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:
  • 金额:
    $ 16.58万
  • 依托单位:
  • 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

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

项目成果

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Rebecca Hofford其他文献

Rebecca Hofford的其他文献

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{{ truncateString('Rebecca Hofford', 18)}}的其他基金

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
  • 批准号:
    10643363
  • 财政年份:
    2021
  • 资助金额:
    $ 16.58万
  • 项目类别:
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
  • 批准号:
    10369599
  • 财政年份:
    2021
  • 资助金额:
    $ 16.58万
  • 项目类别:
Social isolation: effects on the stress axis and stimulant self-administration
社会隔离:对压力轴和兴奋剂自我管理的影响
  • 批准号:
    8783514
  • 财政年份:
    2014
  • 资助金额:
    $ 16.58万
  • 项目类别:

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