In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus function as the major biological clock. SCN-dependent rhythms of physiology and behavior are regulated by changes in the environmental light cycle. Recent work has revealed that a program of rhythmic transcriptional regulation is required for endogenous SCN timekeeping and that light-induced changes in circadian timing result from alterations in this transcriptional program. Given the transcriptional basis of circadian rhythm generation, a characterization of the intracellular signaling pathways and downstream transcription factors involved in biological timing will be critical for understanding the functional properties of the circadian clock. Our preliminary studies reveal that photic stimulation and endogenous pacemaker activity regulate the activation state of the p42/44 mitogen-activated protein kinase (MAPK) signal transduction pathway in the SCN. The MAPK signal transduction pathway is a potent regulator of numerous classes of transcription factors and has been shown to play a role in certain forms of neuronal plasticity. These observations lead us to hypothesize that the MAPK pathway couples photic input to clock entrainment and that signaling via the MAPK pathway functions as an output pathway from the clock.
In Aim 1 we address whether the MAPK signaling pathway is required for endogenous clock timing. We will also investigate the expression of circadian-regulated genes after disruption of MAPK signaling and identify transcription factors regulated by the MAPK signaling pathway.
In Aim 2 we investigate whether MAPK signaling couples photic stimulation to phase shifting of the circadian clock. We will also investigate whether the MAPK pathway couples photic stimulation to transcriptional activation in the SCN.
In Aim 3 we investigate cellular mechanisms that activate and inactivate the MAPK pathway in the SCN. Identification of the signaling and transcriptional pathways that regulate SCN rhythm generation and light-entrainment of the clock will provide new targets for therapeutic treatment of circadian-related ailments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062335-04
Application #
6910907
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$258,125
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Lee, Boyoung; Li, Aiqing; Hansen, Katelin F et al. (2010) CREB influences timing and entrainment of the SCN circadian clock. J Biol Rhythms 25:410-20

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