Neuroinflammation, Inflammatory Challenge, and Memory

神经炎症、炎症挑战和记忆

• 批准号: 7475843
• 负责人: STEVEN F MAIER
• 金额: $ 34.92万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475843
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Animals; Astrocytes; Attention; Bacterial Infections; Blood; Brain; Brain-Derived Neurotrophic Factor; Cells; Clinical; Cognition; Cognitive; Coin; Communication; Complex; Condition; Data; Dendritic Cells; Disease; Disruption; Elderly; Escherichia coli; Escherichia coli Infections; Event; Genetic Transcription; Goals; Hippocampus (Brain); Human; IL6 gene; Immune; Immune system; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Lead; Learning; Life; Literature; Mediating; Mediator of activation protein; Memory; Memory impairment; Methods; Microglia; Motor; Neurodegenerative Disorders; Neuroglia; Norway; Numbers; Operative Surgical Procedures; Organ; Pathology; Peripheral; Play; Postoperative Period; Process; Production; Psychological Stress; Rat Strains; Rattus; Reporting; Research; Rest; Risk; Rodent Model; Role; Route; Short-Term Memory; Signal Transduction; Stress; Tumor Necrosis Factor-alpha; age effect; age related; aged; cognitive function; conditioned fear; cytokine; design; dietary restriction; experience; functional outcomes; juvenile animal; long term memory; macrophage; neuroinflammation; neurotrophic factor; normal aging; novel; prevent; relating to nervous system; response; senescence; social stress

DESCRIPTION (provided by applicant): This proposal is directed at understanding some of the factors that contribute to cognitive decline during aging. It is motivated by the novel hypothesis that aging is a vulnerability factor that sensitizes or primes glial cells, thereby resulting in an age-related exaggerated brain proinflammatory cytokine (PIC) response to certain challenges. It is this sensitized PIC response, and its "downstream" products that are hypothesized to be at the core of the aged humans' (& animals') vulnerability to cognitive dysfunctions often associated with bacterial infection, surgery, and stress. The hypothesis rests on the following findings: 1) In response to infection or injury, immune cells in the periphery release PICs such as interleukin-1beta. 2) PICs can signal the brain and induce the synthesis and release of PICs in the brain, primarily by glial cells. 3) PICs in the brain, particularly ILI beta in the hippocampus, can interfere with memory consolidation, and perhaps other cognitive processes Thus, if aging sensitizes glial cells, then there should be exaggerated brain PIC responses to challenge in the aged, and a resultant impairment in memory formation. The first Aim asks whether the aged rat is more vulnerable to memory impairments associated with immune system activation and other events that induce hippocampal PICs (peripheral infection, surgery, and social stress). The second Aim asks whether glial activation, brain PICs, and downstream products of PICs, particularly reductions in brain derived neurotrophic factor (BDNF) are responsible for the age-related memory impairments produced by these challenges. The third Aim investigates whether a manipulation that is known prevent age-related glial priming, namely dietary restriction (DR), will prevent age-related exaggeration of brain PIC responses and challenge-induced memory impairments.

描述(由申请者提供)：这项建议旨在了解在衰老过程中导致认知能力下降的一些因素。它的动机是新的假设，即衰老是一个脆弱的因素，使神经胶质细胞敏感或启动，从而导致与年龄相关的夸大的脑前炎症细胞因子(PIC)对某些挑战的反应。正是这种敏化的PIC反应及其“下游”产物被认为是老年人(和动物)对通常与细菌感染、手术和压力相关的认知功能障碍的脆弱性的核心。这一假说基于以下发现：1)外周免疫细胞对感染或损伤做出反应，释放白介素1β等PIC。2)PICs可以向大脑发出信号，并诱导脑内PICs的合成和释放，主要是通过神经胶质细胞。3)大脑中的PIC，特别是海马区的ILIβ，可以干扰记忆的巩固，也许还有其他认知过程。因此，如果衰老使神经胶质细胞变得敏感，那么应该有夸大的大脑PIC反应来应对老年人的挑战，从而导致记忆形成的障碍。第一个目的是询问老年大鼠是否更容易受到与免疫系统激活和其他导致海马区疼痛的事件(外周感染、手术和社会应激)相关的记忆损伤的影响。第二个目的是询问胶质细胞激活、脑PICs及其下游产物，特别是脑源性神经营养因子(BDNF)的减少是否与这些挑战造成的年龄相关记忆障碍有关。第三个目的是研究一种已知的防止年龄相关胶质启动的操作，即饮食限制(DR)，是否将防止与年龄相关的大脑PIC反应的夸大和挑战诱导的记忆损伤。