Signaling cascades and memory deficits during aging

衰老过程中的信号级联和记忆缺陷

• 批准号: 9266698
• 负责人: THOMAS C FOSTER
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266698
• 关键词: Age; Aging; Alzheimer' s Disease; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Award; Behavior; Behavioral; Blood specimen; Brain; Brain region; Cellular Stress; Chromatin Structure; Cognitive; Cognitive aging; Cytokine Gene; Data; Dementia; Diagnostic; Early Diagnosis; Elderly; Electrophysiology (science); Exhibits; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Transfer; Genes; Genetic Transcription; Goals; Health; Hippocampus (Brain); Histone Acetylation; Impaired cognition; Impairment; In Vitro; Inflammation; Intervention; Learning; Link; Location; Measures; Medial; Mediating; Memory; Memory Loss; Memory impairment; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neocortex; Neuroimmune; Oxidative Stress; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prefrontal Cortex; Publishing; Rattus; Research; Reverse Transcription; Serum; Serum Markers; Short-Term Memory; Signal Transduction; Specificity; Stress; Synapses; System; Technical Expertise; Techniques; Testing; Training; Viral; Viral Vector; Water; Work; age related; aged; brain tissue; cognitive process; cytokine; dentate gyrus; experience; improved; inflammatory marker; information processing; killings; massive parallel processing; memory consolidation; middle age; neuroinflammation; novel; overexpression; predictive marker; prevent; protein expression; relating to nervous system; response; spatial memory; synaptic function

Summary/Abstract Even in the absence of dementia, a dichotomy remains between successful and unsuccessful cognitive aging. The long range goal is to provide interventions to delay, prevent, or treat cognitive decline associated with unsuccessful aging in order to improve the health and well- being of older Americans. The overall hypothesis for the proposed work is that memory consolidation deficits are an early marker of cognitive decline. It is hypothesized that memory deficits result from impaired activation of NMDA receptor (NMDAR) signaling cascades that direct the expression of genes for maintaining hippocampal function. The studies will examine signaling cascades in two fields of the hippocampus (CA1 and the dentate gyrus) of rats at different ages in order to distinguish when and where changes associated with memory deficits first emerge. Specific aim 1 will combine behavioral characterization, in vitro electrophysiology, protein and gene expression analyses to tests the hypothesis that memory consolidation deficits result from a decreased ability to activate signaling cascades that are important for memory. Preliminary data indicates that NMDAR synaptic responses and the activity of ERK is decreased in middle-aged and aged animals with memory consolidation deficits relative to aged-matched, unimpaired rats. Examination of brain tissue supports the idea that deficits are associated with a reduction in experience induced changes in chromatin structure (histone acetylation) and the expression of genes related to synaptic activity. Specific aim 2 will test the hypothesis that neural inflammation contributes to the decline in the signaling cascade and cognitive decline. It is predicted that non-steroidal anti-inflammatory drugs (NSAIDs) will reverse the decrease in NMDAR activated signaling cascade activity and improve memory in aging animals. The same techniques and measures will be used to examine control and NSAID treated animals. Preliminary data indicates that memory impaired animals exhibit markers of neuroinflammation observed as enhanced expression of cytokines and genes related to cellular stress and memory consolidation deficits associated with neuroinflammation can be reversed by NSAID treatment.

摘要/摘要 即使在没有痴呆症的情况下，成功与失败之间仍然存在二分法 认知衰老。远距离目标是提供延迟，预防或治疗的干预措施 认知能力下降与不成功的衰老相关，以改善健康和良好的健康 是年长的美国人。拟议工作的总体假设是记忆 合并缺陷是认知能力下降的早期标志。假设记忆 NMDA受体（NMDAR）信号级联激活的激活受损而导致缺陷。 指导基因维持海马功能的表达。研究将检查 在大鼠海马（CA1和齿状回）的两个田间的信号传导级联 不同的年龄以区分与内存不足相关的何时何地变化 首先出现。特定的目标1将在体外结合行为表征 电生理学，蛋白质和基因表达分析以检验记忆的假设 合并缺陷是由于激活信号级联反应的能力降低而导致的 对于记忆很重要。初步数据表明NMDAR突触反应和 中年和老年动物的ERK活性与记忆巩固 相对于年龄匹配的，未损坏的大鼠的缺陷。检查脑组织支持 缺陷与降低经验引起的染色质变化有关的想法 结构（组蛋白乙酰化）和与突触活性有关的基因的表达。 具体目标2将检验神经炎症有助于下降的假设 信号级联和认知能力下降。可以预测非甾体类抗炎 药物（NSAIDS）将逆转NMDAR激活信号级联活性的减少和 改善衰老动物的记忆力。相同的技术和措施将用于 检查对照和NSAID治疗的动物。初步数据表明内存受损 动物表现出神经炎症的标志物，观察到了细胞因子的增强表达 以及与细胞应力和记忆巩固缺陷有关的基因 NSAID治疗可以逆转神经炎症。