title: Functional Contributions of Strong and Weak Cellular Oscillators to Synchrony and Light-shifted Phase Dynamics.
abstract: Light is the primary signal that calibrates circadian neural circuits and thus coordinates daily physiological and behavioral rhythms with solar entrainment cues. Drosophila and mammalian circadian circuits consist of diverse populations of cellular oscillators that exhibit a wide range of dynamic light responses, periods, phases, and degrees of synchrony. How heterogeneous circadian circuits can generate robust physiological rhythms while remaining flexible enough to respond to synchronizing stimuli has long remained enigmatic. Cryptochrome is a short-wavelength photoreceptor that is endogenously expressed in approximately half of Drosophila circadian neurons. In a previous study, physiological light response was measured using real-time bioluminescence recordings in Drosophila whole-brain explants, which remain intrinsically light-sensitive. Here we apply analysis of real-time bioluminescence experimental data to show detailed dynamic ensemble representations of whole circadian circuit light entrainment at single neuron resolution. Organotypic whole-brain explants were either maintained in constant darkness (DD) for 6 days or exposed to a phase-advancing light pulse on the second day. We find that stronger circadian oscillators support robust overall circuit rhythmicity in DD, whereas weaker oscillators can be pushed toward transient desynchrony and damped amplitude to facilitate a new state of phase-shifted network synchrony. Additionally, we use mathematical modeling to examine how a network composed of distinct oscillator types can give rise to complex dynamic signatures in DD conditions and in response to simulated light pulses. Simulations suggest that complementary coupling mechanisms and a combination of strong and weak oscillators may enable a robust yet flexible circadian network that promotes both synchrony and entrainment. A more complete understanding of how the properties of oscillators and their signaling mechanisms facilitate their distinct roles in light entrainment may allow us to direct and augment the circadian system to speed recovery from jet lag, shift work, and seasonal affective disorder.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA.
authors.forename: Logan
authors.initials: L
authors.lastname: Roberts
authors.affiliation: Department of Mathematics and Statistics, Amherst College, Amherst, MA.
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Leise
authors.affiliation: Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, CA Veterans Affairs San Diego Healthcare System, San Diego, CA.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA tholmes@uci.edu.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Holmes
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D001921:Brain / Q000502:physiology; D002940:Circadian Rhythm / Q000528:radiation effects; D003199:Computer Systems; D056931:Cryptochromes / Q000502:physiology; D003624:Darkness; D004330:Drosophila; D008027:Light; D008163:Luminescent Measurements; D008322:Mammals; D008962:Models, Theoretical; D009474:Neurons / Q000502:physiology*
chemical_list: D056931:Cryptochromes
keywords: bioluminescence; circadian; light; model simulations; neural circuits; phase dynamics