Epigenetic repression of synaptic plasticity and memory in the aging brain

 描述(申请人提供)：正常衰老伴随着认知障碍，最明显的是记忆形成和更新的中断，即将新信息整合到现有记忆中的能力。随着寿命的延长和美国人口的持续老龄化，开发预防或延长与年龄相关的认知衰退的治疗方法变得越来越重要。因此，研究老年人记忆障碍的分子机制是衰老研究的一个主要目标。在这项提案中，我们将检验组蛋白脱乙酰酶3(HDAC3)在老年啮齿动物记忆形成过程中调节基因表达的作用。HDAC3是一种强大的酶，它能产生一种抑制染色质结构，通常会抑制基因表达。我们假设，在衰老的大脑中，HDAC3参与了一种异常限制性的染色质结构，这种结构抑制了衰老大脑中正常的基因表达、突触可塑性和长期记忆。这项提案中提出的初步数据表明，18个月大的小鼠在海马体依赖的记忆形成和长时程增强(LTP)方面表现出严重的损害，LTP是记忆形成的一种细胞机制。然而，在这些小鼠中，HDAC3的基因缺失可以改善这两个过程中与年龄相关的损伤，这表明HDAC3可能限制了衰老小鼠的记忆形成和突触可塑性。此外，使用一种新的记忆更新范式，我们提供的初步数据显示，老化的小鼠在用新信息更新现有记忆时也显示出严重的障碍。这一新的更新范例允许我们在单个测试会话中独立评估原始内存和更新信息的强度，这是大多数其他内存模型所不可能做到的。由于大多数记忆不是从头开始的联系，而是对现有记忆的增加或改变(更新)，因此了解记忆更新是如何工作的以及为什么它会随着年龄的增长而受损是至关重要的。这项建议的总体目标是确定HDAC3在与年龄相关的突触可塑性、记忆形成和记忆更新的损害中的作用。目标1的重点是确定HDAC3活性在使用病毒和药物操纵HDAC3活性的长期记忆形成和更新中与年龄相关的损害中的作用。目的2建议测试HDAC3在LTP中与年龄相关的损伤中的作用。最后，在目标3中，我们将使用下一代测序方法(包括RNA-SEQ和CHIP-SEQ)来探索HDAC3在3至24个月大的小鼠的记忆形成后限制整个生命周期中的记忆更新的机制。这些实验的结果将阐明HDAC3在老化大脑的记忆形成和更新故障中的作用。了解HDAC3是如何导致年龄相关的记忆衰竭的，这既是一个重大的概念进步，也是一个潜在的治疗进步，可以用来对抗年龄相关的认知衰退。

 DESCRIPTION (provided by applicant): Normal aging is accompanied by cognitive impairments, most notably disruptions in memory formation and updating, the ability to incorporate new information into existing memory. As lifespans increase and the United States population continues to age, it is increasingly important that treatments are developed to prevent or prolong age-related cognitive decline. Thus, it is a major goal of aging research to characterize the molecular mechanisms that contribute to memory failure in aging individuals. In this proposal, we will examine the role of histone deacetylase 3 (HDAC3) in regulating gene expression during memory formation in the aging rodent. HDAC3 is a powerful enzyme that generates a repressive chromatin structure that typically inhibits gene expression. We hypothesize that in the aging brain, HDAC3 contributes to an unusually restrictive chromatin structure that suppresses normal gene expression, synaptic plasticity, and long-term memory in the aging brain. The preliminary data presented in this proposal demonstrates that 18- month-old mice show severe impairments in hippocampus-dependent memory formation, and long-term potentiation (LTP), a cellular mechanism thought to underlie memory formation. Genetic deletion of Hdac3 in these mice, however, ameliorates age-related impairments in both processes, suggesting that HDAC3 may limit memory formation and synaptic plasticity in aging mice. Additionally, using a novel memory update paradigm, we present preliminary data showing that aging mice also show severe impairments in updating existing memories with new information. This new updating paradigm allows us to independently assess the strength of both the original memory and the updated information in a single test session, something that is not possible with most other memory models. As most memories are not de novo associations but, instead, are additions or alterations (updates) to existing memory, it is critically important to understand how memory updating works and why it is impaired with aging. The overall goal of this proposal is to identify the role of HDAC3 in age-related impairments in synaptic plasticity, memory formation, and memory updating. The focus of Aim 1 is to identify the role of HDAC3 activity in age-related impairments in long-term memory formation and updating using both viral and pharmacological manipulations of HDAC3 activity. Aim 2 proposes to test the role of HDAC3 in age-related impairments in LTP. Finally, in Aim 3, we will explore the mechanism by which HDAC3 limits memory updating throughout the lifespan using next-generation sequencing methods (including RNA-seq and ChIP-seq) following memory formation in mice ranging from 3 to 24 months old. The results from these experiments will elucidate the role of HDAC3 in memory formation and updating failures in the aging brain. Understanding how HDAC3 contributes to age-related memory failure is both a significant conceptual advance and a potentially therapeutic advance that could be leveraged to combat age-related cognitive decline.