Circadian clocks are critical time-keeping mechanisms. They ensure that most bodily functions - from basic cellular biochemistry to complex behaviors such as the sleep-wake cycle - are properly adapted to the time of day. Circadian clocks are self-sustained: they persist even under constant environmental conditions. Nevertheless, circadian clocks need to be reset every day to remain properly phased with the environment, because their period length is not exactly 24hr. Light is a critical input for circadin clocks. Our goal is therefore to understand the neural and molecular mechanisms underlying circadian photoreception, using as a model organism Drosophila melanogaster. Our preliminary data demonstrate that two small groups of circadian neurons, the M- and E-oscillators, form a neural network that allows Drosophila to reset their circadian behavior in response to light inputs.
Our first aim will thus elucidate how the M- and E-oscillators communicate with each other to reset circadian behavior after exposure to light. We will define the respective role of neurotransmission in M- and E-oscillators for circadian photoresponses. We will also identify the neurotransmitters and the receptors required for M- and E-oscillators to reset circadian behavior in response to light inputs.
Our second aim will study at the molecular level how light input reaches circadian pacemakers in the M- and E-oscillators. We will determine the role of cell-autonomous circadian photoreceptive mechanisms, as well as elucidate how pacemakers respond to neural input during circadian photoresponses. The proposed work will thus be a comprehensive study of circadian photoreception in Drosophila, from basic cell-autonomous mechanisms synchronizing the molecular pacemakers in circadian neurons, to interactions between neurons that control circadian photoresponses. Because of the relative simplicity of the Drosophila circadian neural network, we will be able to understand circadian photoreception with a remarkable level of precision. In mammals also, synchronization of circadian behavioral rhythms is dependent on molecular input pathways that reset circadian clocks in light- sensitive circadian neurons, which then communicate light information to the rest of the Suprachiasmatic Nucleus, the mammalian brain pacemaker. We thus anticipate that our work will uncover general principles underlying synchronization of circadian rhythms in animals. These principles could ultimately prove important to understand and treat diseases associated with the misalignment of circadian rhythms with the day/night cycle, which is observed in many sleep and mood disorders.

Public Health Relevance

Circadian clocks are critical for animals, because they ensure that their behavior and physiology is properly adapted to the day/night cycle. Since light is the most important environmental cue that synchronizes circadian clocks, our goal is to understand how these pacemakers sense light in the model organism Drosophila melanogaster. Circadian clocks are remarkably well conserved between Drosophila and mammals. Our work should thus help understanding the biological bases of human diseases that are associated with the dysfunction and abnormal synchronization of circadian rhythms.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Sesma, Michael A
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University of Massachusetts Medical School Worcester
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Tataroglu, Ozgur; Emery, Patrick (2015) The molecular ticks of the Drosophila circadian clock. Curr Opin Insect Sci 7:51-57
Tataroglu, Ozgur; Zhao, Xiaohu; Busza, Ania et al. (2015) Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks. Cell 163:1214-1224
Tataroglu, Ozgur; Emery, Patrick (2014) Studying circadian rhythms in Drosophila melanogaster. Methods 68:140-50
Lamba, Pallavi; Bilodeau-Wentworth, Diana; Emery, Patrick et al. (2014) Morning and evening oscillators cooperate to reset circadian behavior in response to light input. Cell Rep 7:601-8
Zhang, Yong; Emery, Patrick (2013) GW182 controls Drosophila circadian behavior and PDF-receptor signaling. Neuron 78:152-65
Karpowicz, Phillip; Zhang, Yong; Hogenesch, John B et al. (2013) The circadian clock gates the intestinal stem cell regenerative state. Cell Rep 3:996-1004
Zhang, Yong; Ling, Jinli; Yuan, Chunyan et al. (2013) A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340:879-82
Ling, Jinli; Dubruille, Raphaƫlle; Emery, Patrick (2012) KAYAK-? modulates circadian transcriptional feedback loops in Drosophila pacemaker neurons. J Neurosci 32:16959-70
Zhang, Yong; Liu, Yixiao; Bilodeau-Wentworth, Diana et al. (2010) Light and temperature control the contribution of specific DN1 neurons to Drosophila circadian behavior. Curr Biol 20:600-5
Dubruille, Raphaƫlle; Murad, Alejandro; Rosbash, Michael et al. (2009) A constant light-genetic screen identifies KISMET as a regulator of circadian photoresponses. PLoS Genet 5:e1000787

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