Intrauterine inflammation affects offspring cognitive function

描述（由申请人提供）：妊娠期间母体感染很常见，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几乎是不可能预防的，因为只有在感染后才能检测到，此时可能已经发生了对胎儿的损害。因此，必须开发策略和治疗方法来促进和支持暴露于母体感染后后代的健康大脑发育。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个方面：（1）动物模型必须具有预防相关性;（2）评价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使用细菌（脂多糖，LPS）或病毒（聚I：C）模拟物的全身施用。然而，这些动物模型对人类妊娠期间最常见的临床情况的有效性尚未得到证实。与全身模型相比，子宫内或局部模型更适合反映子宫内感染和/或绒毛膜炎（胎膜炎症）。宫内炎症是常见的，存在于6%的足月分娩中，每年导致超过240，000例受影响的分娩。 为此，我们开发了一种子宫内炎症的小鼠模型（子宫内LPS给药），该模型导致足月出生的后代患有产后脑损伤， 特征为胎儿神经元的异常树突树枝状化。重要的是，这种小鼠模型用于最恰当地模拟胎儿将暴露于产前炎症的最常见的人类临床情况。在成年期，暴露的后代在神经元和神经胶质通路中表现出显着的基因表达变化，最显着的是在前额叶皮层中。在两个目标中，我们将检查暴露后代的执行功能和焦虑与抑郁相关的行为，以及评估多巴胺能功能障碍作为一种潜在的机制。这个合作团队包括Elovitz博士，一位医生兼科学家，他在床边的经验直接导致了宫内感染的预防相关小鼠模型的开发，以及Reyes博士，一位神经科学家，在发育编程，神经免疫学和小鼠高级认知功能评估方面具有经验。 !

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. !