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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.

项目概要：青少年的首选药物是酒精，当他们喝酒时，这是在狂欢，消费更多喝了四杯还多持续的额叶皮层发育使得青少年饮酒者容易受到长期酗酒的影响。早期饮酒与认知功能相关损害，减少白色物质含量，和突触修剪在额叶皮层。发展的风险酒精使用障碍会增加年轻人开始喝酒的次数。然而，分子机制酒精引起的前额皮质发育的潜在持续变化尚未完全了解。我们最近报道，青少年酗酒改变了乙醇敏感性，增加了认知缺陷，坚持到成年。这些行为变化伴随着基因表达的减少负责调节组蛋白甲基化和髓鞘形成，这表明酗酒改变了转录景观和额叶皮层髓鞘的发展。这项提案将考验酒精过量对组蛋白甲基化调控可能是导致额叶皮质髓鞘减少，导致行为改变，并持续到成年期。这该提案将使用染色质免疫沉淀结合大规模平行RNA- 测序以确定青少年狂欢改变的表观遗传位点和并发基因表达谱乙醇和转录谱持续到成年期。我们将首先描述乙醇在青少年中使用时程和剂量反应对少突胶质细胞发育的损伤。我们将研究组蛋白甲基化对少突胶质细胞成熟的作用，额叶皮层中少突胶质细胞富集的细胞群中的负责基因。最后我们将机械地测试使用病毒载体递送来调节组蛋白甲基化水平以拯救成年人的认知和酒精敏感行为。这些研究将使用发育和性别依赖模型进行综合的表观遗传，基因组和行为分析的反应，青少年酒精暴露我们在本提案中的目标是确定当前和长期的潜在机制， PFC中的持久转录变化，并决定其对持续认知缺陷的贡献以及青春期酗酒导致的酒精敏感性增加。这些研究将开始，确定和机械测试可能的新的治疗目标，用于干预早期酒精中毒，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

Areas of Convergence and Divergence in Adolescent Social Isolation and Binge Drinking: A Review.