Role of HDAC3 in repressing memory formation in the aging brain

 描述(申请人提供)：研究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，这些修饰可能提供瞬时和潜在稳定的表观遗传标记，用于激活和/或维持转录过程。反过来，这些细胞最终参与了神经元变化所需的分子机制，这些变化服从于行为的长期变化。染色质修饰作为一种转录调控的表观遗传学机制，已被证明参与维持细胞记忆(如细胞命运)，并可能是加强和维持长期行为改变所需的突触连接的基础。表观遗传学已经成为神经生物学的几个领域的核心，在这些领域，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具有重要作用。目前的一种假设是，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，我们的表观基因组随着时间的变化而变化，可能会导致染色质结构的变化，使基因表达变得更加困难，从而更难形成长期记忆。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。我们已经确定了一个年龄，在这个年龄，老化的啮齿动物不能形成对物体位置的长期记忆，这是一种记忆形式，在人类中容易受到年龄依赖性下降的影响。HDAC3是一种强大的酶，它能产生一种抑制基因表达的染色质结构。在幼年啮齿动物的记忆形成过程中，HDAC3从特定的基因中移除，导致长期记忆的形成。然而，这种机制在老化的啮齿动物身上失败了。我们假设，在老化的大脑中，HDAC3在抑制基因表达方面表现出异常的活动。我们的初步数据支持这一假设，证明在衰老的啮齿动物中，HDAC3的纯合子局部基因缺失完全恢复了它们对物体位置的长期记忆形成。为了充分检验这一假设，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HDAC3在年龄相关的长期记忆形成中的作用。在目标2中，我们将使用包括染色质免疫沉淀(ChIP)测序和RNA测序在内的下一代测序来识别HDAC3靶基因，以及通过检测一些不同的年龄来确定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HDAC3是衰老大脑中记忆形成的关键调节因子，这将使我们在理解表观遗传机制如何在衰老大脑中发挥作用方面取得重大的概念性进展，并确定新的治疗设计的潜力。

 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.