Our circadian clocks orchestrate endogenous biological rhythms in physiology, metabolism, and behavior that must be adjusted every day to maintain synchrony with the environment and produce optimally timed rhythmic outputs. This daily adjustment, known as entrainment, is achieved through a sensitivity of the brain's central clock neuron network to both external and internal time cues. Postindustrial society has significantly reduced the reliability of the cues that our circadian system uses for entrainment. This modern challenge to our clocks has wide-spread negative health consequences. The complexity of the brain's clock center is a significant barrier to a comprehensive understanding of the daily adjustment of the circadian system. Understanding the network properties of circadian timekeeping in the brain and the ways in which time cues impinge upon clock centers is critical if we are to address the significantly negative effects of circadian misalignment and dysfunction. The broad goal of this competing renewal application is a comprehensive understanding of the network properties of circadian timekeeping and entrainment in Drosophila melanogaster, whose circadian system features highly conserved molecular, anatomical, and physiological features that it shares with mammalian clock networks. Within this well-defined clock center, we will investigate how highly conserved external and internal time cues produce network-wide clock modulation and control sleep. The goals of our three specific aims are to elucidate: 1) the mechanistic basis of cholinergic and GABAergic inputs into the clock neuron network and the roles they play in sleep control and circadian timekeeping and entrainment, 2) the neurophysiological mechanisms by which the various clock neuron classes of the clock network modulate one another to produce coherent circadian rhythms, and 3) the anatomical and neurophysiological basis of the network integration of light and temperature cues from peripheral sensory receptors. The unifying goal of this proposal is to advance our understanding of circadian timekeeping and entrainment in the brain. The results of this work will ultimately inform the development and implementation of interventions designed to alleviate the significantly adverse metabolic and psychological effects of circadian dysfunction in the modern world.

Public Health Relevance

The proper alignment of internal circadian clocks with the 24-hour rhythm of the environment is critical for human health and psychological well-being. Molecular imaging and methods for mapping functional connectivity in the brain make it possible to examine the network properties of the clock and its modulation by environmental cues within the brain of Drosophila melanogaster, an organism that continues to enrich and inform our understanding of circadian timekeeping in the brain. Here we propose experiments to understand how neuronal clocks are physiologically adjusted by internal and external cues, the results of which will ultimately aid in the development of interventions designed to alleviate the widespread adverse effects of human circadian dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
Zip Code
Yadlapalli, Swathi; Jiang, Chang; Bahle, Andrew et al. (2018) Circadian clock neurons constantly monitor environmental temperature to set sleep timing. Nature 555:98-102
Abruzzi, Katharine C; Zadina, Abigail; Luo, Weifei et al. (2017) RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides. PLoS Genet 13:e1006613
Yao, Zepeng; Bennett, Amelia J; Clem, Jenna L et al. (2016) The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms. Cell Rep 17:2873-2881
Schlichting, Matthias; Menegazzi, Pamela; Lelito, Katharine R et al. (2016) A Neural Network Underlying Circadian Entrainment and Photoperiodic Adjustment of Sleep and Activity in Drosophila. J Neurosci 36:9084-96
Oh, Yangkyun; Yoon, Sung-Eun; Zhang, Qi et al. (2014) A homeostatic sleep-stabilizing pathway in Drosophila composed of the sex peptide receptor and its ligand, the myoinhibitory peptide. PLoS Biol 12:e1001974
Shafer, Orie T; Yao, Zepeng (2014) Pigment-Dispersing Factor Signaling and Circadian Rhythms in Insect Locomotor Activity. Curr Opin Insect Sci 1:73-80
Yao, Z; Shafer, O T (2014) The Drosophila circadian clock is a variably coupled network of multiple peptidergic units. Science 343:1516-20
Collins, Ben; Kaplan, Harris S; Cavey, Matthieu et al. (2014) Differentially timed extracellular signals synchronize pacemaker neuron clocks. PLoS Biol 12:e1001959