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 突触可塑性被很好地接受为行为可调性的基础 不断变化的环境。作为沿轴突的电脉冲，我们的生活经验被传播到我们的大脑。 少突胶质细胞（OLS）增加了这些电脉冲通过绝缘传递的速率 带有髓鞘的轴突。令人惊讶的是，运动学习，感官刺激和社会富集会引起 前体细胞分化为髓鞘的OL，导致白色可量化的结构变化 事情。这些发现表明髓鞘可塑性是同时发生的，同样重要的是 神经回路的适应性。但是，髓磷脂可塑性为基础的分子和细胞机制是 不太了解。 单个OL可以产生不同长度和厚度的鞘，以适应 多样的轴突。这些观察结果表明对髓鞘形成的局部和独立调节 单个鞘。护套如何评估特定轴突的需求？动作电位会导致轴突，而不是 仅在其末端释放囊泡，但也沿着轴释放囊泡。我们的实验室和其他实验室表明 轴突通过这些替代释放位点向髓鞘发出信号，髓鞘表达 典型的解释这些信号所需的突触后因素。这些数据表明使用共享 变速器机械使突触和髓磷脂可塑性并行出现作为对同一的响应 刺激。 虽然已经阐明了Axo膜蛋白通信的某些组成部分，但细胞内 桥接信号接收到髓磷脂产生的机制尚不清楚。在树突中，本地化 对单个棘的mRNA转录本和核糖体支持其快速，量身定制的自适应反应。 同样，不同的mRNA组以及核糖体位于髓鞘上，从而提高了可能性 局部RNA翻译基于单个OL鞘的能力微调其对信号的反应 各种轴突。由于RNA翻译的动态性质，如果在体内进行研究，最好理解。 但是，技术方法中的局限性数十年来一直持续了数十年。使用多样的转基因 表达系统，蛋白质光转化技术以及我使用2光量激光切断的专业知识，我将 确定在斑马鱼中是否出现髓磷脂居民成绩单的局部翻译。此外，我将调查 我们确定的富集成绩单的髓鞘定位是否有助于髓磷脂。 为此，我将创建一个功能丧失的khdrbs1，这是一种预测的RNA结合蛋白 与该丰富组的成员结合。最后，我将测试是否操纵神经元活动会改变翻译 有针对性的髓鞘居民mRNA。这项工作将增加我们对Axo-Myelin如何交流的理解 通过为体内局部翻译动力学提供新的见解，影响神经元电路的效率。