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对外界刺激的反应中维持生理动态平衡是必不可少的。这两个系统都在产前成熟。当时，母体内分泌信号驱动胎儿发育，并对后代的生理进行编程。母体糖皮质激素(GC)动态平衡的破坏会增加后代在以后的生活中患精神疾病的风险。我们最近在小鼠身上表明，产前暴露于GC的时间可以预测成年后代的行为表型。与其内源性昼夜节律相比，接受GCs的母亲的后代表现出更高的焦虑，压力应对能力受损，以及功能失调的压力轴调节。我们进一步发现，胎儿的生物钟通过控制下丘脑在一天中不同时间段的GC受体(GR)的可获得性来决定应激轴对GC治疗的脆弱性，这是长期编程的最终责任。本提案的前两个目标旨在剖析产前干预期间GR可获得性的昼夜调节的精确分子机制以及导致后代行为表型的表观遗传学程序。在人类怀孕中，产前GC治疗是在有早产风险的情况下进行的，但没有任何具体的给药时间。GCS加速胎儿肺成熟，降低呼吸窘迫综合征的风险，呼吸窘迫综合征是早产儿死亡的主要原因。虽然极大地改善了新生儿的短期结局，但产前GC治疗与增加在以后的生活中发展成行为障碍的易感性有关。因此，这项建议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治疗的好处(即预防呼吸窘迫综合征和相关病理)，同时从长期降低神经行为并发症的风险。我们为理解生物钟在怀孕期间的作用做出了实质性贡献。尽管如此，关于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谈以协调动态而复杂的发育过程，人们知之甚少。我们建议在时间生理学和脑发育领域探索原创性和创新性的方面，以阐明早期环境线索对晚年行为障碍影响的潜在机制。

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.