Epigenetic repression of synaptic plasticity and memory in the aging brain

衰老大脑中突触可塑性和记忆的表观遗传抑制

• 批准号: 9198722
• 负责人: JANINE LYNN KWAPIS
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198722
• 关键词: Age; Age-associated memory impairment; Aging; Attention; Basic Science; Brain; ChIP-seq; Chromatin; Chromatin Structure; Data; Deacetylase; Dorsal; Enzymes; Epigenetic Process; Failure; Gene Expression; Gene Targeting; Genetic; Genetic Transcription; Goals; HDAC3 gene; Hippocampus (Brain); Histone Acetylation; Human; Impaired cognition; Impairment; Individual; Learning; Location; Long-Term Potentiation; Longevity; Maintenance; Mediating; Memory; Memory Loss; Memory impairment; Methods; Modeling; Molecular; Mus; Neurons; Pharmacology; Phase; Population; Process; Protocols documentation; Repression; Research; Rodent; Role; Slice; Synaptic plasticity; Testing; Therapeutic; Time; Training; United States; Update; Viral; Western Blotting; Work; age related; aging brain; calmodulin-dependent protein kinase II; cognitive function; combat; experimental study; genome-wide; improved; inhibitor/antagonist; long term memory; memory consolidation; mutant; next generation sequencing; normal aging; novel; novel therapeutics; prevent; protein protein interaction; public health relevance; response; transcriptome sequencing; treatment strategy

 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.

 描述（由申请人提供）：正常衰老伴随着认知障碍，最显着的是记忆形成和更新的破坏，随着寿命的延长和美国人口的持续老龄化，将新信息融入现有记忆的能力变得越来越重要。开发治疗方法是为了预防或延长与年龄相关的认知衰退，因此，表征导致衰老个体记忆障碍的分子机制是衰老研究的一个主要目标，在这项提议中，我们将研究组蛋白脱乙酰酶的作用。 HDAC3 3 (HDAC3) 在衰老啮齿动物记忆形成过程中调节基因表达 HDAC3 是一种强大的酶，可产生通常抑制基因表达的抑制性染色质结构。抑制衰老大脑中的正常基因表达、突触可塑性和长期记忆。该提案中提供的初步数据表明，18 个月大的小鼠在大脑中表现出严重的损伤。然而，海马依赖性记忆形成和长时程增强（LTP）（一种被认为是这些小鼠记忆形成的基础的细胞机制）改善了这两个过程中与年龄相关的损伤，这表明 HDAC3 可能限制记忆形成。此外，使用一种新的记忆更新范式，我们提供的初步数据表明，衰老小鼠在用新信息更新现有记忆时也表现出严重的损伤，这种新的更新范式使我们能够独立评估其强度。在单个测试会话中同时包含原始记忆和更新信息，这对于大多数其他记忆模型来说是不可能的，因为大多数记忆不是从头关联，而是对现有记忆的添加或更改（更新）。对于了解记忆更新如何发挥作用以及其为何会因衰老而受损至关重要。该提案的总体目标是确定 HDAC3 在突触可塑性、记忆形成和记忆更新方面的年龄相关损伤中的作用。 1 是要识别HDAC3 活性在长期记忆形成和更新中的年龄相关损伤中的作用目标 2 提议测试 HDAC3 在 LTP 中年龄相关损伤中的作用。我们将利用新一代测序方法（包括 RNA-seq 和 ChIP-seq），在 3 至 24 个月的小鼠记忆形成后，探索 HDAC3 在整个生命周期中限制记忆更新的机制这些实验的结果将阐明 HDAC3 在衰老大脑中记忆形成和更新失败中的作用，了解 HDAC3 如何导致与年龄相关的记忆失败，这既是一个重大的概念进步，也是一个可以利用的潜在治疗进展。对抗与年龄相关的认知能力下降。