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Examining the regulation of resident mRNAs in myelinplasticity

检查常驻 mRNA 对髓鞘可塑性的调节

基本信息

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
项目类别：
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&apos Untranslated Regions 5&apos 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

项目摘要

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