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In the mammalian suprachiasmatic nucleus (SCN), a population of noisycell-autonomous oscillators synchronizes to generate robust circadian rhythmsat the organism-level. Within these cells two isoforms of Cryptochrome, Cry1and Cry2, participate in a negative feedback loop driving circadianrhythmicity. Previous work has shown that single, dissociated SCN neuronsrespond differently to Cry1 and Cry2 knockouts: Cry1 knockouts are arrhythmicwhile Cry2 knockouts display more regular rhythms. These differences have ledto speculation that CRY1 and CRY2 may play different functional roles in theoscillator. To address this proposition, we have developed a new coupled,stochastic model focused on the Period (Per) and Cry feedback loop, andincorporating intercellular coupling via vasoactive intestinal peptide (VIP).Due to the stochastic nature of molecular oscillations, we demonstrate thatsingle-cell Cry1 knockout oscillations display partially rhythmic behavior, andcannot be classified as simply rhythmic or arrhythmic. Our model demonstratesthat intrinsic molecular noise and differences in relative abundance, ratherthan differing functions, are sufficient to explain the range of rhythmicityencountered in Cry knockouts in the SCN. Our results further highlight theessential role of stochastic behavior in understanding and accurately modelingthe circadian network and its response to perturbation.

A Coupled Stochastic Model Explains Differences in Circadian Behavior of Cry1 and Cry2 Knockouts