Role of Tanycytes in the non-classical feedback regulation of the hypothalamic-pituitary-thyroid axis

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.