Signaling cascades and memory deficits during aging

描述（由申请人提供）：即使在没有痴呆症的情况下，成功和不成功的认知衰老之间仍然存在二分法。长期目标是提供干预措施，以延缓、预防或治疗与不成功的衰老相关的认知能力下降，以改善美国老年人的健康和福祉。这项研究的总体假设是，记忆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）信号级联反应的激活受损引起的，该信号级联反应指导维持海马功能的基因表达。这些研究将检查不同年龄的大鼠海马体（CA1和齿状回）的两个区域的信号级联，以区分何时何地与记忆缺陷相关的变化首次出现。具体目标1将结合行为特征、体外电生理学、蛋白质和基因表达分析来验证记忆巩固缺陷是由于激活对记忆很重要的信号级联的能力下降造成的。初步数据表明，与年龄匹配、未受损的大鼠相比，记忆巩固缺陷的中老年动物的NMDAR突触反应和ERK活性降低。对脑组织的检查支持这样一种观点，即缺陷与经验诱导的染色质结构（组蛋白乙酰化）变化的减少以及与突触活性相关的基因表达有关。具体目标2将验证神经炎症导致信号级联下降和认知能力下降的假设。预测非甾体抗炎药（NSAIDs）将逆转NMDAR激活信号级联活性的下降，改善衰老动物的记忆。同样的技术和措施将用于检查对照组和非甾体抗炎药治疗的动物。初步数据表明，记忆受损的动物表现出神经炎症标志物，与细胞应激和神经炎症相关的记忆巩固缺陷相关的细胞因子和基因的表达增强可以通过非甾体抗炎药治疗逆转。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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