Sensing and manipulating neuromodulatory signaling in vivo

体内传感和操纵神经调节信号

基本信息

  • 批准号:
    10650681
  • 负责人:
  • 金额:
    $ 256.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Neuromodulation, such as that mediated by the neuromodulators norepinephrine, acetylcholine, and dopamine, imposes powerful control over brain function. It regulates the excitability, synaptic plasticity, and other aspects of neuronal function. Defects in neuromodulation are associated with many neuropsychiatric diseases. Neuromodulators exert their functions by regulating intracellular signaling events via their corresponding G protein-coupled receptors (GPCRs). Although in vivo interrogation of extracellular neuromodulators has started to become possible, the effects of neuromodulators on subcellular signaling and neuronal function are cell type-specific. Monitoring the cell type-specific outcomes of neuromodulatory subcellular signaling events remains difficult. There is also a lack of practical tools for antagonizing neuromodulatory signaling events with high temporal resolution in vivo, which is required for establishing the causal relationship between the signaling events and neuronal functions or animal behavior. To overcome these problems, we propose to develop novel genetically encoded sensors for examining the activities, in vivo with single-neuron resolution, of an understudied neuromodulatory signaling pathway: the protein kinase C (PKC) pathway. Although prototypic genetically encoded PKC sensors based on Förster resonance energy transfer (FRET) have been used for experiments in vitro, their application in vivo has been difficult due to lower signal-to-noise ratios under the more challenging in vivo imaging conditions. Building on our previous successful experience in developing sensors for the cAMP and protein kinase A (PKA) pathway for in vivo imaging, we will employ a multi-pronged approach to characterize and improve PKC sensors for in vivo imaging. In addition, we will develop novel genetically encoded actuators for both the PKA and PKC pathways that are effective only when they are stimulated by blue light. We will validate the utility of these tools for monitoring or manipulating neuromodulatory activities in awake mice during behavior. The successful tools will be packaged into viral vectors for their easy introduction in vivo, and will be disseminated to the research community. If successful, our efforts will provide the research community with a previously unattainable ability to conduct large-scale monitoring and manipulation of neuromodulatory signaling activities in the brain at the cellular and circuit levels. This ability to quantify and manipulate neuromodulatory signaling will complement the measurements of extracellular neuromodulators and neuronal electric activities to enhance our understanding of brain function underlying animal behavior.
项目总结 神经调节,如由神经调节剂去甲肾上腺素、乙酰胆碱和 多巴胺对大脑功能有强大的控制作用。它调节兴奋性,突触可塑性, 以及神经功能的其他方面。神经调节的缺陷与许多 神经精神疾病。神经调节剂通过调节细胞内信号发挥作用 通过其相应的G蛋白偶联受体(GPCRs)。虽然在体内审问 细胞外神经调节剂已开始成为可能,神经调节剂对 亚细胞信号和神经元功能因细胞类型而异。监控特定于细胞类型的 神经调节性亚细胞信号事件的结果仍然很困难。此外,还缺乏 体内高时间分辨率拮抗神经调节信号事件的实用工具, 这是建立信号事件和神经元之间的因果关系所必需的 功能或动物行为。 为了克服这些问题,我们建议开发用于检测的新型遗传编码传感器 在单个神经元分辨率下,未被充分研究的神经调节信号的活性 途径:蛋白激酶C(PKC)途径。尽管原型遗传编码的PKC传感器 基于Förster的共振能量转移(FRET)已被用于体外实验,其 在体内应用一直是困难的,因为在更具挑战性的 活体成像条件。基于我们之前在开发传感器方面的成功经验 CAMP和蛋白激酶A(PKA)途径进行体内成像,我们将多管齐下 用于体内成像的PKC传感器的特性和改进。此外,我们还将开发小说 用于PKA和PKC通路的基因编码的致动器,仅当它们 都受到蓝光的刺激。我们将验证这些工具用于监视或操作的效用 清醒小鼠在行为过程中的神经调节活动。成功的工具将被打包成 病毒载体易于在体内引入,并将传播到研究界。如果 成功,我们的努力将为研究界提供以前无法达到的能力 对大脑中的神经调节信号活动进行大规模监测和操作 细胞和电路层面。这种量化和操纵神经调节信号的能力将 补充细胞外神经调节剂和神经元电活动的测量 增强我们对动物行为背后的大脑功能的理解。

项目成果

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Haining Zhong其他文献

Haining Zhong的其他文献

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{{ truncateString('Haining Zhong', 18)}}的其他基金

Neuromodulation in the striatum
纹状体的神经调节
  • 批准号:
    10592372
  • 财政年份:
    2022
  • 资助金额:
    $ 256.58万
  • 项目类别:
Fluorescence labeling of PSD-95 at endogenous levels for single cell imaging
内源水平 PSD-95 的荧光标记用于单细胞成像
  • 批准号:
    8702775
  • 财政年份:
    2014
  • 资助金额:
    $ 256.58万
  • 项目类别:
Examining the architecture of synapses in brain tissue at nanometer resolution
以纳米分辨率检查脑组织突触的结构
  • 批准号:
    8145426
  • 财政年份:
    2011
  • 资助金额:
    $ 256.58万
  • 项目类别:

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