Aberrant DNA methylation and parenting behavior associated with caregiver maltreatment

 描述（由申请人提供）：照顾者在早期发育过程中的经历深刻地影响了大脑和行为的发育。照顾者虐待会增加日后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的基础。然而，这主要是基于相关证据，因果关系尚未确立。使用我们开发的啮齿动物模型，我们已经表明，照顾者虐待诱导与脑源性神经营养因子（Bdnf）基因相关的DNA异常甲基化在前额叶皮层（高甲基化），杏仁核（低甲基化）和海马（高甲基化）的雌性大鼠。我们还发现，雌性成年后在怀孕期间表现出更多的焦虑样行为，并虐待自己的后代。最后，我们已经表明，异常的皮质BDNF基因表达和DNA甲基化模式（高甲基化）诱导的照顾者虐待是可逆的，在成年期的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讨中心假设，即表观遗传基因的变化是与照顾者虐待相关的养育行为的基础。第一个目标是确定DNA甲基化的药理学操作是否改善了麦芽糖处理的雌性动物的行为。第二个目标是确定在虐待时用去甲基化剂治疗女性是否可以防止异常甲基化和母性行为的出现。最后，第三个目标的目标是表征基因特异性DNA甲基化模式在maltreated女性在大脑区域与母亲的行为。这些研究提供了一个创新的和翔实的方法，了解暴露于不利的环境中的表观遗传后果。此外，从这些研究中产生的数据将是第一个经验性地建立虐待诱导的DNA甲基化改变和养育行为之间的因果关系。

 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.