The sleep-wake distribution contributes to clock gene expression: a descriptive and a mechanistic study in mice


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PhD thesis: a PhD thesis.
The sleep-wake distribution contributes to clock gene expression: a descriptive and a mechanistic study in mice
Hoekstra Marieke
Franken Paul
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Université de Lausanne, Faculté de biologie et médecine
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The sleep-wake distribution (i.e. the duration and timing of sleep across the 24-h day) is orchestrated by the interaction of two processes: the sleep homeostat, which keeps track of time spent awake and asleep, and the circadian clock, which gates the timing of sleep. The mechanisms underlying the clock are well understood: overt rhythmic behavior in mammals is coordinated by the suprachiasmatic nucleus and at the molecular level by intertwining transcriptional-translational
feedback loops of so-called clock genes, ensuring a period of ca. 24 hours. The substrate underlying the sleep homeostat is unknown, but clock genes appear implicated because: i) mutations and deletions of clock genes affect the sleep homeostat); ii) sleep deprivation (SD) impairs the binding of clock gene proteins to their target clock genes; iii) SD changes clock gene expression. In this thesis, a descriptive and a mechanistic study are presented to inspect more closely the sleep-wake distributions’ contribution to clock gene expression. The descriptive study made use of a mouse model where bioluminescence is measured as a proxy for period-2 (PER2) protein levels, combined with electroencephalogram (EEG) recordings to determine sleep-wake state. Under undisturbed conditions, PER2 bioluminescence changed as a function of sleep and wake. Twelve 2Hr SDs scheduled across two days reduced the amplitude of PER2 bioluminescence in 3 out of 4 mice. Thus, sleep-wake state contributes to PER2 bioluminescence. However, the reliability of PER2 bioluminescence as a proxy for PER2 protein levels remains to be verified. In the second study, the contribution of Cold Inducible RNA Binding Protein (CIRBP) to SD-incurred changes in clock gene expression was investigated, based on the observations that i) daily changes in cortical Cirbp appear mainly sleep-wake driven, possibly through cortical temperature; ii) CIRBP is necessary for high amplitude clock gene expression in vitro. First, we established that the sleep-wake distribution drives the changes in cortical temperature of the mouse. Second, we found that the SD induced changes in cortical Rev-erbα was attenuated in the absence of CIRBP, whereas the expression of Clock and Per2 was amplified. Third, and based on the premise that clock genes contribute to sleep regulation, we observed that Cirbp KO mice loose REM sleep after SD compared to their WT littermates. Altogether, this thesis i) supports the importance of considering the sleep-wake distribution when using clock gene expression as a state variable of the clock; ii) demonstrates that CIRBP modulates the SD incurred changes in cortical clock gene expression and contributes to REM sleep recovery.
sleep, circadian rhythms, mice, clock genes, CIRBP, cortical temperature
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11/10/2018 8:39
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20/08/2019 14:14
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