A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

Abstract

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...

Functional network inference of the suprachiasmatic nucleus

“…Although individual neurons within the SCN act as autonomous circadian pacemakers, they display stochastic variation in period length and must communicate to maintain stable period lengths and phase relationships for system-wide control of daily cycles (8)(9)(10). SCN network dynamics are contingent on properties of the cell-autonomous oscillator (11,12), communication via neurotransmitters (10,(13)(14)(15)(16), and the underlying connectivity of the network.…”

“…Although the single-cell oscillator and coupling pathways have been extensively researched, relatively little is known about the structure of the neuronal network driving synchronization in the SCN. Prominent modeling studies of the past decade have assumed a wide variety of network structures: nearest neighbor (15,20), small-world (21), or mean-field (22,23), or combinations of these depending on coupling pathway (16), pointing to the high degree of uncertainty regarding the general connectivity of the SCN. There has been significant recent interest in attempting to elucidate the network structure and mechanisms driving synchrony the SCN, commonly through light-driven desynchronization assays (19,(24)(25)(26).…”

Determining individual phase response curves from aggregate population data

“…Because ρ(t, θ) can be determined by through measurements ofs(t) using (10), and ∆θ is defined so that it can be found with knowledge of ρ(t, θ), equation (15) allows us to use these observable values in order to infer the phase response curve of the individual oscillators. It should be noted that if ρ(t, θ) = δ(θ − θ o ) equation (15) reduces to ∆Θ(θ o )/ψ = Z(θ o ), i.e.…”

“…Here we have assumed that using the truncated terms for ρ f and Z f in (15) only lead to O(ǫ) errors in the inner product. The Fourier coefficients of the phase distributions immediately preceding and following a δ-function pulse, ρ(τ − , θ), and ρ(τ + , θ), respectively, can be determined from (10). For instance,…”

“…We note that (1) can be appended to include additional terms such as noise and coupling in a population. Phase reduction has been applied fruitfully to many applications to both understand and control populations of phase oscillators [7], [8], [5], [9], [10], [11]. Essential to the understanding of these oscillatory group dynamics is the ability to accurately compute PRCs, which for systems in silico has been rendered nearly trivial with modern computing algorithms and software [12], [13], [14].…”