A compartmentalized SCN model explains temperature resistance through interregional phase differences

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.