Intrauterine inflammation affects offspring cognitive function

描述(申请人提供)：怀孕期间母体感染很常见，可能会导致胎儿的不良神经发育结果，如智力残疾和执行功能障碍。重要的是，孕妇在怀孕期间感染几乎是不可能预防的，因为只有在感染之后才能检测到，那时可能已经对胎儿造成了损害。因此，必须制定策略和治疗方法，以促进和支持暴露在母体感染后的后代的健康大脑发育。这些类型的干预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个：(1)动物模型必须与翻译相关，(2)评估小鼠的更高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全身给药细菌(脂多糖)或病毒(PolyI：C)模拟物。然而，这些动物模型对人类怀孕期间最常见的临床情景的有效性尚未得到证明。与系统模型相比，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，占足月新生儿的6%，每年导致超过24万名受影响的新生儿。为此，我们开发了一种宫内炎症的小鼠模型(宫内注射内毒素)，导致足月出生的后代出生后脑损伤， 以胎儿神经元异常的树突状铁化为特征。重要的是，这个小鼠模型最合适地模拟了最常见的人类临床场景，即胎儿将暴露在产前炎症中。在成年期，暴露的后代在神经元和神经胶质通路上表现出显著的基因表达变化，最明显的是在前额叶皮质。在两个目标中，我们将检查暴露的子代的执行功能和焦虑和抑郁相关行为，以及评估多巴胺能功能障碍作为潜在的机制。这个合作团队包括埃洛维茨博士和雷耶斯博士。埃洛维茨博士是一名内科科学家，他的床边经验直接导致了一种与翻译相关的小鼠宫内感染模型的开发。雷耶斯博士是一名神经科学家，在发育编程、神经免疫学和评估小鼠的高级认知功能方面拥有丰富经验。好了！

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. !