Journal Article

Adenosine‐Dependent Arousal Induced by Astrocytes in a Brainstem Circuit

Feng, Xiang, Shao, Yujin, Liu, Yijun, Ma, Jiale, Tan, Lei, Qiu, Zilong, Sun, Li, Yu, Yan‐qin, Gu, Mengyang, Lou, Hui‐fang, Zhu, Yuwei, Zeng, Ling‐hui, Li, Xiao‐ming, Li, Yulan, Duan, Shumin

2024

Overview

Astrocytes play a crucial role in regulating sleep‐wake behavior. However, how astrocytes govern a specific sleep‐arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep‐wake cycles with state‐differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non‐rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal‐promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level. This study shows that astrocyte activation in the PZ promotes arousal at the expense of NREM and REM sleep. Adenosine, produced by astrocytes via CD73/39, promotes wakefulness through A1 receptors. Additionally, astrocytes suppress GABA release from PZGABA neurons projecting to the PB, emphasizing astrocyte‐neuron communication in arousal regulation at the circuit level.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenosine / Adenosine - metabolism / Animals / arousal / Arousal - physiology / astrocyte / Astrocytes - metabolism / Brain research / Brain Stem - metabolism / Brain Stem - physiology / Eye movements / Male / Mice / Models, Animal / neural circuit / Neurons / parafacial zone / Proteins / Regulation / Roles / Sleep / Sleep - physiology / Wakefulness - physiology