The suprachiasmatic muclei (SCN) of the hypothalamus are endogenous oscillators that serve a well-defined, critical role in the generation and entrainment of the daily (circadian) oscillations of physiology, metabolism and behavior of mammals. Our broad research objective is to understand the molecular, cellular and neurophysiological mechanisms by which the SCN keep 24 hr time. The model species to be studied is the rat. The SCN pacemaker survives intact in the hypothalamic brain slice where it is accessible to experiments aimed at dissecting cellular mechanisms. Our methodological approach combines brain slice culture with conventional neurophysiological techniques that measure the circadian rhythm of neuronal activity nd biochemical analyses that measure cyclic nucleotide levels, enzyme activities and proteins phosphorylated. The present proposal develops naturally from our finding that the SCN rhythm can be reset in the brain slice by treatments affecting cAMP or cGMP pathways. Further, the pacemaker substrates are changing so that the rhythm is reset by cAMP in the donor's days, and by cGMP or high K+(o) during the donor's night.
Our specific aims i nclude: A) to more fully explore the role of cAMP in SCN function )(by examining the level of cAMP action within the SCN, the activity of enzymes regulating cAMP, regulation of the cAMP effect by melatonin, the involvement of cAMP stimulated phosphorylation in phase-shifting, and the involvement of new protein synthesis in cAMP stimulation); B) to examine the nature of the effect of cGMP analogs at night (by examining the specificity of cGMP stimulation, the effect of depolarizing stimuli on cGMP levels, and determining whether protein kinase inhibitors are effective at night); and C) to identify other second messenger pathways underlying the SCN pacemaker (by exploring potential, possibly interactive, roles for Ca++ and phospholipid metabolites). Because the SCN integrates most circadian behaviors and metabolic changes, this Study has basic relevance to understanding many brain and metabolic dysfunctions, including certain forms of mental illness.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 2 (NEUB)
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University of Illinois Urbana-Champaign
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United States
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Gillette, Martha U; Abbott, Sabra M (2009) BIOLOGICAL TIMEKEEPING. Sleep Med Clin 4:99-110
Beaulé, Christian; Mitchell, Jennifer W; Lindberg, Peder T et al. (2009) Temporally restricted role of retinal PACAP: integration of the phase-advancing light signal to the SCN. J Biol Rhythms 24:126-34
Tischkau, Shelley A; Gillette, Martha U (2005) Oligodeoxynucleotide methods for analyzing the circadian clock in the suprachiasmatic nucleus. Methods Enzymol 393:593-610
Buchanan, Gordon F; Gillette, Martha U (2005) New light on an old paradox: site-dependent effects of carbachol on circadian rhythms. Exp Neurol 193:489-96
Gerdin, Matthew J; Masana, Monica I; Rivera-Bermudez, Moises A et al. (2004) Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J 18:1646-56
Tischkau, Shelley A; Mitchell, Jennifer W; Pace, Laura A et al. (2004) Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock. Neuron 43:539-49
Burgoon, P W; Lindberg, P T; Gillette, M U (2004) Different patterns of circadian oscillation in the suprachiasmatic nucleus of hamster, mouse, and rat. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 190:167-71
Tischkau, Shelley A; Weber, E Todd; Abbott, Sabra M et al. (2003) Circadian clock-controlled regulation of cGMP-protein kinase G in the nocturnal domain. J Neurosci 23:7543-50
Barnes, Jessica W; Tischkau, Shelley A; Barnes, Jeffrey A et al. (2003) Requirement of mammalian Timeless for circadian rhythmicity. Science 302:439-42
Tischkau, Shelley A; Mitchell, Jennifer W; Tyan, Sheue-Houy et al. (2003) Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278:718-23

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