Aberrant DNA methylation and parenting behavior associated with caregiver maltreatment

与照顾者虐待相关的异常 DNA 甲基化和养育行为

基本信息

批准号：
9356526
负责人：
Tania Lynn Roth
金额：
$ 29.13万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9356526
关键词：
Aberrant DNA Methylation Adult Adverse event Affect Amygdaloid structure Animals Automobile Driving BDNF gene Behavior Behavioral Behavioral Mechanisms Biochemical Brain Brain region Brain-Derived Neurotrophic Factor Candidate Disease Gene Caregivers Child Abuse and Neglect Child Rearing Chromatin Cytosine DNA Methylation DNA Sequence Data Development Drug vehicle Environment Enzymes Epigenetic Process Exhibits Exposure to Female Future Gene Expression Gene Expression Alteration Gene Expression Regulation Genes Genetic Fingerprintings Genome Genomic DNA Goals Hippocampus (Brain)Histone Deacetylase Histone Deacetylase Inhibitor Hypermethylation Impaired cognition Individual Infant Intervention Link Maternal Behavior Measures Medial Mediating Mediator of activation protein Memory Mental disorders Methylation Molecular Moods Neuronal Plasticity Nucleus Accumbens Oral Outcome Pharmacology Play Postpartum Period Prefrontal Cortex Pregnancy Preoptic Areas Process Psychopathology Public Health Rattus Regimen Rewards Risk Rodent Model Role Sodium Butyrate Stroke Synaptic plasticity Testing Time Ventral Tegmental Area Work Zebularine anxiety-like behavior base behavioral outcome brain behavior caregiving cohort efficacy testing epigenetic regulation experience genomic RNA improved innovation insight maltreatment methylation pattern mood regulation neurodevelopment novel offspring postnatal prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Caregiver experiences during early development profoundly affect development of the brain and behavior. Caregiver maltreatment imparts risk for later cognitive dysfunction and psychiatric disorders. An emerging idea is that epigenetic marking of the genome may underlie the genesis of these outcomes. However, this is based largely on correlational evidence and a causal relationship has not been established. Using a rodent model that we developed, we have shown that caregiver maltreatment induces aberrant methylation of DNA associated with the Brain-derived neurotrophic factor (Bdnf) gene within the prefrontal cortex (hypermethylation), amygdala (hypomethylation), and hippocampus (hypermethylation) of female rats. We have also shown that females when adult exhibit more anxiety-like behavior during gestation and mistreat their own offspring. Finally, we have shown that aberrant cortical Bdnf gene expression and DNA methylation patterns (hypermethylation) induced by caregiver maltreatment are reversible in adulthood by pharmacological manipulation of DNA methylation. The present project will utilize our rodent model to explore the central hypothesis that epigenetic gene changes are a basis for parenting behavior associated with caregiver maltreatment. The goal of the first aim is to determine whether pharmacological manipulation of DNA methylation improves behavior of maltreated-females. The goal of the second aim is to determine whether treatment of females with a demethylating agent at the time of maltreatment can prevent the emergence of aberrant methylation and maternal behavior. Finally, the goal of the third aim is to characterize gene-specific DNA methylation patterns in maltreated-females in brain regions associated with maternal behavior. These studies provide an innovative and informative approach for understanding the epigenetic consequences of exposure to an adverse caregiving environment. Furthermore, data generated from these studies will be the first to empirically establish a causal link between maltreatment-induced DNA methylation alterations and parenting behavior.

描述（由适用提供）：早期发展过程中的护理人员经验深刻影响大脑和行为的发展。照顾者虐待赋予后来认知功能障碍和精神疾病的风险。一个新兴的想法是，基因组的表观遗传标记可能是这些结果的起源。但是，这主要基于相关证据，并且尚未建立因果关系。使用我们开发的啮齿动物模型，我们已经表明，护理人员虐待诱导与脑源性神经营养因子（BDNF）基因相关的DNA异常的甲基化（高甲基化），杏仁核（甲基化），甲基化（高甲基化）和女hiphipmetmethylation（Hippocampus）。我们还表明，当成年人在妊娠期间表现出更多类似焦虑的行为并虐待自己的后代时。最后，我们已经表明，通过药物对DNA甲基化的药物操纵，在成年期诱导的虐待诱导的异常皮质BDNF基因表达和DNA甲基化模式（高甲基化）是可逆的。本项目将利用我们的啮齿动物模型来探讨表观遗传基因变化是与护理人员虐待相关的育儿行为的基础的中心假设。第一个目的的目的是确定对DNA甲基化的药物操纵是否改善了虐待女性的行为。第二个目标的目的是确定在虐待时用脱甲基剂的女性的治疗是否可以防止异常的甲基化和孕产妇行为的出现。最后，第三个目的的目的是表征与母体行为相关的大脑区域中虐待女性的基因特异性DNA甲基化模式。这些研究为理解暴露于不良护理环境的表观遗传后果提供了一种创新且信息丰富的方法。此外，从这些研究产生的数据将是第一个在经验上建立虐待诱导的DNA甲基化改变与育儿行为之间的因果关系的数据。