Transcriptional control of synaptic plasticity by class IIa HDACs

本项目的目标是阐明神经经验依赖性可塑性的分子机制。 学习和记忆所必需的电路。我们专注于IIa类组蛋白脱乙酰酶(Hdac)，转录。 在细胞核和细胞质之间穿梭的抑制物。我们和我们的同事之前 证明了IIa类HDAC亚型HDAC4调节小鼠、果蝇和线虫的记忆。 与这些发现相结合，HDAC4被认为与人类的几种神经疾病有关。在 在项目初期，我们发现HDAC4和它的同源基因HDAC5限制了转录 对感官输入的反应。这些观察结果支持了与可塑性和记忆相关的基因的假设 在任何环境下都会被动态地抑制在大脑中。在这里，我们建议确定IIa类HDAC如何 在电路、细胞和分子水平上工作，以及它们的核信号如何影响小鼠的神经元 海马体。此外，我们将利用第二类HDAC作为快速化学遗传转录控制的工具。 在表现动物方面。 我们的目标是：1)通过使用免疫荧光来确定IIa类HDAC如何在电路水平上运行 显微技术，记忆印记细胞的基于活性的标记，以及体内双光子抑制物和 钙指示剂；2)在特定的遗传定义的神经元类型中识别IIa类HDAC的核效应 通过深度测序和质谱分析；3)定义IIa类HDAC信号在 电路结构和功能。这将通过结合电子显微镜、全脑成像、 和电生理学；以及4)利用IIa类HDAC信号的化学遗传操作 绘制大脑中依赖活动的转录促进记忆编码的区域。 综上所述，这些研究将解释神经元染色质结合蛋白如何与人类 疾病在正常大脑中的功能，并将为潜在的基本机制提供新的见解 网络可塑性和内存存储。

The goal of this project is to elucidate the molecular mechanisms of experience-dependent plasticity of neural circuits essential for learning and memory. We focus on class IIa histone deacetylases (HDACs), transcriptional repressors that shuttle between the nucleus and cytoplasm. We and our colleagues have previously demonstrated that the class IIa HDAC isoform, HDAC4, regulates memory in mice, drosophila and C.elegans. In conjunction with these findings, HDAC4 has been linked to several neurological disorders in humans. In the initial project period, we discovered that HDAC4 and its close homolog, HDAC5, restrict the transcriptional response to sensory input. These observations support the hypothesis that plasticity- and memory-related genes are dynamically repressed in the brain in any environment. Here, we propose to determine how class IIa HDACs operate at circuit, cellular and molecular levels, and how their nuclear signaling impacts neurons in the mouse hippocampus. Moreover, we will exploit class II HDACs as tools for rapid chemical-genetic control of transcription in behaving animals. Our aims are: 1) To determine how class IIa HDAC operate at a circuit level by using immunofluorescent microscopy, activity-based tagging of memory engrams cells, and in vivo 2-photon imaging of repressors and calcium indicators; 2) To identify nuclear effectors of class IIa HDACs in specific genetically-defined neuron types by deep sequencing and mass spectrometry; 3) To define the consequences of class IIa HDACs signaling on circuit structure and function. This will be accomplished by combining electron microscopy, whole-brain imaging, and electrophysiology; and 4) To leverage chemical-genetic manipulation of class IIa HDAC signaling for mapping of brain areas where activity-dependent transcription promotes memory coding. Taken together, these studies will explain how neuronal chromatin-binding proteins associated with human disease function in the normal brain, and will provide novel insights into the basic mechanisms underlying network plasticity and memory storage.