Epigenetic Effects on Brain and Behavior: Testing the Role of Imprinted Genes

哺乳动物的大脑以其复杂性和可塑性而著称，同时也非常敏感。该项目将使用尖端的基因组工具来研究胎盘中表达的基因如何影响母亲及其后代的大脑和行为。该项目的重点是印记基因，一组对胎盘功能和大脑发育至关重要的基因。印记基因的表达取决于父母的起源：有些是专门从母亲的副本，有些是从父亲的副本。破坏小鼠胎盘中这种不寻常的表达模式会改变母亲的行为和生理。在人类中，印记基因与情绪和认知障碍有关。研究小组将使用一种新的小鼠模型和经典的行为测试来评估印记基因如何以及何时对母亲和后代产生影响。他们还将招募和指导美国原住民学生研究人员，并为高中科学教师提供实践研究经验。教师们将根据他们的研究制定课程计划，并将通过学习更多关于进化、遗传学和行为的知识来提高他们的科学素养。胎盘的复杂性、母性护理和高度发达的前脑是真兽目哺乳动物的定义特征。印记基因影响所有三种表型，但对这些影响如何在组织（胎盘，大脑），基因型（母亲，后代）和发育（围产期，成人）中整合知之甚少。研究人员将通过测量胎盘印记丧失（LOI）对母亲的影响，发育LOI对胚胎大脑和新生儿行为的影响，以及LOI和母体环境对成年大脑和行为的综合影响，来评估印记基因在这些相互作用中的作用。他们这样做是在一个易于处理的杂交系统中，其中可以列举出潜在的相反影响的LOI的父系与母系印记基因。胎盘LOI对母亲的影响将通过分析怀孕女性的行为、神经转录组（RNAseq）和激素水平以及哺乳母亲的行为来测试。同时，他们将测量胚胎大脑和胎盘中的表达（RNAseq）和DNA甲基化（还原亚硫酸氢盐测序），以及新生儿的行为。交叉培养将区分暴露于胎盘LOI的母亲中的改变的母体护理的影响与发育LOI对成年动物的行为和神经基因表达和甲基化的影响。这些研究将检验印记基因调节哺乳动物母亲和年轻人之间的亲密和专性关系的假设，并将促进对基因型，表观基因型和养育环境对大脑和行为的综合影响的理解，以及印记基因在胎盘信号传导和塑造成人大脑中的作用。

The mammalian brain, remarkable for its complexity and plasticity, is also profoundly sensitive. This project will use cutting-edge genomic tools to study how genes expressed in the placenta influence the brains and behavior of mothers as well as their offspring. The project focuses on imprinted genes, a group of genes that are critical to placental function and brain development. The expression of imprinted genes depends on parent-of-origin: some are expressed exclusively from the maternal copy, and some from the paternal copy. Disruption of this unusual expression pattern in mouse placenta alters the behavior and physiology of mothers. In humans, imprinted genes are linked to mood and cognition disorders. The research team will use a novel mouse model and classic behavioral tests to assess how and when imprinted genes exert their effects on mothers and offspring. They will also recruit and mentor Native American student researchers, and provide hands-on research experiences for high school science teachers. The teachers will develop lesson plans based on their research, and will enhance their scientific literacy by learning more about evolution, genetics and behavior.Placental complexity, maternal care, and a highly developed forebrain are defining features of eutherian mammals. Imprinted genes affect all three phenotypes but little is known about how these effects are integrated across tissues (placenta, brain), genotypes (mother, offspring), and development (perinatal, adult). The researchers will assess the role of imprinted genes in these interactions by measuring the effects of placental loss of imprinting (LOI) on mothers, of developmental LOI on embryonic brain and neonatal behavior, and the combined effects of LOI and maternal environment on adult brain and behavior. They do so in a tractable hybrid system, in which potentially opposing effects of LOI for paternally vs. maternally imprinted genes can be enumerated. Effects of placental LOI on mothers will be tested by profiling the behavior, neural transcriptomes (RNAseq) and hormone levels of pregnant females, and the behavior of nursing mothers. In parallel, they will measure expression (RNAseq) and DNA methylation (reduced representation bisulfite sequencing) in embryonic brain and placenta, and behavior in neonates. Cross-fostering will separate effects of altered maternal care in mothers exposed to placental LOI, from effects of developmental LOI, on behavior and neural gene expression and methylation in adult animals. These studies will test the hypothesis that imprinted genes regulate the intimate and obligate relationship between mammalian mothers and young, and will advance understanding of the combined effects of genotype, epigenotype and rearing environment on brain and behavior, and the role of imprinted genes in placental signaling and in shaping the adult brain.