Coupling Controls the Synchrony of Clock Cells in Development and Knockouts

Area of Science:

• Chronobiology
• Neuroscience
• Systems Biology

Background:

• Mammalian circadian rhythms are coordinated by coupled hypothalamic neurons, with individual neurons exhibiting noisy transcriptional feedback oscillations.
• Neuropeptide-mediated coupling enhances the precision and robustness of these circadian rhythms.
• Cryptochrome (Cry) double knockout mice lose rhythmicity in adulthood but maintain it as neonates, suggesting developmental changes in rhythm regulation.

Purpose of the Study:

• To quantitatively investigate the relationship between single-cell rhythmicity and intercellular coupling in the circadian system.
• To understand the mechanisms underlying the loss of rhythmicity in adult Cry double knockout mice compared to neonates.

Main Methods:

• Quantitative analysis of dispersed neurons and brain slices from wild-type and Cry double knockout mice.
• Nonlinear regression to characterize oscillator properties of single cells.
• Bifurcation analysis of network models to explore parameter dependencies.

Main Results:

• Experimental and modeling data indicate that oscillator strength, coupling strength, and coupling timing are critical parameters for circadian rhythm synchronization.
• Minor alterations in the timing of intercellular coupling can lead to a loss of synchronization, as observed in adult Cry knockout mouse brain slices.
• A model incorporating these three parameters successfully reproduces experimentally observed features of circadian rhythmicity and arrhythmicity.

Conclusions:

• The interplay between intrinsic cellular oscillator properties and intercellular coupling dynamics is fundamental to robust circadian rhythm generation.
• Developmental changes in coupling timing may explain the transition from robust rhythmicity in neonates to arrhythmicity in adult Cry knockout mice.
• Mathematical modeling provides a powerful framework for dissecting complex biological rhythms and identifying critical regulatory parameters.