Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors

PLoS Comput Biol. 2018 Dec 10;14(12):e1006607. doi: 10.1371/journal.pcbi.1006607. eCollection 2018 Dec.

Abstract

Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine Vasopressin / metabolism*
  • Arginine Vasopressin / physiology
  • Circadian Clocks / physiology
  • Circadian Rhythm / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / physiology
  • Neuropeptides / metabolism
  • Period Circadian Proteins / metabolism
  • Signal Transduction
  • Suprachiasmatic Nucleus / physiology
  • Vasoactive Intestinal Peptide / metabolism*
  • Vasoactive Intestinal Peptide / physiology

Substances

  • Neuropeptides
  • Period Circadian Proteins
  • Arginine Vasopressin
  • Vasoactive Intestinal Peptide

Grant support

The authors acknowledge financial support from Japan Society for the Promotion of Science (KAKENHI Nos. 15H04679, 16K00343, 16H05011, 17H06313, 18H02477), Bundesministerium fuer Bildung und Forschung (Grant No. 01GQ1503), and Deutsche Forschungsgemeinschaft (HE2168/11-1; TRR/SFB 186 A16, A17). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.