The earliest circadian clock in the mammalian brain emerges in the embryonic choroid plexus

Abstract

Maternal chronodisruption is linked to miscarriages and neurodevelopmental risks, yet the earliest brain circadian oscillator in the embryo and the mechanism of its emergence remain unknown. Using bioluminescent reporters for PER2 and Bmal1, we tracked the onset of autonomous [~]24 h oscillations ex vivo. While the suprachiasmatic nucleus (SCN) is widely considered the first circadian structure at embryonic day (E) 14.5-15.5, we find that the fourth ventricle choroid plexus (4VCP) exhibits PER2 oscillations by E11.5-E12.5. These oscillations show hallmarks of a saddle-node on an invariant circle (SNIC) bifurcation, characterized by an initially long period converging toward 24 h and pronounced sensitivity to sub-degree temperature cycles mimicking physiological maternal cues. Transcriptional profiling of maternal and embryonic 4VCPs unveiled three epochs in clock gene expression that parallel tissue differentiation. We identify the 4VCP as the earliest detectable brain circadian oscillator, and demonstrate how its bifurcation dynamics allow the nascent clock to couple to maternal rhythms.