Cargando…

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

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, transcriptiona...

Descripción completa

Detalles Bibliográficos
Autores principales: Tokuda, Isao T., Ono, Daisuke, Honma, Sato, Honma, Ken-Ichi, Herzel, Hanspeter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301697/
https://www.ncbi.nlm.nih.gov/pubmed/30532130
http://dx.doi.org/10.1371/journal.pcbi.1006607
_version_ 1783381845383053312
author Tokuda, Isao T.
Ono, Daisuke
Honma, Sato
Honma, Ken-Ichi
Herzel, Hanspeter
author_facet Tokuda, Isao T.
Ono, Daisuke
Honma, Sato
Honma, Ken-Ichi
Herzel, Hanspeter
author_sort Tokuda, Isao T.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6301697
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-63016972019-01-08 Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors Tokuda, Isao T. Ono, Daisuke Honma, Sato Honma, Ken-Ichi Herzel, Hanspeter PLoS Comput Biol Research Article 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. Public Library of Science 2018-12-10 /pmc/articles/PMC6301697/ /pubmed/30532130 http://dx.doi.org/10.1371/journal.pcbi.1006607 Text en © 2018 Tokuda et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tokuda, Isao T.
Ono, Daisuke
Honma, Sato
Honma, Ken-Ichi
Herzel, Hanspeter
Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title_full Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title_fullStr Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title_full_unstemmed Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title_short Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors
title_sort coherency of circadian rhythms in the scn is governed by the interplay of two coupling factors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301697/
https://www.ncbi.nlm.nih.gov/pubmed/30532130
http://dx.doi.org/10.1371/journal.pcbi.1006607
work_keys_str_mv AT tokudaisaot coherencyofcircadianrhythmsinthescnisgovernedbytheinterplayoftwocouplingfactors
AT onodaisuke coherencyofcircadianrhythmsinthescnisgovernedbytheinterplayoftwocouplingfactors
AT honmasato coherencyofcircadianrhythmsinthescnisgovernedbytheinterplayoftwocouplingfactors
AT honmakenichi coherencyofcircadianrhythmsinthescnisgovernedbytheinterplayoftwocouplingfactors
AT herzelhanspeter coherencyofcircadianrhythmsinthescnisgovernedbytheinterplayoftwocouplingfactors