星形膠質(zhì)細胞源性腺苷激發(fā)腹外側(cè)視前核中的促睡眠神經(jīng)元：星形膠質(zhì)細胞-神經(jīng)元相互作用對睡眠的調(diào)節(jié)

摘要盡管已知來自星形膠質(zhì)細胞的ATP 和/或腺苷可調(diào)節(jié)睡眠，但ATP 和腺苷促眠作用的確切機制仍不清楚。我們在參與睡眠促進的重要腦核腹外側(cè)視前核（VLPO）內(nèi)的星形膠質(zhì)細胞中選擇性表達光敏離子通道視紫紅質(zhì)通道2（ChR2）。然后，我們用全細胞膜片鉗記錄檢查了光刺激星形細胞ChR2 對VLPO兩種不同功能類型的神經(jīng)元興奮性的影響：分別為促進睡眠的GABA 能投射神經(jīng)元和非促進睡眠的局部GABA 能神經(jīng)元。VLPO 星形膠質(zhì)細胞的光遺傳學刺激在兩種類型的VLPO神經(jīng)元中表現(xiàn)出相反的結(jié)果：導致了非睡眠促進神經(jīng)元的抑制和睡眠促進神經(jīng)元的興奮。通過阻斷腺苷A1受體或組織非特異性堿性磷酸酶（TNAP）可減弱這些反應(yīng)。相反，外源性腺苷降低了兩個VLPO神經(jīng)元群的興奮性。此外，TNAP在甘丙肽陰性的VLPO神經(jīng)元中表達，但在甘丙肽陽性促進睡眠的投射神經(jīng)元中不表達?？傊?，這些結(jié)果表明星形膠質(zhì)細胞源性的ATP在非睡眠促進神經(jīng)元中通過TNAP轉(zhuǎn)化為腺苷。腺苷進而降低了局部GABA能神經(jīng)元的興奮性，從而增加了促進睡眠的GABA能投射神經(jīng)元的興奮性。我們提出了一種涉及星形膠質(zhì)細胞-神經(jīng)元相互作用在睡眠調(diào)節(jié)中的新機制，其中來自星形膠質(zhì)細胞的內(nèi)源性腺苷激發(fā)促進睡眠的VLPO神經(jīng)元，從而降低大腦中與喚醒相關(guān)區(qū)域的神經(jīng)元興奮性。

關(guān)鍵詞腺苷；星形膠質(zhì)細胞；膠質(zhì)遞質(zhì)；光遺傳學；睡眠；腹外側(cè)視前核

中圖分類號R741；R741.02文獻標識碼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