Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons

Abstract

The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC 2 (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found that Vip −/− and Vipr2 −/− mice showed two daily bouts of activity in a skeleton photoperiod and multiple circadian periods in constant darkness. Loss of VIP or VPAC 2 also abolished circadian firing rhythms in approximately half of all SCN neurons and disrupted synchrony between rhythmic neurons. Critically, daily application of a VPAC 2 agonist restored rhythmicity and synchrony to VIP −/− SCN neurons, but not to Vipr2 −/− neurons. We conclude that VIP coordinates daily rhythms in the SCN and behavior by synchronizing a small population of pacemaking neurons and maintaining rhythmicity in a larger subset of neurons.The SCN of the mammalian hypothalamus coordinates diverse daily rhythms, including states of vigilance, locomotor activity and hormonal release, through rhythms in neuronal firing 1 . These rhythms 'free-run' with a circadian period in the absence of synchronizing (or entraining) cues such as environmental light cycles. When the SCN are electrically silenced or lesioned, behavioral and physiologic rhythms disappear 2 .Rhythmic circadian firing within the SCN is dependent on cyclic expression of a family of 'clock genes'. Mutations of period 1 (Per1) or Per2, cryptochrome 1 (Cry 1) or Cry2, casein kinase Iε (Csnk1e), RevErbα (Nr1d1), BMAL1 (MOP3, Arntl) or clock lead to altered or abolished circadian periodicity 3 . These results have led to a model in which circadian rhythms are generated and sustained by an intracellular transcription-translation negative feedback loop. In support of this model for cell-autonomous pacemaking, single SCN neurons dispersed at low density onto a multielectrode array (MEA) can express firing rate patterns with different circadian periods 4 , leading to the suggestion that all 20,000 SCN neurons are autonomous circadian pacemakers 4-6 . In the intact SCN, these neurons usually synchronize to one another with defined phase relationships 7-10 . How synchrony is maintained between SCN neurons is Correspondence should be addressed to E.D.H. (herzog@wustl.edu).. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Notably, rhythmicity and synchrony were restored to Vip −/− neurons by daily application of a VPAC 2 agonist. Our data show that many SCN neurons require VIP for rhythmicity, whereas others require it for synchrony. We conclude that a minority of SCN neurons are cellautonomous circadian pacemakers, which coordinate rhythms in the majority through VIP. NIH Public Access RESULTS Mice lacking VIP or VPAC 2 show multiple circadian periodsPrevious studies of locomotor activity in Vip −/− and Vipr2 −/− mutant mice ha...

Exploring Spatiotemporal Organization of SCN Circuits

“…Intercellular signaling through VIP and its receptor VPAC2 is critical in maintaining the synchrony of SCN cellular oscillators and circadian function within the SCN (Aton et al 2005;Maywood et al 2006). In addition, GRP cells are retinorecipient, they communicate with cells in the shell region through GRP receptors, and they function to keep SCN neurons synchronized during entrainment (McArthur et al 2000;Aida et al 2002;Karatsoreos et al 2004;).…”

Development of the mouse suprachiasmatic nucleus: Determination of time of cell origin and spatial arrangements within the nucleus

“…In rats, each nucleus comprises approximately 10,000 neurons [10,21] plus glia in the ratio of about 3:1 neurons to astroglia [10]. Isolated SCN neurons spontaneously generate circadian rhythms, and many SCN neurons appear to have this capacity [6,32].…”

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

“…Notably, Gpr176 is expressed mainly in the brain, with most being found in the SCN, and its protein abundance within the SCN fluctuates in a circadian fashion, peaking during the night. More specifically, Gpr176 colocalizes with the vasoactive intestinal peptide (Vip) receptor Vipr2, a receptor known to play a key role in circadian timing [19,20]. Temporal expression profiles of Gpr176 and Vipr2 reveal that while these two receptors exist in the same SCN neurons, they are opposite in peak expression phase.…”