Multiplexed RNAscope imaging of gene expression in targeted cells across the fly brain

果蝇大脑中靶细胞基因表达的多重 RNAscope 成像

基本信息

  • 批准号:
    10527068
  • 负责人:
  • 金额:
    $ 43.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-15 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Abstract Neurotransmitter specification is a crucial step in defining neural circuit identity and function because it helps establish which neurons communicate with each other. Surprisingly, neurotransmitter specification is neither mutually exclusive nor immutable. That is, some neurons release multiple types of neurotransmitters with different physiological functions, and the relative abundance of different neurotransmitters can be modified based on environmental conditions and neuronal firing patterns. These features endow neurons with a type of functional plasticity that is often overlooked but can have profound effects on neural circuit function and thus on behavior. Unfortunately the mechanisms responsible for neurotransmitter plasticity are poorly understood. This gap in knowledge makes it very difficult to determine the contribution of neurotransmitter plasticity to normal physiology and to psychiatric disorders involving neural circuit dysfunction. To overcome this obstacle using fruit flies as a model system we have pioneered a combination of (1) ribosome profiling to identify all neurotransmitter-associated transcripts in small groups of neurons and (2) RNAscope-based quantification of transcript distribution across those same neurons, which can be simultaneously targeted by reporters and thus identified by immunohistochemistry. In this proposal we will employ these exquisitely sensitive techniques to identify the different neurotransmitters that are used by various arousal-regulating neurons in the circadian clock network and by neurons that control sleep. We will also use RNAscope to measure how neurotransmitter identity is modified by changes in neuronal activity, such as those expected during the sleep/wake cycle, and the extent to which this plasticity is cell-autonomously regulated through synaptic transmission. Lastly, we will use RNAscope to measure the selectivity of commonly used drivers for labeling of neurotransmitter systems. Our studies will thus introduce a new, powerful combination of techniques for studying the central nervous system of the fly, and they will define for the first time the full complement of neurotransmitters used by each cell of a well-studied behavioral circuit. Our studies will also provide a foundation for determining how neurotransmitter identity can be modulated by physiological and pathophysiological events to alter neural circuit function and ultimately behavior. In the long-term such mechanisms are expected to contribute to our understanding of neural circuit dysfunctions underlying neurological disorders.
抽象的 神经递质规范是定义神经回路身份和功能的关键步骤,因为它 帮助确定哪些神经元相互通信。令人惊讶的是,神经递质规格是 既不是相互排斥的,也不是一成不变的。也就是说,一些神经元释放多种类型的神经递质 具有不同的生理功能,并且可以改变不同神经递质的相对丰度 基于环境条件和神经元放电模式。这些特征赋予神经元一种 功能可塑性经常被忽视,但可以对神经回路功能产生深远影响,从而 行为。不幸的是,人们对神经递质可塑性的机制知之甚少。这 知识差距使得很难确定神经递质可塑性对正常的贡献 涉及神经回路功能障碍的生理学和精神疾病。为了克服这个障碍,使用 以果蝇为模型系统,我们首创了 (1) 核糖体分析的组合来识别所有 小群神经元中神经递质相关转录本和 (2) 基于 RNAscope 的定量 转录本分布在这些相同的神经元上,这些神经元可以同时被报告者靶向,从而 通过免疫组织化学鉴定。在本提案中,我们将采用这些精致敏感的技术来 识别昼夜节律中各种唤醒调节神经元使用的不同神经递质 时钟网络和控制睡眠的神经元。我们还将使用 RNAscope 来测量神经递质如何 身份通过神经元活动的变化而改变,例如在睡眠/觉醒周期期间预期的神经元活动的变化,以及 这种可塑性通过突触传递进行细胞自主调节的程度。最后,我们将 使用 RNAscope 测量神经递质系统标记常用驱动程序的选择性。 因此,我们的研究将引入一种新的、强大的技术组合来研究中枢神经 果蝇系统,他们将首次定义每种果蝇使用的全部神经递质 经过充分研究的行为回路的细胞。我们的研究还将为确定如何 神经递质的身份可以通过生理和病理生理事件来调节,以改变神经 电路功能和最终行为。从长远来看,此类机制预计将有助于我们 了解神经系统疾病背后的神经回路功能障碍。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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William J Joiner其他文献

William J Joiner的其他文献

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{{ truncateString('William J Joiner', 18)}}的其他基金

The contribution of Ly6h to Alzheimers Disease
Ly6h 对阿尔茨海默病的贡献
  • 批准号:
    10591330
  • 财政年份:
    2022
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8796238
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8024608
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8235771
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8312959
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8611976
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:
Molecular and anatomical basis of sleep regulation by SLEEPLESS
SLEEPLESS 睡眠调节的分子和解剖学基础
  • 批准号:
    8417679
  • 财政年份:
    2011
  • 资助金额:
    $ 43.45万
  • 项目类别:

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