Physiological, behavioral and environmental factors influence bifurcated circadian entrainment in mice

Under permissive conditions, mice and hamsters exposed to a polyphasic light regime consisting of two light and two dark phases every 24 h (Light:Dark:Light:Dark; LDLD) can adopt a bifurcated entrainment pattern with roughly equal amounts of running wheel activity in each of the two nights. This rhythm "bifurcation" has significant after-effects on increased circadian adaptability: Mice that have been bifurcated show accelerated rates of re-entrainment after a sudden phase shift and have a markedly expanded range of entrainment. Identifying environmental and physiological factors that facilitate or prevent rhythm bifurcation in LDLD conditions will contribute to an understanding of mechanisms underlying enhanced circadian plasticity. Here we investigate the effects of sex, age, light intensity, access to a running wheel, melatonin, and diet composition on bifurcation behaviors of mice (C57Bl/6 J) exposed to LDLD. Female mice and young mice (<20 weeks) express more symmetrically bifurcated activity compared to male mice and older mice (>30 weeks). Additionally and independently, higher photophase intensities (~500 lx) predict more symmetric entrainment than low levels of light (~50 lx). Without access to a functional running-wheel, mice do not adopt bimodal activity patterns and only transiently maintain them, suggesting that high levels of aerobic activity are necessary for rhythm bifurcation. Neither a lifetime exposure to melatonin administered in the drinking water nor a high fat diet affected bifurcation. Collectively, these results demonstrate that circadian plasticity can be strongly modulated by intrinsic and extrinsic factors. With enhanced mechanistic understanding of this modulation, it may be possible to render human clocks more adaptable and thereby ameliorate negative consequences associated with repeated jet-lag or shift-work.