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Defining the role of short-chain fatty acids in adolescent opioid reinforcement and epigenetic regulation

Award Number: K01DA050906
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Defining the role of short-chain fatty acids in adolescent opioid reinforcement and epigenetic regulation - PROJECT SUMMARY/ABSTRACT Adolescence is the time of life when drug use is initiated; for this reason, adolescence represents a sensitive period for the development of substance use disorder. Adolescents are undergoing many physiological changes at this time, including marked changes in the medial prefrontal cortex (mPFC), a brain region responsible for inhibiting motivational drive. However, changes in the brain are co-occurring with changes in the periphery. The adolescent gut microbiome is also in flux and shifts in the predominant species of bacteria during this time have been linked to systemic inflammation, anxiety-like behavior, and stress responses. There is a growing appreciation for peripheral factors in psychiatric disturbance and our lab has shown that the gut microbiome might contribute to substance use disorder. Our preliminary results indicate that adults with gut microbiome depletion have altered cocaine conditioned place preference (CPP). However, adolescent, but not adult, mice demonstrated decreased morphine CPP after short-term gut microbiome knockdown, suggesting that adolescents are more sensitive to disruption of the gut microbiome. While the gut microbiome communicates with the brain in more than one way, one major route of communication is via microbiome- derived metabolites. The short chain fatty acids (SCFAs) are breakdown products of fiber; these metabolites readily cross the blood brain barrier and act as histone deacetylase inhibitors. Given the ability of SCFAs to alter histone post-translational modifications and likely gene expression, we performed transcriptomic profiling of adolescent and adult mPFC after manipulation of the gut microbiome. Microbiome-depleted adolescent mice treated with morphine had 3x the amount of differentially regulated genes compared to depleted adults given morphine. Gene ontology analysis identified patterns of genes involved in chromatin modification including enhanced activity of histone deacetylase inhibitors, decreased histone acetyltransferase activity, decreased DNA binding, and decreased RNA transcription in adolescents with a reduced gut microbiome given morphine, but not in similarly treated adults. Our previous studies have suggested that the reduction in SCFAs produced by microbiome depletion might underlie modulation of drug reward; supplementation of SCFAs eliminated the effect of microbiome knockdown on cocaine place preference. The current proposal will build upon our preliminary results to investigate the role of the adolescent gut microbiome on fentanyl self-administration and will seek mechanistic understanding of its influence by examining the contribution of gut microbiome-derived metabolites in opioid reinforcement and chromatin modification in mPFC.


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 = $0 )
2026	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	6	1/28/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $165,753 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	6	3/17/2025	NON-COMPETING CONTINUATION	$165,753
														Subtotal = $165,753

Issue Date FY: 2024 ( Subtotal = $165,753 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	5	3/14/2024	NON-COMPETING CONTINUATION	$165,753
														Subtotal = $165,753

Issue Date FY: 2023 ( Subtotal = $165,753 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	4	2/17/2023	NON-COMPETING CONTINUATION	$165,753
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	2	4/6/2023	NON-COMPETING CONTINUATION	-$26,373
2023	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	002	3	4/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$26,373
														Subtotal = $165,753

Issue Date FY: 2022 ( Subtotal = $165,901 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	002	3	9/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$108,394
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	2	9/28/2022	NON-COMPETING CONTINUATION	-$108,394
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	2	2/17/2022	NON-COMPETING CONTINUATION	$165,901
														Subtotal = $165,901

Issue Date FY: 2021 ( Subtotal = $165,741 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	1	3/10/2021	NEW	$165,741
														Subtotal = $165,741

Grand Total All Awards = $828,901

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Defining the role of short-chain fatty acids in adolescent opioid reinforcement and epigenetic regulation

Award Number: K01DA050906

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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