Interaction of Epigenetic and Stress Effects on Brain and Behavior

描述(申请人提供)：最近，人们发现早期的经验可以改变影响基因表达的调控因素，使得DNA序列本身不会改变，但个人的生理和行为会受到实质性的影响。在某些情况下，这些表观遗传效应可以通过并入生殖系而代代相传，在那里它们成为永久性的，并往往与性别有关，这一点与许多情感障碍表现出性别偏见有关。这项拟议的工作将集中在关键生活史阶段(青春期周围)的压力如何与表观基因组相互作用，以影响攻击性和附属行为、大脑核团的代谢活动，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来研究多器官疾病的早期发病。将有两组：从22日龄开始，每天6小时的束缚应激，持续21天；以及非应激。在祭祀之前(120天)，动物将接受一系列的行为测试。大脑将被分成三组交替切片，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，第三组用于海马和杏仁基底外侧CA1和CA3的显微分析(使用激光捕获显微解剖获得)。特定目标1将评估跨代印记大鼠的行为表型。特定目标II将确定跨代印记大鼠是否在已知参与激励性和关联性行为的相互连接的边缘和前脑核团的明确网络中表现出不同的代谢活动模式。特定目标III将确定跨代印记大鼠表现出的独特行为特征是否反映在相关大脑区域的独特基因表达模式中。在每个具体目标中，三个假设将在三个基本比较中得到检验。假设1：长春花碱暴露的跨代效应改变了社会和附属关系相关的行为及其在特定脑核的相关代谢活动，并影响了特定基因的丰度和改变了目标脑区的表观基因组。假设2：青春期应激增强社会和附属行为及其在特定脑核的相关代谢活动，并影响特定基因的丰度和改变目标脑区的表观基因组。假设3：青春期应激以协同的方式与环境诱导的跨代表观遗传印记相互作用，以改变社会行为，并影响特定基因的丰度和改变目标脑区的表观基因组。公共卫生相关性：表观遗传修饰如何在大脑水平上调节环境和基因构成的相互作用，最终影响争斗和附属行为是拟议工作的主题。

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.