Interaction of Epigenetic and Stress Effects on Brain and Behavior

描述（由申请人提供）：最近发现，早期经历可以改变影响基因表达的调节因子，使得DNA序列本身不改变，但个体的生理和行为受到实质性影响。在某些情况下，这些表观遗传效应可以通过整合到种系中而跨代传播，在那里它们成为永久性的，并且往往是性连锁的，这是许多情感障碍表现出性别偏见的相关点。拟议的工作将集中在一个关键的生活史阶段（青春期）的压力如何可能与表观基因组相互作用，以影响攻击性和亲和行为，脑核的代谢活动，以及特定脑核的基因表达模式。我们将使用已建立的跨代表观遗传印记雄性大鼠模型用于多器官疾病的早期发作。将有两组：从22日龄开始每天束缚应激6小时，持续21天，以及无应激。在处死前（120天），将对动物进行一系列行为测试。将脑切片分为三个交替组，第一组用于细胞色素氧化酶组织化学，第二组用于原位杂交，第三组用于海马和基底外侧杏仁核的CA1和CA3进行微量分析（使用激光捕获显微切割获得）。特异性目标1将评估转基因印迹大鼠的行为表型。具体目标II将确定是否transgenerationally印迹大鼠表现出不同的模式的代谢活动在一个定义的网络的相互连接的边缘和前脑核参与激动和亲和行为。具体目标III将确定是否跨代印记大鼠表现出的独特行为特征反映在相关大脑区域的基因表达的独特模式中。在每个具体目标中，将在三个基本比较中检查三个假设。假设1：乙烯氯唑林暴露的跨代效应改变了特定脑核中的社会和亲和相关行为及其相关代谢活动，并影响特定基因的丰度和改变靶脑区域中的表观基因组。假设二：围青春期应激增强了特定脑核团中的社会和亲和行为及其相关代谢活动，并影响特定基因的丰度和改变靶脑区域的表观基因组。假设三：围青春期应激与环境诱导的跨代表观遗传印记以协同方式相互作用，以改变社会行为，以及影响特定基因的丰度和改变靶脑区域的表观基因组。公共卫生相关性：表观遗传修饰如何调节环境和遗传结构如何在大脑水平上相互作用，最终影响竞争和亲和行为，这是拟议工作的主题。

DESCRIPTION (provided by applicant): Recently it has been discovered that early experiences can modify regulatory factors affecting gene expression in such a way that the DNA sequence itself is not changed but the individual's physiology and behavior are substantially influenced. In some instances these epigenetic effects can be transmitted across generations via incorporation into the germline where they become permanent and tend to be sex-linked, a relevant point as many affective disorders show gender bias. The proposed work will focus on how stress during a critical life history stage (peripubertal) might interact with the epigenome to influence aggressive and affiliative behaviors, metabolic activity in brain nuclei, and patterns of gene expression in specific brain nuclei. We will use an established male rat model of transgenerational epigenetic imprinting for early onset of multi- organ disease. There will be two groups: daily restraint stress for 6 hours for 21 days beginning at 22 days of age, and unstressed. Prior to sacrifice (120 days) animals will given a battery of behavioral tests. The brains will be sectioned in three alternating sets, the first set for cytochrome oxidase histochemistry, the second set for in situ hybridization, and the third set for the CA1 and CA3 of the hippocampus and basolateral amygdala for microanalysis (obtained using laser-capture microdissection). Specific Aim 1 will evaluate the behavioral phenotype of transgenerationally imprinted rats. Specific Aim II will determine if transgenerationally imprinted rats exhibit different patterns of metabolic activity in a defined network of interconnected limbic and forebrain nuclei known to be involved with agonistic and affiliative behaviors. Specific Aim III will determine if the distinct behavioral profiles exhibited by transgenerationally imprinted rats are reflected in unique patterns of gene expression in relevant brain regions. Within each Specific Aim, three hypotheses will be examined in three basic comparisons. Hypothesis 1: The transgenerational effects of vinclozolin exposure modifies both social and affiliative related behaviors and its related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. Hypothesis 2: Peripubertal stress potentiates both social and affiliative behaviors and its related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. Hypothesis 3: Peripubertal stress interacts with the environmentally induced, transgenerational epigenetic imprinting in a synergistic fashion to modify social behaviors as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. PUBLIC HEALTH RELEVANCE: How epigenetic modification can modulate how the environment and genetic constitution interact at the level of the brain, ultimately influencing agonistic and affiliative behaviors is the subject of the proposed work.