Experience-dependent Cellular Plasticity Mechanisms

经验依赖的细胞可塑性机制

基本信息

批准号：
10433777
负责人：
HOLLIS T. CLINE
金额：
$ 3.89万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-12-31
项目状态：
未结题

项目摘要

Brain activity is essential for the development and plasticity of neurons and circuits, however our understanding of the mechanisms by which activity generates functional circuits is incomplete. This lack of knowledge impedes our ability to take advantage of activity-dependent mechanisms to facilitate circuit plasticity. Plasticity-inducing stimuli induce neuronal protein dynamics, including regulated increases and decreases in protein synthesis. We recently conducted a quantitative in vivo proteomic analysis which identified changes in newly synthesized proteins in the Xenopus tadpole visual system in response to plasticity-inducing visual stimulation. We identified numerous candidate plasticity proteins (CPPs), including several that regulate protein synthesis, whereas others have diverse cellular and synaptic functions. Here we will probe the model that plasticity-inducing stimuli initiate a cascade of protein synthesis-dependent events, beginning with de novo synthesis of upstream translational regulators and culminating in the regulated synthesis of diverse effector proteins, in visual experience dependent circuit plasticity in Xenopus, using proteomics, electrophysiology, in vivo structural and functional imaging, and behavioral assays. Classical studies have revealed circuit-rewiring events in response to CNS damage. We have shown that local damage to the optic tectum impairs visual avoidance behavior in Xenopus and that treating injured animals with brief bouts of visual experience facilitates recovery of the injured circuit. To probe the flexibility of experience-dependent plasticity mechanisms, we will test whether newly synthesized candidate plasticity proteins are required for the visual experience-dependent rehabilitation of the injured visuomotor circuit. Results of these experiments may identify novel mechanisms contributing to experience-dependent plasticity in developing nervous systems.

大脑活动对于神经元和电路的发展和可塑性至关重要，但是我们了解活动产生功能电路的机制是不完整的。这种缺乏知识阻碍了我们利用活动依赖机制来促进电路的能力可塑性。可塑性刺激会诱导神经元蛋白动力学，包括调节的增加和蛋白质合成的减少。我们最近进行了定量的体内蛋白质组学分析，该分析确定了爪蟾t视觉系统中新合成的蛋白质的变化，以响应于可塑性引起视觉刺激。我们确定了许多候选可塑性蛋白（CPP），包括几种调节蛋白质合成的方法，而其他一些则具有多种细胞和突触功能。这里我们将探测一个模型，诱导塑料刺激启动蛋白质合成依赖性的级联事件，从从头综合上游翻译调节器开始，并在调节效应子蛋白的合成，在异武的视觉经验依赖性电路可塑性中，使用蛋白质组学，电生理学，体内结构和功能成像以及行为测定。古典研究揭示了响应中枢神经系统损伤的回路事件。我们已经表明局部对视神经膜的损害会损害爪蟾的视觉回避行为，并治疗受伤短暂的视觉经验的动物有助于恢复受伤的电路。探测灵活性依赖经验的可塑性机制，我们将测试新合成的候选塑性蛋白质是受伤的视觉运动电路的视觉依赖性康复所必需的。这些实验的结果可能会识别出促成经验依赖性的新型机制发展神经系统的可塑性。