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Early Life Infection, Neuroinflammation, and Memory

生命早期感染、神经炎症和记忆

基本信息

批准号：
7862323
负责人：
Staci D Bilbo
金额：
$ 45.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-08 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862323
关键词：
Address Adult Alzheimer&apos s Disease Attention Bacteria Bacterial Infections Behavior Behavioral Brain Cell Count Cell Wall Cell physiology Cells Clinical Cognition Cognitive Computer Systems Development Data Development Disease Employee Strikes Environment Escherichia coli Escherichia coli Infections Event Exhibits Fetus Gene Expression Goals Gram-Negative Bacteria Hippocampus (Brain)Immune Immune response Immune system Immunocompetent Impaired cognition Impairment Infection Inflammation Inflammatory Interleukin-1 Interleukins Learning Life Lipopolysaccharides Longevity Memory Memory impairment Microglia Modeling Neonatal Neuraxis Neurodegenerative Disorders Neuroglia Neurosecretory Systems Newborn Infant Organism Outcome Parkinson Disease Perinatal Peripheral Phosphate Buffer Play Pregnancy Process Production Rattus Role Saline Synapses Systemic infection Techniques Testing Trauma Tumor Necrosis Factor-alpha Tumor Necrosis Factors Uterus brain behavior brain cell cytokine design immune activation insight neonate neurogenesis neuroinflammation novel postnatal prevent programs protein expression public health relevance ranpirnase relating to nervous system research study response

项目摘要

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.

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会对生物体的大脑和行为产生影响，并持续整个生物体的生命周期。据估计，1/3的妊娠会出现并发症，包括子宫、胎儿或新生儿的感染或创伤，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天全身性感染细菌（大肠杆菌）与成年期外周免疫挑战（脂多糖；LPS）与显著的记忆障碍相关。目前的提案旨在解决两个相关的问题：(1)新生儿大脑对感染的反应发生了什么变化，使大脑在以后的挑战中变得脆弱？(2)新生感染的成年大鼠的大脑在LPS刺激下发生了什么变化，从而导致记忆障碍？拟议的实验将验证这样一种假设：大脑小胶质细胞（大脑的主要免疫细胞）的长期变化是在生命早期对感染的反应中发生的，这种变化随后会导致大脑功能的改变（例如，细胞因子的产生、神经发生）和成年期的记忆障碍。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)新生儿大肠杆菌感染是否会导致成年后小胶质细胞反应性增加？(2)新生儿大肠杆菌感染引起的小胶质细胞变化是否会导致成年期大脑细胞因子反应和记忆障碍的加剧？(3)为什么出生后第4天似乎是以后生活中新生儿感染诱发的脆弱性的敏感期？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的妊娠会出现并发症，包括子宫、胎儿或新生儿的感染或创伤，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。