The long term goal of this proposal is to elucidate the roles of intracellular calcium signals in circadian clock neurons. Experiments will be carried out in the fruit fly, Drosophila melanogaster, which has a functionally sophisticated and anatomically well- characterized circadian control system and is uniquely amenable to application of genetic methods that target clock neurons in the intact behaving animal. In addition to canonical transcriptional feedback mechanisms, circadian oscillation also relies upon depolarization-activated ionic membrane conductances. The proposed aims explore the hypothesis that intracellular calcium signals triggered by membrane depolarization are a core component of the cellular circadian oscillator. An engineered calcium buffer protein is specifically targeted to clock neurons in the brains of transgenic flies to disrupt cellular calcium signals in the intact living organism, followed by measurement of effects on circadian rhythms of locomotor activity, cellular accumulation of known transcription factor components of the circadian oscillator, and intracellular calcium dynamics. Preliminary studies using this approach indicate that intracellular calcium buffering in clock neurons leads to dose-dependent slowing of free-running behavioral and cellular rhythms with arrhythmicity at the highest dose. The proposed aims will identify the subcellular location of the relevant calcium signals, their temporal dynamics, the detailed effects their disruption has on cellular rhythms, and the downstream calcium-sensitive signaling pathways required for their transduction. Because of the great similarity in the genetic and cellular bases for circadian rhythmicity in flies and mammals, the information that can uniquely be obtained exploiting the genetic accessibility of Drosophila in the proposed studies will provide insight into general principles of cellular oscillator function that are relevant both to the basic circadian research done in mammalian model systems and to clinical research on human disorders of circadian function. Disruption of daily rhythms of rest and activity in human beings--through genetic mutation (as in advanced sleep phase disorder), disease, or environmental conditions (as in """"""""jet lag"""""""" or for night shift workers)--has many adverse consequences for public health, workplace safety, and economic productivity. Understanding the cellular mechanisms of these rhythms is key to developing drugs and other treatments for their amelioration. The proposed studies will provide insight into general principles of cellular oscillator function that are relevant both to the basic circadian research done in mammalian model systems and to clinical research on human disorders of circadian function. Disruption of daily rhythms of rest and activity in human beings--through genetic mutation (as in advanced sleep phase disorder), disease, or environmental conditions (as in """"""""jet lag"""""""" or for night shift workers)--has many adverse consequences for public health, workplace safety, and economic productivity. Understanding the cellular mechanisms of these rhythms is key to developing drugs and other treatments for their amelioration. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS055035-01A2
Application #
7368145
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Mitler, Merrill
Project Start
2008-01-01
Project End
2012-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
1
Fiscal Year
2008
Total Cost
$361,029
Indirect Cost
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Dandan; Sitaraman, Divya; Chen, Nan et al. (2017) Genetic and neuronal mechanisms governing the sex-specific interaction between sleep and sexual behaviors in Drosophila. Nat Commun 8:154
Ghosh, D Dipon; Sanders, Tom; Hong, Soonwook et al. (2016) Neural Architecture of Hunger-Dependent Multisensory Decision Making in C. elegans. Neuron 92:1049-1062
Raccuglia, Davide; McCurdy, Li Yan; Demir, Mahmut et al. (2016) Presynaptic GABA Receptors Mediate Temporal Contrast Enhancement in Drosophila Olfactory Sensory Neurons and Modulate Odor-Driven Behavioral Kinetics. eNeuro 3:
Sitaraman, Divya; Aso, Yoshinori; Rubin, Gerald M et al. (2015) Control of Sleep by Dopaminergic Inputs to the Drosophila Mushroom Body. Front Neural Circuits 9:73
Sitaraman, Divya; Aso, Yoshinori; Jin, Xin et al. (2015) Propagation of Homeostatic Sleep Signals by Segregated Synaptic Microcircuits of the Drosophila Mushroom Body. Curr Biol 25:2915-27
Kunst, Michael; Tso, Matthew C F; Ghosh, D Dipon et al. (2015) Rhythmic control of activity and sleep by class B1 GPCRs. Crit Rev Biochem Mol Biol 50:18-30
Gui, Junhong; Liu, Boyi; Cao, Guan et al. (2014) A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain. Curr Biol 24:473-83
Aso, Yoshinori; Sitaraman, Divya; Ichinose, Toshiharu et al. (2014) Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila. Elife 4:e04580
Choi, Ben Jiwon; Imlach, Wendy L; Jiao, Wei et al. (2014) Miniature neurotransmission regulates Drosophila synaptic structural maturation. Neuron 82:618-34
Aso, Yoshinori; Sitaraman, Divya; Ichinose, Toshiharu et al. (2014) Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila. Elife 3:e04580

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