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

• 批准号: 262007534
• 负责人: Professor Dr. Jörg Geiger
• 金额: --
• 依托单位: Institut für Neurophysiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262007534?language=en
• 关键词: role; interneuron; plasticity; generation; fast

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大脑区域微电路的可塑性。然而，IN 可塑性的功能重要性仍然未知。在这里，我们提出 IN 兴奋的持久可塑性是调节大脑振荡活动的主要机制，特别是在伽马（g）频率范围（30-90 Hz）内。我们将在这项提案中专门研究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、海马旁皮质前下层和运动皮质M1亚区。 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.这里研究的中心网络功能是快速网络振荡的产生。 All experiments will be performed in acute brain slice preparations of the respective brain areas of mice using extracellular and whole-cell recordings.体外振荡活性将通过药理学诱导。沿着这些思路，我们可以在研究单位 (RU) 的第一个资助期证明，CA3 中的体外 g 振荡会诱导快速尖峰 PV 中间神经元 (PVI) 上的兴奋性突触的长时程增强 (LTP)。为了探究 PVI LTP 是否可以反过来增强 g 振荡，我们在第一次诱导后 1 小时第二次诱导 g 活性。我们发现了第二个 g 模式的增强。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”。这里的中心目标是加深对 PVI 可塑性和 g 振荡之间可能的相互作用的机制分析，并证实这一假设。此外，我们将把这个分析扩展到前下托和 M1。假设所提出的 PVI 可塑性和 g 振荡的相互作用，我们将使用“g 振荡可塑性”作为论文，与我们的合作伙伴（TP1 Bartos、TP5 Wulff）合作在 RU 中测试新的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使用本文进行差异 RNA 测序实验并识别 PVI 可塑性相关的上调转录本来确定。最后，我们将利用这篇文章来识别失去 PVI 可塑性的转基因疾病模型。该分析结果将导致PVI可塑性的新分子假说，并支持新干扰工具的开发。随后与 TP3 Vida 密切合作，使用多膜片钳记录对有前途的动物模型进行可塑性和连接性分析，除了本地网络拓扑的变化之外，还将识别可塑性规则的变化和形态变化。这里获得的结果可以指导计算实验 (TP9 Sprekeler) 和 M1 (TP6 Poulet) 的体内记录。