All eukaryotes have a circadian system responsible for organizing many functions on a daily basis. At the heart of this system is a circadian oscillator that has to be regulated or entrained in order for the oscillator to be adaptive for the organism. Our long term goals are to understand the biochemical events involved in entrainment and to identify molecules involved in the oscillating mechanism itself. The isolated eye of Aplysia produces a circadian rhythm and this rhythm is regulated by light and the neurotransmitter serotonin. The proposed research will define biochemical events in the serotonin and light entrainment pathways and it will identify putative molecular components of the circadian oscillator. First, we will identify specific proteins whose synthesis and state of phosphorylation are regulated by serotonin or light. Then these proteins will be subjected to a number of tests to examine if the proteins are involved in entrainment by serotonin or light. Some of the criteria for a component of the circadian oscillator are the same criteria for an element of the entrainment pathway. Thus, the molecules that are associated with entrainment will be subjected to further tests to examine if they are components of the circadian oscillator. In particular, we will examine cyclic nucleotides, a 34K protein, and other proteins that emerge from the synthesis and phosphorylation work of this proposal. After proteins are identified as putative components of the oscillator, we will make monoclonal antibodies to the proteins. These antibodies will be used as probes to localize the proteins using immunohistochemistry. The research of this proposal should lead to an understanding of the cellular and biochemical regulation of a circadian oscillator. Our results should also pave the way for a molecular analysis of circadian timing. An understanding of the mechanisms that regulate circadian oscillators should hlep elucidate disorders associated with circadian rhythm abnormalities. Evidence indicates that circadian rhythms may play a role in the maintenance of mental health: in sleep disorders, in manic-depressive illnesses, and in the ability to learn and function normally. Our research, whose purpose is to identify molecular elements of circadian timing systems, should help elucidate the role of circadian rhythms in mental health by focusing attention on specific types of molecules that may be related to causes of mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH041979-01
Application #
3380983
Study Section
(BPNB)
Project Start
1986-07-01
Project End
1994-03-31
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Fernandez, Raymond I; Lyons, Lisa C; Levenson, Jonathan et al. (2003) Circadian modulation of long-term sensitization in Aplysia. Proc Natl Acad Sci U S A 100:14415-20
Hattar, Samer; Lyons, Lisa C; Eskin, Arnold (2002) Circadian regulation of a transcription factor, ApC/EBP, in the eye of Aplysia californica. J Neurochem 83:1401-11
Sankrithi, N; Eskin, A (1999) Effects of cyclin-dependent kinase inhibitors on transcription and ocular circadian rhythm of Aplysia. J Neurochem 72:605-13
Sloan, M A; Levenson, J; Tran, Q et al. (1999) Aging affects the ocular circadian pacemaker of Aplysia californica. J Biol Rhythms 14:151-9
Levenson, J; Byrne, J H; Eskin, A (1999) Levels of serotonin in the hemolymph of Aplysia are modulated by light/dark cycles and sensitization training. J Neurosci 19:8094-103
Koumenis, C; Tran, Q; Eskin, A (1996) The use of a reversible transcription inhibitor, DRB, to investigate the involvement of specific proteins in the ocular circadian system of Aplysia. J Biol Rhythms 11:45-56
Koumenis, C; Nunez-Regueiro, M; Raju, U et al. (1995) Identification of three proteins in the eye of Aplysia, whose synthesis is altered by serotonin (5-HT). Possible involvement of these proteins in the ocular circadian system. J Biol Chem 270:14619-27
Byrne, J H; Zwartjes, R; Homayouni, R et al. (1993) Roles of second messenger pathways in neuronal plasticity and in learning and memory. Insights gained from Aplysia. Adv Second Messenger Phosphoprotein Res 27:47-108
Raju, U; Nunez-Regueiro, M; Cook, R et al. (1993) Identification of an annexin-like protein and its possible role in the Aplysia eye circadian system. J Neurochem 61:1236-45
Koumenis, C; Eskin, A (1992) The hunt for mechanisms of circadian timing in the eye of Aplysia. Chronobiol Int 9:201-21

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