While much is known about the core components and the operation of the circadian molecular clock and its neuroanatomical location in the model organism Drosophila, very little is known about how this circadian molecular clock interacts with electrical signaling in the pacemaker neurons. It is an open questions as to how circadian molecular clock controls pacemaker neuronal electrical activity and synaptic output that ultimately controls animal behavior. The physiological interactions between pacemaker neuron electrical signaling and the circadian molecular clock and animal behavior will be studied by direct physiological analysis using patch clamp and imaging of adult whole brain neurons as well as transgenic expression of modified ion channels in the circadian pacemaker neurons of Drosophila. Transgenic strategies have been devised to (1) electrically silence pacemaker neurons and (2) electrically hyper-excite pacemaker neurons. Each of these manipulations of pacemaker neuronal electrical activity causes striking changes in circadian behavior.
The Specific Aims are to: (1) Map the functional subsets of the pacemaker neural circuit by electrical silencing, neurotransmitter markers, and immunocytochemistry; (2) Determine the mechanism of electrically hyper-excitation induced rhythm splitting and NaChBac expression's functional rescue of the electrically silenced pacemaker neural circuit; (3) Map the electrophysiological properties of wild-type and modified channel-expressing Drosophila pacemakers. These studies will elucidate the physiological mechanisms that determine circadian behavior in a well studied model organism. Ultimately, this work may provide powerful new tools for the general study of neural circuits and novel molecular-genetic strategies for studying and treating human diseases of aberrant cellular electrical excitability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046750-03
Application #
7068047
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Stewart, Randall R
Project Start
2004-06-01
Project End
2007-02-28
Budget Start
2006-06-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$95,705
Indirect Cost
Name
New York University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Fogle, Keri J; Baik, Lisa S; Houl, Jerry H et al. (2015) CRYPTOCHROME-mediated phototransduction by modulation of the potassium ion channel ?-subunit redox sensor. Proc Natl Acad Sci U S A 112:2245-50
Das, Antara; Holmes, Todd C; Sheeba, Vasu (2015) dTRPA1 Modulates Afternoon Peak of Activity of Fruit Flies Drosophila melanogaster. PLoS One 10:e0134213
Roberts, Logan; Leise, Tanya L; Noguchi, Takako et al. (2015) Light evokes rapid circadian network oscillator desynchrony followed by gradual phase retuning of synchrony. Curr Biol 25:858-67
Helfrich-Förster, Charlotte; Nitabach, Michael N; Holmes, Todd C (2011) Insect circadian clock outputs. Essays Biochem 49:87-101
Fogle, Keri J; Parson, Kelly G; Dahm, Nicole A et al. (2011) CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science 331:1409-13
Sheeba, Vasu; Fogle, Keri J; Holmes, Todd C (2010) Persistence of morning anticipation behavior and high amplitude morning startle response following functional loss of small ventral lateral neurons in Drosophila. PLoS One 5:e11628
Ayaz, Derya; Leyssen, Maarten; Koch, Marta et al. (2008) Axonal injury and regeneration in the adult brain of Drosophila. J Neurosci 28:6010-21
Sheeba, Vasu; Fogle, Keri J; Kaneko, Maki et al. (2008) Large ventral lateral neurons modulate arousal and sleep in Drosophila. Curr Biol 18:1537-45
Sheeba, Vasu; Sharma, Vijay K; Gu, Huaiyu et al. (2008) Pigment dispersing factor-dependent and -independent circadian locomotor behavioral rhythms. J Neurosci 28:217-27
Sheeba, Vasu; Gu, Huaiyu; Sharma, Vijay K et al. (2008) Circadian- and light-dependent regulation of resting membrane potential and spontaneous action potential firing of Drosophila circadian pacemaker neurons. J Neurophysiol 99:976-88

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