniques to examine how both nicotine and HDAC inhibitors alter mitochondrial morphology and function, as well as individual SPN gene expression and chromatin accessibility, to provide a new mechanistic understanding of nicotine-reward. Using a mouse model of nicotine intravenous self-administration (IVSA) and drug seeking, I will measure NAc mitochondrial respiratory capacity then will assess dendritic, spine, and mitochondrial morphology in the two main SPN populations in NAc (D1- and D2-dopamine receptor containing SPNs). I will also examine these end points after inhibition of multiple classes of HDACs, determining if nicotine’s effects on mitochondria are related to nicotine’s function as an HDAC inhibitor. Parallel single nuclei RNA and ATAC sequencing will identify molecular adaptations in individual NAc cell types after nicotine IVSA. Finally, after identifying and validating molecular targets regulating transcriptional programs within in SPN cell types, I will disrupt the endogenous mitochondria adaptations to IVSA nicotine with cell-type selective CRISPR activation or interference (CRISPRa/i) manipulations. These studies will inform the relationship between drug-induced epigenetic modifications and downstream mitochondrial functioning, a potential intermediary to morphological and electrophysiological plasticity in response to rewarding drugs. In addition to providing training opportunities in mitochondrial and transcriptional profiling this proposal will provide new insights into mechanisms of nicotine use and relapse, which may translate to other used substances and inform novel substance use disorder therapeutics.


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 = $193,320 )
2026	2026	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Drug Use and Addiction Research Programs	001	3	6/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$193,320
2026	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	2	6/5/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	002	2	6/25/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $193,320

Issue Date FY: 2025 ( Subtotal = $193,644 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	2	8/7/2025	NON-COMPETING CONTINUATION	$193,644
														Subtotal = $193,644

Issue Date FY: 2024 ( Subtotal = $169,474 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	8/8/2024	NEW	$169,474
														Subtotal = $169,474

Grand Total All Awards = $556,438

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Cell-Type Selective Transcriptional and Mitochondrial Control of Drug Seeking

Award Number: K01DA061048

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 01/05/2026

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