Signaling cascades and memory deficits during aging

摘要/摘要 即使没有痴呆症，成功和不成功之间仍然存在二分法 认知老化长期目标是提供干预措施以延迟、预防或治疗 与不成功的老龄化相关的认知衰退，以改善健康和良好的， 作为美国老年人。这项工作的总体假设是， 巩固缺陷是认知能力下降的早期标志。据推测，记忆 缺陷是由NMDA受体（NMDAR）信号级联的活化受损引起的， 指导维持海马功能的基因表达。这些研究将检查 信号级联在两个领域的海马（CA 1和齿状回）的大鼠， 不同的年龄，以区分何时何地与记忆缺陷相关的变化 首先出现。具体目标1将在体外结合联合收割机行为表征 电生理学、蛋白质和基因表达分析来检验记忆 整合缺陷是由于激活信号级联的能力降低， 对记忆很重要。初步数据表明，NMDAR突触反应和 中老年记忆巩固动物ERK活性降低 相对于年龄匹配的未受损大鼠的缺陷。脑组织检查支持 这种观点认为，缺陷与经验减少有关， 结构（组蛋白乙酰化）和与突触活动相关的基因表达。 具体目标2将检验神经炎症有助于降低 信号级联和认知能力下降。据预测，非甾体抗炎药 非甾体类抗炎药（NSAID）将逆转NMDAR激活的信号级联活性的降低， 改善老年动物的记忆力。同样的技术和措施将用于 检查对照和NSAID治疗的动物。初步数据显示记忆受损 动物表现出神经炎症的标志物，观察到细胞因子的表达增强 以及与细胞应激和记忆巩固缺陷相关的基因， 神经炎症可以通过NSAID治疗逆转。

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.