Examining the regulation of resident mRNAs in myelinplasticity

检查常驻 mRNA 对髓鞘可塑性的调节

• 批准号: 10640732
• 负责人: KADIDIA PEMBA ADULA
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2026-05-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640732
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Action Potentials; Axon; Behavioral; Binding; Biological Assay; Brain; Cells; Central Nervous System; Co-Immunoprecipitations; Code; Communication; Complex; Data; Dendrites; Diameter; Environment; Genes; Genetic; Image; Individual; Instruction; Kinetics; Larva; Lasers; Learning; Length; Link; Location; Messenger RNA; Molecular; Mus; Mutate; Myelin; Myelin Sheath; Nature; Needs Assessment; Neurons; Oligodendroglia; Pharmacogenetics; Positioning Attribute; Postdoctoral Fellow; Process; Production; Protein Biosynthesis; Proteins; Proxy; RNA; RNA-Binding Proteins; Regulation; Ribosomes; Sensory; Signal Transduction; Site; Societies; Stimulus; Structure; Synapses; Synaptic plasticity; System; Technology; Testing; Thick; Tongue; Training; Transcript; Translations; Vertebral column; Visualization; Work; Zebrafish; developmental neurobiology; electrical potential; experience; experimental study; flexibility; graduate student; in vivo; insight; loss of function; loss of function mutation; member; motor learning; myelination; neural circuit; neuronal circuitry; neurotransmission; paralogous gene; postsynaptic; precursor cell; response; skills; social; tool; transgene expression; transmission process; two-photon; vesicular release; white matter

PROJECT SUMMARY Synaptic plasticity is well accepted as the basis of behavioral adjustability in the face of a constantly changing environment. Our lived experience is transmitted to our brain as electrical impulses along axons. Oligodendrocytes (OLs) increase the rate at which these electrical impulses are transmitted by insulating axons with myelin sheaths. Surprisingly, motor learning, sensory stimulation, and social enrichment induce the differentiation of precursor cells into myelinating OLs resulting in quantifiable structural changes in white matter. These findings point to myelin plasticity as a concurrent, and equally important contributor to the adaptability of neural circuits. However, the molecular and cellular mechanisms underlying myelin plasticity are not well understood. Single OLs can give rise to sheaths of different lengths and thicknesses to accommodate the needs of diverse axons. These observations suggest a local and independent regulation of myelination at the level of individual sheaths. How do sheaths assess the needs of specific axons? Action potentials cause axons to, not only release vesicles at their terminal ends, but also along their shafts. Our lab and others have shown that axons signal to myelin sheaths via these alternative release sites and that myelin sheaths express the canonical post-synaptic factors required to interpret these signals. These data suggest that the use of a shared transmission machinery enables synaptic and myelin plasticities to occur in parallel as a response to the same stimulus. While some components of axo-myelin communication have been elucidated, the intracellular mechanisms bridging signal receipt to myelin production remain unknown. In dendrites, the localization of mRNA transcripts and ribosomes to individual spines support their rapid, tailored adaptive responses. Similarly, diverse groups of mRNAs, along with ribosomes localize to myelin sheaths raising the possibility that local RNA translation underlies the ability of individual OL sheaths to fine-tune their responses to signals from various axons. Due to the dynamic nature of RNA translation, it would be best understood if studied in vivo. However, limitations in technological approaches stood in the way for decades. Using diverse transgene expression systems, protein photoconversion technology, and my expertise with 2-photon laser severing, I will determine if local translation of myelin-resident transcripts occurs in zebrafish. Additionally, I will investigate whether the myelin localization of an enriched group of transcripts we identified contributes to myelin plasticity. To accomplish this, I will create a loss-of-function mutation of Khdrbs1, an RNA binding protein predicted to bind to members of this enriched group. Finally, I will test if manipulating neuronal activity alters the translation of targeted myelin resident mRNAs. This work will add to our understanding of how axo-myelin exchanges impact the efficiency of neuronal circuits by providing new insights into the kinetics of local translation in vivo.

项目总结 突触的可塑性被广泛认为是面对持续不断的 不断变化的环境。我们的生活经验以电脉冲的形式沿着轴突传递到我们的大脑。 少突胶质细胞(OL)通过绝缘提高这些电脉冲的传递速度 有髓鞘的轴突。令人惊讶的是，运动学习、感觉刺激和社交丰富会诱导 前体细胞分化为髓鞘细胞导致白色可量化的结构变化 物质。这些发现表明，髓鞘的可塑性是同时存在的，同样重要的贡献因素 神经回路的适应性。然而，髓鞘可塑性背后的分子和细胞机制是 不是很清楚。 单个OL可以产生不同长度和厚度的鞘，以适应 不同的轴突。这些观察表明，在髓鞘形成的水平上存在局部和独立的调节 单独的鞘。鞘如何评估特定轴突的需求？动作电位导致轴突而不是 只在末端释放囊泡，也沿着轴释放囊泡。我们的实验室和其他实验室已经证明 轴突通过这些替代释放部位向髓鞘发出信号，而髓鞘表达 解释这些信号所需的规范的突触后因子。这些数据表明，使用共享的 传递机制使突触和髓鞘的可塑性同时发生，作为对它们的反应 刺激。 虽然轴突-髓鞘通讯的一些成分已经被阐明，但细胞内 连接信号接收和髓鞘产生的机制仍不清楚。在树突中，定位于 MRNA转录本和核糖体支持它们快速的、量身定制的适应性反应。 同样，不同的mRNAs组以及核糖体定位于髓鞘，增加了这种可能性 局部RNA翻译是个体OL鞘微调其对来自 各种轴突。由于RNA翻译的动态性质，如果在体内进行研究，将是最好的理解。 然而，几十年来，技术方法的局限性一直是障碍。利用多样化的转基因 表达系统，蛋白质光转化技术，以及我在双光子激光切割方面的专业知识，我会 确定在斑马鱼中是否存在髓鞘驻留转录本的本地翻译。另外，我会调查 我们确定的一组丰富的转录体的髓鞘定位是否有助于髓鞘可塑性。 为了实现这一点，我将创造Khdrbs1的功能丧失突变，这是一种RNA结合蛋白，预计 绑定到此丰富组的成员。最后，我将测试操控神经元活动是否会改变翻译 靶向髓鞘驻留的mRNAs。这项工作将增加我们对轴突-髓鞘如何交换的理解 通过为活体内局部翻译的动力学提供新的见解，影响神经元电路的效率。