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.

项目摘要 突触可塑性被广泛认为是面对不断变化的环境时行为适应性的基础。 不断变化的环境我们的生活经历以电脉冲的形式沿着沿着传递到我们的大脑。 少突胶质细胞（OL）通过绝缘增加这些电脉冲的传输速率， 有髓鞘的轴突令人惊讶的是，运动学习，感官刺激和社会充实诱导了 前体细胞分化为髓鞘形成OL，导致白色中可量化的结构变化， 所谓了这些发现指出，髓鞘可塑性作为一个并发的，同样重要的贡献者， 神经回路的适应性然而，髓鞘可塑性的分子和细胞机制是 没有被很好地理解。 单个OL可以产生不同长度和厚度的鞘管，以适应 不同的轴突这些观察结果表明，髓鞘形成的局部和独立的调节水平， 个别的鞘。鞘如何评估特定轴突的需求？动作电位导致轴突 不仅在它们的末端释放囊泡，而且还沿着它们的轴释放囊泡。我们的实验室和其他实验室已经证明， 轴突通过这些替代性释放位点向髓鞘发出信号，髓鞘表达 解释这些信号所需的典型突触后因子。这些数据表明，使用共享 传递机制使突触和髓鞘可塑性能够作为对相同信号的响应而平行发生。 刺激。 虽然已经阐明了轴髓磷脂通讯的一些组分，但细胞内的 桥接信号接收与髓磷脂产生的机制仍然未知。在树突中， mRNA转录物和核糖体到个体刺支持它们快速的、定制的适应性反应。 类似地，不同的mRNA组，沿着核糖体定位于髓鞘，这增加了以下可能性： 局部RNA翻译是单个OL鞘微调其对信号的反应的能力的基础， 各种轴突由于RNA翻译的动态性质，如果在体内研究，将最好地理解。 然而，几十年来，技术方法的局限性一直阻碍着这一进程。使用不同的转基因 表达系统，蛋白质光转换技术，以及我在双光子激光切割方面的专业知识，我将 确定髓鞘驻留转录本的本地翻译是否发生在斑马鱼中。另外，我会调查 我们鉴定的一组丰富的转录物的髓鞘定位是否有助于髓鞘可塑性。 为了实现这一点，我将创建一个Khdrbs1的功能缺失突变，Khdrbs1是一种RNA结合蛋白， 绑定到该丰富组的成员。最后，我将测试是否操纵神经元活动改变翻译 靶向髓磷脂基因的表达。这项工作将增加我们对轴髓磷脂交换的理解 通过提供对体内局部翻译动力学的新见解来影响神经元回路的效率。