The hypothalamus contains numerous populations of neurons with specialized functions, notably the control of food intake in response to hunger or satiety, the storage of excess energy in the form of fats or sugars, and the use of such stored energy to generate heat or meet bodily needs. Previous work from our teams has shown that specialized hypothalamic glial cells called tanycytes replace the blood-brain barrier in a particular part of the hypothalamus, and cooperate with endothelial cells in this region, which harbor “fenestrations” or windows, to allow blood-borne signals to enter the hypothalamus. When the entry of such molecules through the tanycytes is blocked, changes in feeding behavior and metabolic imbalances result, indicating that these seemingly insignificant cells play a primordial role in controlling the exchange of signals between the brain and peripheral tissues. However, among other barriers to understanding this process, the cell populations involved in these various functions are so small and heterogeneous that it is easy to miss changes in the proteins they express or their activity, making it difficult to say with certainty how they control the access of these signals to the brain or how the neurons involved in these functions modulate their response.
In the WATCH project, we would like to understand the process as a whole, as well as the contribution of tanycytes to the entry of metabolic signals from the blood into the brain, and how these signals are interpreted to change the activity of the neurons sensing them in order to affect the behavior or functional response of the individual. Specifically, we aim to go beyond the state of the art regarding this process first by developing new tools or adapting existing tools to allow us to distinguish between different subpopulations of these sparse cell types and to identify and block individual steps in the transport and regulatory mechanisms, and second, by studying which of these subpopulations react to a specific physiological or pathological condition, in conjunction with what other cells and in what manner.
We have developed a number of techniques that can used to separate, observe or interfere with these molecular processes in living cells or animals and made several novel observations. By the end of the project, once we have obtained a more detailed understanding of the mechanisms through which these cells perform their functions and how they are altered with aging or under disease conditions, for example due to obesity, diabetes, Alzheimer disease or other neurodegenerative disorders, we can design ways to interfere with these pathological changes or restore normal function, thus providing a road-map for well-aging.
