The suprachiasmatic nuclei (SCN) are the locus of the brain clock. At the cellular level, rhythmicity is produced by regulation of a cell-based negative feedback loop of transcription/translation of various clock genes. While our understanding of the molecular mechanisms of cell based oscillators has advanced tremendously in recent years, the organization of these oscillators at the level of SCN tissue is less well developed. On the one hand, it has been proposed that all SCN cells are circadian oscillators. On the other hand, our work on hamster SCN, based on Period mRNA (Per1, Per2, Per3) expression, suggests that there are functionally distinct compartments within the SCN; one contains rhythmic oscillators and the other contains circadian-gated, light responsive, non-oscillating cells. This organization suggests that oscillating and entraining information might be integrated at different sites within the SCN. Such a view would rewrite our understanding of such phenomena as phase shifting, entrainment, after-effects, etc.We propose to take advantage of the advances presented by the decoding of the mouse genome, to address questions of SCN organization. In baseline studies, we characterize the circadian and diurnal rhythms, and responses to phase advancing and delaying light pulses in a well characterized mouse strain (Aim I). Pilot studies suggest that the mouse SCN, like that of the hamster is made up of two distinctly different cell types, based on their light responsiveness and oscillating properties. To understand the organization of this circadian regulatory system, we will use transgenic animals with GFP reporters that are markers for the rhythmic (Per1 ::GFP) and light-induced (calbindin::GFP) compartments of the SCN (Aim II and III). Finally, we will characterize the microcircuitry of the SCN using calcium imaging and electrical recording and stimulation to understand the network properties of the SCN, using GFP to characterize the responses of identified (Per1 ::GFP and the CalB::GFP) SCN cell types (Aim IV).

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-1 (03))
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Mitler, Merrill
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Barnard College
Schools of Arts and Sciences
New York
United States
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