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，像这样在不同空间隔间之间划分工作并不只是在整个有机体的水平上发生--你的许多单个细胞也这样做。这种将不同亚细胞区的功能区分开来的现象被称为“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区特化：树突和轴突。这些神经元具有不同的结构和功能属性，这些属性对神经元回路内的信息流至关重要。因此，了解单个神经元是如何组织成轴突和树突的，对于了解健康的大脑是如何运作的至关重要。然而，虽然我们对最初建立神经元极性的过程了解很多，但目前我们对神经元如何在之后保持其极性不变的了解要少得多。神经元如何确保它们的轴突保持轴突，而它们的树突保持树突？考虑到你的脑细胞通常和你一样老，保持这样的极性是一个必须在几十年内成功运作的过程。另一方面，任何维持极性的缺陷都有可能从根本上扰乱大脑的功能。出于这些原因，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。我们将利用一种独特的自然变异性来做到这一点。虽然几乎所有哺乳动物大脑中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组非常不同的细胞。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以不同的极性类型出现。这些释放多巴胺的神经元中，有些有轴突，但另一些则完全没有轴突。我们将通过使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来利用这种自然的异质性。在这样做的过程中，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，我们的提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可能有助于未来治疗令人衰弱的气味障碍的方法，如嗅觉障碍和嗅觉不足，这些疾病至少影响20%的人口，并对生活质量产生重大影响。我们对多巴胺能神经元的关注可能有助于治疗这些细胞在晚年丢失的疾病，如帕金森氏症。最后，我们产生的关于如何保持神经元隔间特性的任何新知识，都可能被证明对修复脑损伤或神经退行性疾病后的损伤的治疗努力至关重要。

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.