Harnessing natural cellular variability to understand how neurons maintain their axodendritic polarity

你身体的不同部位在保持你的生命和健康方面都扮演着不同的角色。但是，像这样在不同的空间隔间之间划分工作并不仅仅发生在整个生物体的水平上——你的许多单个细胞也会这样做。这种在不同的亚细胞区域内划分功能的现象被称为“极性”，它在你的脑细胞或神经元中达到顶峰。大多数神经元大致分为两个主要的极性特化：树突和轴突。它们具有独特的结构和功能属性，这对神经元回路中的信息流至关重要。因此，了解单个神经元如何组织成轴突和树突对于理解健康的大脑如何运作至关重要。然而，虽然我们对建立神经元极性的过程了解得很多，但我们目前对神经元如何在之后保持其极性完整知之甚少。神经元如何确保它们的轴突保持轴突，树突保持树突？考虑到你的脑细胞通常和你的年龄一样大，维持这样的极性是一个必须在几十年里成功运作的过程。另一方面，极性维持的任何缺陷都有可能从根本上破坏大脑功能。基于这些原因，我们的建议的目标是发现神经元用来维持其极性的新机制。我们将利用一个独特的自然变异性案例来做到这一点。虽然哺乳动物大脑中几乎所有的成熟神经元都有一个，而且只有一个轴突，但我们的实验室最近发现了一群非常不同的细胞。嗅球是大脑中第一个处理嗅觉信息的区域，在嗅球中，有一组神经元自然地具有不同的极性类型。这些释放多巴胺的神经元有的具有轴突，有的则完全没有。我们将利用这种天然异质性，利用尖端技术在分子水平上比较和操纵这些不同亚型的多巴胺能细胞。在此过程中，我们将询问哪些机制对于维持轴突作为轴突至关重要，哪些机制对于维持树突作为树突至关重要。通过解决这些重要的基本生物学问题，我们的建议有可能对英国未来的医疗保健产生积极影响。我们对嗅觉系统的研究有助于未来治疗嗅觉障碍的方法，如嗅觉缺失和嗅觉减退，这影响了至少20%的人口，并对生活质量产生了重大影响。我们对多巴胺能神经元的关注可能会为这些细胞在晚年失去的疾病的治疗提供信息，比如帕金森氏病。最后，我们所获得的任何关于维持神经元区室特性的新知识，都可能在脑损伤或神经退行性疾病后修复损伤的治疗努力中证明是至关重要的。

The different parts of your body all play different roles in keeping you alive and healthy. But dividing jobs between different spatial compartments like this doesn't just happen at the level of the whole organism - many of your individual cells do this too. This phenomenon of compartmentalising functions within distinct sub-cellular zones is known as 'polarity', and it reaches its peak in your brain cells, or neurons. Most neurons are broadly divided into two major polar specialisations: dendrites and axons. These have distinct structural and functional attributes that are crucial for information flow within neuronal circuits. Understanding how individual neurons organise themselves into axons and dendrites is therefore vital for understanding how a healthy brain operates. However, while we know a good amount about the processes involved in setting up neuronal polarity in the first place, we currently know a lot less about how neurons keep their polarity intact afterwards. How do neurons make sure that their axons stay axons, and their dendrites stay dendrites? Given that your brain cells are normally about as old as you are, maintaining polarity like this is a process that must operate successfully over decades. On the other hand, any deficits in polarity maintenance have the potential to fundamentally disrupt brain function.For these reasons, the goal of our proposal is to discover novel mechanisms that neurons use to maintain their polarity. We will do this by taking advantage of a unique case of natural variability. Whilst almost all mature neurons in the mammalian brain possess one, and only one axon, our laboratory has recently identified a population of cells that is very different. In the olfactory bulb, the first region of the brain to process information about the sense of smell, there is a set of neurons that naturally come in different polarity types. Some of these dopamine-releasing neurons possess an axon, but others lack an axon entirely. We will exploit this natural heterogeneity by using cutting-edge technology to compare and manipulate these different sub-types of dopaminergic cell at the molecular level. In doing so, we will ask which mechanisms are crucial for maintaining axons as axons and which are vital for maintaining dendrites as dendrites.By addressing these important basic biological questions, our proposal has the potential to positively impact future healthcare in the UK. Our study of the olfactory system could benefit future approaches to treat debilitating smell disorders such as anosmia and hyposmia, which affect at least 20% of the population and have a significant impact on quality of life. Our focus on dopaminergic neurons may inform treatments for disorders where these cells are lost in later life, such as Parkinson's Disease. Finally, any new knowledge we generate about ways to maintain the identity of neuronal compartments could prove crucial in therapeutic efforts to repair damage after brain injury or neurodegenerative disease.