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

项目摘要/摘要 青春期是生命中开始吸毒的时期；因此，青春期代表着一种敏感的 物质使用障碍的发展时期。青少年正在经历许多生理上的 此时的变化，包括大脑区域内侧前额叶皮质(MPFC)的显著变化 负责抑制动机驱动力。然而，大脑的变化与大脑的变化同时发生。 外围。青春期肠道微生物群也在变化，优势细菌种类发生了变化。 在这段时间内，与全身炎症、焦虑样行为和压力反应有关。那里 是对精神障碍中的外围因素的日益重视，我们的实验室已经表明，肠道 微生物群可能导致物质使用障碍。我们的初步结果表明，有肠道疾病的成年人 微生物组的枯竭改变了可卡因条件性位置偏爱(CPP)。然而，青春期，但不是 成年小鼠在短期肠道微生物组敲除后显示吗啡CPP降低，这表明 青少年对肠道微生物群的破坏更敏感。而肠道微生物群 与大脑沟通的方式不止一种，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 容易通过血脑屏障，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，我们进行了转录转录图谱 青春期和成年期肠道微生物组操作后的mPFC。微生物组耗尽的青春期小鼠 与服用吗啡的精疲力竭的成年人相比，服用吗啡的成年人差异调节基因的数量是前者的3倍 吗啡。基因本体论分析确定了参与染色质修饰的基因模式，包括 组蛋白去乙酰酶抑制剂活性增强，组蛋白乙酰转移酶活性降低 在服用吗啡的肠道微生物群减少的青少年中，DNA结合和RNA转录减少， 但在受到类似对待的成年人中则不是这样。我们之前的研究表明，单链脂肪酸的减少产生了 通过微生物组的耗尽可能是药物奖励调节的基础；补充SCFAs可以消除 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 调查青少年肠道微生物群对芬太尼自我给药和 将通过检查肠道微生物群衍生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。

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.