CREB influences timing and entrainment of the SCN circadian clock.
The transcriptional feedback circuit, which is at the core of the suprachiasmatic nucleus (SCN) circadian (i.e., 24 h) clock, is tightly coupled to both external entrainment cues, such as light, as well as rhythmic cues that arise on a system-wide level within the SCN. One potential signaling pathway by which these cues are conveyed to the molecular clock is the CREB/CRE transcriptional cascade. In this study, we employed a tetracycline-inducible CREB repressor mouse strain, in which approximately 60% of the SCN neurons express the transgene, to test CREB functionality in the clock and its effects on overt rhythmicity. We show that attenuated CREB signaling in the SCN led to a significant reduction in light-evoked clock entrainment. An examination of circadian timing revealed that CREB repressor mice exhibited normal free-running rhythms in the absence of external lighting cues. However, under conditions of constant light, which typically leads to a lengthening of the circadian period, CREB repressor mice exhibited a dramatic arrhythmic phenotype, which could be reversed with doxycycline. At a cellular level, the repression of CREB led to a significant reduction in both the expression of the circadian clock proteins PERIOD1 and PERIOD2 and the clock output hormones AVP and VIP. Together, these data support the idea that the CRE transcriptional pathway orchestrates transcriptional events that are essential for both the maintenance of SCN timing and light entrainment of the circadian clock.
Department of Neuroscience, Ohio State University, Columbus, OH, USA.
Boyoung
B
Lee
Aiqing
A
Li
Katelin F
KF
Hansen
Ruifeng
R
Cao
Jae Hwa
JH
Yoon
Karl
K
Obrietan
D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D056950:Period Circadian Proteins; D049452:Green Fluorescent Proteins; D014660:Vasoactive Intestinal Peptide; D004318:Doxycycline