Abstract
Epidemiological and experimental evidence correlates adverse intrauterine conditions with the onset of disease later in life. For a fetus to achieve a successful transition to extrauterine life, a myriad of temporally integrated humoral/biophysical signals must be accurately provided by the mother. We and others have shown the existence of daily rhythms in the fetus, with peripheral clocks being entrained by maternal cues, such as transplacental melatonin signaling. Among developing tissues, the fetal hippocampus is a key structure for learning and memory processing that may be anticipated as a sensitive target of gestational chronodisruption. Here, we used pregnant rats exposed to constant light treated with or without melatonin as a model of gestational chronodisruption, to investigate effects on the putative fetal hippocampus clock, as well as on adult offspring’s rhythms, endocrine and spatial memory outcomes. The hippocampus of fetuses gestated under light:dark photoperiod (12:12 LD) displayed daily oscillatory expression of the clock genes Bmal1 and Per2, clock-controlled genes Mtnr1b, Slc2a4, Nr3c1 and NMDA receptor subunits 1B-3A-3B. In contrast, in the hippocampus of fetuses gestated under constant light (LL), these oscillations were suppressed. In the adult LL offspring (reared in LD during postpartum), we observed complete lack of day/night differences in plasma melatonin and decreased day/night differences in plasma corticosterone. In the adult LL offspring, overall hippocampal day/night difference of gene expression was decreased, which was accompanied by a significant deficit of spatial memory. Notably, maternal melatonin replacement to dams subjected to gestational chronodisruption prevented the effects observed in both, LL fetuses and adult LL offspring. Collectively, the present data point to adverse effects of gestational chronodisruption on long-term cognitive function; raising challenging questions about the consequences of shift work during pregnancy. The present study also supports that developmental plasticity in response to photoperiodic cues may be modulated by maternal melatonin.
Highlights
Day/night alternation provides a persistent cue to which virtually all organisms have adapted through the circadian system
In the fetal hippocampus under control photoperiod (12:12 light:dark; LD), the canonical clock genes period 2 (Per2) and Bmal1 were transcribed with a daily rhythm (P,0.05; by ANOVA and Newman-Keuls; Fig. 1a), with acrophases occurring during dark period and at the beginning of the light hours, respectively
Gestational chronodisruption, suppressed the daily rhythm of expression for all genes studied in the fetal hippocampus (P,0.05 by ANOVA and Newman-Keuls; Fig. 2a-h; red symbols); while mean levels of expression were reduced
Summary
Day/night alternation provides a persistent cue to which virtually all organisms have adapted through the circadian system. Like adult individuals, developing fetuses require complex integrated molecular and physiological systems allowing adaptation to internal and external environmental time cues, in order to achieve an internal temporal order [1,2]. In this context, melatonin has been thoroughly investigated as the main circulating circadian synchronizer. In which the pineal does not synthesize melatonin, is exposed to the maternal melatonin rhythm, and indirectly to light:dark (LD) information [4,5]. When pregnant dams are exposed to constant light at night, plasma melatonin is suppressed in both, diurnal and nocturnal animals [6,7]. We hypothesize that gestational chronodisruption targets the maternal circadian system directly, and the fetal circadian system indirectly; with the latter being probably driven by maternal melatonin
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