Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

Oct 22, 2017The Journal of neuroscience : the official journal of the Society for Neuroscience

Development of Daily Biological Rhythms and Their Coordination in the Brain's Internal Clock

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Abstract

By embryonic day 15.5 (E15.5), the suprachiasmatic nucleus (SCN) of mice exhibits synchronized daily rhythms in the clock protein PERIOD2 (PER2).

Few SCN cells developed circadian rhythms in PER2 by embryonic day 14.5 (E14.5), with no daily cycling observed at E13.5.
A dramatic increase in the number of competent oscillators was observed by E15.5, along with stabilization of their circadian periods.
At E15.5, SCN cells expressed sustained, synchronous daily rhythms, indicating a transition to more organized circadian behavior.
By postnatal day 2 (P2), SCN oscillators showed a dorsal-ventral phase wave in PER2 expression, characteristic of adult SCN.
Detectable levels of vasoactive intestinal polypeptide (VIP) and its receptor, VPAC2R, emerged after birth and the onset of circadian synchrony.
Circadian synchrony at E15.5 persisted despite the presence of blockers for VIP, GABA, or neuronal firing, suggesting alternative signaling mechanisms.

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In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep-wake, hormone release, and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recentstudies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 d after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN. Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism.We recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears before expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears ∼P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN. in vitro SIGNIFICANCE STATEMENT

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Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

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