Hippocampal Network Profiles of Memory Aging

描述(申请人提供)：我们理解记忆老化的主要障碍之一是缺乏有效的工具来解决以下基本问题：记忆痕迹是什么？在老化过程中，网络级动态和内存编码模式的主要变化是什么？我们如何才能确定在老年人大脑中产生高级记忆功能的网络特征？在这一应用中，我们建议应用大规模集成记录方法来识别、可视化和表征CA1区的记忆痕迹，贯穿记忆过程的所有主要阶段，即年轻人和老年大脑的获得、巩固和提取。在我们的应用中，我们假设CA1细胞组件独特的激活和重新激活模式形成了预测记忆测试中行为表现的网络级基础。我们将通过四个具体的问题来检验这一关键假说：1)记忆获得、巩固和提取过程中CA1活动的集合模式？2)与行为记忆表现相关的基本网络特征是什么？3)衰老过程如何影响这些特征？4)NR2B在调节衰老过程中增强记忆的网络水平特征中扮演什么角色？可以想象，CA1记忆痕迹的识别和可视化应该使我们能够操纵和发现老年大脑中潜在的记忆下降的神经过程。这种新的能力和知识应该会导致针对记忆老化的潜在治疗干预的新战略。 与公共卫生相关：人和动物都表现出认知功能随着年龄的增长而恶化。注意力和记忆力逐渐下降的神经基础还知之甚少。基于我们最近成功地应用大规模活体记录技术和计算算法来监测和分析自由行为小鼠CA1区超过数百个单个神经元的活动模式，我们建议识别和表征幼年和老年动物的网络级记忆痕迹。此外，我们还将研究年轻和老年NR2B转基因小鼠增强记忆功能的神经网络基础。我们将比较野生型老龄小鼠和转基因老龄小鼠的异同。可以想象，对网络级记忆痕迹的识别和生物物理描述应该能为记忆是什么，以及记忆是如何随着年龄的增长而改变的问题提供关键的见解。

DESCRIPTION (provided by applicant): One of the major obstacles in our understanding of memory ageing is lack of an effective tool to address the fundamental questions such as: what are memory traces? What are the major alterations in the network-level dynamics and memory-encoding patterns during aging? How can we identify network characteristics that give rise to superior memory function in the aged brain? In this application, we propose to apply large-scale ensemble recording method to identify, visualize, and characterize memory traces in CA1 region throughout all major stage of the memory process, namely, acquisition, consolidation, and retrieval in both young adult and aging brains. In our application, we hypothesize that unique activation and reactivation patterns by CA1 cell assemblies form the network-level basis for predicting behavioral performances in memory tests. We will test this key hypothesis by examining four specific questions: 1) what are the ensemble patterns of CA1 activity during memory acquisition, consolidation, and retrieval? 2) What are the fundamental network-level characteristics that are correlated with behavioral memory performances? 3) How does the aging process affect those characteristics? 4) What is the role of the NR2B in the regulation of network-level features underling the enhanced memory during ageing? It is conceivable that identification and visualization of CA1 memory traces should enable us to manipulate and discover the neural processes underlying memory decline in the old brain. Such a new capacity and knowledge should lead to new strategies for potential therapeutic interventions for memory ageing. PUBLIC HEALTH RELEVANCE: Both people and animals exhibit deterioration of cognitive function as they age. The neural bases for the gradual decline in attention and memory are poorly understood. Based on our recent success in applying large-scale in vivo recording techniques and computational algorithms for monitoring and analyzing activity patterns of over hundreds of individual neurons in the CA1 region of freely behaving mice, we propose to identify and characterize network-level memory traces in both young and old animals. Moreover, we will investigate the neural network basis underlying enhanced memory function in young and aged NR2B transgenic mice. We will compare the similarity and differences between wild-type aged mice and transgenic aged mice. It is conceivable that the identification and biophysical description of network-level memory traces should provide crucial insights into the question of what memory is, and how memory is altered by ageing.