Differential Effects of Physiological Temperature Changes on Central Versus Peripheral Circadian Clocks in Mice.

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Most organisms use rhythms of sunlight to synchronize their activity to the environment. These rhythms of activity are called circadian rhythms. The rhythms persist with near 24 hour periods when external synchronizing cues are absent. In mammals, the circadian clock is generated at the molecular level by a transcriptional/translational feedback loop in which positive activators, CLOCK and BMAL1, initiate the transcription of genes in the Per and Cry families whose proteins then inhibit CLOCK:BMAL1, thus inhibiting their own transcription. The hypothalamic suprachiasmatic nucleus (SCN) in mammals is the master clock. It sets the phase and period for the entire animal. However, most mammalian tissues act as molecular clocks when cultured outside of the body. The SCN is therefore a master synchronizer, rather than a driver of rhythms in peripheral tissues. The rhythms of body temperature have been proposed as a mechanism by which peripheral tissues synchronize. There are likely a number of cues used by peripheral tissues to synchronize their circadian rhythms. Using in vivo techniques, it is often impossible to control one factor without also affecting others. We therefore sought to characterize the phase setting properties of physiological temperature changes using organotypic tissue culture. Tissues of mice carrying the Per2Luciferase insertion exhibit bioluminescence when the PER2 protein is translated. Tissues from these mice were cultured and luminescence was measured while subjected to temperature changes. The phase and amplitude of rhythms of peripheral tissues could be controlled by temperature pulses and cycles within the physiological range. This thermosensitivity was blocked by an inhibitor of Heat Shock Factor-mediated transcription. It was not affected by the deletion of temperature sensitive TRPV3 and TRPV4 channels. SCN cultures were resistant to temperature changes, maintaining their phase during temperature pulses and cycles. This resistance is a result of intracellular communication within the tissue. Blocking action potentials or L-type calcium channels renders the tissue thermosensitive. Also, dissecting the dorsal from the ventral regions reveals a mutual dependence for temperature resistance. These results suggest that the resistance of the SCN to physiologic temperature changes is a result of intracellular communication between the dorsal and ventral regions.

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  • 09/20/2018
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