The role of HDAC3 in age-related impairments in memory updating

HDAC3 在与年龄相关的记忆更新损伤中的作用

• 批准号: 10039300
• 负责人: JANINE LYNN KWAPIS
• 金额: $ 42.97万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039300
• 关键词: Acetylation; Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Brain; CRISPR interference; ChIP-seq; Chromatin Structure; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Data; Diagnosis; Disease; Dorsal; Enzymes; Epigenetic Process; Event; Excision; Future; Gene Expression; Genes; Genetic Transcription; HDAC3 gene; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone H4; Impaired cognition; Impairment; Individual; Learning; Location; Lysine; Memory; Memory Loss; Memory impairment; Molecular; Mus; Pharmacology; Population; Process; Records; Repression; Rodent; Role; Simplexvirus; Techniques; Testing; Therapeutic Intervention; Time; Update; Viral; Work; age related; aging brain; base; chromatin immunoprecipitation; cognitive function; experience; flexibility; genome-wide; human old age (65+); improved; knock-down; long term memory; memory consolidation; middle age; mild cognitive impairment; new therapeutic target; next generation sequencing; normal aging; novel; prevent; response; selective expression; spatial memory; stem; targeted treatment; transcriptome sequencing; treatment strategy

Project Summary/Abstract: Alzheimer’s disease currently affects 5.8 million Americans and 13.8 million people over the age of 65 are expected to develop the disease by 2030. Even more individuals will experience normal age-related cognitive decline, including mild cognitive impairments and memory deficits. Understanding the molecular mechanisms that underlie these impairments is a key step toward developing treatments to prevent or reverse memory decline in both normal aging and Alzheimer’s disease. One hallmark of age-related cognitive decline is an impairment in memory updating, the ability to modify existing memories with new information. Memories do not persist in a fixed, unalterable state, but instead must be capable of being updated in response to new, relevant experiences. Indeed, most memories are updates to existing memories, rather than brand new associations. Despite its fundamental importance, little is known about the mechanisms that support memory updating and even less is understood about how these mechanisms are altered with age. To address this, we have developed a novel paradigm called the Objects in Updated Locations (OUL) task that is ideal for studying memory updating in both young and old rodents. In this proposal, we will examine the role of a key epigenetic mechanism, histone deacetylase 3 (HDAC3), in regulating gene expression during memory updating in the young and old brain. HDAC3 is a powerful enzyme that promotes a repressive chromatin structure to limit gene expression. Deletion or disruption of HDAC3 in the young brain transforms a subthreshold learning event into one that produces robust memory. Further, deleting HDAC3 in the dorsal hippocampus of old mice ameliorates age-related impairments in spatial memory formation. To date, no studies have tested the role of HDAC3 in memory updating or age- related impairments in memory updating. Here, we hypothesize that aberrant HDAC3 function in the old brain contributes to a repressive chromatin structure that disrupts the gene expression necessary for memory updating. In support of this hypothesis, our preliminary data show that pharmacological HDAC3 inhibition can ameliorate age-related memory updating impairments. To fully test this hypothesis, we propose two aims. In Aim 1, we will test the role of HDAC3 in age-related impairments in memory updating using a combination of pharmacological and viral CRISPR-based inhibition of HDAC3 selectively during a memory update. In Aim 2, we will use next generation sequencing including chromatin immunoprecipitation (ChIP) sequencing and RNA sequencing to identify the molecular mechanisms that underlie memory updating and determine how HDAC3 contributes to age-related impairments in this process. Our results will elucidate the mechanisms that support memory updating and identify HDAC3 as a critical regulator of memory updating in the young and old brain. These results represent a significant conceptual advance in our understanding of age-related memory decline and may identify potential targets for therapeutic intervention to improve cognition in old age.

项目概要/摘要： 阿尔茨海默病目前影响着580万美国人，其中1380万65岁以上的人患有阿尔茨海默病 预计到2030年会发展成这种疾病。甚至更多的人会经历正常的与年龄相关的认知障碍。 衰退，包括轻度认知障碍和记忆缺陷。了解分子机制 是开发预防或逆转记忆衰退治疗方法的关键一步 在正常衰老和老年痴呆症中的作用与年龄相关的认知能力下降的一个标志是 在存储器更新中，用新信息修改现有存储器的能力。记忆不会在一个 它不是固定的、不可改变的状态，而是必须能够响应于新的、相关的经验而被更新。 事实上，大多数记忆都是对现有记忆的更新，而不是全新的联想。尽管 基本的重要性，很少有人知道的机制，支持内存更新，甚至更少， 了解这些机制是如何随着年龄的增长而改变的。为了解决这个问题，我们开发了一种新的 一种称为更新位置中的对象（OUL）任务的范式，该任务非常适合研究两种情况下的记忆更新 年轻和年老的啮齿动物。在这个建议中，我们将研究一个关键的表观遗传机制，组蛋白， 去乙酰化酶3（HDAC 3）在年轻和老年大脑记忆更新过程中调节基因表达。 HDAC 3是一种强大的酶，它促进抑制性染色质结构以限制基因表达。删除 或破坏HDAC 3在年轻的大脑中将阈下学习事件转化为产生鲁棒性学习的事件。 记忆此外，在老年小鼠的背侧海马中缺失HDAC 3改善了与年龄相关的损伤。 在空间记忆形成方面。迄今为止，还没有研究测试过HDAC 3在记忆更新或衰老中的作用- 记忆更新的相关损伤。在这里，我们假设老年人大脑中HDAC 3功能异常， 有助于抑制染色质结构，破坏记忆所必需的基因表达 更新中。为了支持这一假设，我们的初步数据表明，药理学HDAC 3抑制可以 改善与年龄相关的记忆更新障碍。为了充分验证这一假设，我们提出了两个目标。在Aim中 1，我们将使用以下组合测试HDAC 3在记忆更新中的年龄相关损伤中的作用： 本发明涉及在记忆更新期间选择性地药理学和基于病毒CRISPR的HDAC 3抑制。在目标2中， 将使用下一代测序，包括染色质免疫沉淀（ChIP）测序和RNA测序。 测序以确定记忆更新的分子机制，并确定HDAC 3 在这个过程中会导致与年龄相关的损伤。我们的研究结果将阐明支持 记忆更新，并确定HDAC 3作为年轻人和老年人大脑中记忆更新的关键调节因子。 这些结果代表了我们对与年龄相关的记忆衰退的理解的一个重要概念性进步 并可能确定治疗干预的潜在目标，以改善老年人的认知能力。