Histone methylation as a potential mechanism for myelin deficits and behavioral alterations following adolescent binge ethanol

组蛋白甲基化是青少年酗酒后髓磷脂缺陷和行为改变的潜在机制

基本信息

批准号：
10408709
负责人：
JENNIFER T WOLSTENHOLME
金额：
$ 34.88万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408709
关键词：
Acute Adolescence Adolescent Adult Affect Alcohol consumption Alcoholism Alcohols Behavior Behavioral Brain Cells ChIP-seq Chromatin Cognitive Cognitive deficits Consumption Coupled Development Dose Epigenetic Process Ethanol Exposure to Female Gene Expression Gene Silencing Genes Genetic Transcription Genomics Goals Heterochromatin Hour Immunohistochemistry Impaired cognition Intervention Link Mediating Memory impairment Methylation Modeling Molecular Mus Myelin Nature Oligodendroglia Pharmaceutical Preparations Population Prefrontal Cortex Regulation Reporting Risk Risk Factors Role Structure Surveys Testing Time Transcript Viral Vector adolescent alcohol exposure alcohol effect alcohol exposure alcohol response alcohol risk alcohol sensitivity alcohol use disorder behavioral response binge drinking brain behavior cerebral atrophy chromatin immunoprecipitation chronic alcohol ingestion delivery vehicle early alcohol use epigenetic regulation executive function frontal lobe gene network genome-wide high risk histone methylation mRNA Expression male molecular marker myelination nervous system disorder new therapeutic target oligodendrocyte precursor protein expression response sex synaptic pruning transcriptome transcriptome sequencing underage drinker underage drinking white matter

项目摘要

Project Summary: Adolescents’ overwhelming drug of choice is alcohol, and when they drink, it is in binges, consuming more than four drinks in a few hours. Ongoing frontal cortex development makes adolescent drinkers particularly vulnerable to long-term consequences of binge ethanol. Early alcohol use is associated with cognitive impairments, reduced white matter content, and synaptic pruning in the frontal cortex. The risk for developing an alcohol use disorder increases the younger one begins to drink. However, the molecular mechanisms underlying alcohol-induced persistent changes in prefrontal cortex development are not fully understood. We recently reported that adolescent binge ethanol altered ethanol sensitivity and increased cognitive deficits that persist into adulthood. These behavioral changes were accompanied by reduced expression of genes responsible for regulating histone methylation and myelination, suggesting that binge ethanol alters the transcriptional landscape and the development of myelin in the frontal cortex. This proposal will test the hypothesis that regulation of histone methylation by binge ethanol may be a mechanism underlying the reduction of myelin in the frontal cortex and consequent behavioral changes that persist into adulthood. This proposal will test these hypotheses using chromatin immunoprecipitation coupled with massively parallel RNA- sequencing to identify the epigenetic loci and concurrent gene expression profiles altered by adolescent binge ethanol and transcript profiles that persist into adulthood. We will first characterize the trajectory of ethanol’s insults on oligodendrocyte development using a time course and dose response in adolescents. We will investigate the role of histone methylation on oligodendrocyte maturation by directly interrogating the responsible genes in oligodendrocyte-enriched cell populations in the frontal cortex. Finally, we will mechanistically test the effects of modulating histone methylation levels using viral vector delivery to rescue the adult cognitive and ethanol sensitive behaviors. These studies will use developmental and sex dependent models to perform a combined epigenetic, genomic, and behavioral analysis of the response to adolescent ethanol exposure. Our goals in this proposal are to identify the mechanisms underlying the immediate and long lasting transcriptional changes in the PFC and determine their contributions to the persistent cognitive deficits and increased ethanol sensitivity resulting from binge ethanol during adolescence. These studies will begin to identify and mechanistically test possible novel therapeutic targets for intervention in early alcoholism or alcohol-related neurological disease.

项目摘要：青少年选择的压倒性药物是酒精，当他们喝酒时，它是在味道中，消耗更多几个小时内的四杯酒。持续的额叶皮层开发使青春期饮酒者尤其容易受到暴饮暴食的长期后果。早期饮酒与认知有关额叶皮层中的损伤，白质含量减少和突触修剪。发展的风险饮酒障碍会增加年轻的人开始喝酒。但是，分子机制尚未完全了解潜在的酒精引起的前额叶皮层发育的持续变化。我们最近报道，青少年的贝格乙醇改变了乙醇的敏感性，并增加了认知缺陷，坚持成年。这些行为变化是通过降低基因表达来实现的负责控制组蛋白甲基化和髓鞘化，表明暴饮暴食会改变转录景观和额叶皮层中髓磷脂的发育。该建议将测试假设通过暴饮暴食乙醇调节组蛋白甲基化可能是一种机制额叶皮质中髓磷脂的减少以及随之而来的行为变化一直持续到成年。这提案将使用染色质免疫沉淀与大量平行RNA-的染色质免疫沉淀检验这些假设测序以识别青少年Benge改变的表观遗传基因座和并发基因表达谱乙醇和成绩单概况一直持续到成年。我们将首先描述乙醇的轨迹使用时间过程和青少年的剂量反应对少突胶质细胞的侮辱。我们将通过直接询问组蛋白甲基化对少突胶质细胞成熟的作用额叶皮质中少突胶质细胞富含细胞群的负责基因。最后，我们会的机械地测试使用病毒载体递送调节组蛋白甲基化水平的影响成人认知和乙醇敏感行为。这些研究将使用发展和性依赖性进行对青少年反应的表观遗传，基因组和行为分析的模型乙醇暴露。我们在此提案中的目标是确定直接和长期的基础机制 PFC的持久转录变化并确定其对持续认知缺陷的贡献并提高了青少年期间暴饮暴食乙醇引起的乙醇敏感性。这些研究将开始识别和机械测试可能的新型治疗靶标，以干预早期酒精中毒或酒精相关的神经系统疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes.

DOI：
10.3389/fnmol.2023.1082104
发表时间：
2023
期刊：
FRONTIERS IN MOLECULAR NEUROSCIENCE
影响因子：
4.8
作者：
Brocato, Emily R.;Wolstenholme, Jennifer T.
通讯作者：
Wolstenholme, Jennifer T.

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice.

DOI：
10.3389/fnins.2023.1287584
发表时间：
2023
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Lodha J;Brocato ER;Nash M;Marcus MM;Pais AC;Pais AB;Miles MF;Wolstenholme JT
通讯作者：
Wolstenholme JT

Connecting the Dots: Adolescent Alcohol, Enhancer RNA, and Anxiety.

连接点：青少年酒精、增强子 RNA 和焦虑。