Role of median eminence cell types in barrier function and energy balance

The arcuate hypothalamus is an evolutionarily conserved brain region with diverse roles in mammalian physiology, including energy homeostasis, reproduction and neuroendocrine control of growth hormone and prolactin release. Aside from its functional diversity, Arc is known for its unique anatomical relationship with the blood-brain barrier (BBB), which protects the cell bodies and dendrites of arcuate neuroendocrine neurons while allowing their axons to enter BBB-free areas of the adjoining median eminence (ME); these axons release signals into fenestrated capillaries that carry blood to the pituitary and periphery. Importantly, blood-borne signals can also diffuse from ME to Arc, giving Arc privileged access to peripheral hormones, nutrients and other metabolic signals. This access is dynamically regulated by tanycytes, a specialized type of ependymal cell lining the third ventricle that extends processes throughout the Arc and ME. In the fasted state, this barrier opens to allow diffusion from the peripheral blood into the arcuate.

We have generated a comprehensive atlas of cell types in the mouse arcuate hypothalamus-median eminence complex using high throughput single cell transcriptional profiling, providing an unparalleled and unbiased molecular characterization of the cell types making up and surrounding this unique blood-brain barrier, including: 1) specialized fenestrated endothelial cells of the ME that allow passage of signals to and from the periphery, 2) β1 and β2 tanycytes, including a discrete population of Sprr1a-expressing tanycytes that reside at the junction between the median eminence and arcuate, and 3) neuroendocrine cells of the pars tuberalis, which line the median eminence and have been suggested to have privileged access to the 3rd ventricle and arcuate. Anatomical and molecular profiling suggest these specific cell types coordinate the formation and regulation of this important barrier, and can affect energy homeostasis. Transcriptional profiling has further allowed us to design recombinase lines specific for each cell type as well as to identify of key genes whose expression may underlie their unique functions. Using tools to induce cell-type specific activation or loss of function, we are beginning to dissect out the functional roles for these cell types in barrier function and energy homeostasis.