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Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture

Author

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  • Alice Braga

    (Tufts University School of Medicine)

  • Martina Chiacchiaretta

    (Tufts University School of Medicine)

  • Luc Pellerin

    (University and CHU of Poitiers)

  • Dong Kong

    (Tufts University School of Medicine
    Boston Children’s Hospital and Harvard Medical School)

  • Philip G. Haydon

    (Tufts University School of Medicine)

Abstract

Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

Suggested Citation

  • Alice Braga & Martina Chiacchiaretta & Luc Pellerin & Dong Kong & Philip G. Haydon, 2024. "Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50166-7
    DOI: 10.1038/s41467-024-50166-7
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    1. Roberto Luca & Stefano Nardone & Kevin P. Grace & Anne Venner & Michela Cristofolini & Sathyajit S. Bandaru & Lauren T. Sohn & Dong Kong & Takatoshi Mochizuki & Bianca Viberti & Lin Zhu & Antonino Zit, 2022. "Orexin neurons inhibit sleep to promote arousal," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Katia Monsorno & Kyllian Ginggen & Andranik Ivanov & An Buckinx & Arnaud L. Lalive & Anna Tchenio & Sam Benson & Marc Vendrell & Angelo D’Alessandro & Dieter Beule & Luc Pellerin & Manuel Mameli & Ros, 2023. "Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
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