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.
|Karelina, Kate; Alzate-Correa, Diego; Obrietan, Karl (2014) Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus. Exp Neurol 253:72-81|
|Hansen, Katelin F; Karelina, Kate; Sakamoto, Kensuke et al. (2013) miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct Funct 218:817-31|
|Sakamoto, Kensuke; Norona, Frances E; Alzate-Correa, Diego et al. (2013) Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock. J Neurosci 33:9021-7|
|Cao, Ruifeng; Butcher, Greg Q; Karelina, Kate et al. (2013) Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock. Eur J Neurosci 37:130-40|
|Choi, Yun-Sik; Karelina, Kate; Alzate-Correa, Diego et al. (2012) Mitogen- and stress-activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus. J Neurochem 123:676-88|
|Antoun, Ghadi; Bouchard-Cannon, Pascale; Cannon, Pascale Bouchard et al. (2012) Regulation of MAPK/ERK signaling and photic entrainment of the suprachiasmatic nucleus circadian clock by Raf kinase inhibitor protein. J Neurosci 32:4867-77|
|Karelina, Kate; Hansen, Katelin F; Choi, Yun-Sik et al. (2012) MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement. Learn Mem 19:550-60|
|Cao, R; Anderson, F E; Jung, Y-J et al. (2011) Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 181:79-88|
|Sakamoto, Kensuke; Karelina, Kate; Obrietan, Karl (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116:1-9|
|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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