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

项目摘要/摘要： 阿尔茨海默氏症目前影响着580万美国人，其中1380万65岁以上的人 预计到2030年将发展成这种疾病。更多的人将经历正常的与年龄相关的认知 下降，包括轻微的认知障碍和记忆障碍。对分子机制的理解 这些损伤的基础是开发预防或逆转记忆衰退的治疗方法的关键一步 在正常衰老和阿尔茨海默病中都是如此。与年龄相关的认知功能减退的一个特征是损害 在内存更新中，用新信息修改现有内存的能力。记忆不会持续在一个 固定、不可更改的状态，但必须能够根据新的、相关的体验进行更新。 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。尽管它的 最重要的是，人们对支持内存更新的机制知之甚少，甚至更少 了解这些机制如何随着年龄的增长而改变。为了解决这个问题，我们开发了一部小说 被称为已更新位置中的对象(OUL)任务的范例，非常适合研究两者中的内存更新 年幼的和年老的啮齿动物。在这个提案中，我们将研究一个关键的表观遗传机制，组蛋白的作用。 脱乙酰酶3(HDAC3)，在年轻人和老年人大脑记忆更新过程中调节基因表达。 HDAC3是一种强大的酶，它促进抑制染色质结构以限制基因表达。删除 或者，年轻大脑中HDAC3的破坏将亚阈值学习事件转变为产生强大信息的事件 记忆。此外，删除老年小鼠背侧海马区的HDAC3可改善与年龄相关的损伤 在空间记忆的形成中。到目前为止，还没有研究测试HDAC3在记忆更新或衰老中的作用。 内存更新中的相关损害。在这里，我们假设HDAC3在老年大脑中的功能异常 有助于抑制染色质结构，扰乱记忆所需的基因表达 正在更新。为了支持这一假说，我们的初步数据显示，药物上的HDAC3抑制可以 改善与年龄相关的记忆更新障碍。为了充分检验这一假设，我们提出了两个目标。在AIM 1，我们将使用以下组合来测试HDAC3在与年龄相关的记忆更新障碍中的作用 在记忆更新期间选择性地抑制基于药物和病毒CRISPR的HDAC3。在目标2中，我们 将使用下一代测序，包括染色质免疫沉淀(CHIP)测序和RNA 测序以确定记忆更新背后的分子机制并确定HDAC3如何 在这一过程中会导致与年龄相关的损害。我们的结果将阐明支持 记忆更新，并确定HDAC3是年轻和老年大脑中记忆更新的关键调节器。 这些结果代表了我们在理解与年龄相关的记忆衰退方面的重大概念上的进步 并可能确定治疗干预的潜在靶点，以改善老年认知能力。

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.