  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 circadian
rhythmicity. Previous work has shown that single, dissociated SCN neurons
respond differently to Cry1 and Cry2 knockouts: Cry1 knockouts are arrhythmic
while Cry2 knockouts display more regular rhythms. 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 (VIP).
Due to the stochastic nature of molecular oscillations, we demonstrate that
single-cell Cry1 knockout oscillations display partially rhythmic behavior, and
cannot be classified as simply rhythmic or arrhythmic. Our model demonstrates
that 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. Our results further highlight the
essential role of stochastic behavior in understanding and accurately modeling
the circadian network and its response to perturbation.
