Transcriptional Control of Synaptic Plasticity by Class IIa HDACs

IIa 类 HDAC 对突触可塑性的转录控制

基本信息

  • 批准号:
    10605220
  • 负责人:
  • 金额:
    $ 68.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

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.
本项目的目的是阐明神经元的经验依赖性可塑性的分子机制, 对学习和记忆至关重要的回路我们专注于IIa类组蛋白去乙酰化酶(HDAC),转录 在细胞核和细胞质之间穿梭的阻遏物。我们和我们的同事以前 证明了IIa类HDAC亚型HDAC 4调节小鼠、果蝇和秀丽隐杆线虫的记忆。 与这些发现相结合,HDAC 4与人类的几种神经系统疾病有关。在 在项目初期,我们发现HDAC 4和它的同源物HDAC 5限制了转录水平, 对感官输入的反应这些观察结果支持了一个假设,即可塑性和记忆相关的基因 在任何环境下都受到动态的抑制。在这里,我们建议确定IIa类HDAC如何 在电路,细胞和分子水平上运作,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II类HDAC作为快速化学遗传控制转录的工具, 动物的行为。 我们的目标是:1)通过免疫荧光技术, 显微镜,记忆记忆印迹细胞的基于活性的标记,以及阻遏物的体内双光子成像, 钙指标; 2)鉴定特定遗传定义的神经元类型中IIa类HDAC的核效应子 通过深度测序和质谱法; 3)为了定义IIa类HDAC信号传导对 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)利用对IIa类HDAC信号传导的化学遗传操纵, 活动依赖性转录促进记忆编码的大脑区域的映射。 总之,这些研究将解释如何神经细胞染色质结合蛋白与人类 疾病的功能在正常的大脑,并将提供新的见解的基本机制, 网络可塑性和记忆存储。

项目成果

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Anton Maximov其他文献

Anton Maximov的其他文献

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{{ truncateString('Anton Maximov', 18)}}的其他基金

New approaches for chemical-genetic targeting of specific circuits and cell types in the mammalian brain
哺乳动物大脑中特定回路和细胞类型的化学遗传靶向新方法
  • 批准号:
    10012597
  • 财政年份:
    2020
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular mechanisms of structural plasticity of inhibitory GABAergic interneurons
抑制性GABA能中间神经元结构可塑性的分子机制
  • 批准号:
    10380127
  • 财政年份:
    2019
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular mechanisms of structural plasticity of inhibitory GABAergic interneurons
抑制性GABA能中间神经元结构可塑性的分子机制
  • 批准号:
    10655280
  • 财政年份:
    2019
  • 资助金额:
    $ 68.76万
  • 项目类别:
Transcriptional Control of Synaptic Plasticity by Class IIa HDACs
IIa 类 HDAC 对突触可塑性的转录控制
  • 批准号:
    10376841
  • 财政年份:
    2014
  • 资助金额:
    $ 68.76万
  • 项目类别:
Transcriptional control of synaptic plasticity by class IIa HDACs
IIa 类 HDAC 对突触可塑性的转录控制
  • 批准号:
    10117286
  • 财政年份:
    2014
  • 资助金额:
    $ 68.76万
  • 项目类别:
Transcriptional control of synaptic plasticity by class IIa HDACs
IIa 类 HDAC 对突触可塑性的转录控制
  • 批准号:
    8806148
  • 财政年份:
    2014
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular Mechanisms Controlling Postsynaptic Secretion
控制突触后分泌的分子机制
  • 批准号:
    8035404
  • 财政年份:
    2009
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular Mechanisms Controlling Postsynaptic Secretion
控制突触后分泌的分子机制
  • 批准号:
    8223314
  • 财政年份:
    2009
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular Mechanisms Controlling Postsynaptic Secretion
控制突触后分泌的分子机制
  • 批准号:
    8426163
  • 财政年份:
    2009
  • 资助金额:
    $ 68.76万
  • 项目类别:
Molecular Mechanisms Controlling Postsynaptic Secretion
控制突触后分泌的分子机制
  • 批准号:
    7800238
  • 财政年份:
    2009
  • 资助金额:
    $ 68.76万
  • 项目类别:

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