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Measuring the Brain Region-Specific Regulatory Impact of Addiction-Associated Genetic Variants in Opioid Self-Administration

Award Number: R21DA062185
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/30/2028

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Measuring the Brain Region-Specific Regulatory Impact of Addiction-Associated Genetic Variants in Opioid Self-Administration - SUMMARY Substance use disorders, including opioid use disorder, are rising across the United States have devastating consequences on those affected as well as their family and friends. Genome-wide association studies have identified hundreds of loci confidently linked with addiction and related traits. Genetic variants associated with addiction-related traits show enrichment in distal open chromatin regions in the neurons of several the brain regions of the reward system: the striatum, cortex, hippocampus, and amygdala. Despite these associations, there are few loci where the consequences of a particular candidate addiction-associated genetic variant has been comprehensively elucidated in the brain of a behaving organism. Thus, how these genetic variants influence gene regulation in response to different drugs of abuse is still not known. The difficulty in understanding the function of candidate addiction-associated genetic variants results from an inability to perform controlled experiments in an intact human brain. Here, we leverage a combination of genomic technologies to measure how candidate human addiction-associated genetic variants impact regulatory activity in the brains of mice. In Aim 1, the R21 component, we synthesize hundreds of candidate human addiction-associated enhancers and then screen their regulatory function regulation in an in vivo massively parallel reporter assays conducted in the mouse striatum, cortex, hippocampus, and amygdala. The in vivo nature of the will allow us to measure the regulatory function not just in animals at baseline, but also in response to opioid and cocaine self-administration. In Aim 2 (R33 component), we will conduct a more detailed study of enhancers that showed substantial variant effects or regulatory activity from Aim 1 by collecting more samples and manipulating candidate transcription factor binding site motifs predicted to be underlying enhancer regulatory activity. Finally, in Aim 3 (R33 component), we will conduct a more detailed analysis of three top candidate addiction-associated genetic variants from Aim 2 by applying spatial transcriptomics. Experiments using the 10x Xenium will allow us to measure how those genetic variants influence regulatory activity across different subtypes of neurons and spatial patterns. These proposed experiments will create a comprehensive map of how candidate addiction-associated genetic variants influence gene regulatory activity across the brain regions of the reward system in response to opioids and cocaine.


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 = $217,672 )
2026	2026	CARNEGIE-MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	1	7/24/2026	NEW	$217,672
														Subtotal = $217,672

Grand Total All Awards = $217,672

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Measuring the Brain Region-Specific Regulatory Impact of Addiction-Associated Genetic Variants in Opioid Self-Administration

Award Number: R21DA062185

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/30/2028

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