Neuron-oligodendrocyte communication underlying myelin distribution in the neocortex
Neuron-oligodendrocyte communication underlying myelin distribution in the neocortex
批准号:
10502460
负责人:
Paola Arlotta
金额:
$42.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-15 至 2027-06-30
关键词:
Action PotentialsAdultAffectAxonBrainCRISPR/Cas technologyCandidate Disease GeneCellsCellular biologyCerebral cortexClassificationCodeCommunicationComplexCuesCuprizoneDataDemyelinationsDevelopmentDevelopmental BiologyEvolutionFunctional disorderGap JunctionsGoalsInterneuronsInvestigationKnowledgeLabelLigandsLipidsLocationMapsMediatingMembraneMembrane ProteinsModelingMolecularMolecular ProfilingMonitorMorphologyMultiple SclerosisMyelinMyelin SheathNatural regenerationNeocortexNeuraxisNeuronsOligodendrogliaParvalbuminsPathologicPatternPopulationPositioning AttributeProcessProtocols documentationRanvier&aposs NodesRegulationReportingResolutionRoleSchizophreniaSignal TransductionSignaling MoleculeSomatostatinStructureSurfaceSynapsesTestingTherapeuticThickVasoactive Intestinal PeptideWorkcell typedesignexperienceexperimental studyin vivo evaluationin vivo two-photon imagingmRNA Differential Displaysmyelinationnervous system disorderneural circuitneurotransmissionreceptorremyelinationresponsetranscriptometranscriptomicsvirtual
中文摘要
摘要:
在脊椎动物进化过程中,髓鞘的发育促进了中央髓鞘的扩张。
神经系统和复杂脑功能的出现。累积的证据表明,
髓鞘形成及其在轴突上的位置可能取决于有髓神经元的分类。一个
典型的例子是L5投射神经元和L5投射神经元之间的差异,L5投射神经元具有广泛和均匀的髓鞘形成。
L2/3的膝状体投射神经元,髓鞘形成较少和更多样,包括“间歇性”。
轮廓,髓鞘束由长的无髓区域而不是兰维尔的短节点隔开。
对髓鞘形成之间的细胞相互作用的机制原理知之甚少。
少突胶质细胞(OL)和中枢神经系统内不同神经元类别的轴突。然而,这一知识是
了解髓鞘形成和再生的细胞和发育生物学。专注于
新皮质,我们建议回答有关控制神经元类型的机制的基本问题
特定的髓鞘形成,并测试关于神经元如何表达“吸引”和“排斥”暗示的假设
子类型动态地调整它们与OL的交互。在这里,我们将使用1)分子图谱
跨不同皮质层的少突胶质细胞和皮质神经元亚型的差异
转录组,并使用这些数据来生成介导神经元的候选基因的分子交互组-
可能调节神经元亚型特异性髓鞘形成的OL通讯。我们将使用一个屏幕来识别
能够诱导或抑制髓鞘形成的候选者(目标1)。然后我们将研究膜蛋白
特定神经元亚细胞中有髓和无髓轴突节段的组成
了解髓鞘沿轴突定位的调节;并进一步研究是否长
无髓鞘区域功能相关结构的差异丰富,如突触、GAP
连接和轴突分支(目标2)。据报道,神经元活动的增加促进了
髓鞘形成,进而稳定轴突结构和神经回路连接。髓鞘形成障碍可能
导致许多令人衰弱的神经疾病,包括多发性硬化症和精神分裂症
促进少突胶质细胞分化和再髓鞘形成是一个重要的治疗目标。我们会调查的
控制髓鞘细胞型特异性适应性重塑及其再生的分子机制
脱髓鞘(目标3)。总之,这里提出的工作旨在提供一个概念性框架,说明如何
不同类别的神经元和少突胶质细胞相互作用,以实现不同的髓鞘形成,机制
对于理解髓鞘在回路功能和功能障碍中的作用将是至关重要的。
英文摘要
Summary:
Over vertebrate evolution, the development of the myelin sheath has contributed to the expansion of the central
nervous system and the emergence of complex brain function. Cumulative evidence indicates that the level of
myelination and its positioning over the axon may be dependent on the class identity of myelinated neurons. A
canonical example is the difference between L5 projection neurons, with extensive and uniform myelination, and
the L2/3 callosal projection neurons, with lower and more diverse patterns of myelination, including “intermittent”
profiles, where myelin tracts are separated by long unmyelinated regions rather than short nodes of Ranvier.
