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

定义短链脂肪酸在青少年阿片类药物强化和表观遗传调控中的作用

基本信息

批准号：
10576350
负责人：
Rebecca Hofford
金额：
$ 16.58万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576350
关键词：
Acceleration Adolescence Adolescent Adult Adverse event Affect Animals Antibiotics Architecture Area Back Bacteria Behavior Behavioral Brain Brain region ChIP-seq Chromatin Cocaine Communication DNA Binding Data Development Drug Modulation Drug usage Emotional Epigenetic Process Essential Drugs Exposure to Female Adolescents Fiber Gene Expression Genes Genetic Transcription Histone Acetylation Histone Deacetylase Inhibitor Histones Inflammation Intake Lesion Life Link Male Adolescents Measures Medial Mental disorders Methods Modeling Molecular Morphine Motivation Mus Ontology Opioid Pathologic Pathway interactions Pattern Peripheral Pharmaceutical Preparations Physiological Post-Translational Protein Processing Predisposition Prefrontal Cortex Production Psychological reinforcement RNA Rattus Rewards Risk Factors Role Route Self Administration Site Substance Use Disorder Supplementation System Testing Time Volatile Fatty Acids Work addiction anxiety-like behavior behavioral response biological adaptation to stress blood-brain barrier crossing chromatin immunoprecipitation chromatin modification cocaine reward conditioned place preference critical developmental period drinking water drug of abuse drug reward epigenetic regulation experimental study fatty acid supplementation fentanyl self-administration gut bacteria gut microbiome gut-brain axis histone acetyltransferase histone modification hypothalamic-pituitary-adrenal axis insight knock-down mesolimbic system microbiome myelination preference prevent response sex synaptic pruning systemic inflammatory response transcriptomic profiling

项目摘要

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.

项目总结/文摘