Inter-dependence of circadian oscillators along the hypothalamo-pituitary lactotroph axis. – Lacto-Clock

The misalignment between our internal timing system and the external environment can be the cause of dramatic consequences. This issue has become critical since the early 20th century, and the emergence of our never-stopping society, busy 24 hours a day. For example, most of the major industrial catastrophes (e.g. Chernobyl, Bhopal or Three Miles Islands) occurred as consequences of mistakes from individuals working at night. Less spectacular but not less alarming, populations chronically exposed to jet-lag and night-shift workers have an increased risk of developing health problems such as cancer, metabolic syndrome or fertility concerns.
Trying to keep our circadian clock in phase with our actual life has been a challenge for several years. Light therapy has been proposed to help resetting biological rhythms through an action upon our central clock located in the suprachiasmatic nuclei of the hypothalamus. However, recent evidences have revealed that the circadian system is actually composed of multiple oscillators, present in virtually every organs of our body. Thus, the challenge now is to understand how these multiple clock team up into a coherent timing system at the level of the organism, so that we could one day identify a way to reset the entire system.
We here propose to investigate whether peripheral circadian oscillators are able to communicate one with each other. This question will be addressed at the level of two well identified circadian oscillators: hypothalamic dopaminergic neurons (TIDA) and prolactin-secreting cells (PRL) of the pituitary gland. These two cell types are dynamically coupled in the female hypothalamo-pituitary lactotroph axis and are key players of female reproduction. We and others already found tight links between circadian timekeeping and the lactotroph axis. We shall now investigate whether the functional relationship between TIDA and PRL is associated to an inter-dependence between their circadian oscillators. This will be addressed in the mouse as an animal model that permits the genetic manipulation of circadian clock genes in specific cell types.
A number of experiments are proposed to assess the relationship between both oscillators at the gene expression level and functional level, in vivo and ex vivo.
The completion of this proposal will provide answers to the question of communication between peripheral circadian clocks, and thus shed light upon how the whole circadian system must be manipulated to get reset faster and more efficiently. Moreover, our focusing on an important axis for reproduction will also expand our view upon the link between fertility and circadian clocks. Our data will thus be valuable in addressing more specific issues in that field as well.