Circadian control of prenatal glucocorticoid programming effects

• Applicant: Mariana Astiz, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Biological Psychiatry
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392599620

In mammals, functional 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, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the offspring’s risk of developing psychiatric disorders later in life. We have recently shown in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress axis regulation. We further found that the fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus at different times of day, being ultimately responsible for the long-term programming. The first two objectives of the present proposal aim at dissecting the precise molecular mechanisms underlying this diurnal regulation of GR availability during prenatal intervention and the epigenetic programs responsible for the offspring's behavioral phenotype.In human pregnancies, antenatal GC therapy is indicated when there is a risk of preterm delivery, without any specification of the administration time. GCs accelerate fetal lung maturation and reduce the risk of respiratory distress syndrome, the main cause of mortality in premature babies. While substantially improving the short-term outcome of the newborns, antenatal GC treatment has been associated with an increased vulnerability to develop behavioral disorders later in life. Therefore the third objective of this proposal aims at providing evidence that the GC injection at the right time would maintain the benefit of the antenatal GC treatment in the short-term (i.e. preventing respiratory distress syndrome and associated pathologies) while reducing the risk of neurobehavioral complications in the long-term.We have made substantial contribution to understand the role of circadian clocks during pregnancy. Still, little is known about the physiological function of the maternal and embryonic clock and how maternal and embryonic clocks talk to each other to coordinate the dynamic and complex process of development. We propose here to explore original and innovative aspects in the field of chronophysiology and brain development to shed light on mechanisms underlying the impact of early environmental cues on behavioral disorders later in life.

• DFG Programme: Research Grants