The circadian organization of behavior determines how complex organisms respond to light/dark cues encountered on a daily and seasonal basis. Circadian rhythms are generated and controlled by an endogenous clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruption of the circadian rhythm in humans can lead to sleep disorders, mental fatigue, and depression, particularly with aging patients. Retinal light signals mediated through the retinohypothalamic tract stimulate glutamate release in the SCN and maintain time-of-day congruence between the SCN and the external environment. Although the mechanism by which light entrains the circadian cycle in the SCN is not defined, it is apparently mediated through a transcriptional cycle involving several genes including CREB (cAMP response element binding protein) as well as the period and timeless genes. Light induces transcriptional changes of several genes in the SCN including the """"""""clock"""""""" genes, period 1 (Per1) and period 2 (Per2). Per1 is upregulated after light pulses given during the subjective night and light-induced increases in Per1 expression correlate with phase shifts of the circadian rhythm. The objective of this proposal is to test the following proposal. We hypothesize that entrainment of the circadian cycle in the SCN is mediated, at least in part, by glutamate stimulation of the CREB/CRE transcriptional pathway and increased transcription of the Per1 gene through CREs in its promoter. We hypothesize that glutamate stimulation of the CREB/CRE transcriptional pathway and Per1 expression in SCN neurons is due to coactivation of the MAPK and cAMP signaling pathways by Ca2+. We propose that the cAMP signal required for this process arises from Ca2 + stimulation of the type 8 adenylyl cyclase (AC8), a Ca2+ stimulated adenylyl cyclase. This project uses several novel mouse strains developed in this lab, including a CRE/LacZ reporter strain and AC8 mutant mice.

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-3 (01))
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Mitler, Merrill
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University of Washington
Schools of Medicine
United States
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DiRocco, Derek P; Scheiner, Zachary S; Sindreu, Carlos Balet et al. (2009) A role for calmodulin-stimulated adenylyl cyclases in cocaine sensitization. J Neurosci 29:2393-403
Nicol, Xavier; Bennis, Mohammed; Ishikawa, Yoshihiro et al. (2006) Role of the calcium modulated cyclases in the development of the retinal projections. Eur J Neurosci 24:3401-14
Chan, Guy C-K; Tonegawa, Susumu; Storm, Daniel R (2005) Hippocampal neurons express a calcineurin-activated adenylyl cyclase. J Neurosci 25:9913-8
Chen, Xi; Garelick, Michael G; Wang, Hongbing et al. (2005) PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nat Neurosci 8:925-31
Fukuhara, Chiaki; Liu, Cuimei; Ivanova, Tamara N et al. (2004) Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina. J Neurosci 24:1803-11
Yang, Huaitao; Scholich, Klaus; Poser, Steve et al. (2002) Developmental expression of PAM (protein associated with MYC) in the rodent brain. Brain Res Dev Brain Res 136:35-42
Chan, G C; Lernmark, U; Xia, Z et al. (2001) DNA elements of the type 1 adenylyl cyclase gene locus enhance reporter gene expression in neurons and pinealocytes. Eur J Neurosci 13:2054-66
Wong, S T; Athos, J; Figueroa, X A et al. (1999) Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron 23:787-98
Obrietan, K; Impey, S; Smith, D et al. (1999) Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274:17748-56