The epigenetic encoding of learning and memory

摘要 神经系统需要对学习和记忆等过程的转录进行严格控制。 队形。表观遗传学领域试图了解基因转录的变化是如何发生的 环境提示和外部信号，例如我们的大脑在学习过程中经历的那些。这项建议 位于神经科学和表观遗传学的交叉点上，特别关注染色质生物学。染色质 是DNA和将DNA包裹成复杂结构的组蛋白的复合体，招募关键 转录调节器，在这样做的过程中，控制基因的表达。近年来，情况变得很明显， 染色质调节的中断会导致一系列神经和精神健康障碍，如后 创伤应激障碍(PTSD)。然而，我们对染色质如何在细胞中发挥作用的了解有限 或者大脑的破坏如何导致疾病。我们将应用表观遗传学领域的工具和技术来 对神经功能的研究。通过这样做，我们希望阐明使我们的大脑 来执行令人难以置信的复杂任务，以及这些机制的破坏如何导致神经元功能障碍。 我们建议使用一种新技术的组合来克服该领域长期存在的障碍 揭示表观遗传景观如何编码作为记忆形成基础的转录变化。 具体地说，我们试图揭示记忆形成和记忆维持的转录特征 在活体背景下的单个神经元中。然后我们将研究表观遗传学的基础。 转录签名和操纵染色质环境的特定组件以定义其 对学习和记忆的维护有贡献。首先，为了阐明与之相关的基因程序 为了学习，我们将使用单核RNA测序结合标记特定基因的小鼠模型 神经元在学习过程中被激活。这将使我们能够检查神经元中激活的转录程序 它们在学习后的不同时间与相邻细胞相比形成了一个记忆印记。接下来，我们将 使用我们组独有的定量生化方法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、 和反转学习。最后，我们将通过操纵特定的组蛋白来改变染色质的情况 结合大量测序方法来阐明染色质是如何控制学习和 转录程序。采用这种新颖的技术组合将使我们能够揭示 表观基因组通过它对神经元内的信息进行编码，以改变在 在正常学习和适应不良反应的背景下，导致创伤后应激障碍等障碍。如果成功， 这些方法将1)识别在神经元中编码记忆的转录签名，2)映射如何 签名由特定的表观遗传调节机制编码，以及3)如何定义染色质景观 影响记忆力的形成，并导致精神健康障碍。

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.