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

Alice Braga, Martina Chiacchiaretta (), Luc Pellerin, Dong Kong and Philip G. Haydon ()
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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
Philip G. Haydon: Tufts University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50166-7

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