Little is known about the mechanistic principles underlying cellular interaction between myelinating
oligodendrocytes (OL) and axons of distinct neuronal classes in the CNS. Yet this knowledge is fundamental to
understanding the cellular and developmental biology of myelination and regeneration. Focusing on the
neocortex, we propose to answer fundamental questions regarding the mechanisms that control neuron-type
specific myelination, and test hypotheses on how “attractive” and “repulsive” cues expressed by neuronal
subtypes dynamically regulate their interactions with OLs. Here, we will 1) use molecular profiling of
oligodendrocytes and cortical neuron subtypes across different cortical layers to map differences in their
transcriptome, and use this data to generate a molecular interactome of candidates for genes mediating neuron-
OL communication that may regulate neuron-subtype-specific myelination. We will 2) employ a screen to identify
candidates able to induce or repress myelination (Aim 1). We will then 3) investigate membrane protein
composition of myelinated and unmyelinated axonal segments of a specific neuronal class at subcellular
resolution to understand the regulation of myelin positioning along the axon; and further 4) study whether long
unmyelinated regions are differentially enriched for functionally-relevant structures such as synapses, gap
junctions, and axonal branches (Aim 2). It has been reported that increased neuronal activity promotes
myelination, which in turn stabilizes axon structure and neural circuit connectivity. Disrupted myelination can
contribute to many debilitating neurological disorders, including multiple sclerosis and schizophrenia, and
promoting oligodendrocyte differentiation and remyelination is an important therapeutic goal. We will investigate
the molecular mechanisms that control cell-type specific adaptive remodeling of myelin and its regeneration after
demyelination (Aim 3). In summary, the work proposed here aims to inform a conceptual framework for how
different classes of neurons and oligodendrocytes interact to achieve differential myelination, mechanisms that
will be critical in understanding the role of myelin in circuit function and dysfunction.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Systematic identification of enhancers to target the breadth of excitatory and inhibitory neuronal cell types in the cerebral cortex
-
批准号:10512459
-
项目类别:
-
资助金额:$1067.93万
-
财政年份:2022
-
负责人:Paola Arlotta
-
依托单位:
Comprehensive single-cell atlas of the developing mouse brain
-
批准号:10686208
-
项目类别:
-
资助金额:$529.86万
-
财政年份:2022
-
负责人:Paola Arlotta
-
依托单位:
Comprehensive single-cell atlas of the developing mouse brain
-
批准号:10523550
-
项目类别:
-
资助金额:$936.46万
-
财政年份:2022
-
负责人:Paola Arlotta
-
依托单位:
Neuron-oligodendrocyte communication underlying myelin distribution in the neocortex
-
批准号:10664007
-
项目类别:
-
资助金额:$42.25万
-
财政年份:2022
-
负责人:Paola Arlotta
-
依托单位:
Molecular principles of neuronal maturation and integration in the adult and aging brain
-
批准号:10404657
-
项目类别:
-
资助金额:$53.35万
-
财政年份:2018
-
负责人:Paola Arlotta
-
依托单位:
Molecular principles of neuronal maturation and integration in the adult and aging brain
-
批准号:10159316
-
项目类别:
-
资助金额:$53.35万
-
财政年份:2018
-
负责人:Paola Arlotta
-
依托单位:
Modeling ASD-linked genetic mutations in 3D human brain organoids
-
批准号:10308455
-
项目类别:
-
资助金额:$51.51万
-
财政年份:2018
-
负责人:Paola Arlotta
-
依托单位:
Genetic neuroscience: How human genes and alleles shape neuronal phenotypes
-
批准号:10223999
-
项目类别:
-
资助金额:$402.66万
-
财政年份:2017
-
负责人:Paola Arlotta
-
依托单位:
Genetic neuroscience: How human genes and alleles shape neuronal phenotypes
-
批准号:9757833
-
项目类别:
-
资助金额:$412.91万
-
财政年份:2017
-
负责人:Paola Arlotta
-
依托单位:
A Comprehensive Center for Mouse Brain Cell Atlas
-
批准号:9415765
-
项目类别:
-
资助金额:$1413.88万
-
财政年份:2017
-
负责人:Paola Arlotta
-
依托单位:
Functional Roles of Long Noncoding RNAs During Neuronal Development
-
批准号:9198251
-
项目类别:
-
资助金额:$42.25万
-
财政年份:2014
-
负责人:Paola Arlotta
-
依托单位:
Functional Roles of Long Noncoding RNAs During Neuronal Development
-
批准号:8788553
-
项目类别:
-
资助金额:$42.25万
-
财政年份:2014
-
负责人:Paola Arlotta
-
依托单位:
Functional Roles of Long Noncoding RNAs During Neuronal Development
-
批准号:8612093
-
项目类别:
-
资助金额:$42.25万
-
财政年份:2014
-
负责人:Paola Arlotta
-
依托单位:
Genetic targeting of cortical pyramidal neuron subtypes
-
批准号:8560453
-
项目类别:
-
资助金额:$86.62万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Projection neuron control over interneuron positioning into neocortical circuitry
-
批准号:9314640
-
项目类别:
-
资助金额:$36.97万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Genetic targeting of cortical pyramidal neuron subtypes
-
批准号:8874302
-
项目类别:
-
资助金额:$76.55万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Genetic targeting of cortical pyramidal neuron subtypes
-
批准号:8690164
-
项目类别:
-
资助金额:$74.88万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Projection neuron control over interneuron positioning into neocortical circuitry
-
批准号:8882565
-
项目类别:
-
资助金额:$36.97万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Projection neuron control over interneuron positioning into neocortical circuitry
-
批准号:8683266
-
项目类别:
-
资助金额:$36.6万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
Projection neuron control over interneuron positioning into neocortical circuitry
-
批准号:8576627
-
项目类别:
-
资助金额:$36.97万
-
财政年份:2013
-
负责人:Paola Arlotta
-
依托单位:
海外基金