Synchronization and Maintenance of Timekeeping in Suprachiasmatic Circadian Clock Cells by Neuropeptidergic Signaling

Mar 21, 2006Current biology : CB

How brain cell signals keep the body's internal clock in sync and running

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Abstract

The Vipr2 gene is essential for maintaining molecular timekeeping and synchronizing SCN neurons.

Circadian timekeeping in mammals relies on feedback loops active in peripheral tissues and the suprachiasmatic nuclei (SCN).
Spontaneous synchronization of molecular loops in SCN neurons is crucial for their pacemaker function.
Vasoactive intestinal polypeptide (VIP) is involved in the activation and synchronization of SCN neurons.
Real-time imaging reveals that the VPAC2 receptor, encoded by the Vipr2 gene, is required for synchronizing timekeeping among SCN neurons.
Both depolarization and gastrin-releasing peptide (GRP) can temporarily enhance synchrony in Vipr2-deficient SCN neurons.
Without VIP signaling, Vipr2-deficient neurons cannot maintain synchrony, indicating the importance of neuropeptidergic signaling in the SCN.

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Circadian timekeeping in mammals is driven by transcriptional/posttranslational feedback loops that are active within both peripheral tissues and the circadian pacemaker of the suprachiasmatic nuclei (SCN). Spontaneous synchronization of these molecular loops between SCN neurons is a primary requirement of its pacemaker role and distinguishes it from peripheral tissues, which require extrinsic, SCN-dependent cues to impose cellular synchrony. Vasoactive intestinal polypeptide (VIP) is an intrinsic SCN factor implicated in acute activation and electrical synchronization of SCN neurons and coordination of behavioral rhythms. Using real-time imaging of cellular circadian gene expression across entire SCN slice cultures, we show for the first time that the Vipr2 gene encoding the VPAC2 receptor for VIP is necessary both to maintain molecular timekeeping within individual SCN neurons and to synchronize molecular timekeeping between SCN neurons embedded within intact, organotypical circuits. Moreover, we demonstrate that both depolarization and a second SCN neuropeptide, gastrin-releasing peptide (GRP), can acutely enhance and synchronize molecular timekeeping in Vipr2-/- SCN neurons. Nevertheless, transiently activated and synchronized Vipr2-/- cells cannot sustain synchrony in the absence of VIP-ergic signaling. Hence, neuropeptidergic interneuronal signaling confers a canonical property upon the SCN: spontaneous synchronization of the intracellular molecular clockworks of individual neurons.

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Synchronization and Maintenance of Timekeeping in Suprachiasmatic Circadian Clock Cells by Neuropeptidergic Signaling

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