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：
9080464
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/9080464
关键词：
Aberrant DNA Methylation Adult Adverse event Affect Amygdaloid structure Animals Automobile Driving Behavior Behavioral Behavioral Mechanisms Biochemical Brain Brain region Brain-Derived Neurotrophic Factor Breeding 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 Genes Genome Genomic DNA Goals Hippocampus (Brain)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 Outcome 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（由申请人提供）：早期发育过程中的照顾者经历深刻影响大脑和行为的发育。照顾者虐待会带来后期认知功能障碍和精神疾病的风险。一个新兴的观点是，基因组的表观遗传标记可能是这些结果的根源。然而，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，护理人员的虐待会导致与脑源性 DNA 相关的 DNA 异常甲基化。我们还发现，雌性大鼠在成年后会表现出更多类似焦虑的行为，并会虐待自己的后代。最后，我们证明了由看护者虐待引起的异常皮质 Bdnf 基因表达和 DNA 甲基化模式（高甲基化）在成年后是可逆的DNA 甲基化的药理学操作本项目将利用我们的啮齿动物模型来探索表观遗传基因变化是与照顾者虐待相关的养育行为的基础的中心假设，第一个目标是确定 DNA 甲基化的药理学操作是否会改善。第二个目标是确定在受虐待时使用去甲基化剂治疗是否可以防止异常甲基化和母性行为的出现。表征受虐待女性大脑区域与母亲行为相关的基因特异性 DNA 甲基化模式，这些研究为了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。第一个凭经验确定虐待引起的 DNA 甲基化改变与养育行为之间的因果关系。