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

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. We manipulated the cell-specific expression of monocarboxylate transporters (MCTs), the major lactate transporters, to examine the involvement of astrocytic lactate supply in maintaining consolidated wakefulness. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to orexin neurons in the lateral hypothalamus (LH), impairing wakefulness stability. We also show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexinergic neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the critical role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability— a crucial step for maintaining physiological functions and overall well-being.