The role of nitric oxide signaling in synaptic plasticity

一氧化氮信号传导在突触可塑性中的作用

基本信息

  • 批准号:
    RGPIN-2014-06085
  • 负责人:
  • 金额:
    $ 2.91万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2019
  • 资助国家:
    加拿大
  • 起止时间:
    2019-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

Learning and memory has at its core modifications to tiny spine like structures that exist on a special subset of neurons in the brain known as "spiny neurons." These spines must move, adapt, grow and retract in response to chemical neurotransmitters in the brain, a process that as a whole is believed to be the cellular manifestation of learning, known as synaptic plasticity. The spines themselves are thought to serve as basic units of memory storage. While much work has focused directly on the chemical signals that mediate communication in the brain and the ion channels that are opened as a result, little is know of the specific signaling pathways that control the actual generation, shape and loss of individual spines. This proposal aims to shed light on this process by focusing on a specific molecule (Nitric Oxide) that is produced in these spines following ion channel opening. Nitric Oxide is unique in that it can directly alter the proteins responsible for dynamic changes to spine morphology. This proposal is driven by the hypothesis that Nitric Oxide signaling regulates synaptic plasticity by altering the density and morphology of spines through a process called S-nitrosylation.**Ion channels link a cell with the environment that surrounds it. These channels allow the cell to interpret its surroundings by responding to neurotransmitters and propagating signals from the environment outside of the cell inward. These signals mediate changes in the structure and shape of the cell itself and facilitate spine growth and retraction. One class of ion channel of interest to this proposal is characterized by its ability to respond to a neurotransmitter called glutamate. Glutamate signaling can increase the efficiency of communication between cells in the brain by both increasing the number and stability of new spines as well by pruning excess or unnecessary spines, leaving a more efficient communication network. Glutamate-mediated opening of the "NMDA" type ion channel results in production of Nitric Oxide that modifies the proteins in spines through a chemical reaction called S-Nitrosylation. This event alters the function of near-by proteins and as a result the dynamic properties of the spines they inhabit. While it is estimated that 50% of proteins in the brain are altered by S-nitrosylation, a comprehensive analysis of the role it plays in synaptic plasticity has never been performed.**Using powerful mouse genetics we will control the level of Nitric Oxide synthesized in spines by altering the genetic composition of the NMDA-type ion channel and thus its ability to open and close. Using live imaging microscopy techniques coupled with fluorescent probes, we will monitor the flux of ions through NMDA-type channels as well the amount Nitric Oxide subsequently produced in cultured brain slices and isolated neurons from these mice. This will allow us to determine how the level of Nitric Oxide correlates with dynamic changes to spine morphology. We will then monitor what proteins are S-nitrosylated by Nitric Oxide under conditions of spine growth, spine stabilization and spine retraction using Mass Spectrometry to analyze changes to proteins composition. This will form the basis of a novel molecular pathway that underlies the processes of synaptic plasticity. Moreover, this research program will further our understanding neural architecture and the means by which cells of the brain communicate.
学习和记忆对小脊柱的核心修饰如大脑中特殊的神经元中存在的结构,称为“刺神经元”。这些刺必须对大脑中的化学神经递质的响应移动,适应,生长和缩回,这一过程总体上被认为是学习的细胞表现,称为突触可塑性。刺本本身被认为是内存存储的基本单位。尽管许多工作直接集中在介导大脑中通信和开放的离子通道的化学信号上,但几乎不知道控制单个棘突的实际产生,形状和损失的特定信号通路。该建议的目的是通过关注离子通道开放后这些棘突中产生的特定分子(一氧化氮)来阐明这一过程。一氧化氮的独特之处在于它可以直接改变负责脊柱形态动态变化的蛋白质。 该建议是由一氧化氮信号传导通过称为s-硝基化的过程改变刺的密度和形态来调节突触可塑性的假设所驱动的。**离子通道将细胞与周围的环境联系起来。这些通道允许细胞通过响应神经递质并从细胞内外的环境传播信号来解释其周围环境。这些信号介导细胞本身的结构和形状变化,并促进脊柱的生长和缩回。该提案的一类离子感兴趣的渠道的特征是其对称为谷氨酸的神经递质反应的能力。谷氨酸信号传导可以通过修剪多余或不必要的棘突来增加新棘的数量和稳定性,从而提高大脑中细胞之间的通信效率,从而留下更有效的通信网络。谷氨酸介导的“ NMDA”型离子通道的开放导致一氧化氮的产生,从而通过称为S-亚硝基化的化学反应来修饰棘突中的蛋白质。该事件改变了接近蛋白质的功能,结果会改变其居住的刺的动态特性。虽然估计据估计,大脑中50%的蛋白质因S-硝基化而改变,但从未执行过对其在突触可塑性中所扮演的作用的全面分析。使用与荧光探针结合的实时成像显微镜技术,我们将通过NMDA型通道监测离子的通量,以及随后在培养的脑切片中产生的一氧化氮量和这些小鼠的分离神经元中产生的量。这将使我们能够确定一氧化氮水平与脊柱形态的动态变化如何相关。然后,我们将在脊柱生长,脊柱稳定和脊柱缩回的条件下,使用质谱法来分析蛋白质组成的变化,并在脊柱生长,脊柱稳定和脊柱缩回条件下通过一氧化氮来监测哪些蛋白质是硝基基因。这将构成一种新的分子途径的基础,该途径是突触可塑性过程的基础。此外,该研究计划将进一步理解神经体系结构以及大脑的细胞传达的方式。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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数据更新时间:2024-06-01

