A compartmentalized SCN model explains temperature resistance through interregional phase differences
- 1School of Mathematical Sciences, Soochow University, Suzhou, China
Abstract
Temperature cycles entrain circadian rhythms in many peripheral tissues, yet the master circadian pacemaker (suprachiasmatic nucleus) in mammals remains largely insensitive to the same input. Despite their similar molecular circuitry, the mechanisms underlying the distinct temperature responses of central and peripheral clocks remain unclear. To address this, we developed a compartmentalized model of the SCN circadian clock that integrates the heat shock protein (HSP) pathway, simulating the response of the SCN network to temperature variations. Using this model, we successfully recapitulated key experimental observations, including the ability of heat stimuli to entrain peripheral clocks to an inverted phase while the SCN maintains its resistance. Further analysis reveals that intrinsic phase heterogeneity among SCN subregions underlies this entrainment resistance. Specifically, the phase difference between the dorsal and ventral SCN leads to divergent phase responses upon simultaneous stimulation, resulting in an attenuated net shift of the overall SCN phase. Moreover, the mode of thermal input, in which the dorsal and ventral regions are stimulated concurrently, may further enhance the SCN’s robustness to temperature entrainment. These results suggest that the SCN’s resistance to temperature entrainment may differ mechanistically from photic entrainment, and highlight the potential importance of its spatial structure in maintaining circadian stability. Author summary: Daily temperature cycles help synchronize biological clocks with the external environment. In many peripheral tissues, these thermal rhythms can strongly shift clock phase. In contrast, the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, remains resistant to temperature entrainment. Why the SCN and peripheral clocks respond so differently to the same thermal signals has remained unclear. We developed a mathematical model of the SCN that combines temperature-responsive signaling with the spatial organization of the SCN network. Our simulations show that the SCN’s resistance to temperature entrainment arises from an intrinsic phase difference between dorsal and ventral regions. When the same thermal input reaches both subregions, their local phase responses diverge and partially cancel, thereby buffering the phase of the SCN as a whole. Therefore, this built-in spatial heterogeneity helps protect the SCN from temperature perturbation. These results provide a mechanistic explanation for the thermal robustness of the SCN and highlight how spatial organization within a biological network can stabilize physiological rhythms. More broadly, one reason the SCN naturally maintains a distributed phase structure may be that such heterogeneity enhances robustness to temperature perturbation.
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BibTeX
@article{yu2026compartmentalized,
title = {{A compartmentalized SCN model explains temperature resistance through interregional phase differences}},
author = {Feng Yu and Ling Yang and Jie Yan},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014831},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014831},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A compartmentalized SCN model explains temperature resistance through interregional phase differences
AU - Feng Yu
AU - Ling Yang
AU - Jie Yan
PY - 2026
DA - 2026/09/29
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014831
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014831
AB - Temperature cycles entrain circadian rhythms in many peripheral tissues, yet the master circadian pacemaker (suprachiasmatic nucleus) in mammals remains largely insensitive to the same input. Despite their similar molecular circuitry, the mechanisms underlying the distinct temperature responses of central and peripheral clocks remain unclear. To address this, we developed a compartmentalized model of the SCN circadian clock that integrates the heat shock protein (HSP) pathway, simulating the response of the SCN network to temperature variations. Using this model, we successfully recapitulated key experimental observations, including the ability of heat stimuli to entrain peripheral clocks to an inverted phase while the SCN maintains its resistance. Further analysis reveals that intrinsic phase heterogeneity among SCN subregions underlies this entrainment resistance. Specifically, the phase difference between the dorsal and ventral SCN leads to divergent phase responses upon simultaneous stimulation, resulting in an attenuated net shift of the overall SCN phase. Moreover, the mode of thermal input, in which the dorsal and ventral regions are stimulated concurrently, may further enhance the SCN’s robustness to temperature entrainment. These results suggest that the SCN’s resistance to temperature entrainment may differ mechanistically from photic entrainment, and highlight the potential importance of its spatial structure in maintaining circadian stability. Author summary: Daily temperature cycles help synchronize biological clocks with the external environment. In many peripheral tissues, these thermal rhythms can strongly shift clock phase. In contrast, the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, remains resistant to temperature entrainment. Why the SCN and peripheral clocks respond so differently to the same thermal signals has remained unclear. We developed a mathematical model of the SCN that combines temperature-responsive signaling with the spatial organization of the SCN network. Our simulations show that the SCN’s resistance to temperature entrainment arises from an intrinsic phase difference between dorsal and ventral regions. When the same thermal input reaches both subregions, their local phase responses diverge and partially cancel, thereby buffering the phase of the SCN as a whole. Therefore, this built-in spatial heterogeneity helps protect the SCN from temperature perturbation. These results provide a mechanistic explanation for the thermal robustness of the SCN and highlight how spatial organization within a biological network can stabilize physiological rhythms. More broadly, one reason the SCN naturally maintains a distributed phase structure may be that such heterogeneity enhances robustness to temperature perturbation.
SN - 1553-7358
ER -