ROLE OF TANYCYTES IN THE NON-CLASSICAL FEEDBACK REGULATION OF THE HYPOTHALAMIC-PITUITARY-THYROID AXIS

伸长细胞是排列在第三脑室的特化胶质细胞。这些细胞表达基因库，通过转运、转化和灭活激素向中枢神经系统提供活性甲状腺激素。它们的可塑性过程覆盖下丘脑的毛细血管，似乎对中隆起（ME）的激素释放很重要。然而，对这种细胞类型的生理功能知之甚少，特别是对下丘脑-垂体-甲状腺（HPT）轴的调节。为了提高对伸长细胞生理功能的认识，我们建立了新的基于raav的工具在体内研究伸长细胞。有了这些工具，我们能够表达基因，编码蛋白质，如[Ca2+]i传感器GCamP6s， cre -重组酶或其他，特别是在伸长细胞中。利用这些工具，我们已经能够通过受体TRH- r1鉴定出TRH是β -伸长细胞中G α q/11通路的特异性激活剂。该途径的抑制降低了血浆中基础TSH水平，表明伸长细胞在调节HPT轴中的重要作用。我们假设了一种新的非经典反馈机制，该机制是由伸长细胞终足形态变化介导的，并由TRH和甲状腺激素诱导。在目前的项目中，我们将研究这一假设，并进一步表征伸长细胞在HPT轴中的作用。具体而言，我们将研究1)HPT激素对TRH诱导的伸长细胞钙反应的影响，2)对伸长细胞形态和基因表达的影响，以及3)这些假设的变化对TRH释放和HPT功能的影响。因此，我们旨在确定伸长细胞在非经典甲状腺激素调节中的作用。

Tanycytes are specialised glial cells lining the 3rd ventricle. These cells express the genetic repertoire to supply active thyroid hormones to the CNS by transporting, converting and inactivating hormones. Their plastic processes cover capillaries in the hypothalamus and seem to be important for the hormonal release in the median eminence (ME). However, only little is known about the physiological functions of this cell type, especially in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. To improve the knowledge of the physiological function of tanycytes we have established new rAAV-based tools to investigate tanycytes in vivo. With these tools we are able to express genes, encoding proteins like the [Ca2+]i sensor GCamP6s, the Cre-recombinase or others, specifically in tanycytes. Using these tools we have been able to identify TRH as a specific activator of the G alpha q/11-pathway in beta-tanycytes via the receptor TRH-R1. An inhibition of this pathway decreased basal TSH levels in plasma suggesting an important role of tanycytes in regulating the HPT axis. We postulate a new non-classical feedback mechanism that is mediated by morphological changes of tanycytic endfeet and is induced by TRH and thyroid hormones. In the present project we will investigate this hypothesis and further characterise the role of tanycytes in the HPT axis. Specifically, we will investigate 1) the effects of the HPT hormones on the TRH-induced calcium response in tanycytes, 2) on the morphology and gene expression in tanycytes as well as 3) the impact of these postulated changes on TRH release and HPT function. Thus, we aim to define the role of tanycytes in the non-classical thyroid hormone regulation.