The role of interneuron plasticity in the generation of fast local network oscillations

中间神经元可塑性在快速局部网络振荡产生中的作用

基本信息

项目摘要

Increasing evidence suggests that interneuron (IN) plasticity is contributing to the plasticity of micro-circuits in many brain regions. However, the functional importance of IN plasticity remains unknown. Here, we propose that long-lasting plasticity of IN excitation is a main mechanism regulating oscillatory brain activity especially in the gamma (g) frequency range (30-90 Hz). We will focus our research in this proposal exclusively on fast-spiking INs expressing the calcium binding protein parvalbumin (PV) in three brain regions: The hippocampal CA3, the presubiculum of the parahippocampal cortex and the M1 subregion of the motor cortex. This approach aims to clarify to which extent synaptic plasticity at one defined IN type could be attributed to a specific neuronal network function across brain regions. The central network function studied here is the generation of fast network oscillations. All experiments will be performed in acute brain slice preparations of the respective brain areas of mice using extracellular and whole-cell recordings. Oscillatory activity in vitro will be induced pharmacologically. Along these lines we could show in the 1st funding period of the research unit (RU) that in vitro g-oscillations in CA3 induce long-term potentiation (LTP) at excitatory synapses onto fast-spiking PV interneurons (PVIs). To probe whether PVI LTP could in turn enhance g-oscillations, we induced g-activity a second time 1h after the first induction. We discovered a potentiation of the second g-pattern. In subsequent experiments we could provide preliminary evidence that PVI LTP is involved in this form of ‘g-oscillation plasticity’. The central Aim here is to deepen the mechanistic analysis of these likely reciprocal interactions of PVI plasticity and g-oscillations and corroborate this hypothesis. In addition we will extent this analysis to the presubiculum and M1. Assuming the proposed reciprocal interactions of PVI plasticity and g-oscillations, we will use ‘g-oscillation plasticity’ as essay to test new molecular tools in the RU in collaboration with our partners (TP1 Bartos, TP5 Wulff) and their impact on interfering with PVI plasticity. The new molecular mechanisms will be identified by using this essay for differential RNA sequencing experiments and to identify PVI plasticity-related up-regulated transcripts. Finally, we will use this essay to identify transgenic disease models which have lost PVI plasticity. The results of this analysis will lead to new molecular hypothesis of PVI plasticity and support the development of new interference tools. Subsequent plasticity and connectivity analysis of promising animal models by using multi-patch-clamp recordings in close collaboration with TP3 Vida will identify changes of plasticity rules and morphological alterations in addition to changes in local network topology. The results obtained here may guide computational experiments (TP9 Sprekeler) and in vivo recordings in M1 (TP6 Poulet).
越来越多的证据表明,中间神经元(IN)的可塑性有助于许多脑区微回路的可塑性。然而,IN可塑性的功能重要性仍不清楚。在这里,我们认为,IN兴奋的长期可塑性是调节脑振荡活动的主要机制,特别是在伽马(G)频率范围(30-90赫兹)。在这项提议中,我们将专注于在三个大脑区域表达钙结合蛋白小白蛋白(PV)的快速尖峰INS:海马CA3区、海马旁皮质的悬垂前叶和运动皮质的M1亚区。这一方法旨在阐明在何种程度上定义的IN类型的突触可塑性可以归因于跨大脑区域的特定神经网络功能。这里研究的中心网络函数是产生快速网络振荡。所有实验都将在小鼠各自大脑区域的急性脑切片准备中进行,使用细胞外和全细胞记录。体外振荡活动将由药物诱导。沿着这些思路,我们可以在研究单位(RU)的第一个资助期表明,在体外,CA3中的g振荡诱导兴奋性突触的长时程增强(LTP)到快速放电的PV中间神经元(PVI)。为了探讨PVI LTP是否可以反过来增强g-振荡,我们在第一次诱导后1h第二次诱导g-活性。我们发现了第二个G型的增强效应。在随后的实验中,我们可以提供初步证据,证明PVI LTP参与了这种形式的g振荡可塑性。这里的中心目的是深化对PVI塑性和g振荡这些可能的相互作用的力学分析,并证实这一假说。此外,我们将把这一分析扩展到小叶前和M1。假设PVI可塑性和g振荡之间存在相互作用,我们将使用“g振荡塑性”作为文章,与我们的合作伙伴(TP1 Bartos,TP5 Wulff)合作,测试RU中的新分子工具及其对干扰PVI可塑性的影响。新的分子机制将通过本文的差异RNA测序实验和鉴定PVI可塑性相关的上调转录本来确定。最后,我们将利用本文来鉴定失去PVI可塑性的转基因疾病模型。这一分析结果将导致PVI可塑性的新的分子假说,并支持新的干扰工具的开发。随后,通过与TP3 VIDA密切合作,使用多膜片钳记录对有希望的动物模型进行可塑性和连通性分析,除了局部网络拓扑的变化外,还将识别可塑性规则和形态变化的变化。所得结果可指导计算实验(TP9 Sprekeler)和在M1(TP6 Poulet)中的活体记录。

项目成果

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Professor Dr. Jörg Geiger其他文献

Professor Dr. Jörg Geiger的其他文献

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{{ truncateString('Professor Dr. Jörg Geiger', 18)}}的其他基金

Mechanismen pathologischer Oszillationen in der Kortex-Basalganglien-Schleife und deren Modulation durch die tiefe Hirnstimulation im Parkinsonmodell der Ratte
帕金森病模型大鼠皮层-基底节环路病理振荡机制及其深部脑刺激的调节
  • 批准号:
    249665548
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
    Clinical Research Units

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