A mouse model for environmentally induced and reversible circadian arrhythmia using gradual exposure to a fragmented day-night cycle

Abstract Arrhythmia is considered the most disrupted state of the biological circadian clock, and usually occurs when circadian regulatory genes are rendered non-functional, or the master clock (Suprachiasmatic Nucleus) is ablated. Since clock gene expression is aligned by the external solar day-night cycle to exhibit a 24-hour rhythm, we hypothesized that ill-timed light and dark exposure could negatively impact endogenous circadian clock function in mice. In this study, we present an environmentally driven approach to induce arrhythmia in mice that is also reversible. Using the previously characterized fragmented day-night cycle (FDN) where the 8-hour night is split into four 2-hour fragments and equally distributed across the 24-hour day, we show that mice gradually exposed to the FDN for 1 month lose their circadian rhythmicity. Furthermore, subsequent exposure to constant light or constant dark conditions does not yield typical circadian rhythms, but instead, reveals circadian arrhythmia. Finally, we show that the arrhythmic locomotion phenotype is reversible with one week of reintroduction to a 12 hr day-12 hr night cycle. This is the first study to show how the light-dark environment induces arrhythmia of an intact circadian clock and how it can be reversed.