The ontogenesis of the circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and its sensitivity to maternal signals are not fully understood. Here, we investigated the development of the clock in the rat SCN from the fetal to the postweaning period and identified rhythmic metabolic signals from the mother to the fetal SCN. We determined daily expression profiles of clock genes (Per2, Nr1d1, Bmal1) and clock- and metabolism-related genes (Dbp, E4bp4) and performed time-resolved analysis of the metabolome and lipidome in the SCN and plasma of 19-day-old embryos (E19) and 2-, 10-, 20-, and 28-day-old pups (P02-28). Our data show that rhythms in the expression of canonical clock genes are absent at E19 and develop gradually until P10, but the Dbp rhythm was still developing between P20 and P28. Expression of the metabolism-sensitive gene E4bp4 and levels of essential amino acids and other metabolites supplied by maternal food are rhythmic in the fetal SCN, which is lost after birth at P02 and reappears later in the postnatal period. Maternal food-derived metabolites were also rhythmic in fetal plasma. The temporal coherence of the fetal SCN metabolome and lipidome declines markedly and its rhythmicity disappears immediately after birth. The results revealed previously unforeseen pathways by which the fetal SCN may receive rhythmic information from the mother before its clock develops.

• MeSH
• Circadian Clocks * physiology   genetics   MeSH
• Period Circadian Proteins genetics   metabolism   MeSH
• Circadian Rhythm physiology   MeSH
• Rats MeSH
• Metabolome MeSH
• Suprachiasmatic Nucleus * metabolism   embryology   physiology   MeSH
• CLOCK Proteins genetics   metabolism   MeSH
• Pregnancy MeSH
• ARNTL Transcription Factors genetics   metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Period Circadian Proteins MeSH
• CLOCK Proteins MeSH
• ARNTL Transcription Factors MeSH

The suprachiasmatic nuclei (SCN) of the hypothalamus harbor the central clock of the circadian system, which gradually matures during the perinatal period. In this study, time-resolved transcriptomic and proteomic approaches were used to describe fetal SCN tissue-level rhythms before rhythms in clock gene expression develop. Pregnant rats were maintained in constant darkness and had intact SCN, or their SCN were lesioned and behavioral rhythm was imposed by temporal restriction of food availability. Model-selecting tools dryR and CompareRhythms identified sets of genes in the fetal SCN that were rhythmic in the absence of the fetal canonical clock. Subsets of rhythmically expressed genes were assigned to groups of fetuses from mothers with either intact or lesioned SCN, or both groups. Enrichment analysis for GO terms and signaling pathways revealed that neurodevelopment and cell-to-cell signaling were significantly enriched within the subsets of genes that were rhythmic in response to distinct maternal signals. The findings discovered a previously unexpected breadth of rhythmicity in the fetal SCN at a developmental stage when the canonical clock has not yet developed at the tissue level and thus likely represents responses to rhythmic maternal signals.

• MeSH
• Circadian Rhythm * genetics   MeSH
• Hypothalamus MeSH
• Rats MeSH
• Suprachiasmatic Nucleus metabolism   MeSH
• Fetus physiology   MeSH
• Proteomics * MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

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.

• Keywords
• circadian clock, development, fetus, maternal entrainment, suprachiasmatic nucleus,
• Publication type
• Journal Article MeSH