Come together, right...now: synchronization of rhythms in a mammalian circadian clock

Abstract

In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus act as a dominant circadian pacemaker, coordinating rhythms throughout the body and regulating daily and seasonal changes in physiology and behavior. This review focuses on the mechanisms that mediate synchronization of circadian rhythms between SCN neurons. Understanding how these neurons communicate as a network of circadian oscillators has begun to shed light on the adaptability and dysfunction of the brain's master clock.

Figure 1

Synchronization of Circadian Timekeeping among SCN Neurons Pacemaking neurons generate near-24-hr rhythms in gene expression, firing rate, and peptide release through a transcription-translation negative-feedback loop. These neurons are all GABAergic, and a subset in the ventral (core) SCN release VIP. VIP and its receptor VPAC₂ are necessary for synchronization of circadian periods among SCN neurons. Daily GABA application can synchronize SCN neurons, and blockade of GABA_A receptors interferes with rhythm coordination between the dorsal (shell) and ventral SCN. Gap junctions have also been implicated in spike-for-spike synchrony between neighboring SCN neurons.

Figure 2

Heterogeneity of Pacemaking Ability among SCN Neurons Robust rhythm generation in SCN neurons is thought to rely on circadian expression of Period (Per1, 2), Cryptochrome (Cry1, 2), Rev-Erb, Ror, and Bmal1 genes, and constitutive expression of Clock. Period and Cryptochrome proteins (PER/CRY) form a negative-feedback loop, repressing transcriptional activation by CLK/BMAL1 through E-Box sequences on Per and Cry promoters. Casein kinase 1 and (CK1Δ) causes a phosphorylation-dependent delay in PER/CRY feedback. REV-ERB and ROR proteins form a second feedback loop, binding to ROR-element (RORE) promoters of the Bmal1 gene to repress and enhance expression, respectively. However, more than half of all SCN neurons require daily VIP-VPAC₂ signaling to maintain robust rhythms. This signaling pathway may impinge on the intracellular molecular clockwork through activation of adenylyl cyclase (AC), cAMP, protein kinase A (PKA), and CREB-dependent transcription of the Period genes (Travnickova-Bendova et al., 2002; Itri and Colwell, 2003). This regulation of clock gene transcription may underlie the synchronization and amplification of neuronal rhythms by daily VIP/VPAC₂ signaling.