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

项目总结/摘要 青春期是开始使用毒品的时期;因此，青春期是一个敏感的 物质使用障碍的发展时期。青少年正在经历许多生理 在这个时候的变化，包括在内侧前额叶皮层（mPFC），一个大脑区域的显着变化 负责抑制动机驱动。然而，大脑的变化与大脑的变化同时发生。 外围。青少年的肠道微生物组也在变化，主要细菌种类也在变化。 在这段时间内，已经与全身炎症，焦虑样行为和应激反应有关。那里 越来越多的人认识到精神障碍的外围因素，我们的实验室已经表明， 微生物组可能导致物质使用障碍。我们的初步结果表明， 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，但不是 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敏感。当肠道微生物组 通过多种方式与大脑沟通，其中一个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;这些代谢产物 容易穿过血脑屏障并作为组蛋白脱乙酰酶抑制剂。鉴于SCFA的能力， 改变组蛋白翻译后修饰和可能的基因表达，我们进行了转录组学分析， 青少年和成人mPFC在肠道微生物组操纵后。微生物组耗竭的青春期小鼠 吗啡治疗组的差异调节基因数量是吗啡耗尽组的3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 组蛋白去乙酰化酶抑制剂活性增强，组蛋白乙酰转移酶活性降低， 在给予吗啡的肠道微生物组减少的青少年中，DNA结合和RNA转录减少， 但在类似治疗的成年人中没有。我们以前的研究表明，减少SCFAs产生 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。目前的建议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的作用的初步结果， 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械理解。 阿片类药物强化和mPFC中的染色质修饰的代谢物。

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.