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In-phasic cytosolic-nuclear Ca²⁺ rhythms in suprachiasmatic nucleus neurons.

ABSTRACT: The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. SCN neurons exhibit circadian Ca²⁺ rhythms in the cytosol, which is thought to act as a messenger linking the transcriptional/translational feedback loop (TTFL) and physiological activities. Transcriptional regulation occurs in the nucleus in the TTFL model, and Ca²⁺-dependent kinase regulates the clock gene transcription. However, the Ca²⁺ regulatory mechanisms between cytosol and nucleus as well as the ionic origin of Ca²⁺ rhythms remain unclear. In the present study, we monitored circadian-timescale Ca²⁺ dynamics in the nucleus and cytosol of SCN neurons at the single-cell and network levels. We observed robust nuclear Ca²⁺ rhythm in the same phase as the cytosolic rhythm in single SCN neurons and entire regions. Neuronal firing inhibition reduced the amplitude of both nuclear and cytosolic Ca²⁺ rhythms, whereas blocking of Ca²⁺ release from the endoplasmic reticulum (ER) via ryanodine and inositol 1,4,5-trisphosphate (IP₃) receptors had a minor effect on either Ca²⁺ rhythms. We conclude that the in-phasic circadian Ca²⁺ rhythms in the cytosol and nucleus are mainly driven by Ca²⁺ influx from the extracellular space, likely through the nuclear pore. It also raises the possibility that nuclear Ca²⁺ rhythms directly regulate transcription in situ.

SUBMITTER: Hiro S

PROVIDER: S-EPMC10765503 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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In-phasic cytosolic-nuclear Ca2+ rhythms in suprachiasmatic nucleus neurons.

Hiro Sota S Kobayashi Kenta K Nemoto Tomomi T Enoki Ryosuke R

Frontiers in neuroscience 20231220

The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. SCN neurons exhibit circadian Ca2+ rhythms in the cytosol, which is thought to act as a messenger linking the transcriptional/translational feedback loop (TTFL) and physiological activities. Transcriptional regulation occurs in the nucleus in the TTFL model, and Ca2+-dependent kinase regulates the clock gene transcription. However, the Ca2+ regulatory mechanisms betwee ...[more]

PMID: 38178840

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Project description: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. Recent in vitro studies 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.SIGNIFICANCE STATEMENT 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.

Dataset Information

In-phasic cytosolic-nuclear Ca²⁺ rhythms in suprachiasmatic nucleus neurons.

Publications

In-phasic cytosolic-nuclear Ca<sup>2+</sup> rhythms in suprachiasmatic nucleus neurons.

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