Novel Animal Models of Impaired Social Behavior and Anxiety: A Role for MeCP2

描述(由申请人提供)：环境因素导致自闭症谱系障碍(ASD)的风险，需要对这些因素有更多的了解。不良的宫内环境会严重影响发育中的中枢神经系统(CNS)，并可能导致严重的神经行为后果，如自闭症和焦虑。出生体重异常是宫内环境不良的生物标志物，可受到母亲饮食或高血压、子宫或胎盘功能障碍、母亲吸烟和/或药物使用的影响。总体而言，小于胎龄(SGA)或大胎龄(LGA)每年可能影响超过50万美国婴儿。重要的是，流行病学证据表明，SGA和LGA婴儿患ASD的风险都增加了。因此，常见的宫内环境条件可能使婴儿易患自闭症和焦虑。我们已经开发了两种基于子宫内不利环境的小鼠模型，分别通过给怀孕母鼠喂低蛋白饮食或高脂肪饮食来产生SGA或LGA后代。这些SGA和LGA后代具有显著的行为和CNS基因表达差异，表明多巴胺能、5-羟色胺和阿片系统功能障碍，这些系统已知在ASD和焦虑中会改变。重要的是，MeCP2在SGA和LGA后代中的表达水平显著不同，这表明MeCP2的表达是一种潜在的重要表观遗传学机制，对宫内条件不利的反应。越来越多的证据表明，MeCP2对突触可塑性至关重要，突触功能缺陷可能是ASD的一些组成部分。此外，MeCP2缺失会导致人类出现雷特综合症，而下丘脑特异的MeCP2缺失会导致小鼠社会行为的改变。在两个目标中，这项建议将(1)检查SGA和LGA后代的社交和焦虑相关行为的发展，并比较怀孕或哺乳的关键时期，(2)使用全基因组染色质免疫沉淀测序(CHIP-SEQ)和内侧前额叶皮质和杏仁核的图谱技术，分析SGA和LGA小鼠全基因组基因表达的变化和MeCP2启动子的驻留。我们假设SGA和LGA动物都面临着社交和焦虑相关行为改变的风险增加，并且MeCP2表达的改变有助于差异基因表达和不良神经行为结果。这些模型的发展将允许未来研究神经生物学机制，将子宫环境中的不利因素和改变的社会和情绪行为与开发有针对性的治疗和干预的最终目标联系起来。 公共卫生相关性：不利的产前条件会影响婴儿大脑的发育，增加神经行为障碍的风险，如自闭症谱系障碍(ASD)或焦虑。本申请中提出的实验将使用动物模型来检查大脑和行为变化，以响应子宫内的不利条件，并潜在地确定可能的干预途径。

DESCRIPTION (provided by applicant): Environmental factors contribute to the risk for autism spectrum disorders (ASD), and a greater understanding of these factors is needed. An adverse in utero environment significantly impacts the developing central nervous system (CNS) and can result in serious neurobehavioral outcomes, such as ASD and anxiety. Abnormal birthweight is a biomarker of adverse in utero environment, and can be affected by maternal diet or hypertension, uterine or placental dysfunction, and maternal smoking and/or drug use. In total, small-for-gestational age (SGA) or large-for-gestational age (LGA) may affect over half a million American infants every year. Importantly, epidemiological evidence indicates that both SGA and LGA infants are at an increased risk for ASD. Thus, common intrauterine environmental conditions may predispose infants to ASD and anxiety. We have developed two mouse models based on an adverse in utero environment that result in SGA or LGA offspring by feeding pregnant dams a low protein diet or high fat diet, respectively. These SGA and LGA offspring have significant behavioral and CNS gene expression differences pointing to dysfunction in the dopaminergic, serotonergic and opioid systems, which are known to be altered in ASD and anxiety. Importantly, expression levels of MeCP2 are significantly different in both SGA and LGA offspring, identifying MeCP2 expression as a potential important epigenetic mechanism responsive to adverse in utero conditions. Accumulating evidence suggests that MeCP2 is critical for synaptic plasticity, and deficits in synaptic function may underlie some components of ASD. Further, MeCP2 deletion results in Rett Syndrome in humans and a hypothalamic specific MeCP2 deletion resulted in altered social behavior in mice. In two aims, this proposal will (1) examine the development of social and anxiety-related behaviors in SGA and LGA offspring and compare the critical periods of pregnancy or lactation and (2) analyze genome-wide gene expression changes in SGA and LGA mice and MeCP2 promoter residency using genome wide chromatin immunoprecipitation-sequencing (ChIP-Seq) and profiling technology in medial prefrontal cortex and amygdala. We hypothesize that both SGA and LGA animals are at increased risk for altered social and anxiety-related behaviors, and that alterations in expression of MeCP2 contribute to differential gene expression and adverse neurobehavioral outcomes. The development of these models will allow for future studies of neurobiological mechanisms that link adverse in utero environment and altered social and emotional behaviors with an eventual goal of the development of targeted therapeutics and interventions. PUBLIC HEALTH RELEVANCE: Adverse prenatal conditions can affect the development of the infant brain, increasing the risk for neurobehavioral disabilities, such as autism spectrum disorders (ASD) or anxiety. Experiments proposed in this application will use animal models to examine brain and behavior changes in response to adverse in utero conditions and potentially identify possible avenues of intervention.