A Molecular Model for Intercellular Synchronization in the Mammalian Circadian Clock

Abstract

The mechanisms and consequences of synchrony among heterogeneous oscillators are poorly understood in biological systems. We present a multicellular, molecular model of the mammalian circadian clock that incorporates recent data implicating the neurotransmitter vasoactive intestinal polypeptide (VIP) as the key synchronizing agent. The model postulates that synchrony arises among circadian neurons because they release VIP rhythmically on a daily basis and in response to ambient light. Two basic cell types, intrinsically rhythmic pacemakers and damped oscillators, are assumed to arise from a distribution of Period gene transcription rates. Postsynaptic neurons show time-of-day dependent responses to VIP binding through a signaling cascade that activates Period mRNA transcription. The heterogeneous cell ensemble model self-synchronizes, entrains to ambient light-dark cycles, and desynchronizes in constant bright light or upon removal of VIP signaling. The degree of synchronicity observed depends on cell-specific features (e.g., mean and variability of parameters within the rhythm-generating loop), in addition to the more commonly studied effect of intercellular coupling strength. These simulations closely replicate experimental data and predict that heterogeneous oscillations (e.g., sustained, damped, and arrhythmic) arise from small differences in the molecular parameters between cells, that damped oscillators participate in entrainment and synchrony of the ensemble of cells, and that constant light desynchronizes oscillators by maximizing VIP release.

Functional network inference of the suprachiasmatic nucleus

“…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).…”

Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons

“…Under these conditions, small perturbations (extrinsic or intrinsic to the cell) could push the molecular oscillator on or off a limit cycle. Other modeling efforts have simulated the SCN as a network of damped (26) or sustained, damped, and driven oscillators (27). Bernard et al (26) found that, compared with self-sustained oscillators, damped oscillators more rapidly synchronized to each other and to environmental cycles, a potential benefit of having cells that change their rhythm amplitude.…”

Synchrony and entrainment properties of robust circadian oscillators

“…Experimental data demonstrate that isolated (uncoupled) neurons exhibit both a broad distribution of periods and temporal (cycle-to-cycle) variability (Herzog et al 2004). Hao et al (2006) and To et al (2007) postulated mechanisms through which VIP signals are received by a cell via signal cascades culminating in the modulation of the parameter associated with per transcription. Using an ODE model, To et al incorporate this coupling mechanism into a population of non-identical cells, each of which is based on the gene regulatory network model of Leloup & Goldbeter (2003).…”