Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei.

Vendula Lužná,Karolína Liška,Alena Sumová,Pavel Houdek

doi:10.3389/fnins.2020.613531

Abstract

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges – a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy – and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1, Per2, and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.

Highlights

In mammalian brain, the paired suprachiasmatic nuclei of the hypothalamus (SCN) harbor principal pacemaker (Moore and Eichler, 1972; Ralph et al, 1990) that generates rhythmic signals with a circadian (“approximately a day”) period and orchestrates the phases of oscillators located throughout the body
The Maternal SCN-Driven Locomotor Activity Rhythm Adjusts Gradually to the 6-h Phase delay in LD12:12 (Delay) of the LD Regime To expose the fetuses to a shift in maternal rhythmic signals, we delayed the LD cycle by 6 h starting on embryonic days 14 (E14) and the pregnant rats were maintained in the new LD regime for the 5 days (Delay group; n = 11)
The results of our study provide the first insights into whether and how the fetal SCN clock responds to situations in which the maternal circadian system is challenged via disruption of the environmental LD regime

Summary

Introduction

The paired suprachiasmatic nuclei of the hypothalamus (SCN) harbor principal pacemaker (central clock) (Moore and Eichler, 1972; Ralph et al, 1990) that generates rhythmic signals with a circadian (“approximately a day”) period and orchestrates the phases of oscillators located throughout the body. The prominent role of the SCN among the clocks in the body is determined by 1) its unique structure, comprising a web of mutually interconnected subpopulations of cellular oscillators that ensures the production of a coherent and robust rhythmic signal (Welsh et al, 1995; Herzog et al, 2004; Liu et al, 2007; Webb et al, 2009) and 2) its ability to adjust (entrain) according to the external light/dark cycle, which is achieved via its direct connection with the retina (Zordan et al, 2001; Morin and Allen, 2006). Temporal organization during fetal development seems to be important for good health in adulthood

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