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A single pair of leucokinin neurons are modulated by feeding state and regulate sleep–metabolism interactions

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  • Maria E Yurgel
  • Priyanka Kakad
  • Meet Zandawala
  • Dick R Nässel
  • Tanja A Godenschwege
  • Alex C Keene

Abstract

Dysregulation of sleep and feeding has widespread health consequences. Despite extensive epidemiological evidence for interactions between sleep and metabolic function, little is known about the neural or molecular basis underlying the integration of these processes. D. melanogaster potently suppress sleep in response to starvation, and powerful genetic tools allow for mechanistic investigation of sleep–metabolism interactions. We have previously identified neurons expressing the neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep. Here, we demonstrate an essential role for Lk neuropeptide in metabolic regulation of sleep. The activity of Lk neurons is modulated by feeding, with reduced activity in response to glucose and increased activity under starvation conditions. Both genetic silencing and laser-mediated microablation localize Lk-dependent sleep regulation to a single pair of Lk neurons within the Lateral Horn (LHLK neurons). A targeted screen identified a role for 5′ adenosine monophosphate-activated protein kinase (AMPK) in starvation-modulated changes in sleep. Knockdown of AMPK in Lk neurons suppresses sleep and increases LHLK neuron activity in fed flies, phenocopying the starvation state. Further, we find a requirement for the Lk receptor in the insulin-producing cells (IPCs), suggesting LHLK–IPC connectivity is critical for sleep regulation under starved conditions. Taken together, these findings localize feeding-state–dependent regulation of sleep to a single pair of neurons within the fruit fly brain and provide a system for investigating the cellular basis of sleep–metabolism interactions.Author summary: Neural regulation of sleep and feeding are interconnected and are critical for survival. Many animals reduce their sleep in response to starvation, presumably to forage for food. Here, we find that in the fruit fly Drosophila melanogaster, the neuropeptide leucokinin is required for the modulation of starvation-dependent changes in sleep. Leucokinin is expressed in numerous populations of neurons within the two compartments of the central nervous system: the brain and the ventral nerve cord. Both genetic manipulation and laser-mediated microablation experiments identify a single pair of neurons expressing this neuropeptide in the brain as being required for metabolic regulation of sleep. These neurons become active during periods of starvation and modulate the function of insulin-producing cells that are critical modulators of both sleep and feeding. Supporting this notion, knockdown of the leucokinin receptor within the insulin-producing cells also disrupts metabolic regulation of sleep. Taken together, these findings identify a critical role for leucokinin signaling in the integration of sleep and feeding states.

Suggested Citation

  • Maria E Yurgel & Priyanka Kakad & Meet Zandawala & Dick R Nässel & Tanja A Godenschwege & Alex C Keene, 2019. "A single pair of leucokinin neurons are modulated by feeding state and regulate sleep–metabolism interactions," PLOS Biology, Public Library of Science, vol. 17(2), pages 1-26, February.
  • Handle: RePEc:plo:pbio00:2006409
    DOI: 10.1371/journal.pbio.2006409
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    References listed on IDEAS

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    1. Vanessa Ruta & Sandeep Robert Datta & Maria Luisa Vasconcelos & Jessica Freeland & Loren L. Looger & Richard Axel, 2010. "A dimorphic pheromone circuit in Drosophila from sensory input to descending output," Nature, Nature, vol. 468(7324), pages 686-690, December.
    2. Yin Peng Zhan & Li Liu & Yan Zhu, 2016. "Taotie neurons regulate appetite in Drosophila," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    3. Akira Muto & Pradeep Lal & Deepak Ailani & Gembu Abe & Mari Itoh & Koichi Kawakami, 2017. "Activation of the hypothalamic feeding centre upon visual prey detection," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
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    Cited by:

    1. Elizabeth B Brown & Kreesha D Shah & Richard Faville & Benjamin Kottler & Alex C Keene, 2020. "Drosophila insulin-like peptide 2 mediates dietary regulation of sleep intensity," PLOS Genetics, Public Library of Science, vol. 16(3), pages 1-26, March.
    2. Qiankun He & Juan Du & Liya Wei & Zhangwu Zhao, 2020. "AKH-FOXO pathway regulates starvation-induced sleep loss through remodeling of the small ventral lateral neuron dorsal projections," PLOS Genetics, Public Library of Science, vol. 16(10), pages 1-21, October.

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