Circuit-based mechanisms of neuronal vulnerability in the adult EC
成人内皮细胞神经元脆弱性的基于回路的机制
基本信息
- 批准号:10615015
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2024-04-14
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAdultAlzheimer&aposs DiseaseApoptosisApoptoticAutomobile DrivingAxonBindingBrainBrain regionCell DeathCell Death InductionCellsCessation of lifeChloride ChannelsChronicCodeCognitive deficitsCommunicationCytoplasmic GranulesDataDevelopmentDevelopmental ProcessDiseaseDisparityElectrophysiology (science)EngineeringExcisionExhibitsFire - disastersFunctional disorderFutureGenerationsGeneticGenetic ModelsGliosisGlutamatesGlycineGoalsHippocampusInfusion proceduresInjuryIvermectinLifeLigandsMediatingMemoryModelingMorphologic artifactsMusNerve DegenerationNeurodegenerative DisordersNeuronsNeurotransmittersPathway interactionsPatternPerforant PathwayPopulationPredispositionProcessSignal TransductionSodium ChannelSymptomsSynapsesSynaptic plasticityTestingTetanus ToxinTetrodotoxinTractioncompetitive environmentcritical perioddentate gyrusentorhinal cortexexperimental studygenetic approachgranule cellin vivoinsightmouse modelneuron lossneuronal survivalneurotransmitter releasepharmacologicpostnatalpostnatal developmentpostnatal periodpostsynapticpreventpro-apoptotic proteinresponseway finding
项目摘要
Project summary/abstract.
Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease (AD). ECII
axons form the perforant pathway and are the major cortical input into the hippocampus. The perforant pathway supports
memory formation and spatial navigation throughout life, and loss of this input is consistent with the cognitive deficits
that present early in AD. To mimic the loss of this input in AD, the Jankowsky lab created a chemogenetic mouse model
of perforant pathway disruption in which a subset of ECII neurons express an engineered chloride channel (GlyCl) to
prevent the generation of action potentials. We unexpectedly discovered that entorhinal neurons were highly vulnerable to
silencing. Shortly after being inactivated, many ECII neurons retract their axons from the dentate gyrus, express pro-
apoptotic proteins, and then are eliminated from the circuit. We observed similar neurodegeneration after eliminating
neurotransmitter release with tetanus toxin (TeTX), confirming that neuronal loss is not an artifact of GlyCl activation.
Further, this silencing-induced degeneration is not shared by other brain regions, as neither the pre/parasubiculum nor
retrosplenial cortex exhibit cell loss after neuronal inactivation. This suggests that specific features of the entorhinal
cortex may confer neuronal vulnerability to inactivity. One possible vulnerability could be related to the formation of
entorhinal-hippocampal circuit. We noted that the pattern of ECII degeneration after silencing was strikingly similar to the
processes that guide to refinement of the perforant pathway during development. In early post-natal periods, inactive ECII
neurons are pruned from the circuit in a process that is mediated by local differences in activity, referred to as activity-
dependent competition. Projections are only pruned when neurons are sparsely inactive - when all cells are equally
inactive, none are removed. This proposal will test two hypotheses about the cellular mechanism driving neuronal death in
the mature entorhinal cortex. Aim 1 will determine whether activity-dependent competition persists in the adult ECII.
Pharmacological and genetic approaches will be used to modulate relative activity levels to determine how cell death is
influenced by activity differences between neighboring cells. Aim 2 will determine whether post-synaptic partners
promote the survival of ECII neurons. Our preliminary data suggests that eliminating neurotransmitter release from ECII
neurons – without blocking action potentials - is sufficient to induce degeneration. I will therefore use pharmacological
and genetic approaches to both reduce neurotransmitter binding in dentate granule cells and eliminate their ability to fire
action potentials in response to ECII input. This will test whether neurotransmitter-mediate signaling, or post-synaptic
activity itself, is required for ECII neuron survival. Data from these aims will determine how activity disruption may
mediate cell death in the adult brain. Further, these data may suggest that mechanisms which drive cell death during
postnatal development are not necessarily limited to critical periods but may persist into adulthood within certain
pathways. Understanding these mechanisms may inform future studies on neurodegenerative disease and how circuit
disruption may contribute to neuronal loss.
项目摘要/摘要。
内嗅皮层 II (ECII) 神经元是阿尔茨海默病 (AD) 中最先退化的细胞之一。
轴突形成穿通通路,是海马体的主要皮质输入。穿通通路支持。
整个生命过程中的记忆形成和空间导航,这种输入的丧失与认知缺陷是一致的
为了模拟 AD 中这种输入的丢失,Jankowsky 实验室创建了一个化学遗传学小鼠模型。
穿通通路破坏,其中一部分 ECII 神经元表达工程氯通道 (GlyCl)
我们意外地发现内嗅神经元非常容易受到影响。
失活后不久,许多 ECII 神经元从齿状回缩回轴突,表达 pro-
凋亡蛋白,然后从回路中消除,消除后我们观察到类似的神经变性。
破伤风毒素 (TeTX) 释放神经递质,证实神经元损失不是 GlyCl 激活的产物。
此外,这种沉默引起的退化并不为其他大脑区域所共有,因为前/副下脑区和下下脑区均不共享这种退化。
压后皮质在神经元失活后表现出细胞损失,这表明内嗅的特定特征。
皮层可能会导致神经对不活动的脆弱性,一种可能的脆弱性可能与神经元的形成有关。
我们注意到沉默后 ECII 退化的模式与沉默后的惊人相似。
在产后早期,ECII 不活跃,指导发育过程中穿通通路的完善。
神经元在由活动的局部差异介导的过程中从回路中被修剪,称为活动-
仅当神经元稀疏不活跃时(即所有细胞均等)时,投影才会被修剪。
该提案将测试关于驱动神经死亡的细胞机制的两个假设。
成熟的内嗅皮层将决定成人 ECII 中是否持续存在活动依赖性竞争。
将使用药理学和遗传学方法来调节相对活性水平,以确定细胞死亡的方式
目标 2 将决定突触后伙伴是否受到相邻细胞之间活动差异的影响。
我们的初步数据表明,消除 ECII 释放的神经递质。
神经元 - 不阻断动作电位 - 足以诱导变性,因此我将使用药物。
和遗传方法可以减少齿状颗粒细胞中神经递质的结合并消除其发射能力
响应 ECII 输入的动作电位 这将测试神经递质介导的信号传导或突触后信号传导。
这些目标的数据将决定活动如何被破坏。
此外,这些数据可能表明驱动细胞死亡的机制。
出生后发育不一定限于关键时期,但可能在某些时间内持续到成年期
了解这些机制可能会为未来关于神经退行性疾病及其回路的研究提供信息。
破坏可能导致神经元损失。
项目成果
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Caleb Wood其他文献
Caleb Wood的其他文献
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{{ truncateString('Caleb Wood', 18)}}的其他基金
Circuit-based mechanisms of neuronal vulnerability in the adult EC
成人内皮细胞神经元脆弱性的基于回路的机制
- 批准号:
10400031 - 财政年份:2021
- 资助金额:
$ 4.77万 - 项目类别:
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