Circadian control of prenatal stress programming effects

In mammals, the coupling between the circadian and stress systems is essential to maintain physiological homeostasis under resting conditions and in response to external stimuli. Both systems maturate during the prenatal period. At that time, exogenous factors such as stress or an altered photoperiod, critically affect, or program, physiological functions later in life. Indeed, prenatally stressed rodents show sleep disorders, elevated anxiety levels and depressive-like behavior, largely associated with altered circadian and stress-induced hypothalamus-pituitary-adrenal (HPA) axis activity. This prenatal programming process -also observed in humans- has been attributed to maternal stress signals (e.g. glucocorticoids (GCs) reaching the embryo, which lastingly change gene regulation by epigenetic mechanisms. Interestingly, by manipulating the concentration of GC in pregnant mice, we observed that the programming deleterious effects of GCs in the offspring depends on the time of the day. Prenatal administration of corticosterone (CORT) at the beginning of the rest-phase causes elevated anxiety levels and depressive-like behavior in the offspring. On the other hand, if the maternal exposure takes place at the beginning of the active phase, the phenotype of the offspring is largely unaffected. We hypothesize that this time-of-day dependent sensitivity of the embryonic stress system to be programmed, is regulated by a circadian gating mechanism driven by an interplay between the maternal and the embryonic circadian clocks. To test our hypothesis and understand the underlying mechanisms we will use the same chrono-stress paradigm as before, to temporally control maternal GC blood levels. In order to identify tissue-specific targets involved in the time-of-day-dependent programming of behavior, we, first, will characterize the HPA axis function at systemic and molecular level in the adult offspring. In a second part, we aim at characterizing the postulated circadian gating mechanism of prenatal programming at the level of key targets for HPA axis function. Finally, in the third part we will explore the role of the maternal and embryonic clocks and it interaction in this context.While in recent years some steps have been taken in understanding the role of circadian clocks during pregnancy, still little is known about the physiological function of the embryonic clock system and how maternal and embryonic clocks communicate to each other in order to coordinate the dynamic and complex process of development. The results of this project will shed new light on the mechanisms underlying the biology of the developing circadian system, the circadian feto-maternal crosstalk and the impact of early environmental stress on behavioral disorders later in life.