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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：
8529885
负责人：
TERESA M REYES
金额：
$ 24万
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/8529885
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）：怀孕期间母体感染是常见的，可导致胎儿神经发育不良，如智力残疾和执行功能缺陷。重要的是，怀孕期间的母体感染实际上是不可能预防的，因为只有在感染后才会发现，此时胎儿可能已经受到损害。因此，必须制定策略和治疗方法，以促进和支持暴露于母体感染后的后代健康的大脑发育。这些类型的干预措施必须首先在动物模型中开发。在这一领域取得进展的主要障碍有两方面；(1)动物模型必须与翻译相关；(2)在小鼠身上评估高级认知功能具有挑战性。最广泛使用的产前母体感染模型涉及使用细菌（脂多糖，LPS）或病毒（聚I:C）模拟物的全身管理。然而，这些动物模型在人类怀孕期间最常见的临床情况下的有效性尚未得到证实。与全身性模型相比，子宫内或局部模型更能反映宫内感染和/或绒毛膜羊膜炎（胎膜炎症）。宫内炎症很常见，在足月分娩中占6%，每年导致超过24万例受影响的分娩。为此，我们开发了一种宫内炎症小鼠模型（宫内LPS给药），导致足月出生的后代患有产后脑损伤。