Experience-dependent Cellular Plasticity Mechanisms

经验依赖的细胞可塑性机制

基本信息

批准号：
10319188
负责人：
HOLLIS T. CLINE
金额：
$ 66.32万
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：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319188
关键词：
Address Amblyopia Animals Behavior Behavioral Behavioral Assay Biological Assay Brain Brain Injuries Cell physiology Development Electrophysiology (science)Event Functional Imaging Goals Image Impairment Injury Investigation Knowledge Label Mass Spectrum Analysis Metabolic Modeling Molecular Molecular Genetics Nerve Degeneration Nervous system structure Neuronal Plasticity Neurons Optics Photic Stimulation Play Protein Biosynthesis Protein Dynamics Proteins Proteomics Protocols documentation RNA Transport RNA-Binding Protein FUS RNA-Binding Proteins Recovery Rehabilitation therapy Role Sensory Stimulus Synapses System Tadpoles Tectum Mesencephali Testing Translations Visual Visual impairment Visual system structure Western Blotting Xenopus Xenopus laevis avoidance behavior base behavioral plasticity cohort developmental disease experience experimental study flexibility genetic manipulation in vivo in vivo imaging injured injury recovery insight multidisciplinary mutant neural circuit neurological rehabilitation newborn neuron novel repaired response superior colliculus Corpora quadrigemina synaptic function treatment strategy visual motor

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育和可塑性至关重要，但是我们的对活动产生功能回路的机制的理解并不完整。这种缺乏知识阻碍了我们利用活动依赖机制来促进循环的能力可塑性。可塑性诱导刺激诱导神经元蛋白质动力学，包括调节性增加和蛋白质合成减少。我们最近进行了定量体内蛋白质组分析发现了非洲爪蟾蝌蚪视觉系统中新合成蛋白质的变化，以响应可塑性诱导的视觉刺激。我们鉴定了许多候选可塑性蛋白 (CPP)，包括其中一些调节蛋白质合成，而另一些则具有不同的细胞和突触功能。这里我们将探讨可塑性诱导刺激启动一系列依赖于蛋白质合成的级联的模型事件，从上游翻译调节因子的从头合成开始，最终以调节不同效应蛋白的合成，在爪蟾视觉体验依赖的电路可塑性中，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。经典研究揭示了针对中枢神经系统损伤的电路重新布线事件。我们已经证明视顶盖的局部损伤会损害非洲爪蟾的视觉回避行为以及治疗受伤的情况具有短暂视觉体验的动物有助于受伤回路的恢复。探索灵活性经验依赖的可塑性机制，我们将测试新合成的候选可塑性是否受损视觉运动回路的视觉体验依赖性康复需要蛋白质。这些实验的结果可能会确定有助于经验依赖的新机制神经系统发育中的可塑性。