Early Life Infection, Neuroinflammation, and Memory

描述（由申请人提供）：围产期环境中发生的神经内分泌或免疫事件通常对大脑和行为产生影响，并持续整个生物体的寿命。估计有1/3的孕妇患有涉及子宫、胎儿或新生儿感染或创伤的并发症，围产期感染或炎症的最常见后果之一是认知功能障碍，包括学习、记忆和注意力障碍。大鼠出生后第4天全身感染细菌（大肠杆菌）与成年期外周免疫攻击（脂多糖; LPS）相关的显著记忆障碍。目前的建议旨在解决两个相关的问题：（1）新生儿大脑在感染后发生了什么变化，使大脑容易受到后来的挑战？以及（2）在LPS刺激下，成年大鼠脑内发生了什么样的变化，从而导致记忆障碍？拟议的实验将测试以下假设：脑小胶质细胞（脑的主要免疫细胞）的长期变化是对生命早期感染的反应，然后导致脑功能改变（例如，细胞因子产生、神经发生）和成年期记忆障碍。这一假说将通过研究以下问题，使用基因表达，蛋白质表达，和行为技术进行检验：（1）新生儿E。大肠杆菌感染导致成年期小胶质细胞反应性增加？(2)做新生儿E.大肠杆菌感染引起的小胶质细胞变化是成年期脑细胞因子反应过度和记忆障碍的基础？以及（3）为什么出生后第4天似乎是新生儿感染诱导的脆弱性在以后的生活中的敏感时期？这些集体数据将为早期免疫激活对神经和免疫系统发育的影响，大脑免疫反应在认知中的作用以及最终的治疗决策提供新的见解。公共卫生相关性：估计有1/3的孕妇患有涉及子宫、胎儿或新生儿感染或创伤的并发症，围产期感染或炎症的最常见后果之一是认知功能障碍，包括学习、记忆和注意力障碍。从该提案中收集的数据将为早期免疫激活对神经和免疫系统发育的影响，大脑免疫反应在认知中的作用以及最终旨在预防早期感染或创伤的负面后果的治疗决策提供新的见解。

DESCRIPTION (provided by applicant): Neuroendocrine or immune events occurring within the perinatal environment often produce effects on brain and behavior that endure throughout an organism's life span. An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. Systemic infection with bacteria (Escherichia coli) on postnatal day 4 in rats is associated with dramatic memory impairments in conjunction with a peripheral immune challenge (lipopolysaccharide; LPS) in adulthood. The current proposal is designed to address two related questions: (1) What changes occur in the neonatal brain in response to the infection that render the brain vulnerable to a later challenge? and (2) What changes occur in the brains of neonatally-infected adult rats in response to the LPS challenge, which produce the memory impairments? The proposed experiments will test the hypothesis that long-term changes in brain microglia, the primary immune cells of the brain, occur in response to infection early in life, which then contribute to altered brain function (e.g., cytokine production, neurogenesis) and memory impairment in adulthood. This hypothesis will be tested by examining the following questions, using gene expression, protein expression, and behavioral techniques: (1) Does neonatal E. coli infection result in increased microglial reactivity in adulthood? (2) Do neonatal E. coli infection-induced changes in microglia underlie exaggerated brain cytokine responses and memory impairments in adulthood? and (3) Why does postnatal day 4 appear to be during a sensitive period for neonatal infection- induced vulnerabilities later in life? These collective data will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimate treatment decisions. PUBLIC HEALTH RELEVANCE: An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. The data collected from this proposal will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimately treatment decisions aimed at preventing the negative consequences of early infection or trauma.