Weakly Circadian Cells Improve Resynchrony

Abstract

The mammalian suprachiasmatic nuclei (SCN) contain thousands of neurons capable of generating near 24-h rhythms. When isolated from their network, SCN neurons exhibit a range of oscillatory phenotypes: sustained or damping oscillations, or arrhythmic patterns. The implications of this variability are unknown. Experimentally, we found that cells within SCN explants recover from pharmacologically-induced desynchrony by re-establishing rhythmicity and synchrony in waves, independent of their intrinsic circadian period We therefore hypothesized that a cell's location within the network may also critically determine its resynchronization. To test this, we employed a deterministic, mechanistic model of circadian oscillators where we could independently control cell-intrinsic and network-connectivity parameters. We found that small changes in key parameters produced the full range of oscillatory phenotypes seen in biological cells, including similar distributions of period, amplitude and ability to cycle. The model also predicted that weaker oscillators could adjust their phase more readily than stronger oscillators. Using these model cells we explored potential biological consequences of their number and placement within the network. We found that the population synchronized to a higher degree when weak oscillators were at highly connected nodes within the network. A mathematically independent phase-amplitude model reproduced these findings. Thus, small differences in cell-intrinsic parameters contribute to large changes in the oscillatory ability of a cell, but the location of weak oscillators within the network also critically shapes the degree of synchronization for the population.

Inhibitory and excitatory networks balance cell coupling in the suprachiasmatic nucleus: A modeling approach

“…Moreover, Fig. 4B showed that GABA signaling allowed delayers to shift faster by increasing the width of the delay region, in agreement with previous research showing that shortened re-entrainment times could be explained by increases in the area of velocity response curves (Webb et al, 2012). Overall, GABA significantly increased the area of the delay region by 8.4% while decreasing the advance region area by 2.1%.…”

Socially synchronized circadian oscillators

“…It is clear that SCN cells are a heterogenous population with distinct oscillatory properties [61,[70][71][72]. Computational models have predicted that inclusion of more damped oscillators or placement of damped oscillators at more highly connected hubs in the network can yield higher and faster synchrony [73][74][75][76][77][78]. Notably, animals with as little as 25 per cent of SCN cells still show circadian rhythms in locomotor behaviour [79][80][81][82].…”

Measuring Synchrony in the Mammalian Central Circadian Circuit

“…When the gene for Vip or its receptor, Vipr2 , were deleted, the sync index dropped to 0.05 (Aton, Colwell, Harmar, Waschek, & Herzog, 2005). Similarly, pharmacological disruption of cell-cell communication with drugs like tetrodotoxin or pertussis toxin can reduce the sync index of PER2::Luc rhythms in a SCN slice from nearly 0.7 to 0.1(Aton, Huettner, Straume, & Herzog, 2006; Webb, Taylor, Thoroughman, Doyle III, & Herzog, 2012). Importantly, the reduction in phase synchrony was accompanied by a broadened distribution of periods expressed by the cells, demonstrating that these genetic and pharmacological interventions disrupted the mechanisms underlying synchronization.…”