The epigenetic encoding of learning and memory

学习和记忆的表观遗传编码

• 批准号: 10238292
• 负责人: Erica Megan Korb
• 金额: $ 143.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238292
• 关键词: Affect; Behavior; Biochemical; Biology; Brain; Cell Nucleus; Cells; Chromatin; Complex; Cues; DNA; Disease; Environment; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Histones; Institutes; Label; Lead; Learning; Maintenance; Maps; Memory; Mental disorders; Methods; Molecular; Nervous system structure; Neurologic; Neuronal Dysfunction; Neurons; Neurosciences; Post-Traumatic Stress Disorders; Proteins; Regulation; Reversal Learning; Signal Transduction; Structure; Techniques; Time; Transcription Process; Transcriptional Regulation; Work; epigenome; experience; in vivo; mouse model; novel; programs; recruit; response; tool; transcriptome sequencing

Abstract The nervous system requires tight control of transcription for processes such as learning and memory formation. The field of epigenetics seeks to understand how changes to gene transcription occur in response to environmental cues and external signals such as those that our brains experience during learning. This proposal lies at the intersection of neuroscience and epigenetics, with a particular focus on chromatin biology. Chromatin is the complex of DNA and the histone proteins that wrap up DNA into complex structures, recruit key transcriptional regulators, and in doing so, control gene expression. In recent years, it has become clear that disruptions to chromatin regulation lead to a range of neurological and mental health disorders such as post- traumatic stress disorder (PTSD). However, we have a limited understanding of how chromatin functions in the brain or how its disruption can lead to disease. We will apply the tools and techniques of the epigenetics field to the study of neuronal function. In doing so, we hope to elucidate the molecular mechanisms that allow our brains to perform incredibly complex tasks and how disruption of these mechanisms can lead to neuronal dysfunction. We propose overcome long-standing hurdles in the field using a combination of novel techniques to reveal how the epigenetic landscape encodes the transcriptional changes that underlie memory formation. Specifically, we seek to uncover the transcriptional signature of memory formation and memory maintenance within single neurons in an in vivo context. We then will examine the epigenetic underpinnings of this transcriptional signature and manipulate specific components of the chromatin environment to define their contribution to learning and memory maintenance. First, in order to elucidate the gene program associated with learning, we will use single-nucleus RNA-sequencing in combination with mouse models that label the specific neurons activated during learning. This will allow us to examine the transcriptional programs activated in neurons that form a memory engram compared to their neighboring cells at various times after learning. Next, we will employ a quantitative biochemical approach uniquely available to our group as part of the Epigenetics Institute to characterize the chromatin landscape changes the occur during memory formation, memory maintenance, and reversal learning. Finally, we will modify the chromatin landscape by manipulating specific histone proteins in combination with numerous sequencing approaches to elucidate how chromatin controls learning and the transcriptional program. Employing this novel combination of techniques will allow us to uncover the mechanisms through which the epigenome encodes information within neurons to modify behavior both in the context of normal learning and in the context of maladaptive responses that lead to disorders such as PTSD. If successful, these methods will 1) identify the transcriptional signature that encodes a memory in neurons, 2) map how this signature is encoded by specific epigenetic regulatory mechanisms, and 3) define how the chromatin landscape affects memory formation and contributes to mental health disorders.

摘要 神经系统需要严格控制转录过程，如学习和记忆 阵表观遗传学领域试图了解基因转录的变化是如何发生的， 环境线索和外部信号，如我们的大脑在学习过程中经历的信号。这项建议 位于神经科学和表观遗传学的交叉点，特别关注染色质生物学。染色质 是DNA和组蛋白的复合体，组蛋白将DNA包裹成复杂的结构， 转录调控因子，并在这样做，控制基因表达。近年来，人们已经清楚地认识到， 染色质调节的中断导致一系列神经和精神健康障碍，例如后- 创伤性应激障碍（PTSD）。然而，我们对染色质在细胞中的功能了解有限。 大脑或其破坏如何导致疾病。我们将应用表观遗传学领域的工具和技术， 对神经功能的研究。在这样做的过程中，我们希望能够阐明使我们的大脑 来执行极其复杂的任务，以及这些机制的破坏如何导致神经元功能障碍。 我们建议使用新技术的组合来克服该领域长期存在的障碍， 揭示了表观遗传景观如何编码记忆形成的转录变化。 具体来说，我们试图揭示记忆形成和记忆维持的转录特征 在单个神经元内的一个活体环境中。然后，我们将研究这一现象的表观遗传基础， 转录签名和操纵染色质环境的特定成分，以确定其 有助于学习和记忆的维持。首先，为了阐明与 学习，我们将使用单核RNA测序结合小鼠模型，标记特定的 学习期间神经元被激活。这将使我们能够检查在神经元中激活的转录程序 在学习后的不同时间，与相邻的细胞相比，形成了一个记忆印迹。接下来我们就 作为表观遗传学研究所的一部分， 为了表征在记忆形成，记忆维持， 和逆向学习。最后，我们将通过操纵特定的组蛋白来改变染色质的面貌 结合众多的测序方法来阐明染色质如何控制学习， 转录程序采用这种新的技术组合将使我们能够揭示机制 表观基因组在神经元内编码信息，以改变行为， 正常的学习和适应不良的反应，导致如创伤后应激障碍的背景下。如果成功， 这些方法将1）识别神经元中编码记忆的转录特征，2）绘制这种转录特征如何在神经元中编码记忆的图， 签名是由特定的表观遗传调控机制编码，3）定义如何染色质景观 影响记忆形成并导致心理健康障碍。