A Coupled Stochastic Model Explains Differences in Cry Knockout Behavior

In the mammalian suprachiasmatic nucleus (SCN), a population of noisy cell-autonomous oscillators synchronizes to generate robust circadian rhythms at the organism level. Within these cells, two isoforms of Cryptochrome, Cry1 and Cry2, participate in a negative feedback loop driving oscillation. Previous work has shown that single, dissociated SCN neurons respond differently to Cry1 and Cry2 knockouts. These differences have led to speculation that CRY1 and CRY2 may play different functional roles in the oscillator. To address this proposition, we have developed a new coupled, stochastic model focused on the Period (Per) and Cry feedback loop, and incorporating intercellular coupling via vasoactive intestinal peptide. We show that single dissociated Cry1 knockouts display partially rhythmic behavior. Additionally, intrinsic molecular noise and differences in relative abundance, rather than differing functions, are sufficient to explain the range of rhythmicity encountered in Cry knockouts in the SCN. The results further highlight the essential role of stochastic behavior in understanding and accurately modeling the circadian network.