Understanding the role of tanycytes in the mammalian brain

了解单细胞在哺乳动物大脑中的作用

• 批准号: RGPIN-2017-05184
• 负责人: PragerKhoutorsky, Masha
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711424
• 关键词: Understanding; role; tanycytes; mammalian; brain

OBJECTIVES: The proposed research program will explore the role of hypothalamic tanycytes. BACKGROUND however, given their strategic location, bridging between the general circulation and the central nerve system, these cells might play an important role in transmitting signals between the circulation and the brain. Our recent work has revealed the presence of a large population of tanycytes in organum vasculosum of lamina terminalis (OVLT). OVLT is one of the most important BBB-lacking sensory areas providing the brain with the information from the periphery and contributing to the generation of centrally-mediated physiological responses. Our data show that OVLT tanycytes create a dense network tightly embedding local neurons. Although the tanycytes constitute a prevalent population in this vital brain region, their function remains elusive. AIMS & METHODS: 1. Studying the role of OVLT tanycytes in detecting blood-borne circulating signals to modify the activity of neurons. To selectively target tanycytes, we will manipulate the levels and activity of vimentin (a major structural component of tanycytes) with genetic (tamoxifen-inducible Vimentin-Cre mouse line) and pharmacological tools, and will modulate the expression of membrane receptors and transporters in tanycytes by conditional knockout and/or overexpression using adeno-associated virus. These approaches will be combined with functional analysis of tanycyte activity using electrophysiology and calcium imaging in vitro and in vivo. 2. Investigating the structural organization of OVLT tanycytes. We will characterize tanycyte morphology and organization, and their contacts with neurons and vasculature using superresolution imaging. 3. Studying the stem cell potential of OVLT tanycytes. We will assess the stem cell potential of OVLT tanycytes using markers for different lineages, performing long-term tanycyte lineage tracing in vivo using tamoxifen-inducible Nestin-Cre mice, and studying the neurogenesis by examining neurospherogenic potential of OVLT tanycytes and evaluating the functionality of newborn neurons using electrophysiology. OUTCOME: The proposed work will explore the function of previously undescribed cell population in the vital brain area which serves as an interface between the peripheral circulation and the central nervous system. Deciphering the role of tanycytes in this area will provide new insights into one of the least-explored corners of the mammalian brain.

目的：拟议的研究计划将探索下丘脑张力细胞的作用。 然而，由于它们的战略位置，连接全身循环和中枢神经系统的桥梁，这些细胞可能在循环和大脑之间的信号传递中发挥重要作用。 我们最近的工作揭示了终板血管器(OVLT)中存在大量的伸展细胞。OVLT是最重要的缺乏血脑屏障的感觉区域之一，为大脑提供来自外周的信息，并有助于产生中枢介导的生理反应。我们的数据显示，OVLT柔韧细胞创建了一个紧密嵌入局部神经元的致密网络。尽管在这一重要的大脑区域，伸展细胞构成了一个普遍的群体，但它们的功能仍然难以捉摸。 目标和方法： 1.研究OVLT张力细胞在检测血液循环信号中的作用，以调节神经元的活动。为了选择性地以伸展细胞为靶点，我们将利用遗传学(他莫昔芬诱导的Vimentin-CRE小鼠品系)和药物工具来操纵伸展细胞的主要结构成分--波形蛋白的水平和活性，并将通过条件敲除和/或使用腺相关病毒过度表达来调节伸展细胞的膜受体和转运蛋白的表达。这些方法将与在体外和体内使用电生理学和钙成像对Tanycell活性的功能分析相结合。 2.观察OVLT松弛细胞的结构组成。我们将使用超分辨率成像来表征Tanycell的形态和组织，以及它们与神经元和血管系统的接触。 3.研究OVLT柔韧细胞的干细胞潜能。我们将使用不同谱系的标记物评估OVLT伸缩细胞的干细胞潜力，使用他莫昔芬诱导的Nestin-CRE小鼠进行体内长期伸缩细胞谱系追踪，并通过检测OVLT伸缩细胞的神经球状细胞的潜能和使用电生理学评估新生神经元的功能来研究神经发生。 结果：这项拟议的工作将探索以前未描述的细胞群在重要脑区的功能，该区域是外周循环和中枢神经系统之间的接口。破译伸缩细胞在这一区域的作用，将为我们对哺乳动物大脑中最少被探索的角落之一提供新的见解。