Intrauterine inflammation affects offspring cognitive function

宫内炎症影响后代认知功能

基本信息

批准号：
8666670
负责人：
TERESA M REYES
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666670
关键词：
Adult Adverse effects Affect Animal Model Animals Anxiety Area Attention Autistic Disorder Automobile Driving Behavior Behavioral Behavioral Model Biological Birth Boxing Brain Brain Injuries Clinical Cognitive Data Detection Development Dopamine Evaluation Exposure to Female Fetal Membranes Fetus Functional disorder Gene Expression Human Immunohistochemistry Impulsivity Infant Infection Infection of amniotic sac and membranes Inflammation Intellectual functioning disability Intervention Light Lipopolysaccharides Litter Size Measures Mental Depression Messenger RNA Modeling Mus Neurons Outcome Pathway interactions Physicians Poly I-C Population Prefrontal Cortex Pregnancy Premature Birth Relative (related person)Risk Schizophrenia Scientist Tail Suspension Task Performances Term Birth Testing Therapeutic Training Viral Weight Western Blotting Work cognitive function design endophenotype executive function experience fetal flexibility in utero male mimetics mouse model neurobehavioral neuroimmunology novel novel therapeutics offspring postnatal premature prenatal prevent programs protein expression public health relevance pup research study

项目摘要

DESCRIPTION (provided by applicant): Maternal infection during pregnancy is common and can cause adverse neurodevelopmental outcomes in the fetus, such as intellectual disability and deficits in executive function. Importantly, maternal infection during pregnancy is virtually impossible to prevent as detection occurs only after infection, when damage to the fetus may have occurred. Therefore, strategies and therapeutics must be developed to promote and support healthy brain development in the offspring subsequent to exposure to maternal infection. These types of interventions must first be developed in an animal model. The primary barriers to progress in this area are two-fold; (1) the animal model must be translationally relevant and (2) evaluation of higher cognitive function in a mouse is challenging. The most widely used model of prenatal maternal infection involves the use of systemic administration of bacterial (lipopolysaccharide, LPS) or viral (poly I:C) mimetics. However, the validity of these animal models to the most common clinical scenarios during human pregnancy has not been demonstrated. In contrast to the systemic models, an in utero or local model more aptly mirrors intrauterine infection and/or chorioamnionitis (inflammation of the fetal membranes). Intrauterine inflammation is common, present in 6% of term births, and results in over 240,000 affected births per year. To that end, we have developed a mouse model of intrauterine inflammation (intrauterine LPS administration) that leads to offspring born at term with postnatal brain injury, characterized by aberrant dendritic arboritization of fetal neurons. Importantly, this mouse model serves to most aptly mimic the most common human clinical scenario by which a fetus would be exposed to prenatal inflammation. In adulthood, exposed offspring demonstrate significant gene expression changes in neuronal and glial pathways, most notably in the prefrontal cortex. In two aims, we will examine executive function and anxiety and depression-related behaviors in exposed offspring, as well as evaluate dopaminergic dysfunction as a potential mechanism. This collaborative team includes Dr. Elovitz, a physician-scientist whose experience at the bedside led directly to the development of a translationally relevant mouse model of intrauterine infection and Dr. Reyes, a neuroscientist with experience in developmental programming, neuroimmunology and assessment of higher cognitive function in the mouse. !

描述（由申请人提供）：怀孕期间的孕产妇感染很普遍，可能会导致胎儿的不良神经发育结果，例如智力残疾和执行功能中的缺陷。重要的是，在怀孕期间的孕产妇感染实际上是不可能防止的，因为只有在感染后发生检测，可能发生了对胎儿的损害。因此，必须制定策略和治疗剂，以促进和支持在暴露于孕产妇感染之后的后代中健康的大脑发育。这些类型的干预措施必须首先在动物模型中开发。该地区进步的主要障碍是两个倍。（1）动物模型必须在翻译上相关，并且（2）评估小鼠中较高的认知功能是具有挑战性的。产前孕产妇感染的最广泛使用的模型涉及使用全身性施用细菌（脂多糖，LPS）或病毒（Poly I：C）模拟物。但是，尚未证明这些动物模型对人类怀孕期间最常见的临床情况的有效性。与全身模型相反，子宫或局部模型更恰当地反映了宫内感染和/或绒毛膜膜炎（胎儿膜的炎症）。宫内炎症很常见，占6％的定期出生，每年产生超过240,000次出生。为此，我们开发了一种宫内炎症（宫内LPS给药）的小鼠模型，该模型导致后代在产后脑损伤时出生，其特征是胎儿神经元异常的树突状树皮化。重要的是，该小鼠模型最适合地模仿了最常见的人类临床情况，胎儿会暴露于产前炎症。在成年期，暴露的后代表现出神经元和神经胶质途径的显着基因表达变化，最著名的是在前额叶皮层中。在两个目标中，我们将研究裸露后代的执行功能，焦虑和与抑郁症相关的行为，并评估多巴胺能功能障碍作为潜在机制。这个合作团队包括一位医生科学家Elovitz博士，他在床边的经验直接导致了宫内感染的翻译相关的鼠标模型，而神经科学家Reyes博士则是一名具有发展性编程，神经免疫学经验的神经科学家，并且在鼠标中评估了较高的认知功能。呢