星形胶质细胞源性腺苷激发腹外侧视前核中的促睡眠神经元：星形胶质细胞-神经元相互作用对睡眠的调节

摘要尽管已知来自星形胶质细胞的ATP 和/或腺苷可调节睡眠，但ATP 和腺苷促眠作用的确切机制仍不清楚。我们在参与睡眠促进的重要脑核腹外侧视前核（VLPO）内的星形胶质细胞中选择性表达光敏离子通道视紫红质通道2（ChR2）。然后，我们用全细胞膜片钳记录检查了光刺激星形细胞ChR2 对VLPO两种不同功能类型的神经元兴奋性的影响：分别为促进睡眠的GABA 能投射神经元和非促进睡眠的局部GABA 能神经元。VLPO 星形胶质细胞的光遗传学刺激在两种类型的VLPO神经元中表现出相反的结果：导致了非睡眠促进神经元的抑制和睡眠促进神经元的兴奋。通过阻断腺苷A1受体或组织非特异性碱性磷酸酶（TNAP）可减弱这些反应。相反，外源性腺苷降低了两个VLPO神经元群的兴奋性。此外，TNAP在甘丙肽阴性的VLPO神经元中表达，但在甘丙肽阳性促进睡眠的投射神经元中不表达。总之，这些结果表明星形胶质细胞源性的ATP在非睡眠促进神经元中通过TNAP转化为腺苷。腺苷进而降低了局部GABA能神经元的兴奋性，从而增加了促进睡眠的GABA能投射神经元的兴奋性。我们提出了一种涉及星形胶质细胞-神经元相互作用在睡眠调节中的新机制，其中来自星形胶质细胞的内源性腺苷激发促进睡眠的VLPO神经元，从而降低大脑中与唤醒相关区域的神经元兴奋性。

关键词腺苷；星形胶质细胞；胶质递质；光遗传学；睡眠；腹外侧视前核

中图分类号R741；R741.02文献标识码ADOI10.16780/j.cnki.sjssgncj.2022.06.019

Astrocyte-derived adenosine excites sleep-promoting neurons in the ventrolateral preoptic nucleus:Astrocyte-neuron interactions in the regulation of sleep

In-Sun Choi1，Jae-Hong Kim2，Ji-Young Jeong2，Maan-Gee Lee2，3，Kyoungho Suk2，3，Il-Sung Jang1，3

摘自Glia. 2022 May 31.doi:10.1002/glia.24225.Online ahead of print.

1.Department of Pharmacology，School of Dentistry，Kyungpook National University，Daegu，South Korea

2.Department of Pharmacology，School of Medicine，Kyungpook National University，Daegu，South Korea

3.Brain Science&Engineering Institute，Kyungpook National University，Daegu，South Korea

AbstractAlthough ATP and/or adenosine derived from astrocytes are known to regulate sleep，the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively expressed channelrhodopsin-2 (ChR2)， a light-sensitive ion channel， in astrocytes within the ventrolateral preoptic nucleus (VLPO)，which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole-cell patch-clamp recordings in two functionally distinct types of VLPO neurons: sleep-promoting GABAergic projection neurons and non-sleep-promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non-sleep-promoting neurons and excitation of sleep-promoting neurons.These responses were attenuated by blocking of either adenosine A1 receptors or tissue-nonspecific alkaline phosphatase (TNAP). In contrast， exogenous adenosine decreased the excitability of both VLPO neuron populations.Moreover， TNAP was expressed in galanin-negative VLPO neurons， but not in galanin-positive sleep-promoting projection neurons. Taken together， these results suggest that astrocyte-derived ATP is converted into adenosine by TNAP in non-sleep-promoting neurons. In turn， adenosine decreases the excitability of local GABAergic neurons，thereby increasing the excitability of sleep-promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte-neuron interactions in sleep regulation，wherein endogenous adenosine derived from astrocytes excites sleep-promoting VLPO neurons， and thus decreases neuronal excitability in arousal-related areas of the brain.

Key wordsadenosine;astrocyte;gliotransmitters;optogenetics;sleep;ventrolateral preoptic nucleus