Ryan, Scott其他文献

The Experiences of Gay Men and Lesbians in Becoming and Being Adoptive Parents
  • DOI:
    10.1080/10926750903313294
    10.1080/10926750903313294
  • 发表时间:
    2009-01-01
    2009-01-01
  • 期刊:
  • 影响因子:
    0.8
  • 作者:
    Brown, Suzanne;Smalling, Susan;Ryan, Scott
    Brown, Suzanne;Smalling, Susan;Ryan, Scott
  • 通讯作者:
    Ryan, Scott
    Ryan, Scott
An Evaluation of Gay/Lesbian and Heterosexual Adoption
  • DOI:
    10.1080/10926750903313278
    10.1080/10926750903313278
  • 发表时间:
    2009-01-01
    2009-01-01
  • 期刊:
  • 影响因子:
    0.8
  • 作者:
    Averett, Paige;Nalavany, Blace;Ryan, Scott
    Averett, Paige;Nalavany, Blace;Ryan, Scott
  • 通讯作者:
    Ryan, Scott
    Ryan, Scott
共 2 条
  • 1
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Ryan, Scott的其他基金

Cysteine oxidation in the remodelling of dendritic spines
树突棘重塑中的半胱氨酸氧化
  • 批准号:
    RGPIN-2021-02418
    RGPIN-2021-02418
  • 财政年份:
    2022
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Discovery Grants Program - Individual
    Discovery Grants Program - Individual
Cysteine oxidation in the remodelling of dendritic spines
树突棘重塑中的半胱氨酸氧化
  • 批准号:
    RGPIN-2021-02418
    RGPIN-2021-02418
  • 财政年份:
    2021
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Discovery Grants Program - Individual
    Discovery Grants Program - Individual
Fast protein liquid chromatography (FPLC) based ultra-pure protein preperations for the study of structural biology
基于快速蛋白质液相色谱 (FPLC) 的超纯蛋白质制剂,用于结构生物学研究
  • 批准号:
    RTI-2022-00047
    RTI-2022-00047
  • 财政年份:
    2021
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Research Tools and Instruments
    Research Tools and Instruments
A ratiometric imaging platform to advance COVID-19 counter measures
用于推进 COVID-19 应对措施的比例成像平台
  • 批准号:
    552990-2020
    552990-2020
  • 财政年份:
    2020
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Alliance Grants
    Alliance Grants
Dietary omega-3 (n-3) and omega-6 (n-6) fatty acids as novels activators of the anti-oxidant response
膳食 omega-3 (n-3) 和 omega-6 (n-6) 脂肪酸作为抗氧化反应的新型激活剂
  • 批准号:
    490841-2015
    490841-2015
  • 财政年份:
    2019
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Collaborative Research and Development Grants
    Collaborative Research and Development Grants
The role of nitric oxide signaling in synaptic plasticity
一氧化氮信号传导在突触可塑性中的作用
  • 批准号:
    RGPIN-2014-06085
    RGPIN-2014-06085
  • 财政年份:
    2018
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Discovery Grants Program - Individual
    Discovery Grants Program - Individual
Dietary omega-3 (n-3) and omega-6 (n-6) fatty acids as novels activators of the anti-oxidant response
膳食 omega-3 (n-3) 和 omega-6 (n-6) 脂肪酸作为抗氧化反应的新型激活剂
  • 批准号:
    490841-2015
    490841-2015
  • 财政年份:
    2018
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Collaborative Research and Development Grants
    Collaborative Research and Development Grants
The role of nitric oxide signaling in synaptic plasticity
一氧化氮信号传导在突触可塑性中的作用
  • 批准号:
    RGPIN-2014-06085
    RGPIN-2014-06085
  • 财政年份:
    2017
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Discovery Grants Program - Individual
    Discovery Grants Program - Individual
Dietary omega-3 (n-3) and omega-6 (n-6) fatty acids as novels activators of the anti-oxidant response
膳食 omega-3 (n-3) 和 omega-6 (n-6) 脂肪酸作为抗氧化反应的新型激活剂
  • 批准号:
    490841-2015
    490841-2015
  • 财政年份:
    2017
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Collaborative Research and Development Grants
    Collaborative Research and Development Grants
The role of nitric oxide signaling in synaptic plasticity
一氧化氮信号传导在突触可塑性中的作用
  • 批准号:
    RGPIN-2014-06085
    RGPIN-2014-06085
  • 财政年份:
    2016
  • 资助金额:
    $ 2.91万
    $ 2.91万
  • 项目类别:
    Discovery Grants Program - Individual
    Discovery Grants Program - Individual

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