The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

Abstract

During pregnancy, maternal endocrine signals drive fetal development and program the offspring's physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child's risk of developing psychiatric disorders later in life. We here show 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 stressaxis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.

The trophoblast clock controls transport across placenta in mice

“…There is already evidence that the circadian system synchronizes maternal metabolic adaptations in the liver to support fetal growth (Papacleovoulou et al, 2017;Wharfe et al, 2016). Meanwhile, the fetal circadian system develops and gains autonomy towards term (Astiz et al, 2020;Landgraf et al, 2015;Wharfe et al, 2011) under the influence of endogenous and exogenous signals crossing the feto-maternal interphase, the placenta (Mendez et al, 2016;Smarr et al, 2017;Varcoe et al, 2011Varcoe et al, , 2013Varcoe et al, , 2018Vilches et al, 2014). Recent evidence has shown clock gene expression in several fetal tissues including the LZ of the placenta by mid gestation in rodents (C ̌ecmanová et al, 2019;Landgraf et al, 2015;Waddell et al, 2012;Crew et al, 2018).…”

“…However, the functionality of clocks of fetal origin have been questioned as not all the members of the interlocked TTFL are rhythmically expressed in the circadian range, as they are in adult tissues. Therefore, fetal clocks have been considered to be slave oscillators entrained by maternal rhythmic signals crossing placenta (Astiz et al, 2020;Crew et al, 2018;Honma, 2020;Houdek and Sumová, 2014;Mendez et al, 2012;Reppert and Schwartz, 1984;Serón-Ferré et al, 2012). Some of those signals freely cross the placenta (and convey the external time to the fetus) and some others are metabolized by enzymes expressed in the LZ (Christ et al, 2012;Houdek et al, 2016;Krozowski et al, 1999;Mark et al, 2017;Okatani et al, 1998;Waddell et al, 2012).…”

Feto-Maternal Crosstalk in the Development of the Circadian Clock System

“…Interestingly, most rodent prenatal stress paradigms entail some degree of circadian disruption because the animals are manipulated during their normal rest phase. We have recently demonstrated that the offspring from mothers exposed to GCs during the rest phase show worse circadian and stress-related behavioral phenotypes than those from mothers exposed to the same GC concentration, but during the active phase (Astiz et al, 2020). Much less is known about other signals that are also rhythmic in the mother and are known to cross the placenta or to impact on fetus development such as leptin.…”

“…Recent data from our lab show that the circadian phase of GCs that reach fetal tissues determines their effectiveness in programing the offspring’s circadian behavior. This temporal gating originates from the embryonic clock system and may involve rhythmic expression of the negative GR modulator Reverse erythroblastoma (REV-ERB α/β aka Nr1d1/2 ) ( Astiz et al, 2020 ).…”

Breastfeeding for 3 Months or Longer but Not Probiotics Is Associated with Reduced Risk for Inattention/Hyperactivity and Conduct Problems in Very-Low-Birth-Weight Children at Early Primary School Age

“…Endogenous factors such as brain immaturity and dysregulated immune responses leading to inflammation-mediated morbidity play a crucial role [3]. Environmental factors such as intensive care, stress, maternal separation, nutritional deficits, circadian rhythm disruption, antibiotics and steroids have also been associated with altered brain development and may therefore contribute to the risk profile of VLBW children [2][3][4][5][6][7]. All these factors have an impact on fragile immune-microbiome co-establishment in preterm children, which occurs in timely association with central nervous system (CNS) development.…”