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：
10369599
负责人：
Rebecca Hofford
金额：
$ 5.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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 2022-06-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369599
关键词：
Adolescence Adolescent Adult Adverse event Affect Animals Antibiotics Architecture Area Back Bacteria Behavior Behavioral Blood - brain barrier anatomy 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 Fentanyl 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 Prefrontal Cortex Production Psychological reinforcement RNA Rattus Regulation 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 chromatin immunoprecipitation chromatin modification conditioned place preference critical developmental period drinking water drug of abuse drug reward epigenetic regulation experimental study fatty acid supplementation 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 transcriptomics

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.

项目概要/摘要青春期是生命中开始吸毒的时期；因此，青春期是一个敏感的时期物质使用障碍的发展时期。青少年正经历着许多生理变化此时的变化，包括内侧前额皮质（mPFC）（大脑区域）的显着变化负责抑制动机驱动。然而，大脑的变化与身体的变化同时发生。外围。青少年肠道微生物组的主要细菌种类也在不断变化和变化在此期间与全身炎症、焦虑样行为和压力反应有关。那里人们越来越认识到精神障碍的外围因素，我们的实验室已经表明肠道微生物组可能会导致物质使用障碍。我们的初步结果表明，患有肠道疾病的成年人微生物组耗竭改变了可卡因条件性位置偏好（CPP）。然而，青春期，却不成年小鼠在短期肠道微生物组敲低后表现出吗啡 CPP 降低，表明青少年对肠道微生物组的破坏更加敏感。虽然肠道微生物组与大脑沟通的方式不止一种，其中一种主要的沟通途径是通过微生物组—— 衍生代谢物。短链脂肪酸 (SCFA) 是纤维的分解产物；这些代谢物容易穿过血脑屏障并充当组蛋白脱乙酰酶抑制剂。鉴于 SCFA 有能力为了改变组蛋白翻译后修饰和可能的基因表达，我们进行了转录组分析肠道微生物组调控后青少年和成人 mPFC 的变化。微生物组耗尽的青春期小鼠与接受吗啡治疗的成年人相比，接受吗啡治疗的差异调节基因数量是其三倍吗啡。基因本体分析确定了参与染色质修饰的基因模式，包括组蛋白脱乙酰酶抑制剂活性增强，组蛋白乙酰转移酶活性降低，给予吗啡肠道微生物组减少的青少年中 DNA 结合和 RNA 转录减少，但在接受类似治疗的成年人中则不然。我们之前的研究表明，SCFA 的产生减少微生物组耗竭可能是药物奖励调节的基础；补充 SCFA 消除了微生物组敲除对可卡因位置偏好的影响。目前的提案将建立在我们的基础上研究青少年肠道微生物组对芬太尼自我给药和作用的初步结果将通过检查肠道微生物组来源的贡献来寻求对其影响的机制理解 mPFC 中阿片类药物强化和染色质修饰中的代谢物。