Genetic access to synaptic mechanisms of memory in the behaving animal - Axo-axonal synaptic integration in control of neurotransmitter release

行为动物记忆突触机制的遗传途径——控制神经递质释放的轴突突触整合

• 批准号: 282979116
• 负责人: Professor Dr. David Owald
• 金额: --
• 依托单位: Institut für Neurophysiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282979116?language=en
• 关键词: Genetic; access; synaptic; mechanisms; memory

This Emmy Noether project focuses on understanding the synaptic mechanisms of appetitive memory storage within the mushroom bodies (MBs) of the model organism Drosophila at an axo-dendritic synaptic junction (Owald et al., 2015; Perisse, Owald et al., 2016; Barnstedt, Owald et al., 2016). As a key result of this project, we were able to identify a novel mechanism of postsynaptic memory storage involving nicotinic acetylcholine receptors (Pribbenow et al., manuscript attached). While we have come to a good understanding of memory-storage mechanisms, how novel and learnt information are instantaneously integrated remains largely unclear. The here proposed project now builds on the discovery of an axo-axonal synaptic motif that we uncovered one synapse downstream of memory storage sites (unpublished). Functionality of this connection relies on signaling through the alpha7 nicotinic receptor that has also been identified in presynaptic signaling in vertebrates. Importantly, alpha7 nicotinic receptor knock-down interfered with behavioral programs and altered neurophysiological properties of individual boutons along the same axonal branch. Molecularly, our data suggest that alpha7 subunits can directly interact with proteins of the synaptic vesicle release machinery. We thus hypothesize that alpha7 can shape neurotransmitter release in parallel to canonical pathways via voltage-gated calcium channels. Because we uncovered a similar motif within a network signaling sleep pressure in this Emmy Noether project (Raccuglia et al., 2019), we follow the hypothesis that alpha7-signalling at axo-axonal connections represents a general motif for network integration.Here, we will investigate the molecular structure of axo-axonal contacts utilizing flies harboring GFP-tagged endogenous alpha7 that we constructed in this project. In parallel, we will investigate neurophysiological principles of axo-axonal signaling in the context of olfactory and visual integration of MB output neurons and R5 ring neurons respectively, interrogating subsequent steps of neurotransmitter release using optical sensors. Together, this project aims at structurally (molecularly) and functionally investigating a novel synaptic motif potentially capable of partaking in information integration and instant decision making.

这个Emmy Noether项目专注于理解在轴-树突突触连接处的模式生物果蝇的蘑菇体（MB）内的食欲记忆存储的突触机制（Owald等人，2015; Perisse，Owald等人，2016; Barnstedt，Owald等人，2016年）。作为该项目的关键结果，我们能够鉴定涉及烟碱乙酰胆碱受体的突触后记忆储存的新机制（Pribbenow et al.，附手稿）。虽然我们已经对记忆存储机制有了很好的理解，但新的和学习过的信息是如何瞬间整合的，在很大程度上仍然不清楚。这里提出的项目现在建立在发现轴-轴突触基序的基础上，我们发现了记忆储存位点下游的一个突触（未发表）。这种连接的功能依赖于通过alpha 7烟碱受体的信号传导，alpha 7烟碱受体也已在脊椎动物的突触前信号传导中被鉴定。重要的是，α 7烟碱受体敲低干扰了行为程序，并改变了同一轴突分支上沿着单个终扣的神经生理学特性。分子上，我们的数据表明，α 7亚基可以直接与突触囊泡释放机制的蛋白质相互作用。因此，我们假设α 7可以通过电压门控钙通道平行于经典途径塑造神经递质释放。因为我们在这个Emmy Noether项目中发现了一个类似的网络信号睡眠压力的基序（Raccuglia et al.，2019），我们遵循这样的假设，即轴索-轴索连接处的α 7信号传导代表了网络整合的一般基序。在这里，我们将利用携带我们在本项目中构建的GFP标记的内源性α 7的苍蝇来研究轴索-轴索接触的分子结构。与此同时，我们将分别在MB输出神经元和R5环神经元的嗅觉和视觉整合的背景下研究轴突-轴突信号传导的神经生理学原理，使用光学传感器询问神经递质释放的后续步骤。总之，这个项目的目的是在结构上（分子）和功能上研究一种新的突触基序可能能够参与信息整合和即时决策。