Early Life Infection, Neuroinflammation, and Memory

描述(申请人提供)：发生在围产期环境中的神经内分泌或免疫事件通常会对大脑和行为产生影响，持续整个有机体的生命周期。据估计，三分之一的孕妇患有子宫、胎儿或新生儿感染或创伤的并发症，围产期感染或炎症最常见的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)与成年后严重的记忆障碍和外周免疫挑战(脂多糖；脂多糖)有关。目前的提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哪些变化，使其容易受到后来的挑战？以及(2)新生感染的成年大鼠的大脑在应对内毒素攻击时发生了什么变化，这会导致记忆障碍？拟议中的实验将检验这一假设，即大脑的主要免疫细胞--大脑小胶质细胞的长期变化是对生命早期感染的反应，感染之后会导致成年后大脑功能(如细胞因子的产生、神经发生)和记忆障碍的改变。这一假设将通过使用基因表达、蛋白质表达和行为技术来检验以下问题：(1)新生儿感染大肠杆菌是否会导致成年后小胶质细胞反应性增加？(2)新生儿感染大肠杆菌是否会导致成年后夸大的脑细胞因子反应和记忆障碍？以及(3)为什么出生后第4天似乎处于新生儿感染导致的脆弱性的敏感期？这些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、大脑的免疫反应在认知中所起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：据估计，三分之一的孕妇患有涉及子宫、胎儿或新生儿感染或创伤的并发症，围产期感染或炎症最常见的后果之一是认知功能障碍，包括学习、记忆和注意力障碍。从这项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所起的作用以及最终旨在防止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.