Our long-term goal is to understand the mechanisms by which environmental signals regulate circadian oscillators as well as how circadian oscillators are coupled to each other, using neurons in the rodent suprachiasmatic nucleus (SCN) as a model system. A variety of evidence suggests that glutamate plays a critical role in the transmission of photic information from the environment to the SCN and that the peptide PACAP is a co-transmitter with glutamate at the RHT/SCN synaptic connection. A major goal of this application is to understand the mechanisms by which PACAP modulates glutamate-induced signaling in SCN neurons. We will present data indicating that PACAP enhances AMPA currents in SCN neurons from mice. Furthermore, data from a new line of transgenic animals in which the PACAP gene has been inactivated demonstrate a reduction in the magnitude of the effects of light on the circadian system. Thus, we feel confident that both glutamate and PACAP play a role, be it as yet undetermined, in mediating the effects of light on the circadian system. Many of the retino-recipient SCN neurons receiving this photic information themselves express the peptide VIP as well as GABA. These SCN cells synapse largely onto other SCN cells and presumably use these molecules to communicate photic information to other cells in the SCN. Thus, a second goal is to understand the mechanisms by which VIP modulates GABA-induced signaling pathways in SCN neurons. For this project, we will present data consistent with our hypothesis that VIP acts to modulate GABA currents in SCN neurons in mice. Encouragingly, data from a new line of transgenic animals in which the VIP gene has been inactivated demonstrate major disruptions in the circadian system that are consistent with VIP's role as a coupling agent within the SCN. By carrying out this research, we will address important questions about how SCN cells are coupled to the environment as well as how SCN cells are coupled to each other. In addition, we hope to use the SCN as model system to better understand the role of peptide co-transmitters in mediating cell-to-cell communication. These questions will be addressed using electrophysiological and calcium imaging techniques on SCN neurons in a mouse brain slice preparation. In addition, transgenic mice lacking PACAP and VIP will be analyzed with behavioral and anatomical tools. These newly developed mice are likely to prove a useful tool for circadian rhythms research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043169-03
Application #
6844735
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Mitler, Merrill
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$360,013
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Colwell, Christopher S (2011) Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 12:553-69
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Dragich, Joanna M; Loh, Dawn H; Wang, Louisa M et al. (2010) The role of the neuropeptides PACAP and VIP in the photic regulation of gene expression in the suprachiasmatic nucleus. Eur J Neurosci 31:864-75
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Loh, Dawn H; Abad, Catalina; Colwell, Christopher S et al. (2008) Vasoactive intestinal peptide is critical for circadian regulation of glucocorticoids. Neuroendocrinology 88:246-55
Wang, L M; Schroeder, A; Loh, D et al. (2008) Role for the NR2B subunit of the N-methyl-D-aspartate receptor in mediating light input to the circadian system. Eur J Neurosci 27:1771-9
Choi, Hee Joo; Lee, C Justin; Schroeder, Analyne et al. (2008) Excitatory actions of GABA in the suprachiasmatic nucleus. J Neurosci 28:5450-9
Brown, T M; Colwell, C S; Waschek, J A et al. (2007) Disrupted neuronal activity rhythms in the suprachiasmatic nuclei of vasoactive intestinal polypeptide-deficient mice. J Neurophysiol 97:2553-8

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