ZeDiAx: Using zebrafish to discover how axons grow in diameter

轴突直径在中枢神经系统不同神经元之间的差异可达100倍。这种多样性与回路功能有关，因为轴突直径增加与神经传导速度加快之间存在正相关关系。事实上，轴突直径的动态调节可能有助于微调信号传播的时间，从而调节神经回路的功能。此外，不同大小的轴突在神经发育到神经退行性疾病中被观察到改变。因此，如果我们想要充分了解神经系统是如何构建、功能成熟和保持健康的，我们需要了解是什么调节轴突直径的增长。目前，我们对神经系统中轴突如何长到如此不同的直径知之甚少。通过这个项目，我将通过利用斑马鱼作为模型系统的各种机会来揭示轴突直径增长的分子机制。通过首先采用基于化学的筛选方法和可视化轴突直径的变化，我将确定影响直径增长的新分子信号。然后，我将采用先进的实时成像技术，进一步精确地研究这些分子如何随着时间的推移影响直径的增长。通过行为分析和功能成像技术，我还将研究轴突直径的变化如何影响动作电位传导和电路功能。这种多学科方法的结果将为我们对轴突直径生长和调节的理解提供新的见解，我最终的目标是将其转化为哺乳动物和人类。这个项目将有助于欧洲的研究产出和知名度，并将促进我未来的研究生涯的启动。

Axon diameter varies up to 100-fold between distinct neurons in the central nervous system. This diversity is relevant for circuit function because there is a positive correlation between increased axon diameters and faster nerve conduction velocity. Indeed, the dynamic regulation of axon diameter might help fine-tune the timing of signal propagation and thus neural circuit function. In addition, axons of distinct sizes are observed altered in neurodevelopmental through to neurodegenerative disorders. Therefore, if we want to fully understand how nervous systems are built, functionally mature, and remain healthy, we need to understand what regulates axon diameter growth. At present, we know surprisingly little about how axons grow to such different diameters in the living nervous system. Through this project, I will unravel the molecular mechanisms underlying axon diameter growth by utilizing the diverse opportunities of zebrafish as a model system. By first undertaking a chemical-based screen approach and visualizing changes in axon diameters I will identify novel molecular signals that impact diameter growth. I will then employ cutting-edge live imaging techniques to further investigate precisely how these molecules influence diameter growth over time. Through behavioural assays and functional imaging techniques, I will also investigate how changes in axon diameter impact action potential conduction and circuit function. The outcomes of this multidisciplinary approach will provide new insights into our understanding of axon diameter growth and regulation that I ultimately aim to translate to mammals and humans. This project will contribute to the research output and visibility of Europe and will foster the launch of my future research career.