Circadian control of prenatal glucocorticoid programming effects

在哺乳动物中，昼夜节律和应激系统之间的功能耦合对于在静息条件下和响应于外部刺激维持生理稳态是必不可少的。这两种系统都在产前发育成熟。在那个时候，母体内分泌信号驱动胎儿发育并规划后代的生理。母体糖皮质激素（GC）稳态的破坏增加了后代在以后生活中发展为精神疾病的风险。我们最近在小鼠中发现，产前GC暴露的时间可以预测成年后代的行为表型。与内源性GC昼夜节律相比，接受GC异相的母亲的后代表现出焦虑升高、压力应对受损和压力轴调节功能障碍。我们进一步发现，胎儿生物钟通过在一天中的不同时间控制下丘脑中GC受体（GR）的可用性来确定应激轴对GC治疗的脆弱性，最终负责长期编程。本提案的前两个目标旨在解剖的精确的分子机制，这种昼夜调节GR的可用性在产前干预和表观遗传程序负责后代的行为phenotype.In人类pregnancies，产前GC治疗时，有早产的风险，没有任何规格的管理时间。GC加速胎儿肺成熟，降低呼吸窘迫综合征的风险，这是早产儿死亡的主要原因。虽然大大改善了新生儿的短期结果，产前GC治疗已与增加的脆弱性，在以后的生活中发展行为障碍。因此，本提案的第三个目标旨在提供证据，证明在正确的时间注射GC将在短期内保持产前GC治疗的益处（即预防呼吸窘迫综合征和相关病理），同时降低长期神经行为并发症的风险。我们为了解妊娠期间生物钟的作用做出了重大贡献。尽管如此，人们对母体和胚胎生物钟的生理功能以及母体和胚胎生物钟如何相互交流以协调动态而复杂的发育过程知之甚少。我们建议在这里探索原始和创新的方面在时间生理学和大脑发育的领域，揭示机制的影响，早期的环境线索行为障碍以后的生活。

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.