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:
- 金额:$ 6.91万
- 依托单位:
- 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:
- 关键词:3&apos Untranslated Regions5&apos Untranslated RegionsAction PotentialsAxonBehavioralBindingBiological AssayBrainCellsCentral Nervous SystemCo-ImmunoprecipitationsCodeCommunicationComplexDataDendritesDiameterEnvironmentGenesGeneticImageIndividualInstructionKineticsLarvaLasersLearningLengthLinkLocationMessenger RNAMolecularMusMutateMyelinMyelin SheathNatureNeeds AssessmentNeuronsOligodendrogliaPharmacogeneticsPositioning AttributePostdoctoral FellowProcessProductionProtein BiosynthesisProteinsProxyRNARNA-Binding ProteinsRegulationRibosomesSensorySignal TransductionSiteSocietiesStimulusStructureSynapsesSynaptic plasticitySystemTechnologyTestingThickTongueTrainingTranscriptTranslationsVertebral columnVisualizationWorkZebrafishdevelopmental neurobiologyelectrical potentialexperienceexperimental studyflexibilitygraduate studentin vivoinsightloss of functionloss of function mutationmembermotor learningmyelinationneural circuitneuronal circuitryneurotransmissionparalogous genepostsynapticprecursor cellresponseskillssocialtooltransgene expressiontransmission processtwo-photonvesicular releasewhite 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
项目成果
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