Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase

An, Sungwon; Irwin, Robert P.; Allen, Charles N.; Tsai, Connie; Herzog, Erik D.

doi:10.1152/jn.00966.2010

Cited by 70 publications

(102 citation statements)

References 69 publications

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“…SCN were treated with either 10 μM VIP or vehicle at 4:00 PM, 11 h before the shift in the temperature cycle. We chose to deliver VIP at the same relative time as the in vivo experiment (Zeitgeber time, ZT, 3), a time when it also produces minimal shifts in vitro (18)(19)(20)(21). SCN were defined as entrained to the new cycle once the phase relationship between the daily warming and peak PER2 was stable for at least 48 ± 0.25 h with a phase of 17.2 ± 1 (VIP-treated cultures) or 15.5 ± 1 (vehicle-treated cultures).…”

Section: Constant Light Requires Vip To Reduce Circadian Amplitude Inmentioning

confidence: 99%

“…In the absence of VIP or its receptor, VPAC2R, SCN neurons fail to synchronize to each other and consequently many daily rhythms of the organism are lost (8)(9)(10)(11)(12). The addition of VIP to SCN cultures induces the production of Period (Per) 1 and 2 (13), two genes implicated in light-induced resetting (14)(15)(16), and shifts rhythms in behavior and SCN physiology (17)(18)(19)(20)(21). Notably, daily addition of VIP or an agonist to the VIP receptor, VPAC2R, entrains rhythms in SCN explants and Vip −/− SCN neurons (21,22).…”

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confidence: 99%

“…The addition of VIP to SCN cultures induces the production of Period (Per) 1 and 2 (13), two genes implicated in light-induced resetting (14)(15)(16), and shifts rhythms in behavior and SCN physiology (17)(18)(19)(20)(21). Notably, daily addition of VIP or an agonist to the VIP receptor, VPAC2R, entrains rhythms in SCN explants and Vip −/− SCN neurons (21,22). Thus, VIP is thought to play a role in both the synchronization between SCN cells when the organism is in the dark and the entrainment of the SCN when the organism is exposed to a light cycle.…”

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confidence: 99%

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A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

Harang

Meeker

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light-dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase-and the dosedependent response to VIP and that the transient phase desynchronization, or "phase tumbling", could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8-h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag.circadian oscillator | biological clock | vasopressin | vasoactive intestinal peptide | period gene C ircadian rhythms of living organisms entrain (synchronize) to daily environmental cues such as light and dark. Living organisms have not evolved to make large daily adjustments in their circadian timing, so it is a challenge for them to respond to changes such as those that humans are subjected to during shift work and travel across time zones. Long-term misalignment between internal circadian rhythms in mammals and environmental cycles can induce physiological and psychological abnormalities, including depression, cancer, heart problems, obesity, and increased mortality (1, 2).The master circadian pacemaker in mammals, the bilateral suprachiasmatic nucleus (SCN), is composed of ∼20,000 neurons that synchronize their daily rhythms to each other and entrain to ambient light cycles (3, 4). Vasoactive intestinal polypeptide (VIP), released in the SCN as a function of circadian time and light intensity (5-7), plays a critical role in this circadian synchronization. In the absence of VIP or its receptor, VPAC2R, SCN neurons fail to synchronize to each other and consequently many daily rhythms of the organism are lost (8-12). The addition of VIP to SCN cultures induces the production of Period (Per) 1 and 2 (13), two genes implicated in light-induced resetting (14-16), and shifts rhythms in behavior and SCN physiology (17-21). Notably...

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Section: Constant Light Requires Vip To Reduce Circadian Amplitude Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

Harang

Meeker

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

112

117

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“…To generate a coherent circadian signal across the SCN, the intracellular loops are synchronized between cells by neuropeptidergic cues that act via signaling cascades triggered by cAMP and intracellular Ca 2+ ([Ca 2+ ] i ) (4,5). In addition, synchronization to the cycle of light and darkness is mediated by specialized glutamatergic retinal innervation of SCN neurons (6) that acts via [Ca 2+ ] i (7).…”

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confidence: 99%

Analysis of core circadian feedback loop in suprachiasmatic nucleus of mCry1-luc transgenic reporter mouse

Maywood

Drynan

Chesham

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of Period (Per) and Cryptochrome (Cry) genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences in Per and Cry to inhibit their transactivation by CLOCK/ BMAL1 heterodimers. To function effectively, these closed intracellular loops need to be synchronized between SCN cells and to the light/dark cycle. For Per expression, this is mediated by neuropeptidergic and glutamatergic extracellular cues acting via cAMP/ calcium-responsive elements (CREs) in Per genes. Cry genes, however, carry no CREs, and how CRY-dependent SCN pacemaking is synchronized remains unclear. Furthermore, whereas reporter lines are available to explore Per circadian expression in real time, no Cry equivalent exists. We therefore created a mouse, B6.CgTg(Cry1-luc)01Ld, carrying a transgene (mCry1-luc) consisting of mCry1 elements containing an E-box and E′-box driving firefly luciferase. mCry1-luc organotypic SCN slices exhibited stable circadian bioluminescence rhythms with appropriate phase, period, profile, and spatial organization. In SCN lacking vasoactive intestinal peptide or its receptor, mCry1 expression was damped and desynchronized between cells. Despite the absence of CREs, mCry1-luc expression was nevertheless (indirectly) sensitive to manipulation of cAMPdependent signaling. In mPer1/2-null SCN, mCry1-luc bioluminescence was arrhythmic and no longer suppressed by elevation of cAMP. Finally, an SCN graft procedure showed that PER-independent as well as PER-dependent mechanisms could sustain circadian expression of mCry1. The mCry1-luc mouse therefore reports circadian mCry1 expression and its interactions with vasoactive intestinal peptide, cAMP, and PER at the heart of the SCN pacemaker.gene expression | period gene | adenylate cyclase | VPAC2 | afterhours T he suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker in mammals, coordinating daily programs of gene expression across the body that ultimately underpin adaptation to day and night (1). SCN pacemaking revolves around an autoregulatory feedback loop in which expression of Period (Per) and Cryptochrome (Cry) genes is suppressed by their protein products on a daily basis. Specifically, PER/CRY complexes act at E-box regulatory sequences in Per and Cry to inhibit their transactivation by CLOCK/BMAL1 heterodimers (2). Supplementary feedback loops involving bZIP-family proteins [albumin D-element binding protein (Dbp) and nuclear factor, interleukin 3 regulated (Nfil3) acting at D-boxes] and REV-ERB family nuclear receptors (acting at RORE elements) confer additional robustness and amplitude (3), but E-box-mediated transcription is the principal determinant of SCN molecular pacemaking.To generate a coherent circadian signal across the SCN, the intracellular loops are synchronized between cells by neuropeptidergic cues tha...

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“…A prevailing view holds that these neuropeptides act through their G protein-coupled receptors to modulate cAMP levels to upregulate expression of clock genes and, ultimately, adjust the circadian phase of each cell (13). Here, Maywood et al provided a surprising insight.…”

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confidence: 99%