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
- 来源:
- 关键词:AccelerationAdolescenceAdolescentAdultAdverse eventAffectAnimalsAntibioticsArchitectureAreaBackBacteriaBehaviorBehavioralBrainBrain regionChIP-seqChromatinCocaineCommunicationDNA BindingDataDevelopmentDrug ModulationDrug usageEmotionalEpigenetic ProcessEssential DrugsExposure toFemale AdolescentsFiberGene ExpressionGenesGenetic TranscriptionHistone AcetylationHistone Deacetylase InhibitorHistonesInflammationIntakeLesionLifeLinkMale AdolescentsMeasuresMedialMental disordersMethodsModelingMolecularMorphineMotivationMusOntologyOpioidPathologicPathway interactionsPatternPeripheralPharmaceutical PreparationsPhysiologicalPost-Translational Protein ProcessingPredispositionPrefrontal CortexProductionPsychological reinforcementRNARattusRewardsRisk FactorsRoleRouteSelf AdministrationSiteSubstance Use DisorderSupplementationSystemTestingTimeVolatile Fatty AcidsWorkaddictionanxiety-like behaviorbehavioral responsebiological adaptation to stressblood-brain barrier crossingchromatin immunoprecipitationchromatin modificationcocaine rewardconditioned place preferencecritical developmental perioddrinking waterdrug of abusedrug rewardepigenetic regulationexperimental studyfatty acid supplementationfentanyl self-administrationgut bacteriagut microbiomegut-brain axishistone acetyltransferasehistone modificationhypothalamic-pituitary-adrenal axisinsightknock-downmesolimbic systemmicrobiomemyelinationpreferencepreventresponsesexsynaptic pruningsystemic inflammatory responsetranscriptomic 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
项目成果
期刊论文数量(0)
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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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