Aberrant DNA methylation and parenting behavior associated with caregiver maltreatment

 描述(由申请人提供)：照顾者在早期发育期间的经历深刻地影响大脑和行为的发育。照顾者虐待会增加日后认知功能障碍和精神障碍的风险。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根源。然而，这在很大程度上是基于相关证据，因果关系尚未建立。利用我们建立的啮齿动物模型，我们发现虐待照顾者会导致雌性大鼠前额叶皮质(高甲基化)、杏仁核(低甲基化)和海马区(高甲基化)中与脑源性神经营养因子(BDNF)基因相关的DNA异常甲基化。我们还表明，成年后的雌性在怀孕期间表现出更多的焦虑行为，并虐待自己的后代。最后，我们通过对DNA甲基化的药理学操作，证明了由照顾者虐待引起的皮质BDNF基因异常表达和DNA甲基化模式(超甲基化)在成年是可逆的。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父母行为的基础这一中心假设。第一个目标是确定对DNA甲基化的药理学操作是否能改善被虐待女性的行为。第二个目标是确定在虐待时用去甲基剂治疗女性是否可以防止异常甲基化和母体行为的出现。最后，第三个目标的目标是确定受虐女性大脑中与母亲行为相关的区域中特定基因的DNA甲基化模式。这些研究为理解暴露在不利照料环境中的表观遗传后果提供了一种创新和信息丰富的方法。此外，这些研究产生的数据将首次经验性地建立虐待引起的DNA甲基化改变和父母行为之间的因果联系。

 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.