How do the spatiotemporal dynamics of insulin signalling control neuron size and function?

胰岛素信号的时空动态如何控制神经元的大小和功能？

• 批准号: BB/T013869/1
• 负责人: Darren Williams
• 金额: $ 79.02万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT013869%2F1
• 关键词: How; do; spatiotemporal; dynamics; insulin

The brain is staggeringly complex. It is made of billions of neurons that extend tree-like branches and connect with 1000s of partners. These complex networks of connections are essential for the correct functioning of the nervous system, they need to be stable enough to process and store information (memories) but also dynamic to respond and change from experience (learning). How brains are built is still one of the biggest questions in biology.How neuron growth is controlled and how a particular neuron 'knows' what size to reach is intriguing. The growth of a neurons branches determines the potential partners it can make connections with and also sets in place some electrical properties which dictate how it fires. Some neurons have small trees with branches that don't spread very far and process local information within brain circuits whereas others send information long distances, like the neurons that run from your spine down to the muscles that control your big toe. We would like to understand what allows the small neurons to be small and big neurons to be big. To gain new insights into neuron size control we are using the powerful genetics and complex nervous system of fruit flies (Drosophila). Our preliminary data show a pathway called the Insulin/Insulin-like Growth factor signalling and Target of Rapamycin is required to generate appropriately sized trees. We have tested many different neurons in flies and these experiments point toward insulin signalling being a global player in the nervous system. Each neuron appears to have a distinct tuning that sets what size it should be. How this is controlled and what part it plays shaping neurons will be investigated.We are able to watch neurons growing live during metamorphosis using fluorescent proteins from jellyfish and high-magnification microscopes. We are now able to do many new experiments with specially engineered flies where the gene have peen precisely edited. This will allow us to get fine measurements of the components in the pathways we are interested in.Our hope is that we will find something important and universal about nervous system design principles. Alongside this we know that developmental wiring defects can have very serious consequences and manifest as disorders such as autism, schizophrenia and epilepsy. All of which have a massive impact on society. The genes in the pathways above have been found in patients with autism and epilepsy. For both fundamental and medical science we need to know more about how neurons grow and set their size.

大脑是惊人的复杂。它由数十亿个神经元组成，这些神经元延伸出树状分支，并与数千个伙伴连接。这些复杂的连接网络对于神经系统的正确运作至关重要，它们需要足够稳定以处理和存储信息（记忆），但也需要动态响应和改变经验（学习）。大脑是如何构造的仍然是生物学中最大的问题之一。神经元的生长是如何被控制的，以及一个特定的神经元是如何“知道”要达到什么样的大小的，这些都很有趣。神经元分支的生长决定了它可以与之建立联系的潜在伙伴，也决定了一些决定它如何放电的电特性。一些神经元有小树，树枝不会传播得很远，并在大脑回路中处理本地信息，而另一些神经元则将信息发送到长距离，比如从脊椎到控制大脚趾的肌肉的神经元。我们想知道是什么让小神经元变小，让大神经元变大。为了获得对神经元大小控制的新见解，我们正在使用果蝇强大的遗传学和复杂的神经系统。我们的初步数据显示，需要一种称为胰岛素/胰岛素样生长因子信号传导和雷帕霉素靶点的途径来产生适当大小的树木。我们已经测试了果蝇中许多不同的神经元，这些实验表明胰岛素信号在神经系统中起着全球性的作用。每个神经元似乎都有一个独特的调谐，它应该是什么大小。这是如何被控制的，以及它在塑造神经元中扮演了什么角色，我们将进行研究。我们能够使用水母的荧光蛋白和高倍显微镜观察神经元在变态过程中的生长。我们现在能够用经过特殊工程改造的果蝇做许多新的实验，这些果蝇的基因经过精确编辑。这将使我们能够对我们感兴趣的通路中的组件进行精细测量，我们希望我们将发现一些重要的和普遍的神经系统设计原则。除此之外，我们知道发育性布线缺陷可能会产生非常严重的后果，并表现为自闭症，精神分裂症和癫痫等疾病。所有这些都对社会产生了巨大的影响。上述通路中的基因已在自闭症和癫痫患者中发现。对于基础科学和医学科学，我们需要更多地了解神经元如何生长和设置它们的大小。