Role of HDAC3 in repressing memory formation in the aging brain

HDAC3 在抑制衰老大脑记忆形成中的作用

• 批准号: 9267406
• 负责人: Marcelo Andres Wood
• 金额: $ 19.31万
• 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: 2016-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267406
• 关键词: Acetylation; Affect; Age; Age-associated memory impairment; Aging; Behavior; Behavioral; Cell physiology; Cells; ChIP-seq; Chromatin Structure; Chronology; Data; Deacetylase; Dependovirus; Dorsal; Drug Addiction; Enterobacteria phage P1 Cre recombinase; Environment; Enzymes; Epigenetic Process; Epilepsy; Excision; Failure; Future; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; HDAC3 gene; Hippocampus (Brain); Histone H4; Human; Impaired cognition; Impairment; Lead; Learning; Location; Longevity; Lysine; Maintenance; Memory; Memory impairment; Mental Depression; Modification; Molecular; Mus; Neurobiology; Neurodegenerative Disorders; Neurons; Organism; Pattern; Population; Regulation; Repressed Memory; Research; Research Personnel; Rodent; Role; Services; Signal Transduction; Synapses; Testing; Time; Transcription Process; Transcriptional Regulation; United States; Viral; Wood material; age related; aged; aging brain; aging hippocampus; base; chromatin immunoprecipitation; chromatin modification; cognitive function; conditioned fear; design; epigenome; experience; experimental study; genome-wide; improved; long term memory; memory consolidation; memory process; mutant; next generation sequencing; normal aging; novel; novel strategies; novel therapeutics; object recognition; prevent; protein protein interaction; public health relevance; stem; transcriptome sequencing; treatment strategy

 DESCRIPTION (provided by applicant): One of the alluring aspects of examining the role of chromatin modifications in modulating transcription required for long-term memory processes is that these modifications may provide transient and potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These in turn ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. As an epigenetic mechanism of transcriptional control, chromatin modification has been shown to participate in maintaining cellular memory (e.g. cell fate) and may underlie the strengthening and maintenance of synaptic connections required for long-term changes in behavior. Epigenetics has become central to several fields of neurobiology where researchers have found that regulation of chromatin modification has a significant role in epilepsy, drug addiction, depression, neurodegenerative diseases, and memory. A current hypothesis is that specific patterns of chromatin modification may have specific effects on cellular function and subsequent behavior. Recent research suggests that our epigenome changes as a function of time, potentially leading to a shift in chromatin structure that makes gene expression more difficult, and thus forming long-term memories more difficult. In this proposal, we will examine the role of histone deacetylase 3 (HDAC3) in regulating gene expression during memory formation in the aging rodent. We have identified an age at which aging rodents fail to form long-term memory for object location, which is a form of memory susceptible to age-dependent decline in humans. HDAC3 is a powerful enzyme that generates a repressive chromatin structure that inhibits gene expression. During memory formation in young rodents, HDAC3 is removed from specific genes, resulting in long-term memory formation. However, this mechanism fails in aging rodents. We hypothesize that in the aging brain, HDAC3 develops abnormal activity in repressing gene expression. Our preliminary data support this hypothesis by demonstrating that homozygous focal genetic deletion of Hdac3 in aging rodents completely restores their long-term memory formation for object location. To fully test this hypothesis, we propose two aims. In aim 1 we will examine the role of HDAC3 in age-dependent long-term memory formation using genetically modified mice, viral approaches, and several behavioral tasks. In aim 2, we will use next generation sequencing including chromatin immunoprecipitation (ChIP) sequencing and RNA sequencing to identify HDAC3 target genes and how those genes are regulated throughout the lifespan by examining a number of different ages. Results from these experiments would demonstrate that HDAC3 is a key regulator of memory formation in the aging brain, which would lead to a significant conceptual advance in our understanding of how epigenetic mechanisms function in the aged brain and also identify potential for novel therapeutic design.

 描述（由申请人提供）：检查染色质修饰在调节长期记忆过程所需的转录中的作用的诱人方面之一是，这些修饰可以在激活和/或维持转录过程的服务中提供瞬时和潜在稳定的表观遗传标记。这些反过来又最终参与神经元变化所需的分子机制，从而使行为发生持久的变化。作为转录控制的表观遗传机制，染色质修饰已被证明参与维持细胞记忆（例如细胞命运），并且可能是行为长期变化所需的突触连接的加强和维持的基础。表观遗传学已经成为神经生物学的几个领域的核心，研究人员发现，染色质修饰的调节在癫痫，药物成瘾，抑郁症，神经退行性疾病和记忆中起着重要作用。目前的假设是，染色质修饰的特定模式可能对细胞功能和随后的行为产生特定的影响。最近的研究表明，我们的表观基因组作为时间的函数发生变化，可能导致染色质结构的变化，使基因表达更加困难，从而更难形成长期记忆。在这个提议中，我们将研究组蛋白去乙酰化酶3（HDAC 3）在调节衰老啮齿动物记忆形成过程中的基因表达中的作用。我们已经确定了一个年龄，在这个年龄，衰老的啮齿动物无法形成对物体位置的长期记忆，这是一种对人类年龄依赖性衰退敏感的记忆形式。HDAC 3是一种强大的酶，可产生抑制基因表达的抑制性染色质结构。在年轻啮齿动物的记忆形成过程中，HDAC 3从特定基因中被移除，导致长期记忆的形成。然而，这种机制在衰老的啮齿动物中失败了。我们推测，在衰老的大脑中，HDAC 3在抑制基因表达方面产生了异常活性。我们的初步数据支持这一假设，证明了纯合的局灶性遗传缺失的Hdac 3在老龄啮齿动物完全恢复其长期记忆形成的对象位置。为了充分验证这一假设，我们提出了两个目标。在目标1中，我们将使用转基因小鼠，病毒方法和几种行为任务来研究HDAC 3在年龄依赖性长期记忆形成中的作用。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，通过检查许多不同的年龄来确定HDAC 3靶基因以及这些基因在整个生命周期中是如何调节的。这些实验的结果将证明HDAC 3是衰老大脑中记忆形成的关键调节因子，这将导致我们对表观遗传机制如何在衰老大脑中发挥作用的理解的重大概念性进展，并确定新的治疗设计的潜力。