Network Properties of Circadian Clock Modulation and Entrainment

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Abstract Circadian clocks orchestrate endogenous daily rhythms in physiology, metabolism, and behavior that must be adjusted (i.e., entrained) to environmental cycles to maintain properly timed outputs. Post- industrial environments have significantly reduced the reliability of the time cues that the circadian system relies upon for entrainment and this has had widespread and negative consequences for human health. Understanding the network properties of circadian timekeeping in the brain and the ways in which time cues impinge upon it is required if we are to address the adverse effects of circadian misalignment and dysfunction. The complexity of the brain’s clock center is a significant barrier to our understanding of the daily adjustment of the circadian system. Work in relatively “simple” clock neuron networks can therefore enrich and inform our understanding of circadian timekeeping and entrainment in the mammalian brain. The goal of this competing renewal application is to continue a productive and impactful research program on the network properties of circadian timekeeping and entrainment in Drosophila melanogaster, which, despite its relative simplicity, shares molecular, anatomical, and physiological features that are remarkably similar to those of mammalian clock networks. Within the fly’s clock neuron network, we will determine how endogenous circadian timekeeping is supported by the network structure of the of the brain’s clock center and how specific neural pathways and neurotransmitters mediate entrainment to environmental cycles. The goals of our three specific aims are to elucidate: 1) the nature and timekeeping functions of the synaptic and modulatory connections of the circadian clock neuron network, 2.) how the CCNN integrates light input to entrain circadian rhythms, and 3) how neurons that do not themselves express molecular clocks participate in the clock neuron network to support endogenous timekeeping. The unifying goal of this research program is to advance our understanding of circadian timekeeping and entrainment in the brain. The results of this work will inform future interventions for the alleviation of the adverse health effects of circadian dysfunction in post-industrial environments.